Degraders of TEAD transcription factors

Abstract

This disclosure provides compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, that induce degradation of a TEA Domain (TEAD) transcription factor (also referred to herein as TEAD proteins) (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4). These compounds are useful, for example, for treating a disease, disorder, or condition in which decreased activity in the Hippo pathway contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) DEGRADERS OF TEAD TRANSCRIPTION FACTORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial Nos.63 / 687,272, filed August 26, 2024; 63 / 707,710, filed October 15, 2024; 63 / 724,095, filed November 22, 5 2024; 63 / 748,695, filed January 23, 2025; and 63 / 814,335, filed May 29, 2025, each of which is incorporated by reference it its entirety herein. TECHNICAL FIELD This disclosure provides compounds of Formula (AA) (e.g., Formula (A1), Formula 10 (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, that induce degradation of a transcriptional enhancer factor family member (also referred to herein as TEAD transcription factors and TEAD proteins) (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4). These compounds are useful, for example, for treating a disease, disorder, or 15 condition in which decreased activity in the Hippo pathway contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically 20 acceptable salts thereof, as well as methods of using and making the same. BACKGROUND Aberrant activation of Yes-associated protein 1 (YAP, also known as YAP1) and / or WW domain-containing transcription regulator protein 1 (TAZ) (referred to herein collectively 25 as YAP / TAZ) has been shown to be involved in cancer initiation, progression, and metastasis in tumors. YAP / TAZ are part of and regulated by the Hippo signaling pathway; when YAP / TAZ are phosphorylated by upstream kinases such as large tumor suppressor kinase 1 / 2 (LATS1 / 2), they are sequestered in the cellular cytoplasm and are eventually degraded. When not sequestered in the cytoplasm, YAP / TAZ can translocate to the nucleus, where they act as30 transcriptional coactivators of TEAD transcription factors to activate expression of pro- proliferative and pro-survival genes. Accordingly, dysregulation of components of the Hippo pathway can result in increased expression of pro-proliferative and pro-survival genes. The 1 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) TEAD proteins, therefore, may be an attractive biological target for diseases having a dysregulation of the Hippo pathway. SUMMARY 5 This disclosure provides compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, that induce degradation of a TEAD protein. The compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula 10 (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, are useful, for example, for treating a disease, disorder, or condition in which decreased activity in the Hippo pathway contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (AA) (e.g., Formula (A1), Formula 15 (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. Provided herein are compounds of Formula (AA): 20 Formula (AA) or pharmaceutically acceptable salts thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; 25 R3and R4are independently selected from the group consisting of: H and halo; 2 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) R5is selected from the group consisting of: H and C1-3alkyl optionally substituted with 1-3 F; X1is selected from the group consisting of: N, CH, and CR6; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; 5 R6is H, or R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; 10 R10is selected from the group consisting of: (a) C1-6 alkyl optionally substituted with 1-3 Rc; (b) –(C0-2 alkylene)-phenyl optionally substituted with 1-3 Rd; L0is selected from the group consisting of: 15 (a) Cy; (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and (c) straight-chain C1-4alkylene optionally substituted with 1-3 Ra; Cy is selected from the group consisting of: phenylene, C3-10 cycloalkylene, and 4-10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; 20 L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), and - C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1; Ring A1 is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; 25 L2is selected from the group consisting of: a bond, O, C(=O), and a straight-chain C1-3 alkylene, wherein the straight-chain C1-3 alkylene is optionally substituted with 1-3 Ra; Ring A2 is a 4-12 membered heterocyclylene optionally substituted with 1-3 Ra; 3 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Ring C is selected from the group consisting of: , , , wherein cc represents the point of attachment to Ring A2; Y is N or CH; RY1is selected from the group consisting of: 5 (a) C1-3alkyl optionally substituted with 1-3 F; and (b) –(C0-2alkylene)-(C3-6cycloalkyl); Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; 10 R11is H or C1-3 alkyl; each Rais independently selected from the group consisting of: halo, CN, OH, C1-3 alkoxy, and C1-3alkyl, wherein the C1-3alkyl is optionally substituted with 1-3 F; each Rcis independently selected from the group consisting of: halo, CN, OH, and C1-3 alkoxy; 15 each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3 alkoxy, N(RN)2, and C1-3alkyl optionally substituted with 1-3 Re; each Reis independently selected from the group consisting of: halo, CN, C1-3 alkoxy, OH, and N(RN)2; and each RNis independently selected from the group consisting of: H and C1-3alkyl 20 optionally substituted with 1-3 F. 4 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Also provided herein are compounds of Formula (I) or (II): 5 Formula (II) or pharmaceutically acceptable salts thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; 10 R5is selected from the group consisting of: H and C1-3alkyl optionally substituted with 1-3 F; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; R8is selected from the group consisting of: H and halo; 15 X1is N or CH; X2is N or CH; L1is C(=O) or CH2; 5 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Ring A1 is selected from the group consisting of: C3-8cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, CH2, CH2CH2, O, and C(=O); Ring A2 is a 4-10 membered heterocyclylene optionally substituted with 1-3 Ra; 5 Y is N or CH; RY1is C1-3alkyl; Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; 10 each Rais independently selected from the group consisting of: halo, CN, OH, and C1-3 alkyl optionally substituted with 1-3 F; and each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 3 alkoxy. 15 Also provided herein are pharmaceutical compositions comprising a compound of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 20 Provided herein are methods for treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 25 In some embodiments, the cancer has a Hippo pathway dysregulation. In some embodiments, the cancer does not have a Hippo pathway dysregulation. Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising (a) determining that the cancer has a Hippo pathway dysregulation; and (b) administering to the subject a therapeutically effective amount of a compound of Formula 30 (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to a subject identified or diagnosed as having a cancer 6 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) that has a Hippo pathway dysregulation a therapeutically effective amount of a compound of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. 5 Also provided herein is a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) non-covalently bound with a compound of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or a pharmaceutically acceptable salt thereof. Also provided herein is a ternary complex including a TEAD protein (e.g., TEAD1, 10 TEAD2, TEAD3, or TEAD4), a compound of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or a pharmaceutically acceptable salt thereof, and an E3 ligase (e.g., CRBN) or fragment thereof. To facilitate understanding of the disclosure set forth herein, a number of terms are 15 provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published 20 applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In the case of conflict between the present disclosure and any content incorporated by reference, the present disclosure controls. The details of one or more embodiments of the invention are set forth in the 25 accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure provides compounds of Formula (AA) (e.g., Formula (A1), Formula 30 (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, that induce degradation of a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4). The compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or 7 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) pharmaceutically acceptable salts thereof, are useful, for example, for treating a disease, disorder, or condition in which decreased activity in the Hippo pathway contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human) contributes to the pathology and / or symptoms and / or 5 progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. 10 The Hippo pathway is conserved across many species. One of the main functions of the Hippo pathway is to restrain cellular growth through the inactivation of YAP / TAZ. Alterations have been found to cause diseases of overgrowth (e.g., cancer). There are many implicated cancer types, including bladder, breast, cervical, esophageal, head and neck, lung, liver, prostate, and colorectal. Different types of molecular alterations can result in dysregulation of 15 the Hippo pathway. For example, amplification of STK3, TAZ, TEAD4, YAP1, and STK4 are associated with various cancers. As another example, deletion of LATS1 / 2, as well as mutations in NF2 and LATS1 / 2 are also associated with cancers. As a particular example, a study of malignant pleural mesothelioma showed a 23.2% mutation rate in NF2 and a 9.8% mutation rate in LATS2. See, e.g., Steinhardt, Angela A., et al. Human Pathology 39.11 (2008): 1582- 20 1589, doi: 10.1016 / j.humpath.2008.04.012; Harvey, Kieran F., Xiaomeng Zhang, and David M. Thomas. Nature Reviews Cancer 13.4 (2013): 246-257, doi: 10.1038 / nrc3458; Moroishi, Toshiro, Carsten Gram Hansen, and Kun-Liang Guan. Nature Reviews Cancer 15.2 (2015): 73-79, doi: 10.1038 / nrc3876; Yu, Fa-Xing, Bin Zhao, and Kun-Liang Guan. Cell 163.4 (2015): 811-828, doi: 10.1016 / j.cell.2015.10.044; Zanconato, Francesca, Michelangelo Cordenonsi, 25 and Stefano Piccolo. Cancer Cell 29.6 (2016): 783-803, doi: 10.1016 / j.ccell.2016.05.005; Wang, Yumeng, et al., Cell Reports 25.5 (2018): 1304-1317, doi: 10.1016 / j.celrep.2018.10.001; Sekido, Yoshitaka. Cancers 10.4 (2018): 90, doi: 10.3390 / cancers10040090; Chen, Rui, et al. Nature Cell Biology 21.12 (2019): 1565-1577, doi: 10.1038 / s41556-019-0426-y; Fu, Minyang, et al. Signal Transduction and Targeted 30 Therapy 7.1 (2022): 376, doi: 10.1038 / s41392-022-01191-9; Zhao, Yang, et al. Cancers 15.23 (2023): 5497, doi: 10.3390 / cancers15235497; Chene, Patrick. ChemMedChem (2024): e202400361, doi: 10.1002 / cmdc.202400361; and Papavassiliou, Kostas A., Amalia A. Sofianidi, and Athanasios G. Papavassiliou. Journal of Cellular and Molecular Medicine 28.8 (2024): e18330; doi: 10.1111 / jcmm.18330. 8 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Accordingly, as downstream effectors of the Hippo pathway, degradation of TEAD proteins presents an attractive target for a variety of molecular alterations of the Hippo pathway associated with diseases such as cancer. Compounds that induce degradation of a target protein are sometimes referred to as 5 heterobifunctional compounds, PROTACs, or degraders. Such compounds generally include a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply an E3), these two moieties being optionally separated by a linker. To induce degradation, heterobifunctional compounds are believed to induce formation of a ternary complex between the target protein, the compound, and an E3 10 ligase. Formation of the ternary complex is then followed by ubiquitination of the target protein and degradation of the ubiquitinated target protein by a proteosome. Several E3 ligases have been used as the partner E3 ligase for heterobifunctional degraders. Herein, the cereblon (CRBN) E3 ligase (also referred to herein as a CRBN protein) is used. A degradation approach for a target protein can have potential advantages compared to, 15 e.g., small molecule inhibition of the target protein. One potential advantage is that the duration of effect of a heterobifunctional compound is generally based on the resynthesis rate of the target protein. Another potential advantage is that many heterobifunctional compounds are believed to be released from the ubiquitinated target protein-E3 ligase complex and made available for formation of further ternary complexes; this is sometimes referred to as “catalytic” 20 turnover of the heterobifunctional compound. Degradation of a target protein can also be advantageous over small molecule inhibition in some cases, as degradation can impair a scaffolding function of a target protein, whereas a small molecule might not. It is also generally believed that for formation of a ternary complex, high affinity to the target protein is not always required. 25 International Patent Application Publication No. WO 2023 / 031801 discloses examples of degraders of TEAD transcription factors. Additional examples of TEAD modulators (e.g., inhibitors) are disclosed in International Patent Application Publication Nos. WO 2021 / 186324, WO 2023 / 155927, WO 2023 / 098815, WO 2023 / 137634, WO 2024 / 235254, WO 2024 / 240840, WO 2024 / 176131, WO 2024 / 176130, and WO 2024 / 176128; Chinese 30 Patent Application Publication Nos. CN 117700420 and CN 119060028; and Lu, Y., et al., J. Med. Chem.2025, DOI: 10.1021 / acs.jmedchem.4c02884. Compound Embodiments Provided herein are compounds of Formula (AA): 9 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 5 or pharmaceutically acceptable salts thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3 alkyl optionally substituted with 10 1-3 F; X1is selected from the group consisting of: N, CH, and CR6; R7is C1-3alkoxy optionally substituted with 1-3 Rc; R6is H, or R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 15 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; R10is selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; 20 (b) –(C0-2 alkylene)-phenyl optionally substituted with 1-3 Rd; L0is selected from the group consisting of: (a) Cy; (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and 25 (c) straight-chain C1-4alkylene optionally substituted with 1-3 Ra; 10 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Cy is selected from the group consisting of: phenylene, C3-10cycloalkylene, and 4-10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), and - C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1; 5 Ring A1 is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, O, C(=O), and a straight-chain C1-3 alkylene, wherein the straight-chain C1-3 alkylene is optionally substituted with 1-3 Ra; 10 Ring A2 is a 4-12 membered heterocyclylene optionally substituted with 1-3 Ra; Ring C is selected from the group consisting of: , , , wherein cc represents the point of attachment to Ring A2; Y is N or CH; 15 RY1is selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 F; and (b) –(C0-2 alkylene)-(C3-6 cycloalkyl); Y1, Y2, and Y3are each independently selected from the group consisting of: CH and 20 CRY2, wherein each RY2is an independently selected halo; R11is H or C1-3 alkyl; each Rais independently selected from the group consisting of: halo, CN, OH, C1-3 alkoxy, and C1-3alkyl, wherein the C1-3alkyl is optionally substituted with 1-3 F; each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 25 3 alkoxy; each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, N(RN)2, and C1-3alkyl optionally substituted with 1-3 Re; 11 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) each Reis independently selected from the group consisting of: halo, CN, C1-3alkoxy, OH, and N(RN)2; and each RNis independently selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F. 5 In some embodiments of Formula (AA), R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; 10 R5is selected from the group consisting of: H and C1-3alkyl optionally substituted with 1-3 F; X1is selected from the group consisting of: N, CH, and CR6; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; R6is H, or 15 R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; R10is selected from the group consisting of: 20 (a) C1-6 alkyl optionally substituted with 1-3 Rc; (b) –(C0-2 alkylene)-phenyl optionally substituted with 1-3 Rd; L0is selected from the group consisting of: (a) Cy; 25 (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and (c) straight-chain C1-4alkylene optionally substituted with 1-3 Ra; Cy is selected from the group consisting of: phenylene, C3-10cycloalkylene, and 4-10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), and - 30 C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1; 12 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Ring A1 is selected from the group consisting of: C3-8cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, O, C(=O), and a straight-chain C1- 3 alkylene, wherein the straight-chain C1-3alkylene is optionally substituted with 1-3 Ra; 5 Ring A2 is a 4-12 membered heterocyclylene optionally substituted with 1-3 Ra; Ring C is selected from the group consisting of: , wherein cc represents the point of attachment to Ring A2; Y is N or CH; 10 RY1is selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 F; and (b) –(C0-2alkylene)-(C3-6cycloalkyl); Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; 15 R11is H or C1-3alkyl; each Rais independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 F; each Rcis independently selected from the group consisting of: halo, CN, OH, and C1-3alkoxy; 20 each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3 alkoxy, N(RN)2, and C1-3 alkyl optionally substituted with 1-3 Re; each Reis independently selected from the group consisting of: halo, CN, C1-3alkoxy, OH, and N(RN)2; and each RNis independently selected from the group consisting of: H and C1-3 alkyl 25 optionally substituted with 1-3 F. In some embodiments of Formula (AA): R11is H; 13 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3 alkyl optionally substituted with 5 1-3 -F; X1is selected from the group consisting of: N, CH, and CR6; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; R6is H, or R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 10 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; R10is selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; 15 (b) –(C0-2alkylene)-phenyl optionally substituted with 1-3 Rd; L0is selected from the group consisting of: (a) Cy; (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and 20 (c) straight-chain C1-4 alkylene optionally substituted with 1-3 Ra; Cy is selected from the group consisting of: phenylene, C3-10 cycloalkylene, and 4-10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), and - C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1; 25 Ring A1 is selected from the group consisting of: C3-8cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, O, C(=O), and a straight-chain C1- 3 alkylene, wherein the straight-chain C1-3alkylene is optionally substituted with 1-3 Ra; 30 Ring A2 is a 4-12 membered heterocyclylene optionally substituted with 1-3 Ra; 14 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Ring C is selected from the group consisting of: , wherein cc represents the point of attachment to Ring A2; Y is N or CH; RY1is C1-3 alkyl; 5 Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; each Rais independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, and C1-3alkyl, wherein the C1-3alkyl is optionally substituted with 1-3 F; 10 each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 3 alkoxy; each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, N(RN)2, and C1-3 alkyl optionally substituted with 1-3 Re; each Reis independently selected from the group consisting of: halo, CN, C1-3 alkoxy, 15 OH, and N(RN)2; and each RNis independently selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F. In some embodiments of Formula (AA), Ring . 20 In some embodiments of Formula (AA), Ring . In some embodiments of Formula (AA), Y is N. In some embodiments of Formula (AA), Y is CH. 15 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (AA), RY1is C1-3alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments of Formula (AA), RY1is methyl. In some embodiments of Formula (AA), RY1is C1-3alkyl substituted with 1-3 -F (e.g., 5 -CH2CF3). In some embodiments of Formula (AA), RY1is C3-6 cycloalkyl (e.g., cyclopropyl). In some embodiments of Formula (AA), at least one of Y1, Y2, and Y3is CRY2. In some embodiments of Formula (AA), two or three (e.g., two) of Y1, Y2, and Y3are 10 independently selected CRY2. In some embodiments of Formula (AA), Y1and Y2are each CF; and Y3is CH. In some embodiments of Formula (AA), Y1, Y2, and Y3are each CF. In some embodiments of Formula (AA), Y1, Y2, and Y3are each CH. 15 In some embodiments of Formula (AA), Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments of Formula (AA), Ring A2 is a 4-6 membered nitrogen- containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, Ring 20 A2 is selected from the group consisting of: piperidinylene, tetrahydropyridylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with 1-2 Ra. In some embodiments of Formula (AA), Ring A2 is selected from the group consisting 25 , each of which is optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. For example, Ring A2 can , wherein bb represents the point of attachment to L2. 16 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (AA), Ring optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. For example, Ring A2 can , wherein bb represents the point of attachment to L2. 5 In some embodiments of Formula (AA), Ring . In some embodiments of Formula (AA), L2is selected from the group consisting of: a bond, CH2, CH2CH2, and -C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2. 10 In some embodiments of Formula (AA), L2is CH2. In some embodiments of Formula (AA), L2is CH(Me). In some embodiments of Formula (AA), L2is CH2CH2 or -C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2. In some embodiments of Formula (AA), L2is a bond. 15 In some embodiments of Formula (AA), Ring A1 is a 4-6 membered nitrogen- containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, Ring A1 is selected from the group consisting of: piperidinylene, pyrrolidinylene, azabicyclo[3.1.0]hexanylene, and azetidinylene, each optionally substituted with 1-2 Ra. 20 In some embodiments of Formula (AA), Ring A1 is selected from the group consisting 17 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) point of attachment to L2. For example, Ring A1 can be , wherein aa represents the point of attachment to L2. 5 In some embodiments of Formula (AA), Ring A1 is selected from the group consisting attachment to L2. 10 In some embodiments of Formula (AA), Ring A1 is a 7-12 membered nitrogen- containing heterocyclylene optionally substituted with 1-2 Ra. In some embodiments, Ring A1 is a 7-12 membered nitrogen-containing spirocyclic heterocyclylene. In some embodiments of Formula (AA), Ring A1 is selected from the group consisting 15 18 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) L2. For example, Ring A1 can , wherein aa represents the point of attachment to L2. In some embodiments of Formula (AA), Ring A1 is selected from the group consisting , wherein aa represents the point 5 of attachment to L2. In some embodiments of Formula (AA), Ring A1 is a C3-8cycloalkylene optionally substituted with 1-3 Ra. In some embodiments of Formula (AA), Ring A1 is selected from the group consisting 10 In some embodiments of Formula (AA), L1is C(=O). In some embodiments of Formula (AA), L1is CH2. In some embodiments of Formula (AA), L1is -C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1. 15 In some embodiments of Formula (AA), L0is Cy. In some embodiments of Formula (AA), Cy is selected from the group consisting of: 1,3-phenylene, 1,4-phenylene, C3-10 cycloalkylene, and 4-6 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; 20 In some embodiments of Formula (AA), Cy is a C4-6monocyclic cycloalkylene optionally substituted with 1-3 Ra. In some embodiments, Cy is selected from the group consisting of: , , , each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: F and C1-3 alkyl 19 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) optionally substituted with 1-3 F. For example, Cy can be selected from the group consisting , wherein dd represents the point of attachment to L1. In some embodiments of Formula (AA), Cy is a C6-10bridged bicyclic cycloalkylene. 5 In some embodiments, Cy is selected from the group consisting of: , In some embodiments of Formula (AA), Cy is a 4-6 membered heterocyclylene 10 , wherein dd represents the point of attachment to L1. In some embodiments of Formula (AA), L0is Cy; and Cy is , wherein X2is selected from the group consisting of: CH, CRa(e.g., CMe), and N; and dd represents the point of attachment to L1. 15 In some embodiments of Formula (AA), L0is a straight-chain C1-4 alkylene optionally substituted with 1-3 Ra. In some embodiments, L0is a straight-chain C2-4alkylene. In some embodiments of Formula (AA), L1is C(=O); L0is Cy, wherein Cy is , wherein X2is selected from the group consisting of: CH and CRa(e.g., CMe); 20 and dd represents the point of attachment to L1. 20 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (AA), L1is C(=O); and L0is Cy, wherein Cy is a C6-10bridged bicyclic cycloalkylene (e.g., , , , or In some embodiments of Formula (AA), L1is C(=O) or CH2; and L0is Cy, wherein the 5 , wherein dd represents the point of attachment to L1. In some embodiments of Formula (AA), L1is CH2 or C(=O); and L0is a straight- chain C2-4alkylene. In some embodiments of Formula (AA), R9is H. 10 In some embodiments of Formula (AA), R1is phenyl. In some embodiments of Formula (AA), R2is methyl. In some embodiments of Formula (AA), R3and R4are each an independently selected halo. In some embodiments of Formula (AA), R3is Cl; and R4is F. 15 In some embodiments of Formula (AA), R5is H. In some embodiments of Formula (AA), R8is F. In some embodiments of Formula (AA), X1is CH or N. In some embodiments of Formula (AA), X1is CH. In some embodiments of Formula (AA), X1is N. 20 In some embodiments of Formula (AA), R7is C2-3 alkoxy substituted with 1-3 Rc, wherein each Rcis independently selected from the group consisting of: F, CN, OH, and C1-3alkoxy. For example, R7can be . For example, R7can be selected from the group In some embodiments of Formula (AA), R7is C1-3alkoxy (e.g., methoxy). 21 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (AA), X1is CR6; and R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 RaIn some embodiments, R6and R7, taken together with the two ring carbon atoms connecting them, form . 5 In some embodiments of Formula (AA), R11is H. In some embodiments, the compounds of Formula (AA) are compounds of Formula (A1), (A2), or (A3): 10 Formula (A1) Formula (A2) 22 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Formula (A3) or pharmaceutically acceptable salts thereof, wherein: 5 X2is CH, CRa, or N (e.g., CH or CMe); Cy is a C6-10 bridged bicyclic cycloalkylene; L0is a straight-chain C2-4alkylene; L1is selected from the group consisting of: C(=O) and CH2; and L2is selected from the group consisting of: a bond, CH2, CH2CH2, and -C(Me)2CH2-*, 10 wherein the * represents point of attachment to Ring A2. In some embodiments, the compounds of Formula (AA) are compounds of Formula (I) or (II): 15 Formula (I) 23 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Formula (II) or pharmaceutically acceptable salts thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; 5 R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; 10 R8is selected from the group consisting of: H and halo; X1is N or CH; X2is N or CH; L1is C(=O) or CH2; 15 Ring A1 is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, CH2, CH2CH2, O, and C(=O); Ring A2 is a 4-10 membered heterocyclylene optionally substituted with 1-3 Ra; 20 Y is N or CH; RY1is C1-3alkyl; Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; 24 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) each Rais independently selected from the group consisting of: halo, CN, OH, and C1-3 alkyl optionally substituted with 1-3 F; and each Rcis independently selected from the group consisting of halo, CN, OH, and C1-3 alkoxy. 5 In some embodiments, the compounds are compounds of Formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the compounds are compounds of Formula (II), or pharmaceutically acceptable salts thereof. 10 In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Y is N. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), RY1is methyl. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), at least one of Y1, Y2, and Y3is CRY2. In some embodiments of Formula (I), at least one of Y1, Y2, and Y3is CRY215 (e.g., CF). In some embodiments of Formula (A1), (A2), (A3), (I), or (II), two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2. In some embodiments of Formula (I), two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Y1and Y2are each CF; 20 and Y3is CH. In some embodiments of Formula (I), Y1and Y2are each CF; and Y3is CH. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Y1, Y2, and Y3are each CF. In some embodiments of Formula (I), Y1, Y2, and Y3are each CF. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Y1, Y2, and Y3are each CH. In some embodiments of Formula (I), Y1, Y2, and Y3are each CH. In some embodiments 25 of Formula (II), Y1, Y2, and Y3are each CH. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments of Formula (I), Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A2 is a 4-6 30 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. 25 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A2 is selected from the group consisting of: piperidinylene, tetrahydropyridylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with 1-2 Ra. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A2 is selected 5 from the group consisting of: , , , each of which is optionally substituted with 1-2 Ra; wherein bb represents the point of attachment to L2. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A2 is 10 optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. For example, Ring A2 can be , wherein bb represents the point of attachment to L2. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A2 is 15 . In some embodiments of Formula (A1), (A2), (A3), (I), or (II), L2is selected from the group consisting of: a bond, CH2, and CH2CH2. For example, L2can be CH2. For example, L2can be a bond. 20 In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A1 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, Ring A1 is selected from the group consisting of: piperidinylene, pyrrolidinylene, and azetidinylene, each optionally substituted with 1-2 Ra. 26 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A1 is selected from the group consisting of: , , , wherein aa represents the point of attachment to L2. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A1 is a 7-12 5 membered nitrogen-containing bicyclic heterocyclylene optionally substituted with 1-2 Ra. In some embodiments, Ring A1 is a 7-12 membered nitrogen-containing spirocyclic bicyclic heterocyclylene. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A1 is selected from the group consisting of: 10 , wherein aa represents the point of attachment to L2. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), Ring A1 is a C3-8 cycloalkylene (e.g., ) optionally substituted with 1-3 Ra. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), L1is C(=O). In some embodiments of Formula (A1), (A2), (A3), (I), or (II), X2is CH. 15 In some embodiments of Formula (A1), (A2), or (A3), X2is CMe. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), X1is CH; L1is C(=O); L2is selected from the group consisting of: a bond and CH2; and Ring optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. In some embodiments, Ring A1 is a 4-6 membered nitrogen-containing heterocyclylene optionally 20 substituted with 1-3 Ra. For example, Ring A1 can be selected from the group consisting of: , , , wherein aa represents the point of 27 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) attachment to L2. In some embodiments, Ring A1 is a 7-12 membered nitrogen-containing spirocyclic bicyclic heterocyclylene. For example, Ring A1 can be selected from the group 5 In some embodiments of Formula (I), X1is CH; L1is C(=O); L2is selected from the group consisting of: a bond and CH2; and Ring optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. In some embodiments, Ring A1 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. For 10 example, Ring A1 can be selected from the group consisting of: , , , wherein aa represents the point of attachment to L2. In some embodiments, Ring A1 is a 7-12 membered nitrogen-containing spirocyclic bicyclic heterocyclylene. For example, Ring A1 can be selected from the group consisting of: 15 represents the point of attachment to L2. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R1is phenyl. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R2is methyl. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R3and R4are 20 independently selected halo. In some embodiments, R3is Cl; and R4is F. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R5is H. 28 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (A1), (A2), (A3), (I), or (II), X1is CH. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), X1is N. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R8is F. In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R7is C2-3alkoxy 5 substituted with OH. For example, R7can be . In some embodiments of Formula (A1), (A2), (A3), (I), or (II), R7is C1-3alkoxy. For example, R7can be methoxy. In some embodiments, the compounds of Formula (I) are compounds of Formula (I-a): 10 Formula (I-a) or pharmaceutically acceptable salts thereof, wherein: R7is C1-3 alkoxy optionally substituted with F or OH; and Y1, Y2, and Y3are independently selected from the group consisting of: CH and CF. 15 In some embodiments, the compounds of Formula (II) are compounds of Formula (II- a): 29 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Formula (II-a) or pharmaceutically acceptable salts thereof, wherein: R7is C1-3 alkoxy optionally substituted with F or OH; and 5 Y1, Y2, and Y3are independently selected from the group consisting of: CH and CF. In some embodiments of Formula (I-a) or (II-a), Ring A2 is a 4-6 membered nitrogen- containing heterocyclylene optionally substituted with 1-3 Ra; and L2is selected from the group consisting of: a bond, CH2, and CH2CH2. In some embodiments, L2is CH2. 10 In some embodiments of Formula (I-a) or (II-a), Ring A2 is optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2; and L2is selected from the group consisting of: a bond and CH2. In some embodiments, Ring A2 is , wherein bb represents the point of attachment to L2. In some 15 embodiments, L2is CH2. In some embodiments of Formula (I-a) or (II-a), L2is CH2. In some embodiments of Formula (I-a) or (II-a), Ring A1 is a 4-6 membered nitrogen- containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, Ring A1 20 , 30 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) wherein aa represents the point of attachment to L2. For example, Ring A1 can be , wherein aa represents the point of attachment to L2. In some embodiments of Formula (I-a) or (II-a), Ring A1 is a 7-12 membered nitrogen- 5 containing spirocyclic bicyclic heterocyclylene. In some embodiments, Ring A1 is selected from the group consisting of: , wherein aa represents the point of attachment to L2. In some embodiments of Formula (I-a) or (II-a), R7is . In some embodiments of Formula (I-a) or (II-a), Y is N. 10 In some embodiments of Formula (I-a) or (II-a), Y1and Y2are each CF; and Y3is CH. In some embodiments of Formula (I-a) or (II-a), Y1, Y2, and Y3are each CH. In some embodiments of Formula (I-a) or (II-a), RY1is methyl. In some embodiments, the compounds of Formula (AA) are selected from the group 15 consisting of the compounds depicted in Table C1, or pharmaceutically acceptable salts thereof. Table C1 31 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 32 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 33 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 34 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 35 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 36 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 37 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 38 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 39 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 40 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 41 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 42 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 43 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 44 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 45 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 46 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 47 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 48 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 49 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 50 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 51 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 52 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 53 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 54 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 55 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 56 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 57 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 58 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 59 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 60 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 61 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 62 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 63 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 64 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 65 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 66 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 67 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 68 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 69 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 70 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 71 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 72 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 73 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 74 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 75 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 76 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 77 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 78 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 79 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 80 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 81 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 82 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 83 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 84 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 85 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 86 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 87 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 88 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 89 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 90 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 91 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 92 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 93 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 94 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 95 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 96 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 97 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 98 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 99 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 100 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 101 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 102 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 103 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 104 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 105 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 106 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 107 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 108 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 109 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 110 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 111 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 112 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 113 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 114 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 115 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 116 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 117 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 118 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 119 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 120 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 121 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 122 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 123 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 124 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 125 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 126 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 127 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 128 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 129 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 130 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 131 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 132 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 133 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 134 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 135 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 136 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 137 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 138 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 139 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 140 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 141 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 142 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 143 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 144 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 145 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 146 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 147 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 148 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 149 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 150 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 151 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 152 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 153 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 154 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 155 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 156 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 157 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 158 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 159 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 160 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 161 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 162 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 163 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 164 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 165 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 166 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 167 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 168 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 169 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 170 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 171 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 172 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 173 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 174 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 175 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 176 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 177 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 178 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 179 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 180 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 181 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 182 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 183 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 184 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 185 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 186 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 187 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 188 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 189 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 190 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 191 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 192 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 193 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 194 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 195 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 196 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 197 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 198 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 199 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 200 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 201 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 202 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 203 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 204 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 205 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 206 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 207 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 208 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 209 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 210 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 211 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 212 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 213 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 214 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 215 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 216 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 217 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 218 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 219 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 220 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 221 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 222 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 223 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 224 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 225 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 226 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 227 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 228 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 229 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 230 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 231 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 232 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 233 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 234 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 235 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 236 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 237 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 238 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 239 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 240 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 241 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 242 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 243 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 244 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 245 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 246 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 247 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 248 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 249 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 250 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 251 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 252 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 253 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 254 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 255 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 256 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 257 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 258 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 259 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 260 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 261 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 262 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 263 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 264 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 265 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 266 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 267 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 268 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 269 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 270 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 271 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 272 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 273 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 274 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 275 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 276 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 277 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 278 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 279 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 280 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In certain compounds of Table C1, C2, C3, or C4, one or more stereogenic centers are denoted with the “V3000 enhanced stereochemical notation” (see: support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry- 5 Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chirality, accessed on December 23, 2022 and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each of which is incorporated by reference herein in its entirety). Using this stereochemical notation, certain stereogenic centers are denoted with “abs”, “&x”, or “orx”, wherein x is an integer (e.g., 1 or 2). For avoidance of doubt, the stereochemical notations in 10 Table C1, C2, C3, or C4 have the following meaning: 281 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) (1) When a stereogenic center (e.g., a stereogenic carbon) is depicted with “flat" bonds (i.e., none of the chemical bonds at the stereogenic center is depicted with wedges or dashes) in a structural formula, each of the stereogenic centers can independently adopt the (R)- or (S)- configurations. For example, the structure represents (S)-(1-5 methylpyrrolidin-2-yl)methanol, (R)-(1-methylpyrrolidin-2-yl)methanol, or a mixture thereof. As another non-limiting example, the structure represents: (3S,5S)-5- methylpiperidine-3-carboxylic acid; (3R,5S)-5-methylpiperidine-3-carboxylic acid; (3S,5R)-5- methylpiperidine-3-carboxylic acid; (3R,5R)-5-methylpiperidine-3-carboxylic acid; or a mixture thereof. 10 When a stereogenic center or a plurality of stereogenic centers is depicted with wedges and dashes, the following notations are used: (2) When a stereogenic center is denoted with “abs” or when a stereogenic center is not denoted with an enhanced stereochemical notation (e.g., “abs”, “&x”, or “orx”), the 15 stereogenic center has the absolute configuration as depicted by the structural formula. For example, both of the structures and refer to (S)-(1-methylpyrrolidin-2-yl)methanol. (3) When a stereogenic center is denoted with “orx” in a structural formula, the stereogenic center has been resolved but the configuration at the stereogenic center has not20 been determined. For example, the structure refers to one stereoisomer selectedfrom the group consisting of (S)-(1-methylpyrrolidin-2-yl)methanol and (R)-(1- methylpyrrolidin-2-yl)methanol. (4) When two or more stereogenic centers are denoted with “orx” in a structural formula, each of these stereogenic centers has been resolved but the configurations at the 25 stereogenic centers have not been determined. Specifically: a. For any pair of stereogenic centers denoted with “orx” in a structural formula, when the numerical parts in the notation are different (e.g., two stereogenic 282 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) centers denoted with “or1” and “or2” respectively), each stereogenic center is independently defined according to (3) (vide supra). For example, the structure 5 b. For any pair of stereogenic centers denoted with “orx” in a structural formula, when the numerical part in the notation is identical (e.g., two stereogenic centers each denoted with “or1”), the structural formula refers to one stereoisomer having the relative stereochemistry at these stereogenic centers as depicted in the structural formula, but the absolute configurations of these stereogenic 10 centers have not been determined. For example, the structure refers to one of the two “syn” stereoisomers: . As another example, the structure one of the “anti” stereoisomers: . (5) When two or more stereogenic centers are denoted with “&x” in a structural 15 formula, the structural formula refers to a mixture of stereoisomers that differ in the configuration at the stereogenic centers. Specifically: a. For any pair of stereogenic centers denoted with “&x” in a structural formula, when the numerical parts in the notation are different (e.g., two stereogenic centers denoted with “&1” and “&2” respectively), the structural formula 283 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) refers to a mixture of stereoisomers at these two stereogenic centers, wherein the configuration at each stereogenic center can vary independently of one another. For example, the structure refers to a mixture of four 5 . b. For any pair of stereogenic centers denoted with “&x” in a structural formula, when the numerical part in the notation is identical (e.g., two stereogenic centers each denoted with “&1”), the structural formula refers to a mixture of stereoisomers at these two or more stereogenic centers, wherein the relative 10 configurations are as depicted in the structural formula. For example, the . 15 In some embodiments, the compounds of Formula (I) are selected from the group consisting of the compounds depicted in Table C1 of U.S. Provisional Application Serial Nos. 284 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 63 / 687,272, filed August 26, 2024; 63 / 707,710, filed October 15, 2024; 63 / 724,095, filed November 22, 2024; 63 / 748,695, filed January 23, 2025; and 63 / 814,335, filed May 29, 2025, each Table C1 is incorporated by reference in its entirety herein. 5 Also provided herein are compounds of Formula (A): Formula (A) 10 or salts thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3alkyl optionally substituted with 15 1-3 F; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; R10is selected from the group consisting of: 20 (a) C1-6 alkyl optionally substituted with 1-3 Rc; (b) –(C0-2alkylene)-phenyl optionally substituted with 1-3 Rd; X1is N or CH; X2is N or CH; 25 L1is C(=O) or CH2; 285 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Ring A1 is selected from the group consisting of: C3-8cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, CH2, CH2CH2, O, and C(=O); Ring A2 is a 4-10 membered heterocyclylene optionally substituted with 1-3 Ra; 5 Ring C is selected from the group consisting of: , wherein cc represents the point of attachment to Ring A2; Y is N or CH; RY1is C1-3alkyl; 10 Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; each Rais independently selected from the group consisting of: halo, CN, OH, and C1- 3 alkyl optionally substituted with 1-3 F; 15 each Rcis independently selected from the group consisting of: halo, CN, OH, and C1-3 alkoxy; each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3 alkoxy, N(RN)2, and C1-3alkyl optionally substituted with 1-3 Re; each Reis independently selected from the group consisting of: halo, CN, C1-3alkoxy, 20 OH, and N(RN)2; and each RNis independently selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F. In some embodiments, provided herein are compounds of Formula (A), or pharmaceutically acceptable salts thereof. 25 In some embodiments of Formula (A), R1, R2, R3, R4, R5, X1, R7, R8, X2, L1, Ring A1, L2, Ring A2, RY1, Y1, Y2, Y3, and Y can each independently be as defined for Formula (I) or (II) herein. 286 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (A), R9is H. In some embodiments of Formula (A), R9is C(=O)OR10. In some embodiments, R10is -CH2-phenyl, wherein the phenyl is substituted with 1-2 Rd. In some embodiments of Formula (A), R9is . In some 5 embodiments, Rdis C1-3alkyl substituted with 1-3 Re(e.g., Rdcan be -CH2OH; or Rdcan be - CH2N(RN)2; or Rdcan be -CH2CF3). In some embodiments, Rdis C1-3 alkoxy (e.g., -OMe). In some embodiments, compounds of Formula (A) are selected from the group consisting of the compounds depicted in Table C2, or salts thereof. 10 Table C2 287 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 288 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 289 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Also provided herein are compounds of Formula (BB): 290 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Formula (BB) or pharmaceutically acceptable salts thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; 5 R2is selected from the group consisting of: H, methyl, and -CH2OH; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F; X1is selected from the group consisting of: N, CH, and CR6; 10 R7is selected from the group consisting of: (a) C1-6alkoxy optionally substituted with 1-3 Rc; (b) C1-3alkyl optionally substituted with 1-3 Rc; and (c) -OH; R6is H, or 15 R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; R10is selected from the group consisting of: 20 (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) –(C0-2 alkylene)-phenyl optionally substituted with 1-3 Rd; L0is selected from the group consisting of: (a) Cy; 25 (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and 291 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) (c) straight-chain C1-4alkylene optionally substituted with 1-3 Ra; Cy is selected from the group consisting of: phenylene, C3-10cycloalkylene, and 4-10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), -C(=O)N(H)- 5#, and -C(=O)N(C1-6alkyl)-#, wherein the # presents the point of attachment to Ring A1; a1 is 0 or 1; Ring A1 is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; 10 L2is selected from the group consisting of: a bond, O, C(=O), -N(RN)-, and a straight- chain C1-3 alkylene, wherein the straight-chain C1-3 alkylene is optionally substituted with 1-3 Ra; Ring A2 is selected from the group consisting of: C3-8cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; 15 Ring C is selected from the group consisting of: , , , wherein cc represents the point of attachment to Ring A2; Y is N or CH; 20 RY1is selected from the group consisting of: (a) C1-3 alkyl optionally substituted with 1-3 F; and (b) –(C0-2 alkylene)-(C3-6 cycloalkyl); Y1, Y2, and Y3are each independently selected from the group consisting of: CH, CRY2, 25 and N, wherein each RY2is an independently selected Ra(e.g., each RY2is an independently selected halo); 292 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Y4is selected from the group consisting of: O, S, and N(RY1); Y5is N or CH; Y6and Y7are independently selected from the group consisting of: N, O, S, and N(RY1), and each is independently a single or double bond, provided that the 5-membered ring 5 containing Y6and Y7is aromatic; each R11is independently selected from the group consisting of: H and C1-3alkyl; each Rais independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 F; each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 103alkoxy; each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3 alkoxy, N(RN)2, and C1-3 alkyl optionally substituted with 1-3 Re; each Reis independently selected from the group consisting of: halo, CN, C1-3alkoxy, OH, and N(RN)2; and 15 each RNis independently selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F. In some embodiments of Formula (BB), Ring C is . In some embodiments, at least one of Y1, Y2, and Y3is CRY2. In some embodiments, two or three (e.g., 20 two) of Y1, Y2, and Y3are independently selected CRY2. In some embodiments, Y1and Y2are each CF; and Y3is CH. In some embodiments, Y1, Y2, and Y3are each CF. In some embodiments, Y1, Y2, and Y3are each CH. In some embodiments, Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments, Y1is N; and Y2and Y3are independently CH or CRY2(e.g., CH or CF). In some embodiments, RY1is C1-3alkyl (e.g., 25 methyl, ethyl, or isopropyl). In some embodiments, RY1is methyl. In some embodiments, RY1is C1-3 alkyl substituted with 1-3 -F (e.g., -CH2CF3). In some embodiments, RY1is C3-6 cycloalkyl (e.g., cyclopropyl). 293 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (BB), Ring . some embodiments, at least one of Y1, Y2, and Y3is CRY2. In some embodiments, two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2. In some embodiments, Y1and Y2are each CF; and Y3is CH. In some embodiments, Y1, Y2, and Y3are each CF. In some 5 embodiments, Y1, Y2, and Y3are each CH. In some embodiments, Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments, RY1is C1-3 alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, RY1is methyl. In some embodiments, RY1is C1-3 alkyl substituted with 1-3 -F (e.g., -CH2CF3). In some embodiments, RY1is C3-6cycloalkyl (e.g., cyclopropyl). 10 In some embodiments of Formula (BB), Ring . some embodiments, Y4is S. In some embodiments, Y4is O. In some embodiments, Y4is NRY1(e.g., NMe). In some embodiments, at least one of Y1, Y2, and Y3is CRY2. In some embodiments, two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2. In some embodiments, Y1and Y2are each CF; and Y3is CH. In some embodiments, Y1, Y2, and Y3are 15 each CF. In some embodiments, Y1, Y2, and Y3are each CH. In some embodiments, Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments of Formula (BB), Ring C is . In some embodiments, RY1is C1-3 alkyl (e.g., methyl). In some embodiments, Y5is N. In some embodiments, Y1, Y2, and Y3are each CH. 20 In some embodiments of Formula (BB), Ring C is . In some embodiments, one of Y6and Y7is O; and the other of Y6and Y7is N. In some embodiments, one of Y6and Y7is N(RY1); and the other of Y6and Y7is N. 294 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (BB), Ring . example, Ring C In some embodiments of Formula (BB), Y is N. In some embodiments of Formula (BB), Y is CH. 5 In some embodiments of Formula (BB), Ring A2 is a 4-6 membered nitrogen- containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, Ring A2 is selected from the group consisting of: piperidinylene, tetrahydropyridylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with 1-2 Ra. 10 In some embodiments of Formula (BB), Ring A2 is selected from the group consisting of: , , each of which is optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. In some embodiments of Formula (BB), Ring optionally 15 substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. For example, Ring A2 can , wherein bb represents the point of attachment to L2. In some embodiments of Formula (BB), Ring . 295 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (BB), L2is selected from the group consisting of: a bond, CH2, CH2CH2, and -C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2. In some embodiments of Formula (BB), L2is CH2. 5 In some embodiments of Formula (BB), L2is CH2CH2 or -C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2. In some embodiments of Formula (BB), L2is a bond. In some embodiments of Formula (BB), Ring A1 is a 4-6 membered nitrogen- 10 containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, Ring A1 is selected from the group consisting of: piperidinylene, pyrrolidinylene, azabicyclo[3.1.0]hexanylene, and azetidinylene, each optionally substituted with 1-2 Ra. In some embodiments of Formula (BB), Ring A1 is selected from the group consisting 15 point of attachment to L2. In some embodiments of Formula (BB), Ring A1 is selected from the group consisting20 296 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) , wherein aa represents the point of attachment to L2. In some embodiments of Formula (BB), a1 is 1; and Ring A1 is a 7-12 membered 5 nitrogen-containing heterocyclylene optionally substituted with 1-2 Ra. In some embodiments, Ring A1 is a 7-12 membered nitrogen-containing spirocyclic heterocyclylene. In some embodiments of Formula (BB), a1 is 1; and Ring A1 is selected from the group consisting , wherein aa represents the 10 point of attachment to L2. In some embodiments of Formula (BB), a1 is 1; and Ring A1 is selected from the group consisting of: wherein aa represents the point of attachment to L2. In some embodiments of Formula (BB), a1 is 1; and Ring A1 is a C3-8cycloalkylene 15 optionally substituted with 1-3 Ra. In some embodiments of Formula (BB), a1 is 1; and Ring A1 is selected from the group In some embodiments of Formula (BB), a1 is 0. In some embodiments of Formula (BB), L1is C(=O). 20 In some embodiments of Formula (BB), L1is CH2. 297 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (BB), L1is -C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1. In some embodiments of Formula (BB), L1is -C(=O)N(C1-6 alkyl)-#. 5 In some embodiments of Formula (BB), L0is Cy. In some embodiments of Formula (BB), Cy is selected from the group consisting of: 1,3-phenylene, 1,4-phenylene, C3-10cycloalkylene, and 4-6 membered heterocyclene, each of which is optionally substituted with 1-3 Ra. In some embodiments of Formula (BB), Cy is a C4-6 monocyclic cycloalkylene 10 optionally substituted with 1-3 Ra. In some embodiments, Cy is selected from the group consisting of: , , , each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: F and C1-3 alkyl optionally substituted with 1-3 F. For example, Cy can be selected from the group consisting , wherein dd represents the point of attachment to L1. 15 In some embodiments of Formula (BB), Cy is a C6-10 bridged bicyclic cycloalkylene. In some embodiments, Cy is selected from the group consisting of: , 20 In some embodiments of Formula (BB), Cy is a 4-6 membered heterocyclylene , wherein dd represents the point of attachment to L1. 298 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) In some embodiments of Formula (BB), L0is Cy; and Cy is , wherein X2is selected from the group consisting of: CH, CRa(e.g., CMe), and N; and dd represents the point of attachment to L1. In some embodiments of Formula (BB), L0is a straight-chain C1-4alkylene optionally 5 substituted with 1-3 Ra. In some embodiments, L0is a straight-chain C2-4 alkylene. In some embodiments of Formula (BB), L1is C(=O); L0is Cy, wherein Cy is , wherein X2is selected from the group consisting of: CH and CRa(e.g., CMe); and dd represents the point of attachment to L1. 10 In some embodiments of Formula (BB), L1is C(=O); and L0is Cy, wherein Cy is a C6-10bridged bicyclic cycloalkylene (e.g., , , , or 15 In some embodiments of Formula (BB), L1is CH2 or C(=O); and L0is a straight- chain C2-4 alkylene. In some embodiments of Formula (BB), R9is H. In some embodiments of Formula (BB), R1is phenyl. In some embodiments of Formula (BB), R2is methyl. 20 In some embodiments of Formula (BB), R3and R4are each an independently selected halo. In some embodiments, R3is Cl; and R4is F. In some embodiments of Formula (BB), R5is H. In some embodiments of Formula (BB), R8is F. In some embodiments of Formula (BB), X1is CH. 25 In some embodiments of Formula (BB), X1is N. In some embodiments of Formula (BB), R7is C2-3 alkoxy substituted with 1-3 Rc, wherein each Rcis independently selected from the group consisting of: F, CN, OH, and C1-3299 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) alkoxy. For example, R7can be . For example, R7can be selected from the group consisting of: In some embodiments of Formula (BB), R7is C1-3alkoxy (e.g., methoxy). In some embodiments of Formula (BB), R11is H. 5 In some embodiments of Formula (BB), R9is H; R1is phenyl; R2is methyl; R3is Cl; R4is F; R5is H; and R8is F. In some embodiments of Formula (BB), R9is H; R1is phenyl; R2is methyl; R3is Cl; R4is F; R5is H; R8is F; and R7is C2-3 alkoxy substituted with 1-3 Rc, wherein each Rcis independently selected from the group consisting of: F, CN, OH, and C1-3 alkoxy. For example, 10 R7can be . For example, R7can be selected from the group consisting of: In some embodiments of Formula (BB), a1 is 0; L1is -C(=O)N(C1-6alkyl)-#; Ring A2 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra; L2is a straight-chain C1-3 alkylene, wherein the straight-chain C1-3 alkylene is optionally 15 substituted with 1-3 Ra; and Ring . some embodiments, Ring A2 is optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2. For example, Ring A2 can , wherein bb represents the point of attachment to L2. In some embodiments, R9is H; R1is phenyl; R2is methyl; R3is Cl; R4is F; R5is H; and R8is F. In some embodiments, R7is C2-3 alkoxy 20 substituted with 1-3 Rc, wherein each Rcis independently selected from the group consisting of: F, CN, OH, and C1-3alkoxy. For example, R7can be . For example, R7can 300 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) be selected from the group consisting of: . In some embodiments, at least one of Y1, Y2, and Y3is CRY2. In some embodiments, two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2. In some embodiments, Y1and Y2are each CF; and Y3is CH. In some embodiments, Y1, Y2, and Y3are each CF. In some 5 embodiments, Y1, Y2, and Y3are each CH. In some embodiments, Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. In some embodiments, Y1is N; and Y2and Y3are independently CH or CRY2(e.g., CH or CF). In some embodiments, RY1is C1-3alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, RY1is methyl. In some embodiments, RY1is C1-3 alkyl substituted with 1-3 -F (e.g., -CH2CF3). In some embodiments, RY1is C3-6 10 cycloalkyl (e.g., cyclopropyl). In some embodiments, the compounds of Formula (BB) are selected from the group consisting of the compounds depicted in Table C1, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (BB) are selected from the group 15 consisting of the compounds depicted in Table C3, or pharmaceutically acceptable salts thereof. Table C3 301 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 302 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 303 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 304 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 305 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 306 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 307 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 308 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 309 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 310 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 311 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 312 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 313 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 314 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 315 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 316 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 317 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 318 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 319 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 320 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 321 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 322 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 323 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 324 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 325 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 326 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 327 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 328 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 329 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 330 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 331 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 332 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 333 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 334 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 335 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 336 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 337 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 338 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 339 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 340 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 341 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 342 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 343 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 344 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 345 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 346 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 347 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 348 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 349 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 350 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 351 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 352 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 353 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 354 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 355 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 356 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 357 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 358 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 359 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 360 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 361 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 362 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 363 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 364 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 365 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 366 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Also provided herein are compounds selected from the group consisting of the compounds depicted in Table C4, or pharmaceutically acceptable salts thereof. Table C4 367 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 368 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 369 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 370 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 371 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 372 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 373 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 374 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 375 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 376 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 377 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 378 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 379 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 380 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 381 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 382 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 383 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 384 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 385 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 386 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 387 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 388 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 389 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 390 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 391 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 392 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 393 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 394 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 395 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 396 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 397 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 398 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 399 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 400 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 401 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 402 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 403 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 404 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 405 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 406 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 407 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 408 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 409 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 410 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 411 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 412 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 413 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 414 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 415 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 416 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 417 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 418 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 419 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 420 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 421 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 422 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 423 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 424 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 425 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 426 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 427 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 428 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 429 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 430 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 431 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 432 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 433 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 434 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 435 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 436 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 437 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 438 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 439 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 440 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 441 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 442 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 443 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 444 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 445 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 446 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 447 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Certain examples of Formula (AA) or Formula (BB) compounds were synthesized using methods involving resolution of stereoisomeric mixture(s) (e.g., SFC separation of stereoisomers). In Table C1 or Table C3, the resolved stereogenic centers in these compounds 5 are labelled with the “or1” and / or “or2” enhanced stereochemical notations. In some instances, 448 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) the stereoisomeric resolutions were performed during the last step of the synthesis, thereby providing the individual stereoisomers of the compounds. Alternatively, in some other instances, the resolutions were performed on an intermediate or starting material, wherein each of the constituent stereoisomers of the intermediate or starting material could be separately 5 subjected to the subsequent steps of the synthesis to provide the respective compounds as separate stereoisomers. A person of ordinary skill in the art would understand that, under either approach for stereoisomeric resolution, stereoisomers having both (R)- and (S)-configurations at a resolved stereogenic center are provided. See Table C5, wherein Table C1 or Table C3 compounds whose stereoisomers contain the or1 and / or or2 stereochemical notations are 10 provided in non-stereogenic form, followed by the respective stereoisomers having the (R)- and (S)-configurations. 449 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 450 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 451 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 452 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 453 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 454 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 455 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 456 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 457 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 458 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 459 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 460 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 461 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 462 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 463 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 464 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 465 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 466 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 467 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 468 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 469 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 470 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 471 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 472 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 473 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 474 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 475 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 476 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 477 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 478 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 479 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 480 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 481 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 482 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Chemical definitions The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used 5 herein, oxo groups are attached to carbon atoms to form carbonyls. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples 10 include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F). 15 The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3, -OCHF2, or -OCH2F). The term “alkylene” refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two 20 radicals can be on the same ring carbon atom (e.g., a geminal diradical such 483 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms) The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety 5 contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents. The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains 10 the indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents. The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14- 15 carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to mono-, bi-, tri-, or polycyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 20 15 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. Examples of saturated cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl may 25 have any degree of unsaturation provided that one or more double bonds is present in the cycloalkyl, none of the ring system are aromatic, and the partially unsaturated cycloalkyl group is not fully saturated overall. Examples of partially unsaturated cycloalkyl include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged 30 cycloalkyl includes: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, 484 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, 5 spiro[3.6]decyl, spiro[5.5]undecyl, and the like. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (inclusive of oxidized forms such as: and at least 10 one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, 15 thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3- c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3- 20 dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each25 ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- 485 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) , ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially 5 unsaturated ring system with 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, the heteroatoms selected from O, N, and S (inclusive of oxidized forms such as: ) (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, S, or P if monocyclic, bicyclic, or tricyclic, 10 respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl 15 groups may have any degree of unsaturation provided that one or more double bonds is present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. 20 Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3- azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7- azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-25 azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, and the like. Heterocyclyl also includes 486 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4- azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2- azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl 2,5- 5 diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1- oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6- oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1- oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl and the like. A nitrogen-containing heterocyclyl as used herein refers to a heterocyclyl having 1-2 10 ring nitrogen atoms and 0-2 additional ring heteroatoms selected from the group consisting of O and S (inclusive of oxidized such as: The nitrogen-containing heterocyclyl can be monocyclic, bicyclic, or polycyclic as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclyl 15 include 7-azaspiro[3.5]nonyl, 1,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, 2,6-diazaspiro[3.3]heptanyl, and the like. As used herein, when a ring is described as being “partially unsaturated”, it means the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between 20 constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like 25 described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring systems) (e.g., , 487 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) or ). In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having 5 the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: 10 encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of 15 enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. 20 Compounds of the present disclosure may exhibit conformational, rotational isomerism, referred to as atropisomerism. The atropisomers as disclosed herein are named using the (R) and (S) convention under the Cahn-lngold-Prelog (CIP) rule. Alternatively, the atropisomers may also be named using the Cahn-lngold-Prelog (CIP) helicity rule, with stereodescriptors (P) or (M). See Nomenclature of Organic Chemistry: IUPAC 25 Recommendations and Preferred Names 2013 {the IUPAC “Blue Book”), Cambridge, UK: Royal Soc. of Chem., 2014, DOI: 10.1039 / 9781849733069. Chapter P-9, “Specification of Configuration and Conformation”, DOI: 10.1039 / 9781849733069-01156); See also: Eliel, E. L.; Wilen, S.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley Interscience: New 488 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) York, 1994, pp.1119–1190. The structural depiction provided in Table C1 controls in cases of ambiguity or inconsistency resulting from chemical naming / parsing software. Methods of Treatment 5 Indications Provided herein are methods for inducing degradation of a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4) useful for treating or preventing diseases or disorders associated with decreased activity in the Hippo pathway, such as cancer (e.g., a cancer having a Hippo pathway dysregulation). 10 As used herein, “Hippo pathway gene” refers to a gene encoding a Hippo pathway protein. As used herein, “Hippo pathway protein” refers to a protein involved in Hippo pathway signaling or regulation. Non-limiting examples include: TEAD1, TEAD2, TEAD3, TEAD4, YAP, TAZ, LATS1, LATS2, Mps one binder kinase activator-like 1A (MOB1A), Mps one 15 binder kinase activator-like 1B (MOB1B), protein Salvador homolog 1 (SAV1), mammalian STE20-like kinase 1 (MST1, also known as STK4), mammalian STE20-like kinase 2 (MST2, also known as STK3), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), RhoA, neurofibromin 2 (NF2), Kibra (also known as WWC1), WWC2, WWC3, Rhophilin, TAO kinases (TAOKs), and the straitin (STRN)-interacting phosphatase and kinase 20 (STRIPAK) complex (which includes a Serine / threonine-protein phosphatase 2A catalytic subunit (PP2AC), a scaffolding subunit (PP2AA) and the STRN (regulatory subunit) that recruits other proteins, including STRN-interacting protein (STRIP1 / 2) and sarcolemmal membrane-associated protein (SLMAP)). The phrases “dysregulation of the Hippo pathway” or “a Hippo pathway dysregulation” 25 as used herein refer to: (i) a genetic mutation in a Hippo pathway gene (e.g., a mutation in a Hippo pathway gene that results in the expression of the corresponding Hippo pathway protein that includes a deletion of at least one amino acid as compared to the wild type Hippo pathway protein, a mutation in a Hippo pathway gene that results in the expression of the corresponding Hippo pathway protein with one or more point mutations as compared to the wild type Hippo 30 pathway protein, a mutation in a Hippo pathway gene that results in the expression of the corresponding Hippo pathway protein with at least one inserted amino acid as compared to the wild type Hippo pathway protein, a gene amplification (e.g., duplication) that results in an increased level of a Hippo pathway protein in a cell, a gene deletion (e.g., partial or full deletion) that results in a decreased level of a Hippo pathway protein in a cell, a mutation in a 489 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) regulatory sequence (e.g., a promoter and / or enhancer) that results in an altered level of the Hippo pathway protein in a cell, a partial or full fusion of a Hippo pathway gene with another partial or full gene), provided that the genetic mutation results in increased TEAD protein transcriptional activity compared to a cell having a wild type version of the Hippo pathway 5 gene; (ii) an alternative spliced version of a Hippo pathway mRNA that results in the corresponding Hippo pathway protein having an insertion or deletion of at least one amino acid in the Hippo pathway protein as compared to the wild type Hippo pathway protein, provided that the alternative spliced version of a Hippo pathway mRNA results in increased TEAD protein transcriptional activity compared to a cell having a wild type version of the Hippo 10 pathway gene; and / or (iii) increased expression (e.g., increased levels) of a wild type Hippo pathway protein in a mammalian cell due to aberrant cell signaling, provided that the alternative spliced version of the Hippo pathway mRNA results in increased TEAD protein transcriptional activity compared to a cell having a wild type version of the Hippo pathway mRNA; and / or (iv) an epigenetic alteration that results in an altered level of the Hippo pathway protein in a 15 cell, provided that the altered level of the Hippo pathway protein results in increased TEAD protein transcriptional activity compared to a cell lacking the epigenetic alteration. Non-limiting examples of Hippo pathway dysregulations include amplification of TAZ, TEAD4, and / or YAP1; deletion of LATS1 / 2, NF2, and / or TAOK1; methylation of TAOK1, TAOK2, and / or TAOK3, mutations in NF2, SAV1, and / or LATS1 / 2; and fusions of YAP or 20 TAZ. Hippo pathway dysregulations are also discussed in, e.g., Wang, Yumeng, et al. Cell Reports 25.5 (2018): 1304-1317, doi: 10.1016 / j.celrep.2018.10.001. The term “compound(s) provided herein” refers to compound(s) of Formula (AA) (e.g., Formula (A1), Formula (A2), Formula (A3), Formula (I) (e.g., Formula (I-a)), Formula (II) (e.g., Formula (II-a)), or Formula (A)) or Formula (BB) or compounds of Table C4 as 25 disclosed herein. Exemplary assays for validating the degradation-inducing mechanism of a compound as provided herein are known in the art and include assays such as co-dosing with a proteasome inhibitor or knocking out the relevant E3 ligase, and are described, for example, in International Publication No. WO 2021 / 207172 and Wu, et al. Nature Structural & Molecular Biology 27.7 30 (2020): 605-614. Degradation assays can be used to quantify both on- and off-target degradation- inducing effects of compounds, such as those provided herein. Exemplary assays include quantitative immunoblotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogenous time resolved florescence (HTRF), and HiBiT. For example, 490 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) cells can be contacted with a compound provided herein, or a pharmaceutically acceptable salt thereof, incubated, and then the lysate can be prepared for gel electrophoresis (e.g., SDS- PAGE), followed by immunoblotting and quantification compared to a control (e.g., a DMSO- treated control). In another example, cells can be contacted with a compound provided herein, 5 or a pharmaceutically acceptable salt thereof, incubated, and then the lysate can be treated with a pair of TEAD antibodies (e.g., binding to non-mutually exclusive epitopes) labeled with a FRET pair of fluorophores, followed by fluorescence quantification compared to a control (e.g., a DMSO-treated control). As another example, a cell line can be engineered to express a HiBiT-tagged TEAD protein, and the amount of luminescence observed when the 10 complementary LgBiT peptide is added can be compared between cells treated with a compound provided herein, or a pharmaceutically acceptable salt thereof, and a control (e.g., a DMSO-treated control). In some embodiments, off-target degradation inducing effects can be assessed for the proteins Eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), and / or Aiolos (IKZF3). 15 Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined by IC50 value. As used herein, IC50 refers to the concentration of the compound provided herein that results in a 50% decrease in the concentration of a protein (e.g., a TEAD protein) in a cell compared to the concentration of the protein before the cell is contacted with the compound provided herein, or compared to the 20 concentration of the protein in a cell not contacted with the compound provided herein. IC50can be measured by a HiBiT assay as described in Example B1. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more efficient inducer of degradation relative to a compound with a higher IC50 value. In some embodiments, an IC50 value can be determined (e.g., using HiBiT detection) in vitro or in vivo in cells (e.g., in tumor 25 cells (e.g., cell lines such as MSTO-211H, NCI-H2052, and / or NCI-H226) or HEK293 cells) expressing a TEAD protein, or a fragment thereof. Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by Yminvalue. As used herein, refers to the ratio of trough concentration of a protein (e.g., a TEAD protein) in a cell 30 compared to the concentration of the protein before the cell is contacted with the compound provided herein, or compared to the concentration of the protein in a cell not contacted with the compound provided herein expressed as a percentage. As used herein, Dmax is 1 can be measured by a HiBiT assay as described in Example B1. A compound with a lower Yminvalue, as determined under substantially similar conditions, is a more efficient inducer of 491 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) degradation relative to a compound with a higher Yminvalue. In some embodiments, value can be determined (e.g., using HiBiT detection) in vitro or in vivo in cells (e.g., in tumor cells (e.g., cell lines such as MSTO-211H, NCI-H2052, and / or NCI-H226) or HEK293 cells) expressing TEAD protein, or a fragment thereof. 5 Potency of degradation by a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by EC50 value. As used herein, EC50refers to the concentration of the compound provided herein that results in a 50% decrease in the concentration of a protein (e.g., a TEAD protein) relative to the trough concentration of the protein in a cell, when compared to the concentration of the protein before the cell is 10 contacted with the compound provided herein, or compared to the concentration of the protein in a cell not contacted with the compound provided herein. EC50can be measured by a HiBiT assay as described in Example B1. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent compound relative to a compound with a higher EC50value. In some embodiments, an EC50value can be determined (e.g., using HiBiT 15 detection) in cells (e.g., in tumor cells, (e.g., cell lines such as MSTO-211H, NCI-H2052, and / or NCI-H226) or HEK293 cells) expressing a TEAD protein or a fragment thereof. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Yminfor a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4) of about 0% to about 70% (e.g., about 0% to about 50%, about 25% to about 50%, or 20 about 0% to about 25%) in a HiBiT based degradation assay (e.g., an assay as described in Example B1). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Ymin for a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4) of about 0% to about 50% (e.g., about 25% to about 50% or about 0% to about 25%) in a HiBiT based degradation assay. In some embodiments, a compound provided herein, 25 or a pharmaceutically acceptable salt thereof, exhibits a Ymin for a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4) of about 0% to about 25% in a HiBiT based degradation assay. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Ymin for a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or 30 TEAD4) of about 0% to about 70% (e.g., about 0% to about 50%, about 25% to about 50%, or about 0% to about 25%) in the assay described in Example B1. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a Ymin for a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4) of about 0% to about 50% (e.g., about 25% to about 50% or about 0% to about 25%) in the assay described in Example 492 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) B1. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, exhibits a for a TEAD protein (e.g., TEAD1, TEAD2, TEAD3, and / or TEAD4) of about 0% to about 25% in the assay described in Example B1. It is understood that the effect of protein degradation typically increases over time, 5 though the appearance of degradation (e.g., as expressed by the percentage degradation compared to a control, or the parameters Ymin, IC50, EC50, and / or Dmax) is affected by the resynthesis rate of the protein. Degradation can be evaluated after a specified period of time, such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or more. For example, degradation can be expressed as the percent degradation after 24 hours. 10 An exemplary assay for determining the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on cell proliferation. Cell proliferation assays can be performed in a number of formats, including 2D and 3D. Similarly, a cell proliferation assay can be performed with any appropriate cell line, including, for 15 example, MSTO-211H, NCI-H2052, and / or NCI-H226. As an illustrative example, a 3D cell proliferation assay can include growing cells in a 3D medium, contacting the cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO® 3D), and then comparing the signal from the experiment with the compound provided herein, or a 20 pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound provided herein, or a pharmaceutically acceptable salt thereof). As another illustrative example, a 2D cell proliferation assay can include plating cells onto a growth surface, optionally letting the cells grow for a period of time, contacting the cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, measuring the 25 cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO®), and then comparing the signal from the experiment with a compound provided herein, or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound provided herein, or a pharmaceutically acceptable salt thereof). In some embodiments, cellular proliferation can be assessed using a platform for live cell imaging (e.g., 30 an INCUCYTE® SX5 Live-Cell Analysis Instrument). Additional cell viability assays include MTT assays, which are colorimetric assays based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to the insoluble purple formazan, and other similar assays based on related tetrazolium salts, ATPlite assays, and other methods are known in the art. See also, e.g., Example B2. 493 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) As another example, the potency and / or efficacy of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a xenograft model (e.g., using an established cancer cell line such as MSTO-211H, NCI-H2052, and / or NCI-H226 or a patient-derived xenograft (PDX) model). 5 Provided herein are methods of treating a cancer in a subject in need of such treatment, the methods comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound provided herein, 10 or a pharmaceutically acceptable salt thereof, as a monotherapy. In some embodiments, the subject is treatment naïve with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer. Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, for example, any of the cancers provided herein. 15 Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, as a medicament for the treatment of cancer, for example, any of the cancers provided herein. Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, for example, any 20 of the cancers provided herein. Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, for use as a medicament. Also provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of cancer, for example, any of the cancers provided herein. 25 Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, for use in treating a cancer, for example, any of the cancers provided herein. As used herein, “monotherapy”, when referring to a compound provided herein, or a pharmaceutically acceptable salt thereof, means that the compound provided herein, or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., 30 anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). It is understood that monotherapy does not exclude the co-administration of medicaments for the treatment of side effects or general symptoms associated with the cancer or treatment, such as pain, rash, edema, 494 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) photosensitivity, pruritus, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite. 5 As used herein, “the subject has previously received one or more received one or more lines of previous therapy for the cancer” means that the subject has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy) for the cancer other than a compound provided herein, or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. In some embodiments, the subject cannot tolerate the 10 one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject has stopped responding to the one or more therapeutic agents 15 or therapies previously administered for the cancer. In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1). In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician. 20 As used herein, “the subject is treatment naïve with respect to the cancer” means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer. For any of the solid tumors described herein, the solid tumors can be primary tumors or metastatic (or secondary) tumors. As used herein, “primary” tumors are those located at the 25 site where the tumor began to grow (i.e., where it originated). As used herein, “metastatic” (or “secondary”) tumors are those that have spread to other parts of body from the original tumor site. In some embodiments, the metastatic or secondary tumors are the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumors are not genetically identical to the primary tumor. 30 In some embodiments, the subject has been identified or diagnosed as having a cancer with a Hippo pathway dysregulation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a cancer (e.g., a tumor sample) that has a Hippo pathway dysregulation (e.g., as determined using a regulatory agency- approved assay or kit). The subject can be a subject with a cancer (e.g., one or more tumor 495 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) samples) that is positive for a Hippo pathway dysregulation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a clinical record indicating that the subject has a cancer (e.g., a tumor sample) that has a Hippo pathway dysregulation (and optionally the clinical record indicates that the subject 5 should be treated with any of the compounds and / or compositions provided herein). In some embodiments, determining that a cancer in a subject has a Hippo pathway dysregulation includes consulting the subject’s medical record. In some embodiments, determining that a cancer has a Hippo pathway dysregulation includes performing an assay on a sample (e.g., a tumor sample) from the subject. 10 Hippo pathway dysregulations can be detected using a variety of methods. Exemplary methods include next generation sequencing, pyrosequencing, immunohistochemistry, fluorescence microscopy, Southern blotting, Western blotting, FACS analysis, Northern blotting, PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR), and utilization of a high-sensitivity diagnostic assay (with CE-IVD mark). In some embodiments, 15 the assay is performed on a tumor biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the assay is a liquid biopsy. Liquid biopsies can be performed on biological samples obtained from a subject (e.g., via a blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or Hippo pathway dysregulation. 20 In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA- approved kit. In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., breast invasive carcinoma, breast invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, 25 glioma, oligoastrocytoma, medulloblastoma), ependymoma), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and type II tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., 30 cholangiocarcinoma), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma, esophageal squamous cell carcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic 496 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) islet cell cancer), small intestine cancer, or stomach cancer (e.g., stomach adenocarcinoma, signet ring cell carcinoma of the stomach)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e.g., prostate adenocarcinoma), 5 testicular cancer (e.g., testicular germ cell tumors, seminoma), or ureter cancer), gynecologic cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine 10 corpus endometrial carcinoma), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharynx cancer (e.g., hypopharynx cancer, nasopharynx cancer, oropharyngeal cancer)), hematological cancer (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) (e.g., Philadelphia chromosome positive ALL), acute myeloid 15 leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML)), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B- cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), small 20 lymphocytic lymphoma (SLL))), or myeloma (e.g., multiple myeloma)), Li-Fraumeni tumors, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., larynx cancer, lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma (e.g., pleural mesothelioma, non-pleural mesothelioma), non-small cell lung cancer (NSCLC)), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, 25 chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymus cancer (e.g., thymoma), epithelioid hemangioendothelioma (EHE), or a combination thereof. In some embodiments, the cancer is bladder cancer (e.g., bladder urothelial carcinoma), brain cancer (e.g., medulloblastoma), breast cancer (e.g., triple negative breast cancer), 30 colorectal cancer (e.g., colon cancer or rectal cancer), cervical cancer (e.g., cervical squamous cell carcinoma), ependymoma, esophageal cancer (e.g., esophageal squamous cell carcinoma), epithelioid hemangioendothelioma, gastric cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., kidney renal papillary cell carcinoma), lung cancer (e.g., mesothelioma, lung squamous cell carcinoma, or NSCLC), liver cancer (e.g., 497 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) hepatocellular carcinoma), ovarian cancer pancreatic cancer, prostate cancer, sarcoma (e.g., bone cancer (e.g., osteosarcoma), rhabdomyosarcoma), or a combination thereof. In some embodiments, the cancer is bladder cancer (e.g., bladder urothelial carcinoma), breast cancer (e.g., triple negative breast cancer), colorectal cancer (e.g., colon cancer or rectal 5 cancer), cervical cancer (e.g., cervical squamous cell carcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), epithelioid hemangioendothelioma, gastric cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., kidney renal papillary cell carcinoma), lung cancer (e.g., mesothelioma or lung squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), prostate cancer, sarcoma, or a 10 combination thereof. In some embodiments, the cancer is a squamous cell-involved cancer. In some embodiments, the squamous cell-involved cancer is bladder urothelial carcinoma, cervical squamous cell carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, or a combination thereof. 15 In some embodiments, the cancer is mesothelioma (e.g., a pleural mesothelioma, sometimes also called malignant pleural mesothelioma (MPM), or non-pleural mesothelioma). In some embodiments, the mesothelioma has an NF2 mutation (e.g., a truncating NF2 mutation). In some embodiments, the mesothelioma has a LATS2 mutation. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid 20 tumor has a Hippo pathway dysregulation. Also provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a Hippo pathway dysregulation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 25 as described herein. Also provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a Hippo pathway dysregulation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical 30 composition as described herein. As used herein, an “advanced solid tumor” is a solid tumor that has spread extensively to other anatomic sites and / or that is no longer responding to treatment. In some embodiments, classification of an advanced solid tumor can be made by one of skill in the art (e.g., the subject’s physician). 498 Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system. For example, “contacting” a TEAD protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a TEAD 5 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the TEAD protein. Also provided is a method for modulating (e.g., decreasing) TEAD protein activity in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, 10 the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of a compound provided herein, or a pharmaceutically acceptable salt thereof,to a subject having a cell having a Hippo pathway dysregulation. In some embodiments, the contacting is ex vivo, wherein the method comprises contacting a cell from a subject having a Hippo pathway dysregulation with a compound 15 provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein. Also provided is a method of modulating (e.g., decreasing) the level of TEAD protein 20 in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the level of the TEAD protein is decreased by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) compared to a cell not contacted with the compound provided herein, or a pharmaceutically acceptable salt thereof. In some 25 embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject having a cell having a Hippo pathway dysregulation. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, 30 the cell is a mammalian cancer cell. Also provided is a method of inducing ubiquitination of a TEAD protein in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method 499 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0002] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) comprises administering an effective amount of a compound of provided herein, or a pharmaceutically acceptable salt thereof, to a subject having a cell having a Hippo pathway dysregulation. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some

[0003] 5 embodiments, the cancer cell is any cancer as described herein.

[0004] Also provided is a method of forming a ternary complex comprising a TEAD protein, a compound provided herein, or a pharmaceutically acceptable salt thereof, and an E3 ligase (e.g., CRBN) in a cell, comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In

[0005] 10 some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject having a cell having a Hippo pathway dysregulation. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0006] Also provided herein is a method of inhibiting cell proliferation, in vitro, in vivo, or ex vivo, the method comprising contacting a cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In some embodiments, the cell has a Hippo pathway dysregulation.

[0007] 20 Further provided herein is a method of increasing cell death, in vitro, in vivo, or ex vivo, the method comprising contacting a cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. In some embodiments, the cell has a Hippo pathway dysregulation.

[0008] The term “wild type” or “wild-type” describes a nucleic acid (e.g., a Hippo pathway gene or a Hippo pathway mRNA) or protein (e.g., a Hippo pathway protein) sequence that is typically found in a subject that does not have a disease or disorder related to the reference

[0009] 30 nucleic acid or protein. Although a wild type nucleic acid or protein sequence is the sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein, it is not necessarily the case that a subject that has a disease or disorder related to the reference nucleic acid or protein lacks the wild type sequence. For example, a subject with a gene duplication of the reference gene may have the wild type PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0010] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) sequence but could still have a disease or disorder related to the reference nucleic acid or protein due to the duplication event. As another example, a subject with a disease or disorder related to the reference nucleic acid or protein may have one allele that encodes wild type protein, and another allele that encodes a mutant protein.

[0011] 5 The term “inhibitor”, as used herein, means a compound or agent (e.g., a peptide or an antibody) that prevents a biomolecule, (e.g., a protein) from completing or initiating a reaction. An inhibitor can inhibit a reaction by competitive, uncompetitive, or non-competitive means.

[0012] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in

[0013] 10 part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0014] As used herein, the terms “subject,” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at

[0015] 20 least one symptom of the disease or disorder to be treated and / or prevented.

[0016] In some embodiments, the subject is a pediatric subject.

[0017] The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph ’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed.

[0018] 30 Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0019] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less

[0020] 5 than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0021] The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0022] The term “regulatory agency” refers to a country's agency for the approval of the

[0023] 10 medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0024] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease, disorder, or condition as provided herein, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of the particular disease, disorder, or condition described herein. The amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need

[0025] 20 of treatment.

[0026] As used herein, an “effective amount” refers to an amount of the compound sufficient to effect a beneficial or desired result. For example, an “effective amount” as used herein can refer to an amount of the compound sufficient to modulate (e.g., increase or decrease) (1) activity or amount of a protein; (2) proliferation of a cell (e.g., a cancer cell); and / or (3) one or more cellular signaling pathways associated with a protein’s activity.

[0027] Combinations

[0028] In any of the indications described herein, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments,

[0029] 30 a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0030] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) a compound provided herein, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.

[0031] In some embodiments, a subject in need thereof can be administered one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of

[0032] 5 time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound provided herein, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0033] In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic

[0034] 10 tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a kinase inhibitor, immunotherapy, or radiation). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a kinase inhibitor, immunotherapy, and / or radiation). In some embodiments, a subject has a cancer (e.g., an advanced or a metastatic tumor) that has no standard therapy. In some embodiments, a subject has undergone prior therapy, for example, treatment with surgery, radiation, a chemotherapeutic agent, an immunotherapy, or a combination thereof.

[0035] In some embodiments of any the methods described herein, the compound provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a

[0036] 20 therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

[0037] Hippo pathway signaling has also been implicated in resistance to various therapies, including chemotherapy, immunotherapy, and targeted therapeutics. See, e.g., Kapoor, Avnish, et al. Cell 158.1 (2014): 185-197, doi: 10.1016 / j .cell.2014.06.003; Shao, Diane D., et al. Cell 158.1 (2014): 171-184, doi: 10.1016 / j. cell.2014.06.004; Lin, Luping, et al. Nature Genetics (2015): 250-256, doi: 10.1038 / ng.3218; Ghiso, Elena, et al. Neoplasia 19.12 (2017): 1012-1021, doi: 10.1016 / j. neo.2017.10.003; Lee, Ting-Fang, et al. Scientific Reports 8.1 (2018): 271, doi: 1 10.1038 / s41598-017-18527-z; Nguyen, Chan DK, and Chunling Yi. Trends in Cancer 5.5 (2019): 283-296, doi: 10.1016 / j.trecan.2019.02.010.

[0038] 30 In some embodiments, the additional therapy or therapeutic agent is a kinase inhibitor or degrader. In some embodiments, the kinase inhibitor is a BRaf inhibitor or degrader, a MEK inhibitor or degrader, an EGFR inhibitor or degrader, or anti-EGFR therapy. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0039] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0040] In some embodiments, the BRaf inhibitor or degrader is avutometinib, dabrafenib (e.g., dabrafenib mesylate), encorafenib, naporafenib, sorafenib (e.g., sorafenib tosylate), vemurafenib, C17071479-F, CHIR-265, FORE-8394, HLX-208, or a combination thereof.

[0041] In some embodiments, the EGFR inhibitor or degrader is abivertinib, afatinib (e.g.,

[0042] 5 afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), asandeutertinib, befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib (e.g., icotinib hydrochloride), lapatinib (e.g., lapatinib ditosylate monohydrate), larotinib, lazertinib (e.g., lazertinib mesylate), limertinib, mobocertinib (e.g., mobocertinib succinate), nazartinib,

[0043] 10 neratinib (e.g., neratinib maleate), olmutinib, osimertinib (e.g., osimertinib mesylate), pelitinib, pirotinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), rezivertinib (e.g., rezivertinib mesylate), ruserontinib (SKLB-1028), sacibertinib, sapitinib, sevabertinib, sunvozertinib, sutetinib, tarloxotinib, tesevatinib, vandetanib, varlitinib, zipalertinib, zorifertinib, BEBT-109, BIBW-2948, FHND-9041, HA- 121-28, PLB-1004, SH-1028, or a combination thereof.

[0044] In some embodiments, the anti-EGFR therapy is ametumumab, amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), becotatug, cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), dalmitamig, depatuxizumab, duligotuzumab, ficerafusp alfa, futuximab, imgatuzumab, izalontamab (SI-B-

[0045] 20 001), matuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof), panitumumab (e.g., VECTIBIX® (panitumumab), or a biosimilar thereof (e.g., QL- 1203)), petosemtamab, tomuzotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, biosimilars thereof, or a combination thereof. In some embodiments, the anti-EGFR therapy is cetuximab, panitumumab, or a biosimilar thereof.

[0046] In some embodiments, the MEK inhibitor or degrader is avutometinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, nedometinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide, GSK- 1120212), tunlametinib, zapnometinib, FCN-159, NFX-179, TAK-733, or a combination

[0047] 30 thereof. In some embodiments, the MEK inhibitor is a MEK-Raf protein-protein interaction stabilizer, such as NST-628 or avutometinib (VS6766).

[0048] In some embodiments, the additional therapy or therapeutic agent is a KRas inhibitor or degrader. In some embodiments, the KRas inhibitor or degrader is adagrasib (MRTX-849), ALTA3263, AMG410, AN9025, ARS-1620, ARS-3248, ARS-853, ARV-806, ASP-4396, PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0049] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0050] ATG-012, AZD-0022, BBO-11818, BBO-8520, BGB-53038, BI 3706674, BI-1701963, BI- 1823911, BPI-421286, BPI-572270, BPI-585725, BRSD-143, CGT9109, daraxonrasib (RMC- 6236), divarasib (GDC-6036), elisrasib (D-3S-001), ERAS-0015, ERAS-3490, ERAS-4001, FMC-376, fulzerasib (GFH-925), garsorasib (D-1553), GDC-7035, GEC-255, GFH276,

[0051] 5 GFH375, GFH547, GFS784, GH-35, glecirasib (JAB-21822), HBW-012336, HBW-016-K, HEC211909, HRS-4642, HS-10370, HS-10529, INCB-161734, INCB186748, JAB-23E73, JDQ-443, LY3962673, LY4066434, MK-1084, MRTX1133, MRTX-1257, olomorasib (LY- 3537982), PF-07934040, PF-07985045, PT0253, QLC-1101, QTX3034, QTX3046, QTX3544, RCZY-680, RCZY-690, RMC-5127, RMC-6291, RMC-7977, RNK-08954,

[0052] 10 RO7673396, RP-03707, RP04340, RSC-1255, setidegrasib (ASP-3082), SHR-1127, sotorasib (AMG-510), TSN-1611, YL-15293, YL-17231, ZG-19018, zoldonrasib (RMC-9805), or a combination thereof. In some embodiments, the KRas inhibitor is a pan-Ras inhibitor. In some embodiments, the pan-Ras inhibitor is daraxonrasib (RMC-6236), RMC-7977, ERAS-0015, GFH276, GFH547, AN9025, RO7673396, BPI-572270, RCZY-690, RCZY-680, GFS784, or a combination thereof. In some embodiments, the KRas inhibitor is a pan-KRas inhibitor. In some embodiments, the pan-KRas inhibitor is BI 3706674, YL-17231, PF-07934040, PF- 07985045, BGB-53038, LY4066434, JAB-23E73, ALTA3263, BBO-11818, QTX3544, QTX3034, ERAS-4001, AMG410, BRSD-143, CGT9109, HBW-016-K, HEC211909, RP04340, BPI-585725, or a combination thereof. In some embodiments, the KRas inhibitor is

[0053] 20 a Ras G12V inhibitor. In some embodiments, the Ras G12V inhibitor is RMC-5127. In some embodiments, the KRas inhibitor is a KRas G12D inhibitor. In some embodiments, the KRas G12D inhibitor is MRTX1133, HRS-4642, GDC-7035, LY3962673, GFH375, RNK-08954, AZD-0022, QTX3046, INCB-161734, INCB186748, ASP-4396, setidegrasib (ASP-3082), ARV-806, PT0253, RP-03707, TSN-1611, QLC-1101, HS-10529, HBW-012336, zoldonrasib (RMC-9805), or a combination thereof. In some embodiments, the KRas inhibitor is a KRas G12C inhibitor. In some embodiments, the KRas G12C inhibitor is sotorasib (AMG-510), adagrasib (MRTX-849), garsorasib (D-1553), fulzerasib (GFH-925), olomorasib (LY- 3537982), divarasib (GDC-6036), MK-1084, glecirasib (JAB-21822), GH-35, elisrasib (D-3S- 001), ZG-19018, FMC-376, YL-15293, HS-10370, BBO-8520, GEC-255, BI-1823911,

[0054] 30 ERAS-3490, or a combination thereof.

[0055] In some embodiments, the additional therapy or therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is anti-PD-1 therapy, anti-PD-Ll therapy, or anti-CTLA4 therapy. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0056] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0057] In some embodiments, the anti-PDl therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab (e.g., cemiplimab-rwlc, or a biosimilar thereof), cetrelimab, danvilostomig, dostarlimab (e.g., dostarlimab-gxly, or a biosimilar thereof), enlonstobart (SG- 001), ezabenlimab, geptanolimab, iparomlimab (QL-1604), ivonescimab, lorigerlimab,

[0058] 5 nivolumab (e.g., OPDIVO® (nivolumab), or a biosimilar thereof (e.g., ABP-206, BCD-263, or JPB-898)), nofazinlimab, pembrolizumab (e.g., KEYTRUDA® (pembrolizumab), or a biosimilar thereof (e.g., ABP-234, BAT-3306, BCD-201, CT-P51, FYB-206, GME-751, MB- 12, QL-2107, RPH-075, or SB-27)), penpulimab, pidilizumab, pimivalimab, prolgolimab, pucotenlimab, retifanlimab (e.g., retifanlimab-dlwr, or a biosimilar thereof), rilvegostomig,

[0059] 10 rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab (e.g., TYVYT® (sintilimab), or a biosimilar thereof), spartalizumab, tebotelimab, tislelizumab, toripalimab, treprilimab, volrustomig, vudalimab, zimberelimab, 609-A, BAT- 1306, BAT- 1308, HX-009, IBI-363, INCB-086550, JS-207, LZM-009, MHB-039A, RC-148, RG-6139, SSGJ-707, ZG-005, biosimilars thereof, or a combination thereof. In some embodiments, the anti-PDl therapy is a bispecific antibody or antigen-binding fragment thereof (e.g., cadonilimab, danvilostomig, ivonescimab, lorigerlimab, rilvegostomig, tebotelimab, volrustomig, vudalimab, AZD7709, HX-009, JS-207, MHB-039A, RC-148, RG-6139, SSGJ-707, ZG-005, biosimilars thereof, or a combination thereof). In some embodiments, the anti-PDl therapy is an anti-PDl and anti- CD47 bispecific antibody or antigen-binding fragment thereof (e.g., HX-009, or a biosimilar

[0060] 20 thereof). In some embodiments, the anti-PD-1 therapy is nivolumab, pembrolizumab, or a biosimilar thereof.

[0061] In some embodiments, the anti-PD-Ll therapy is adebrelimab, atezolizumab (e.g., TECENTRIQ® (atezolizumab), or a biosimilar thereof), avelumab (e.g., BAVENCIO® (avelumab), or a biosimilar thereof), benmelstobart (APL-502), bintrafusp alfa, cosibelimab, danburstotug, durvalumab (e.g., IMFINZI® (durvalumab), or a biosimilar thereof), envafolimab (e.g., ENWEIDA® (envafolimab), or a biosimilar thereof), erfonrilimab, lesabelimab, pacmilimab, socazolimab, sugemalimab (e.g., CEJEMLY® (sugemalimab), or a biosimilar thereof), tagitanlimab (A-167), AUPM-170, BNT-311, SHR-1701, biosimilars thereof, or a combination thereof. In some embodiments, the anti-PD-Ll therapy is a bispecific

[0062] 30 antibody or antigen-binding fragment thereof (e.g., erfonrilimab, BNT-311, biosimilars thereof, or a combination thereof). In some embodiments, the anti-PD-Ll therapy is atezolizumab, avelumab, sugemalimab, or a biosimilar thereof.

[0063] In some embodiments, the anti-CTLA4 therapy is abatacept (e.g., ORENCIA® (abatacept), or a biosimilar thereof), botensilimab, cadonilimab, erfonrilimab, gotistobart, PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0064] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO) ipilimumab (e.g., YERVOY® (ipilimumab), or a biosimilar thereof), nurulimab, quavonlimab, tremelimumab (ticilimumab) (e.g., IMIUDO® (tremelimumab), or a biosimilar thereof), volrustomig, vudalimab, zalifrelimab, BMS-986218, PSB-205, biosimilars thereof, or a combination thereof. In some embodiments, the anti-CTLA4 therapy is ipilimumab, or a

[0065] 5 biosimilar thereof.

[0066] In some embodiments, the additional therapy or therapeutic agent is chemotherapy. In some embodiments, the chemotherapy is a microtubule inhibitor, an antimetabolite, a DNA alkylator, a topoisomerase inhibitor, or a combination thereof.

[0067] In some embodiments, the chemotherapy is a microtubule inhibitor. In some

[0068] 10 embodiments, the microtubule inhibitor is cabazitaxel, colchicine, desoxyepothilone B, docetaxel, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, plinabulin, sabizabulin, tirbanibulin, vinblastine, vinflunine, vinorelbine, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, or a combination thereof.

[0069] In some embodiments, the chemotherapy is an anti metabolite. In some embodiments, the anti metabolite is fluorouracil (5-FU) or gemcitabine.

[0070] In some embodiments, the chemotherapy is a DNA crosslinker. In some embodiments, the DNA crosslinker is a platinum complex. In some embodiments, the platinum complex is carboplatin, cisplatin, lobaplatin, miriplatin, oxaliplatin, or a combination thereof.

[0071] 20 In some embodiments, the chemotherapy is a topoisomerase inhibitor. In some embodiments, the topoisomerase inhibitor is aclarubicin, amsacrine, belotecan, camptothecin, daunorubicin, dexrazoxane, elliptinium, epirubicin, etoposide, gepotidacin, idarubicin, mitoxantrone, nemonoxacin, pirarubicin, pixantrone, razoxane, rubitecan, sobuzoxane, temozolomide, teniposide, topotecan, SN-38, or a combination thereof.

[0072] Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof (a) a compound provided herein, or a pharmaceutically acceptable salt thereof, (b) an additional therapy or therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound provided

[0073] 30 herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.

[0074] These additional therapies or therapeutic agents may be administered with one or more doses of the compound provided herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof as part of the same or separate dosage forms, via the same PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0075] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[0076] Pharmaceutical Compositions and Administration

[0077] 5 General

[0078] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0079] 10 In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica,

[0080] 20 magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, 0-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-0- cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound provided herein, or a pharmaceutically acceptable salt thereof, as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a compound provided herein, or a pharmaceutically acceptable salt thereof, provided herein, in one embodiment 0.1-95%, in

[0081] 30 another embodiment 75-85%, in a further embodiment 20-80%. Methods of preparing such dosage forms can be found in, for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012). PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0082] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0083] Routes of Administration and Composition Components

[0084] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salts thereof, can be administered to a subject in need thereof by

[0085] 5 any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary,

[0086] 10 intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

[0087] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered orally to a subject in need thereof. Without being bound by any particular theory, it is believed that oral dosing (e.g., versus IV dosing) can be preferred by patients for convenience,

[0088] 20 perception of efficacy, and / or past experience.

[0089] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.

[0090] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be

[0091] 30 easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0092] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0093] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for

[0094] 5 example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0095] Sterile injectable solutions are prepared by incorporating the active compounds in the

[0096] 10 required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0097] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based

[0098] 20 Drug Delivery Systems” Neoplasia. 2006, 10, 788-795, doi: 10.1593 / neo.06436.

[0099] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl capryl ocaprate,

[0100] 30 isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0101] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0102] In certain embodiments, suppositories can be prepared by mixing a compound provided herein, or a pharmaceutically acceptable salt thereof, with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release

[0103] 5 the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0104] In other embodiments, the compounds described herein, or a pharmaceutical composition thereof, are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0105] 10 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound provided herein, or a pharmaceutically acceptable salt thereof, is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate,

[0106] 20 h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0107] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound provided herein, or a pharmaceutically acceptable salt thereof, provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like;

[0108] 30 and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEGs, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein, or pharmaceutically acceptable salts thereof, provided PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0109] Docket No. TRLN-024-003WO I / 37998-02015 / WO (TBIO-OOI / OIWO) herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0110] Other physiologically acceptable compounds include wetting agents, emulsifying

[0111] 5 agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0112] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization

[0113] 10 techniques. For various oral dosage form excipients, such as tablets and capsules, sterility is not required. The USP / NF standard is usually sufficient.

[0114] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery of the compound provided herein, or a pharmaceutically acceptable salt thereof, to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, doi: 10.2174 / 1568026611313070002.

[0115] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0116] 20 Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0117] 30 Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0118] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0119] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams

[0120] 5 containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in

[0121] 10 volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating, and non-sensitizing.

[0122] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0123] Dosages

[0124] 20 The dosages may be varied depending on the requirement of the patient, the severity of the condition being treated, and the particular compound being employed. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0125] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to

[0126] 30 about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg). PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0127] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0128] Regimens

[0129] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0130] 5 In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which

[0131] 10 administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period (e.g., a “dosing holiday”), followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a

[0132] 20 therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0133] 30

[0134] The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0135] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO)

[0136] “API” refers to an active pharmaceutical ingredient.

[0137] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is

[0138] 5 “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed , Lippincott Williams & Wilkins:

[0139] 10 Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe el al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed:, Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed., ' Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0140] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,

[0141] 20 methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, -methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The term “pharmacologically acceptable salts” is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum;

[0142] 30 salts thereof with organic bases such as methylamine, ethylamine, and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0143] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0144] In some embodiments, a pharmaceutically acceptable salt is an anion salt selected from

[0145] 5 the group consisting of: a mesylate salt, a besylate salt, an acetate salt, a benzenesulfonate salt, a benzoate salt, a bicarbonate salt, a bitartrate salt, a bromide salt, a calcium edetate salt, a camsylate salt, a carbonate salt, a chloride salt, a citrate salt, a dihydrochloride salt, an edetate salt, an edisylate salt, an estolate salt, an esylate salt, a fumarate salt, a gluceptate salt, a gluconate salt, a glucuronate salt, a glutamate salt, a glycollylarsanilate salt, a hexylresorcinol

[0146] 10 salt, a hydramine salt, a hydrobromide salt, a hydrochloride salt, a hydroxynaphthoate salt, an iodide salt, an isethionate salt, a lactate salt, a lactobionate salt, a malate salt, a maleate salt, a mandelate salt, a mesylate salt, a methylbromide salt, a methylnitrate salt, a methylsulfate salt, a mucate salt, a napsylate salt, a nitrate salt, a pamoate (embonate) salt, a pantothenate salt, a phosphate / diphosphate salt, a polygalacturonate salt, a salicylate salt, a stearate salt, a subacetate salt, a succinate salt, a sulfate salt, an oleate salt, a tannate salt, a tartrate salt, a teoclate salt, and a triethiodide salt.

[0147] In some embodiments, a pharmaceutically acceptable salt is a cation salt selected from the group consisting of: a benzathine salt, a chloroprocaine salt, a choline salt, a tromethamine salt, a diethanolamine salt, an ethylenediamine salt, a meglumine salt, a procaine salt, an

[0148] 20 aluminum salt, a calcium salt, a lithium salt, a magnesium salt, a potassium salt, a sodium salt, and a zinc salt.

[0149] Examples of pharmaceutically acceptable salts also include those disclosed in e.g., Berge, Stephen M., Lyle D. Bighley, and Donald C. Monkhouse. "Pharmaceutical salts." Journal of pharmaceutical sciences 66.1 (1977): 1-19 doi: 10.1002 / jps.2600660104, Bharate, Sonali S. "Recent developments in pharmaceutical salts: FDA approvals from 2015 to 2019." Drug Discovery Today 26.2 (2021): 384-398 doi: 10.1016 / j .drudis.2020.11.016, and Bharate, Sonali S. "Modulation of biopharmaceutical properties of drugs using sulfonate counterions: A critical analysis of FDA-approved pharmaceutical salts." Journal of Drug Delivery Science and Technology 66 (2021): 102913 doi: 10.1016 / j.jddst.2021.102913.

[0150] 30 The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0151] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0152] Compound Preparation

[0153] 5 The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein.

[0154] Standard synthetic methods and procedures for the preparation of organic molecules

[0155] 10 and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of

[0156] 20 the present disclosure.

[0157] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0158] EXAMPLES

[0159] In some of the examples disclosed herein, one or more compounds in a described chemical reaction sequence (e.g., starting materials, intermediates, or products) is structurally

[0160] 30 depicted with enhanced stereochemical notation(s) at one or more defined stereogenic center(s). Examples of such notations include orl, or2, &1, &2, and the like. In some such examples, in the chemical name of the same compound, each of such defined stereogenic center(s) is assigned a tentative configuration (e.g., (R)- or (5)-) shown by the wedge / hash PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0161] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) representation of its structural formula. However, the defined stereogenic center(s) should be understood to have configurations consistent with the enhanced stereochemical notation(s), as described herein, based e.g., on the conventions explained below. For avoidance of doubt, the chemical names of these compounds, having one or more enhanced stereochemical notation(s),

[0162] 5 adopt the following conventions:

[0163] When the chemical name of a compound having only one stereogenic center contains the prefix “rel,” the stereogenic center is resolved, but its absolute configuration is either (7?) or (5), thereby corresponding to an orl enhanced stereochemical notation at the corresponding stereogenic center in its structural formula. For example, the chemical name re / -(7?)-(l-

[0164] 10 methylpyrrolidin-2-yl)methanol represents one stereoisomer selected from the group consisting

[0165] When one stereogenic center is labelled with an asterisk (“*”) in the chemical name of a compound having more than one stereogenic centers (e.g., when a stereogenic center is denoted as (R*)), the stereogenic center labeled with the asterisk is resolved, but its absolute configuration is either (R) or (5), thereby corresponding to an orl enhanced stereochemical notation at the corresponding stereogenic center in its structural formula. For example, the chemical name ((27?*,47?)-l,4-dimethylpyrrolidin-2-yl)methanol represents one stereoisomer selected from the group consisting of

[0166] When the chemical name of a compound contains two stereogenic centers labelled with

[0167] 20 asterisks, these two stereogenic centers may have (R) or (5) configurations, either concertedly or independently, in conformity with the orx (e.g., orl or or 2) notations in its structural formula in Table Cl

[0168] When two stereogenic centers are labelled orl and orl in a compound structure, and they are labelled with asterisks in the chemical name, then the relative stereochemistry between

[0169] 25 the two stereogenic centers (e.g., syn or anti relationship) is as represented by the name, but the absolute configurations of the two stereogenic centers can vary concertedly (e.g., a compound designated (R*, R*) is one stereoisomer selected from (R,R) and (5,5); for avoidance of doubt, the compound designated (R*, R*) does not have (S,R) or (R,S) configurations across these stereogenic centers). For example, the chemical name of is PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0170] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0171] ((25*,35,45*)-3-cyclopropyl-l,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents one stereoisomer selected from the group

[0172] When two stereogenic centers are labelled orl and or2 in a compound structure, and

[0173] 5 they are labelled with asterisks in the chemical name, then the configuration of the two stereogenic centers can vary independently (e.g., a compound designated (R*,R*) is one stereoisomer selected from (R, R), (5,5), (5,5), and (5,5)). For example, the chemical name of is ((25*,35,45*)-3-cyclopropyl-l,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents one stereoisomer selected from the

[0174] When the chemical name of a compound contains two stereogenic centers designated “55’ and / or “SR,” a mixture of stereoisomers is provided wherein among the constituent stereoisomers these two stereogenic centers differ either concertedly or independently, in conformity with the &x (e.g., &1 or < 2) notations in Table Cl for the corresponding compound.

[0175] When two defined stereogenic centers are labelled &1 and &1 in a chemical structure, and they are designated “55’ and / or “55” in the corresponding chemical name, then a mixture

[0176] 20 of two stereoisomers is provided, wherein each constituent stereoisomer has the relative stereochemistry between these two stereogenic centers (e.g., syn or anti relationship) as depicted by the structural formula and by the name. As an example, a chemical name designated (RS, SR) represents a mixture of (R,S) and (S,R) stereoisomers, and this mixture does not include (5,5) or (5,5) stereoisomers. As a second example, a chemical name designated PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0177] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0178] (SR, SR) represents a mixture of (S,S) and (R, R) stereoisomers, and this mixture does not include

[0179] (R,S) or (S,R) stereoisomers. For example, the chemical name of is ((27?5',35',47?S)-3-cyclopropyl-l,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents a mixture of two stereoisomers:

[0180] When two defined stereogenic centers are labelled &1 and &2 in a chemical structure, and they are designated “ ?S” and / or “57?” in the corresponding chemical name, then a mixture of four stereoisomers is provided each differing in configuration at one or both of these two stereogenic centers (e.g., a chemical name designated (RS, SR) represents a mixture of (R,S),

[0181] 10 (S,R), (R,R), and (S,S) stereoisomers). For example, the chemical name

[0182] ((27?5)35)47?5)-3-cyclopropyl-l,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents a mixture of four stereoisomers:

[0183] PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0184] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO)

[0185] Example 1: Synthesis of Compound 154a

[0186] Compound 154a O

[0187] Step 1: l-(2-bromo-4,6-difluorophenyl)ethan-l-ol

[0188] 5 A mixture of l-bromo-3,5-difluoro-2-iodo-benzene (50 g, 156.80 mmol, 1 equiv. in 2- methyltetrahydrofuran (500 mL) was degassed and purged with N2 three times. Isopropylmagnesium chloride lithium chloride (1.3 M, 144.74 mL, 1.2 equiv.) was then added at -65 °C, and the resulting reaction mixture was stirred for 0.5 hours at -65 °C. Acetaldehyde (5 M, 62.72 mL, 2 equiv.) was then added at -65 °C, and the resulting mixture was stirred for

[0189] 10 0.5 hours at -65 °C under a N2 atmosphere. The reaction mixture was then quenched with aqueous ammonium chloride (100 mL) and extracted with methyl tert-butyl ether (300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give l-(2-bromo-4,6-difluorophenyl)ethan-l-ol (24.5 g) as a

[0190] 15 yellow oil.

[0191] ’H NMR (400 MHz, DMSO-t / ,) 8 = 7.42 (d, J= 8.0 Hz, 1H), 7.34 - 7.24 (m, 1H), 5.42 (d, J= 4.4 Hz, 1H), 5.16 (q, 7= 6.0 Hz, 1H), 1.41 (d, J= 6.4 Hz, 3H)

[0192] Step 2: l-bromo-2-(l-bromoethyl)-3,5-difluorobenzene

[0193] 20 A mixture of l-(2-bromo-4,6-difluorophenyl)ethan-l-ol (24.5 g, 103.36 mmol, 1 equiv.), CB (51.41 g, 155.04 mmol, 1.5 equiv.), and PPI13 (40.66 g, 155.04 mmol, 1.5 equiv.) in DCM (245 mL) at 0 °C was degassed and purged with N2 three times. The mixture was stirred at 0 °C for 0.5 hours under a N2 atmosphere. The reaction mixture was quenched by the addition of a saturated solution of sodium bicarbonate (100 mL) and extracted with DCM (200 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0194] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography followed by distillation at 100 °C to give l-bromo-2-(l-bromoethyl)-3,5- difluorobenzene (31 g) as a white oil.

[0195] 5 ’H NMR (400 MHz, DMSO-t / 6) 8 = 7.60 - 7.52 (m, 1H), 7.50 - 7.39 (m, 1H), 5.66 (d, J= 6.4 Hz, 1H), 2.05 (dd, 7= 1.6, 7.2 Hz, 3H)

[0196] Step 3: (2N,55)-5-(l-(2-bromo-4,6-difluorophenyl)ethyl)-2-(tert-butyl)-5-phenyl- l,3-dioxolan-4-one

[0197] 10 A mixture of l-bromo-2-(l-bromoethyl)-3,5-difluorobenzene (1 g, 3.33 mmol, 1 equiw . (25,55)-2-tert-butyl-5-phenyl-l,3-dioxolan-4-one (1.14 g, 5.00 mmol, 1.5 equiw . and NaH (200.04 mg, 5.00 mmol, 60% purity, 1.5 equiv.) in DMF (10 mL) at 0 °C was degassed and purged with N2 three times. The mixture was stirred at 0 °C for 0.5 hours under a N2 atmosphere. The mixture was quenched by the addition of a saturated solution of sodium bicarbonate (30 mL) and extracted with methyl tert-butyl ether (30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give (2£,55)-5-(l-(2-bromo-4,6-difluorophenyl)ethyl)-2-(tert-butyl)-5-phenyl-l,3-dioxolan-4-one (784 mg) as a light-yellow oil.

[0198] 20 ’H NMR (400 MHz, DMSO-t / 6) 6 = 7.66 (d, J= 7.2 Hz, 1H), 7.51 (d, J= 6.8 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.37 - 7.32 (m, 2H), 7.31 - 7.27 (m, 1H), 7.25 (t, J= 7.6 Hz, 3H), 7.14 (d, J= 7.6 Hz, 2H), 5.81 (s, 1H), 4.03 (d, J= 7.2 Hz, 1H), 0.99 (d, J= 7.2 Hz, 3H), 0.81 (s, 9H)

[0199] Step 4: methyl (2 )-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2- phenylbutanoate

[0200] A mixture of (2£,55)-5-(l-(2-bromo-4,6-difluorophenyl)ethyl)-2-(tert-butyl)-5-phenyl- l,3-dioxolan-4-one (200 mg, 455.28 pmol, 1 equiv.) and NaOMe (122.98 mg, 682.92 pmol, 30% purity, 1.5 equiv.) in MeOH (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C for 3 hours under a N2 atmosphere. The reaction mixture was

[0201] 30 concentrated, and the residue was poured into a solution of ammonium chloride (200 mg) and citric acid (40 mg) in water (2.5 mL). The organic layer was separated, washed with brine (1 mL), dried, and filtered. The filtrate was concentrated under reduced pressure to afford methyl (25)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-phenylbutanoate (213 mg, crude) as a yellow oil and used in the next reaction without purification. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0202] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO)

[0203] Step 5: methyl (2N,3»V)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-carboxylate

[0204] A mixture of methyl (25)-3-(2-bromo-4,6-difluorophenyl)-2-hydroxy-2-

[0205] 5 phenylbutanoate (6.4 g, 16.61 mmol, 1 equiv.) in NMP (64 mL) was degassed and purged with N2 three times. NaH (598.13 mg, 14.95 mmol, 60% purity, 0.9 equiv.) was added at 15 °C, and the resulting mixture was stirred at 15 °C for 0.25 hours under a N2 atmosphere. The mixture was quenched by the addition of a saturated solution of ammonium chloride (200 mL) and extracted with methyl tert-butyl ether (300 mL). The combined organic layers were washed

[0206] 10 with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (2% to 3% ethyl acetate / petroleum ether) to afford a yellow solid. The solid was recrystallized from petroleum ether / ethyl acetate (30 mL, heated to 70 °C with stirring to dissolve all solid, and allowed to cool to 10 °C). The solid was collected by filtration to give methyl (25,35)-4-bromo-6-fluoro- 3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carboxylate (1.4 g) as a white crystal.

[0207] ’H NMR (400 MHz, DMSO-t / 6) 8 = 7.62 (d, J= 6.8 Hz, 2H), 7.44 - 7.28 (m, 3H), 7.13 - 6.97 (m, 2H), 3.92 (q, J= 6.8 Hz, 1H), 3.74 (s, 3H), 1.32 (d, J= 6.8 Hz, 3H)

[0208] Step 6: methyl (2N,3»V)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-3H-

[0209] 20 benzofuran-2-carboxylate

[0210] A mixture of methyl (2 ,35)-4-bromo-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-carboxylate (1.8 g, 4.93 mmol, 1 equiv.) in acetonitrile (19 mL) was degassed and purged with N2 three times. NCS (789.79 mg, 5.91 mmol, 1.2 equiv.) and TsOH H2O (1.41 g, 7.39 mmol, 1.5 equiv.) were added, and the resulting mixture was stirred at 45 °C for 12 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting residue was dissolved in EtOAc (20 mL) and washed with a saturated solution of sodium bicarbonate (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from / / -hexane (20 mL) to afford methyl (2 ,35)-4-bromo-5-chloro-6-fluoro-3-

[0211] 30 methyl-2-phenyl-3H-benzofuran-2-carboxylate (1.9 g) as a yellow oil, which was used in the next reaction without purification.

[0212] 1H NMR (400 MHz, DMSO-t / 6) 6 = 7.62 (dd, J= 1.2, 8.0 Hz, 2H), 7.46 - 7.24 (m, 4H), 4.09 - 3.92 (m, 1H), 3.75 (s, 3H), 1.33 (d, J= 6.8 Hz, 3H) PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0213] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0214] Step 7: ((2N,3»V)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-yl)methanol

[0215] A mixture of methyl (2 ,35)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-3H- benzofuran-2-carboxylate (1.9 g, 4.75 mmol, 1 equiv.) in THF (19 mL) was degassed and

[0216] 5 purged with N2 three times. MeOH (609.31 mg, 19.02 mmol, 769.53 pL, 4 equiv. and LiBJD (2 M, 4.75 mL, 2 equiv. were then added, and the mixture was stirred at 15 °C for 0.5 hours under a N2 atmosphere. The reaction mixture was quenched by the addition of a saturated solution of sodium bicarbonate (20 mL) and extracted with EtOAc (40 mL). The combined organic layers were washed with a saturated solution of sodium bicarbonate (20 mL), dried

[0217] 10 over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by SFC (column: (s,s) Whelk-Ol (250 mm x 30 mm, 10 pm); mobile phase: [CO2- MeOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to give ((25,35)-4-bromo-5-chloro- 6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methanol (1.08 g).

[0218] ’H NMR (400 MHz, DMSO-t / 6) 8 = 7.45 (d, J= 7.6 Hz, 2H), 7.33 (t, J= 7.6 Hz, 2H), 7.28 - 7.20 (m, 2H), 5.07 (t, J= 5.6 Hz, 1H), 3.98 - 3.89 (m, 2H), 3.55 (q, J= 7.2 Hz, 1H), 3.17 (d, 7= 5.2 Hz, 1H), 1.44 (d, J= 7.2 Hz, 3H)

[0219] Step 8: (2N,3»V)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-carbaldehyde

[0220] 20 A solution of oxalyl dichloride (590.18 mg, 4.65 mmol, 407.02 pL, 1.6 equiv.} in DCM (6 mL) was added to a stirred solution of DMSO (726.61 mg, 9.30 mmol, 726.61 pL, 3.2 equiv.} in DCM (5 mL) at -78 °C. The resulting reaction mixture was stirred at -78 °C for 15 minutes. A solution of ((2,S',3k)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran- 2-yl)methanol (1.08 g, 2.91 mmol, 1 equiv.} in DCM (8 mL) was then added, and the mixture was stirred at -78 °C for 15 minutes. TEA (1.47 g, 14.53 mmol, 2.02 mL, 5 equiv.} was then added, and the resulting reaction mixture was warmed to 0 °C over 30 minutes. The mixture was diluted with DCM and water, and extracted with DCM (30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2,S',3k)-4-bromo-5-chloro-6-fluoro-3-methyl-2-

[0221] 30 phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (108 mg) as a yellow oil and used in the next reaction without purification.

[0222] ’H NMR (400 MHz, DMSO-t / 6) 6 = 9.93 (s, 1H), 7.69 - 7.56 (m, 2H), 7.50 - 7.34 (m, 4H), 3.89 (q, J= 7.2 Hz, 1H), 1.36 (d, J= 7.2 Hz, 3H) PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0223] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0224] Step 9: methyl (15',4r)-4-((((25',3A)-4-bromo-5-chloro-6-fluoro-3-methyl-2-phenyl- 2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l-carboxylate

[0225] A solution of methyl (lr,4r)-4-aminocyclohexane-l-carboxylate (505.30 mg, 3.21 mmol, 1.1 equiv.) in DCE (12 mL) was added to a stirred solution of (25,35)-4-bromo-5-chloro-

[0226] 5 6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2-carbaldehyde (1.08 g, 2.92 mmol, 1 equiv. in DCE (5 mL), AcOH (175.47 mg, 2.92 mmol, 167.27 pL, 1 equiv. , and 4A molecular sieves (600 mg). The resulting reaction mixture was stirred at 25 °C for 16 hours. NaBH(OAc)3 (1.24 g, 5.84 mmol, 2 equiv.} was added in portions, and the reaction mixture was stirred at 25 °C for an additional 3 hours. The residue was quenched with aqueous sodium bicarbonate (10

[0227] 10 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give methyl (15',4r)-4-((((25',35)-4-bromo-5-chloro-6-fluoro-3-methyl-2- phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l -carboxylate (1.3 g) as a white powder.

[0228] ’H NMR (400 MHz, DMSO-t / 6) 8 = 7.44 (d, J= 7.6 Hz, 2H), 7.33 (t, J= 7.6 Hz, 2H), 7.28 - 7.19 (m, 2H), 3.56 (s, 3H), 3.54 - 3.49 (m, 1H), 3.30 - 3.17 (m, 2H), 2.25 - 2.10 (m, 2H), 1.85 - 1.72 (m, 4H), 1.40 (d, J= 7.2 Hz, 3H), 1.24 (s, 2H), 0.96 - 0.78 (m, 3H)

[0229] Step 10: methyl (15',4r)-4-((((25',3A)-5-chloro-4-(6-cyano-2-fluoro-3-

[0230] 20 methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l-carboxylate

[0231] A mixture of methyl (15',4r)-4-((((25',35)-4-bromo-5-chloro-6-fluoro-3-methyl-2- phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l -carboxylate (200 mg, 391.53 pmol, 1 equiv.}, 3-fhioro-4-methoxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (433.96 mg, 1.57 mmol, 4 equiv.}, and SPhos Pd G3 (30.55 mg, 39.15 pmol, 0.1 equiv.} in cyclopentyl methyl ether (2 mL) was degassed and purged with N2 three times. K3PO4 (249.33 mg, 1.17 mmol, 3 equiv.} was added, and the mixture was stirred at 100 °C for 72 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give methyl ( LS’,4r)-

[0232] 30 4-((((25,35)-5-chloro-4-(6-cyano-2-fluoro-3-methoxyphenyl)-6-fluoro-3-methyl-2-phenyl- 2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l-carboxylate (589 mg) as a yellow solid.

[0233] LC-MS (ESI): m / z = 581.1 [M+H]+ PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0234] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0235] Step 11: INT-1

[0236] A mixture of methyl (lS,4r)-4-((((2S,3S)-5-chloro-4-(6-cyano-2-fluoro-3-

[0237] 5 methoxyphenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l -carboxylate (589 mg, 1.01 mmol, 1 equiw . Ghaffar-Parkins Catalyst (21.65 mg, 50.68 pmol, 0.05 equiv.) in EtOH (6 mL) and H2O (1.2 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 16 hours under a N2 atmosphere. The reaction mixture was then concentrated under reduced pressure to give a

[0238] 10 residue, which was purified by flash silica gel chromatography to give INT-1 (117 mg) as a yellow solid.

[0239] ’H NMR (400 MHz, DMSO-t / 6) 8 = 7.64 - 7.57 (m, 2H), 7.43 - 7.38 (m, 2H), 7.33 (t, J= 7.6 Hz, 2H), 7.29 - 7.23 (m, 2H), 7.13 - 7.04 (m, 2H), 3.88 (s, 3H), 3.55 (s, 3H), 3.26 - 3.21 (m, 1H), 3.17 - 3.10 (m, 2H), 2.21 - 2.11 (m, 2H), 1.83 - 1.72 (m, 4H), 1.23 (s, 3H), 0.92 (d, J

[0240] 15 = 7.2 Hz, 3H), 0.89 - 0.81 (m, 2H)

[0241] LC-MS (ESI): m / z = 599.3 [M+H]+

[0242] Step 12: INT-2

[0243] 20

[0244] A mixture of INT-1 (10.00 mg, 16.69 pmol, 1 equiv.) and LiOH.H2O (1.40 mg, 33.39 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0245] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) pmol, 2 equiv.) in dioxane (0.15 mL) was degassed and purged with N2 three times, and the mixture was stirred at 25 °C for 16 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reversed-phase HPLC to give INT-2 (9 mg) as a white solid.

[0246] 5 ’H NMR (400 MHz, DMSO-t / ,) 8 = 12.19 (s, 1H), 8.62 - 8.40 (m, 1H), 7.98 - 7.89 (m, 1H), 7.80 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.51 (d, J= 7.6 Hz, 2H), 7.47 - 7.35 (m, 3H), 7.28 (t, J= 8.4 Hz, 1H), 7.19 - 7.07 (m, 2H), 3.87 (s, 4H), 3.61 - 3.48 (m, 1H), 3.24 - 3.15 (m, 1H), 3.03 - 2.91 (m, 1H), 2.15 - 1.89 (m, 5H), 1.41 - 1.19 (m, 4H), 0.94 (d, 7= 7.2 Hz, 3H)

[0247] 10 Step 13: tert-butyl 4-(3-(2.4-dioxotetrahydropyriniidin-l (2 / / )-yl)-l-niethyl-l / / - indazol-6-yl)-5-methyl-3,6-dihydropyridine-l(2Z / )-carboxylate

[0248] A solution of l-(6-bromo-l-m ethyl- 177-indazol-3-yl)dihydropyrimidine-2, 4(177, 377)- dione (300.00 mg, 928.36 pmol, 1 equiv. in 1,4-dioxane (6.0 mL) was added to tert-butyl 5- methyl-4-(4, 4,5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-3,6-dihydropyri dine- 1(277)- carboxylate (900.25 mg, 2.7851 mmol, 3 equiv.). potassium carbonate (384.90 mg, 2.7851 mmol, 3 equiv.), Pd(dppf)C12 CH2C12 (75.814 mg, 92.836 pmol, 0.1 equiv), and water (1.2 mL). The reaction mixture was heated to 80 °C for 1 hour. The reaction was cooled to room temperature, filtered through a 0.45 pm syringe filter, diluted with EtOAc, washed with water, 5% aqueous citric acid, water, saturated aqueous sodium bicarbonate, and brine. The organic

[0249] 20 layer was dried over magnesium sulfate, filtered, and concentrated to give oil (1.239 g) as a brown solid. This material was treated with Et2O to give a white solid that was removed by filtration, leaving oil (970 mg) as an orange solid in the filtrate. The solid was purified by flash chromatography (hexanes to ethyl acetate) to afford tert-butyl 4-(3-(2,4- dioxotetrahydropyrimidin-l(277)-yl)-l-methyl-177-indazol-6-yl)-5-methyl-3,6- dihydropyridine-l(277)-carboxylate (178 mg) as an off-white solid.

[0250] LC-MS (ESI): m / z = 440.3 [M+H]+

[0251] Step 14: l-(l-methyl-6-(5-methyl-l,2,3,6-tetrahydropyridin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2, 4(177, 377)-dione

[0252] 30 A solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(277)-yl)-l -methyl- 177- indazol-6-yl)-5-methyl-3,6-dihydropyridine-l(277)-carboxylate (120 mg, 272 pmol, 1 equiv.) in DCM (5 mL) was treated with trifluoroacetic acid (7 g, 0.06 mol, 0.02 equiv.) and HC1 (19.8 mg, 544 pmol, 136 pL, 4 M, 2 equiv). The mixture was stirred at room temperature for 12 hours. The reaction was concentrated under a stream of N2, and the residue was washed with PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0253] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0254] Et20 to give l-(l-methyl-6-(5-methyl-l,2,3,6-tetrahydropyridin-4-yl)-17 / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 377)-di one (110 mg) as a yellow glass-like solid.

[0255] LC-MS (ESI): m / z = 340.1 [M+H]+

[0256] 5 Step 15: 1 -( 1 -ni el Iiy l-6-((3.S' / ?.4.S’ / ?)-3-m et Iiy 1 piperid in-4-y 1 )- 1 / / -indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione

[0257] A mixture of l-(l-methyl-6-(5-methyl-l,2,3,6-tetrahydropyridin-4-yl)-l / / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione (110 mg, 270 pmol, 1 equiv.) and palladium on carbon (35 mg, 33.0 pmol, 0.1 equiv., 10% wt) in MeOH (3 mL) was evacuated and backfilled with

[0258] 10 H2. The mixture was stirred for 24 hours. The reaction was diluted with EtOAc and MeOH, filtered through Celite, concentrated, and dried under high vacuum to afford l-(l-methyl-6- ((357?, 457?)-3-methylpiperidin-4-yl)-l / / -indazol-3-yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-di one (100 mg) as a white solid.

[0259] LC-MS (ESI): m / z = 342.1 [M+H]+

[0260] Step 16: tert-butyl 4-(((357?,457?)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)-l- methyl-l / / -indazol-6-yl)-3-methylpiperidin-l-yl)methyl)piperidine-l-carboxylate

[0261] A solution of tert-butyl 4-formylpiperidine-l -carboxylate (106 mg, 498 pmol, 2 equiv.) and 1 -(1 -methyl-6-((357?,457?)-3 -methylpiperidin-4-yl)- l / Z-indazol-3 -yl)dihydropyrimidine-

[0262] 20 2,4(17 / ,377)-dione (85.0 mg, 249 pmol, 1 equiv.) in DCE (2 mL) was stirred at 70 °C for 30 minutes. The solution was cooled to room temperature, and sodium triacetoxyhydroborate (106 mg, 498 pmol, 2 equiv.) was added. The resulting yellow solution was stirred at 70 °C for 5 hours. The reaction was diluted with EtOAc, then washed successively with water, saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to a residue, which was purified by flash chromatography (heptanes to ethyl acetate, then ethyl acetate with 10% 7N NH3 in methanol) to afford tertbutyl 4-(((357?,457?)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)-l-methyl-l / / -indazol-6- yl)-3-methylpiperi din- l-yl)methyl)piperi dine- 1 -carboxylate (8 mg) as a colorless oil.

[0263] LC-MS (ESI): m / z = 539.4 [M+H]+

[0264] 30

[0265] Step 17: l-(l-methyl-6-((357?,457?)-3-methyl-l-(piperidin-4-ylmethyl)piperidin-4- yl)-l / 7-indazol-3-yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione

[0266] A solution of tert-butyl 4-(((357?,457?)-4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)- 1 -methyl- 17 / -indazol-6-yl)-3-methylpiperi din- l-yl)methyl)piperi dine- 1 -carboxylate (8 mg, PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0267] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0268] 0.01 mmol, 1 equiv. in DCM (2 mL) was treated with trifluoroacetic acid (3 g, 0.03 mol, 300 equiv.) and HC1 (1 mg, 7 pL, 0.03 mmol, 4 M, 3 equiv.). The mixture was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure to afford 1- (l-methyl-6-((357?,457?)-3 -methyl- l-(piperi din-4-ylmethyl)piperi din-4-yl)-l JT-indazol-3-

[0269] 5 yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione (7 mg) as a semi-solid.

[0270] LC-MS (ESI): m / z = 439.3 [M+H]+

[0271] Step 18: Compound 154a

[0272] To a solution of INT-2 (5.00 mg, 8.55 pmol, 1 equiv.) and l-(l-methyl-6-((357?,457?)- 3 -methyl- l-(piperi din-4-ylmethyl)piperi din-4-yl)- l / Z-indazol-3 -yl)dihy dropyrimidine- 2,4(17 / ,3J7)-dione (5.62 mg, 12.8 pmol, 1.5 equiv.) in DMF (1 mL) at ambient temperature was added N-ethyl-N-isopropylpropan-2-amine (11.0 mg, 14.9 pL, 85.5 pmol, 10 equiv), followed by HATU (4.22 mg, 11.1 pmol, 1.3 equiv.). The resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was filtered and purified by prep-HPLC to give a white

[0273] 15 solid. The solid was taken up in water, frozen, and lyophilized to give Compound 154a (2 mg) as a white solid.

[0274] LC-MS (ESI): m / z = 1005.5 [M+H]+

[0275] ’H NMR (400 MHz, DMSO-t / 6) 8 ppm 10.54 (s, 1 H) 7.57 - 7.65 (m, 2 H) 7.54 (d, J=8.38 Hz, 1 H) 7.39 - 7.45 (m, 2 H) 7.31 - 7.38 (m, 3 H) 7.23 - 7.30 (m, 2 H) 7.10 - 7.14 (m, 1 H) 7.08 (d, J=9.76 Hz, 1 H) 7.00 (d, J=8.50 Hz, 1 H) 4.35 (br dd, J=11.44, 1.69 Hz, 1 H) 3.96 (s, 3 H) 3.89 - 3.93 (m, 2 H) 3.88 (s, 3 H) 3.81 - 3.86 (m, 1 H) 3.19 - 3.27 (m, 2 H) 3.08 - 3.19 (m, 2 H) 2.87 - 3.03 (m, 3 H) 2.77 - 2.83 (m, 1 H) 2.75 (t, J=6.75 Hz, 2 H) 2.37 - 2.45 (m, 2 H) 2.16 - 2.28 (m, 3 H) 2.06 - 2.16 (m, 3 H) 1.98 - 2.05 (m, 1 H) 1.71 - 1.83 (m, 4 H) 1.67 - 1.71 (m, 1 H) 1.60 - 1.66 (m, 1 H) 1.52 - 1.59 (m, 2 H) 1.18 - 1.34 (m, 3 H) 0.97 (br s, 1 H) 0.93 (br

[0276] 25 d, J=7.25 Hz, 3 H) 0.81 - 0.90 (m, 2 H) 0.72 (d, J=6.88 Hz, 3 H)

[0277] PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0278] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0279] Example 2: Synthesis of Compound 112a

[0280] Step 1: 2-bromo-3-fluoro-4-hydroxy-benzonitrile

[0281] A mixture of 2-bromo-3,4-difluoro-benzonitrile (2 g, 9.17 mmol, 1 equiw .

[0282] 5 ethanehydroxamic acid (2.07 g, 27.52 mmol, 3 equiv.), and potassium carbonate (6.34 g, 45.87 mmol, 5 equiv. in DMSO (20 mL) was degassed and purged with N2 three times. The mixture was then stirred at 80 °C for 4 hours under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was treated with HC1 (0.1 M) to pH = 5 and extracted with ethyl acetate (150 mL). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-34% ethyl acetate / petroleum ether) to give 2-bromo-3-fluoro-4- hydroxy -benzonitrile (1.9 g) as a yellow solid.

[0283] Hl NMR (400 MHz, DMSO-tL) 8 = 11.69 (d, J = 3.6 Hz, 1H), 7.60 (dd, J = 1.6, 8.8

[0284] 15 Hz, 1H), 7.08 (t, J= 8.4 Hz, 1H)

[0285] Step 2: 2-bromo-4-(2-(( rt-butyldimethylsilyl)oxy)ethoxy)-3-fluorobenzonitrile

[0286] A mixture of 2-bromo-3-fluoro-4-hydroxy-benzonitrile (1.9 g, 8.80 mmol, 1 equiv. , tert-butyl-(2-iodoethoxy)-dimethylsilane (3.78 g, 13.19 mmol, 1.5 equiv.}, and potassium carbonate (2.43 g, 17.59 mmol, 2 equiv.} in DMF (19 mL) was degassed and purged with N2 three times. The mixture was then stirred at 80 °C for 12 hours under a N2 atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue

[0287] 25 was purified by flash silica gel chromatography (0-9% ethyl acetate / petroleum ether) to give PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0288] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0289] 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluorobenzonitrile (3.17 g) as a yellow solid.

[0290] ’H NMR (400 MHz, DMSO-tL) 8 = 7.78 (dd, J= 1.6, 8.8 Hz, 1H), 7.41 (t, J= 8.4 Hz, 1H), 4.31 - 4.22 (m, 2H), 3.99 - 3.88 (m, 2H), 0.83 (s, 9H), 0.05 - 0.03 (m, 6H)

[0291] 5

[0292] Step 3: 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoro-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile

[0293] To a solution of 2-bromo-4-(2-((te / 7-butyldimethylsilyl)oxy)ethoxy)-3- fluorobenzonitrile (34 g, 90.83 mmol, 1 equiv. in THF (340 mL) was added dropwise w-BuLi

[0294] 10 (2.5 M, 54.50 mL, 1.5 equiv. at -70 °C. The mixture was stirred at -70 °C for 0.5 hours. Then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (33.80 g, 181.66 mmol, 37.06 mL, 2 equiv. in THF (340 mL) was added, and the resulting mixture was stirred at -70 °C for 1 hour. The mixture was quenched with HC1 (I M, 1000 mL) and extracted with ethyl acetate (3000 mL). The combined organic layers were washed with saturated brine (1000 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-15% ethyl acetate / petroleum ether) to give 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoro-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile (18.6 g) as a yellow solid.

[0295] ’H NMR (400 MHz, DMSO-tL) 6 = 7.66 (d, J= 8.0 Hz, 1H), 7.42 (t, J= 8.0 Hz, 1H),

[0296] 20 4.21 (s, 2H), 3.93 (s, 2H), 1.33 (s, 12H), 0.84 (s, 9H), 0.04 (s, 6H)

[0297] Step 4: methyl ( l.S'.4r)-4-((((2.S'.3.S')-4-(3-(2-(( / crM)utyldimethylsilyl)oxy)ethoxy)-6- cyano-2-fluorophenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l-carboxylate

[0298] A mixture of methyl (l ,4r)-4-((((2 ,35)-4-bromo-5-chloro-6-fluoro-3-methyl-2- phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l -carboxylate (185 mg, 362.16 pmol, 1 equiv.}, 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluoro-2-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (610.44 mg, 1.45 mmol, 4 equiv.}, potassium phosphate (230.62 mg, 1.09 mmol, 3 equiv.}, and SPhos Pd G3 (28.26 mg, 36.22 pmol, 0.1

[0299] 30 equiv.} in cyclopentyl methyl ether (1 mL) was degassed and purged with N2 three times. The mixture was then stirred at 100 °C for 16 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-87% ethyl acetate / petroleum ether) to give methyl ( LS',4 / -4-((((2A',3k)- 4-(3-(2-((te / 7-butyldimethylsilyl)oxy)ethoxy)-6-cyano-2-fluorophenyl)-5-chloro-6-fluoro-3- PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0300] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) methyl-2-phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l -carboxylate (85 mg) as a yellow solid.

[0301] LC-MS (ESI): m / z = 725.4 [M+H]+

[0302] 5 Step 5: methyl (15',4r)-4-((((25',3» )-5-chloro-4-(6-cyano-2-fluoro-3-(2- hydroxyethoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l-carboxylate

[0303] A mixture of methyl (15',4r)-4-((((25',35)-4-(3-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-6-cyano-2-fluorophenyl)-5-chloro-6-fluoro-3-methyl-2-

[0304] 10 phenyl-2,3-dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l -carboxylate (85 mg, 117.19 pmol, 1 equiv.) in THF (0.85 mL) was degassed and purged with N2 three times. Tetrabutyl ammonium fluoride trihydrate (1 M, 140.62 pL, 1.2 equiv. was added at 0 °C, and the mixture was stirred at 25 °C for 1 hour under a N2 atmosphere. The reaction mixture was washed with water (5 mL) and extracted with ethyl acetate (15 mL). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (LS’,4 / -4-((((2k,3k)-5-chloro-4-(6- cyano-2-fluoro-3-(2-hydroxyethoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3- dihydrobenzofuran-2-yl)methyl)amino)cyclohexane-l -carboxylate (71 mg, crude) as a yellow oil.

[0305] 20 LC-MS (ESI): m / z = 611.1 [M+H]+

[0306] Step 6: methyl (15',4r)-4-((((25',3» )-4-(6-carbamoyl-2-fluoro-3-(2- hydroxyethoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l-carboxylate

[0307] A mixture of methyl (l£,4r)-4-((((2£,35 -5-chloro-4-(6-cyano-2-fluoro-3-(2- hydroxyethoxy)phenyl)-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l -carboxylate (71 mg, 116.19 pmol, 1 equiv. and Ghaffar- Parkins catalyst (2.48 mg, 5.81 pmol, 0.05 equiv.} in EtOH (1 mL) and H2O (0.2 mL) was degassed and purged with N2 three times. The mixture was then stirred at 80 °C for 16 hours

[0308] 30 under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford methyl (15',4r)-4-((((25',35)-4-(6-carbamoyl-2-fluoro-3-(2- hydroxyethoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l -carboxylate (70 mg) as a yellow solid. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0309] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0310] LC-MS (ESI): m / z = 629.3 [M+H]+

[0311] 5 Isomers of methyl (l£,4r)-4-((((2£,35)-4-(6-carbamoyl-2-fluoro-3-(2- hydroxyethoxy)phenyl)-5-chloro-6-fluoro-3-methyl-2-phenyl-2,3-dihydrobenzofuran-2- yl)methyl)amino)cyclohexane-l -carboxylate (1.2 g, 1.91 mmol, 1 equiv.) were separated by SFC (column: Daicel Chiralpak IC (250 mm x 30 mm, 10 pm); mobile phase: [CO2 - MeOH (0.1% NH3H2O)]; B%: 42%, isocratic elution mode) to give INT-3 (367 mg) as a yellow solid

[0312] 10 and INT-4 (577 mg) as a yellow solid.

[0313] INT-3:

[0314] LC-MS (ESI): tR= 0.344 min, m / z: 629.3 [M+H]+

[0315] INT-4:

[0316] LC-MS (ESI): tR= 0.369 min, m / z: 629.3 [M+H]+

[0317] 15

[0318] Step 8: INT-5

[0319] 20 A mixture of INT-3 (24 mg, 38.15 pmol, 1 equiv.) and LiOH LO (3.20 mg, 76.30 pmol, 2 equiv.) in dioxane (0.25 mL) and water (0.05 mL) was degassed and purged with N2 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0320] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) three times. The mixture was then stirred at 25 °C for 9 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (0.1% TFA) to give INT-5 (16 mg) as a white solid.

[0321] LC-MS (ESI): m / z = 615.1 [M+H]+

[0322] 5 ’H NMR (400 MHz, DMSO-t / 6) 5 = 12.18 (d, J = 2.0 Hz, 1H), 8.56 - 8.44 (m, 1H), 7.93 (s, 1H), 7.80 (s, 1H), 7.60 - 7.52 (m, 3H), 7.48 - 7.37 (m, 3H), 7.34 - 7.28 (m, 1H), 7.18 - 7.09 (m, 2H), 4.14 - 4.07 (m, 2H), 3.93 - 3.86 (m, 1H), 3.71 (t, J= 4.8 Hz, 2H), 3.56 (d, J= 9.6 Hz, 2H), 3.22 (q, 7= 6.8 Hz, 1H), 3.03 - 2.95 (m, 1H), 2.16 - 1.90 (m, 6H), 1.46 - 1.36 (m, 1H), 1.34 - 1.23 (m, 3H), 0.95 (d, J= 7.2 Hz, 3H)

[0323] 10

[0324] Step 9: tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2ET)-yl)-5,7-difluoro-l- inethyl-l / / -ind:izol-6-yl)piperidin-l-yl)niethyl)piperidine-l -carboxylate

[0325] To a solution of l-(5,7-difluoro-l-methyl-6-(piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (100 mg, 275.21 pmol, 1 equiv.) in DCE (2 mL) and DMF (1 mL) was added tert-butyl 4-formylpiperidine-l -carboxylate (117.39 mg, 550.42 pmol, 2 equiv.), 4A molecular sieves (50 mg), and AcOH (18.18 mg, 302.73 pmol, 17.33 pL, 1.1 equiv. The mixture was stirred at 25 °C for 1 hour. NaBH(OAc)s (116.66 mg, 550.42 pmol, 2 equiv. ) was then added, and the mixture was stirred at 25 °C for 32 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica

[0326] 20 gel chromatography (0-7% DCM / methanol) to give tert-butyl 4-((4-(3-(2,4- dioxotetrahydropyrimidin-1 (27 / )-yl )-5,7-di fluoro- 1 -methyl- U / -indazol-6-yl)piperidin- 1 - yl)methyl)piperidine-l -carboxylate (51 mg) as a white solid.

[0327] ’H NMR (400 MHz, DMSO-t / 6) d = 10.58 (s, 1H), 7.28 (d, J = 10.8 Hz, 1H), 4.09 (s, 3H), 3.97 - 3.86 (m, 4H), 3.03 - 2.92 (m, 3H), 2.79 - 2.68 (m, 4H), 2.16 (d, J = 6.8 Hz, 2H), 2.10 - 1.93 (m, 5H), 1.69 (d, J= 11.2 Hz, 5H), 1.39 (s, 10H)

[0328] Step 10: l-(5,7-difluoro-l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-lH- indazol-3-yl)dihydropyrimidine-2,4( l / / .3 / / )-dione

[0329] To a solution of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)-5,7-

[0330] 30 difluoro- 1 -methyl- U / -indazol-6-yl)piperidin- 1 -yl)methyl)piperidine- 1 -carboxylate (50 mg, 89.18 pmol, 1 equiv.) in DCM (0.6 mL) was added trifluoroacetic acid (307.00 mg, 2.69 mmol, 0.2 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give l-(5,7-difluoro-l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin- 4-yl)-U / -indazol-3-yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione (50 mg, crude) as a brown solid. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0331] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0332] LC-MS (ESI): m / z = 461.3 [M+H]+

[0333] Step 11: Compound 112a

[0334] To a solution of l-(5,7-difluoro-l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-

[0335] 5 U / -indazol-3-yl)dihydropyrimidine-2,4(U / ,3J7)-dione (8.98 mg, 19.51 pmol, 1.2 equiv.) in DMF (0.3 mL) was added INT-5 (10 mg, 16.26 pmol, 1 equiv.\ DIEA (4.20 mg, 32.52 pmol, 5.66 pL, 2 equiv.), EDCI (3.74 mg, 19.51 pmol, 1.2 equiv). and HOBt (2.64 mg, 19.51 pmol, 1.2 equiv.}. The mixture was stirred at 25 °C for 12 hours. The mixture was purified by prep- HPLC to give Compound 112a (4.01 mg) as a yellow solid.

[0336] LC-MS (ESI): m / z = 1057.4 [M+H]+

[0337] ’H NMR (400 MHz, DMSO-t / 6) d = 10.63 - 10.52 (m, 1H), 7.60 - 7.54 (m, 2H), 7.45 - 7.38 (m, 2H), 7.37 - 7.24 (m, 5H), 7.13 - 7.05 (m, 2H), 4.92 (t, J= 5.6 Hz, 1H), 4.35 (dd, J = 4.0, 13.2 Hz, 1H), 4.16 - 4.06 (m, 5H), 3.92 - 3.82 (m, 3H), 3.76 - 3.68 (m, 2H), 3.14 (s, 3H), 2.98 - 2.92 (m, 3H), 2.79 - 2.72 (m, 2H), 2.23 - 2.11 (m, 4H), 2.09 - 1.96 (m, 4H), 1.81 - 1.64

[0338] 15 (m, 8H), 1.59 - 1.51 (m, 2H), 1.35 - 1.20 (m, 3H), 0.98 - 0.82 (m, 8H)

[0339] Example 3: Synthesis of Compound Illa

[0340] Step 1: tert-butyl 4-((4-(3-(2.4-dioxotetr:ihydropyrimidin-l (2 / / )-yl)-l -methyl- 1 / / - indazol-6-yl)piperazin-l-yl)methyl)piperidine-l-carboxylate

[0341] A solution of l-(l-methyl-6-piperazin-l-yl-indazol-3-yl)hexahydropyrimidine-2,4- dione (20.05 g, 152.27 pmol, 1 equiv.} and tert-butyl 4-formylpiperidine-l -carboxylate (35.72 mg, 167.49 pmol, 1.1 equiv.} in DCM (0.5 mL) was stirred at 25 °C for 30 minutes. NaBH(OAc)s (64.54 mg, 304.54 pmol, 2 equiv.} was then added, and the mixture was stirred

[0342] 25 at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0343] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) residue, which was purified by column chromatography (SiCE, DCM / MeOH = 1 :0 to 20: 1) to give tert-butyl 4-((4-(3-(2, 4-dioxotetrahydropyrimidin-l(2 / 7)-yl)-l -methyl- 1 / 7-indazol -6- yl)piperazin-l-yl)methyl)piperidine-l -carboxylate (0.04 g) as a white solid.

[0344] ’H NMR (400 MHz, CDCh-tZ) 8 = 7.82 - 7.77 (m, 1H), 7.57 - 7.51 (m, 1H), 6.92 (dd,

[0345] 5 J = 1.6, 9.2 Hz, 1H), 3.93 (s, 3H), 3.28 (s, 4H), 2.88 (t, J = 6.8 Hz, 2H), 2.78 - 2.65 (m, 4H), 2.63 (s, 4H), 2.31 - 2.25 (m, 2H), 1.77 (d, J = 13.2 Hz, 2H), 1.74 - 1.59 (m, 3H), 1.45 (d, J = 2.8 Hz, 9H), 1.18 - 1.07 (m, 2H)

[0346] Step 2: 1 -( 1 -ni el hy l-6-( 4-( piperid in-4-y 1 in et hy 1 )piperazin- 1 -y 1 )- 1 / / -indazol-3-

[0347] 10 yl)dihydropyrimidine-2,4( l / / .3 / / )-dione

[0348] To a solution of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)-l-methyl- l / 7-indazol-6-yl)piperazin-l-yl)methyl)piperidine-l -carboxylate (0.04 g, 76.10 pmol, 1 equiv. in DCM (0.3 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred at 25 °C for 0.5 hours to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give l-(l-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-l-yl)-l / 7-indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione (0.03 g, crude) as a yellow oil, which was used in the next step without further purification.

[0349] Step 3: Compound Illa

[0350] 20 To a solution of l-(l-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-l-yl)-l / 7-indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione (0.03 g, 70.50 pmol, 1 equiv.) and INT-5 (43.36 mg, 70.50 pmol, 1 equiv.) in DMF (1 mL) was added EDCI (16.22 mg, 84.60 pmol, 1.2 equiv), HOBt (11.43 mg, 84.60 pmol, 1.2 equiv.), and DIEA (27.34 mg, 211.50 pmol, 36.84 pL, 3 equiv). The mixture was stirred at 25 °C for 12 hours to give a clean solution. The reaction mixture was purified by prep-HPLC to give Compound Illa (0.00307 g) as a white solid.

[0351] LC-MS (ESI): m / z = 1022.4 [M+H]+

[0352] ’H NMR (400 MHz, DMSO-t / 6) 6 = 10.49 (s, 1H), 7.57 (d, J= 8.4 Hz, 2H), 7.48 - 7.39 (m, 3H), 7.34 (t, J= 7.6 Hz, 2H), 7.31 (s, 2H), 7.09 (s, 1H), 7.07 (d, J= 9.6 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.81 (s, 1H), 5.07 - 4.80 (m, 1H), 4.40 - 4.30 (m, 1H), 4.17 - 4.04 (m, 2H),

[0353] 30 3.97 - 3.79 (m, 6H), 3.72 (t, J= 4.4 Hz, 2H), 3.25 (s, 5H), 3.21 (s, 5H), 3.14 (s, 2H), 3.01 - 2.91 (m, 1H), 2.73 (t, 7= 6.8 Hz, 2H), 2.49 - 2.38 (m, 2H), 2.18 (d, 7= 6.4 Hz, 3H), 1.86 - 1.65 (m, 5H), 1.56 (d, J= 12.0 Hz, 2H), 1.36 - 1.18 (m, 2H), 1.08 - 0.79 (m, 7H) PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0354] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0355] Example 4: Synthesis of Compound 106a

[0356] Compound 106a

[0357] Step 1: Compound 106a

[0358] To a solution of INT-2 (10 mg, 17.09 pmol, 1 equiv.) in DMF (0.3 mL) was added 1- 5 (5,7-difluoro-l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione (9.45 mg, 20.51 pmol, 1.2 equiv.), DIE A (4.42 mg, 34.19 pmol, 5.95 pL, 2 equiv.), EDCI (3.93 mg, 20.51 pmol, 1.2 equiv.), and HOBt (2.77 mg, 20.51 pmol, 1.2 equiv). The mixture was stirred at 25 °C for 12 hours. The mixture was purified by prep-HPLC to give Compound 106a (2.34 mg) as a white solid.

[0359] 10 LC-MS (ESI): m / z: 514.6 [M / 2+H]+.

[0360] ’H NMR (400 MHz, DMSO-t / ,) d = 10.59 (s, 1H), 7.63 - 7.57 (m, 2H), 7.43 - 7.38 (m, 2H), 7.36 - 7.23 (m, 5H), 7.13 - 7.05 (m, 2H), 4.40 - 4.30 (m, 1H), 4.13 - 4.06 (m, 3H), 3.93 - 3.83 (m, 6H), 3.26 - 3.21 (m, 2H), 3.17 - 3.10 (m, 2H), 3.04 - 2.91 (m, 4H), 2.75 (t, J= 6.8 Hz, 2H), 2.22 - 1.92 (m, 7H), 1.81 - 1.64 (m, 7H), 1.60 - 1.51 (m, 2H), 1.34 - 1.20 (m, 3H), 1.00 -

[0361] 15 0.82 (m, 8H)

[0362] PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0363] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0364] Example 5: Synthesis of Compound 160a

[0365] Compound 160a

[0366] Step 1: tert-butyl 3-(4-(3-(2.4-dioxot el rahydropy riniidin- 1 (2 / / )-yI )- 1 -met Iiyl- 1 / / - indazol-6-yl)piperidin-l-yl)pyrrolidine-l-carboxylate

[0367] 5 A mixture of l-[l-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2, 4-dione (1.0 g, 3.05 mmol, 1.0 equiv. and tert-butyl 3 -oxopyrrolidine- 1 -carboxylate (622.34 mg, 3.36 mmol, 1.1 equiv.) in DCM (10 mL) was stirred at 25 °C for 2 hours. NaBH(OAc)3 (776.86 mg, 3.67 mmol, 1.2 equiv.) was then added, and the mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, DCM = 20: 1) to give tert-butyl 3-(4-(3-(2,4- dioxotetrahydropyrimi din- l(2J7)-yl)-l -methyl- l / 7-indazol-6-yl)piperi din- l-yl)pyrrolidine-l- carboxylate (700 mg) as a yellow solid.

[0368] Step 2: l-(l-methyl-6-(l-(pyrrolidin-3-yl)piperidin-4-yl)-l / / -indazol-3-

[0369] 15 yl)dihydropyrimidine-2,4( l / / .3 / / )-dione

[0370] A mixture of tert-butyl 3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)-l-methyl-l / 7- indazol-6-yl)piperidin-l-yl)pyrrolidine-l -carboxylate (13 mg, 26.18 pmol, 1 equiv.) and trifluoroacetic acid (153.50 mg, 1.35 mmol, 0.1 mL, 51.43 e^wzv.) in DCM (0.3 mL) was stirred at 25 °C for 0.5 hours. The mixture was concentrated under reduced pressure to give 1-(1- methyl-6-(l-(pyrrolidin-3-yl)piperidin-4-yl)-l / 7-indazol-3-yl)dihydropyrimidine-2, 4(177, 377)- di one (10 mg) as a yellow oil and used in the next step without further purification.

[0371] LC-MS (ESI): m / z: 397.1 [M+H]+.

[0372] Step 3: Compound 160a

[0373] 25 A mixture of INT-2 (10 mg, 17.09 pmol, 1.0 equiv), l-(l-methyl-6-(l-(pyrrolidin-3- yl)piperidin-4-yl)-177-indazol-3-yl)dihydropyrimidine-2,4(177,377)-dione (8.81 mg, 22.22 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0374] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) pmol, 1.3 equiv.), HOBt (2.77 mg, 20.51 pmol, 1.2 equiv.), EDCI (3.93 mg, 20.51 pmol, 1.2 eqniv.\ and DIEA (6.63 mg, 51.28 pmol, 8.93 pL, 3.0 equiv.) in DMF (0.4 mL) was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was purified by reversed-phase HPLC and lyophilized to give Compound 160a (3.23

[0375] 5 mg) as a white solid.

[0376] LC-MS (ESI): m / z = 963.2 [M+H]+

[0377] ’H NMR (400 MHz, DMSO-t / 6) d = 10.53 (s, 1H), 7.59 (d, J= 8.4 Hz, 2H), 7.54 (dd, J= 2.4, 8.4 Hz, 1H), 7.44 (s, 1H), 7.43 - 7.39 (m, 2H), 7.33 (t, J= 6.8 Hz, 2H), 7.29 - 7.22 (m, 2H), 7.10 (s, 1H), 7.07 (d, J= 10.0 Hz, 1H), 7.03 (d, 7= 8.8 Hz, 1H), 3.96 (d, J= 1.6 Hz, 3H), 3.93 - 3.89 (m, 2H), 3.88 (d, J= 0.8 Hz, 3H), 3.66 - 3.57 (m, 1H), 3.52 - 3.42 (m, 1H), 3.42 - 3.36 (m, 1H), 3.23 (d, J= 7.2 Hz, 2H), 3.14 (s, 3H), 3.08 - 3.02 (m, 1H), 2.95 (s, 1H), 2.91 - 2.81 (m, 1H), 2.77 - 2.72 (m, 2H), 2.68 - 2.61 (m, 1H), 2.34 - 2.18 (m, 2H), 2.17 - 2.04 (m, 3H), 1.89 - 1.66 (m, 7H), 1.64 - 1.57 (m, 2H), 1.25 (dd, 7= 2.4, 6.0 Hz, 2H), 0.93 (d, J= 7.2 Hz, 4H), 0.87 (d, J= 14.4 Hz, 1H)

[0378] 15

[0379] Example 6: Synthesis of Compound 108a

[0380] Compound 108a

[0381] Step 1: tert-butyl 4-((4-(3-(2.4-dioxotetrahydropyrimidin-l (2 / / )-yl)-l -methyl- 1 / / - indazol-6-yl)piperidin-l-yl)methyl)piperidine-l-carboxylate

[0382] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3J7)-dione, 2Hydrochloric acid (61 mg, 0.15 mmol, 1 equiv.) in tetrahydrofuran (2.00 mL) and DMF (500 pL) was added tert-butyl 4-formylpiperidine-l -carboxylate (65 mg, 0.30 mmol, 2.0 equiv.) and potassium acetate (75 mg, 0.76 mmol, 5.0 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (65 mg, 0.30

[0383] 25 mmol, 2.0 equiv.) was then added, and the mixture was stirred for an additional 17 hours. The PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0384] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted with ethyl acetate once more, followed by 10% isopropanol in DCM, and DCM. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a tan solid. The solid

[0385] 5 was taken up in DMSO and purified by prep-HPLC to give tert-butyl 4-((4-(3-(2,4- di oxotetrahydropyrimi din- l (27 / )-yl)- l -methyl- IT / -indazol-6-yl)piperi din- 1- yl)methyl)piperidine-l -carboxylate (43 mg) as a white solid.

[0386] LC-MS (ESI): m / z = 525.4 [M+H]+

[0387] 10 Step 2: 1 -( 1 -nielIiyl-6-( 1 -(piperidin-4-ylnielhyl )piperidin-4-yl )- 1 / / -indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. 2trifluoroacetic acid

[0388] To a solution of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2rt)-yl)-l-methyl- 1 J / -indazol-6-yl)piperi din- l-yl)methyl)piperi dine- 1 -carboxylate (44 mg, 84 pmol, 1 equiv. in DCM (2.0 mL) was added trifluoroacetic acid (1.11 g, 750 pL, 9.74 mmol, 120 equiv.). The reaction mixture was stirred at ambient temperature for 90 minutes. Volatile organics were removed under reduced pressure to give l-(l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4- yl)-U / -indazol-3-yl)dihydropyrimidine-2,4(U / ,3rt)-dione, 2trifluoroacetic acid (57 mg) as a white solid.

[0389] LC-MS (ESI): m / z = 425.4 [M+H]+

[0390] 20

[0391] Step 3: Compound 108a

[0392] To a solution of INT-2 (5.0 mg, 8.5 pmol, 1 equiv.) in DMF (500 pL) was added 1-(1- methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-17 / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3rt)-dione, 2trifhioroacetic acid (8.4 mg, 13 pmol, 1.5 equiv. , DIEA (5.5 mg, 7.4 pL, 43 pmol, 5.0 equiv.), and HATU (3.9 mg, 10 pmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was filtered and purified by prep- HPLC to give Compound 108a (7 mg) as a white solid.

[0393] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.54 (s, 1H), 7.60 (br d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 - 7.38 (m, 3H), 7.33 (t, J = 7.5 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.11 (br s,

[0394] 30 1H), 7.07 (d, J = 9.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.35 (br d, J = 11.9 Hz, 1H), 3.96 (s, 3H), 3.93 - 3.86 (m, 5H), 3.27 - 3.04 (m, 7H), 2.95 (br d, J = 10.1 Hz, 3H), 2.75 (t, J = 6.6 Hz, 2H), 2.61 (dt, J = 5.6, 10.3 Hz, 1H), 2.46 - 2.38 (m, 1H), 2.24 - 2.11 (m, 3H), 2.05 - 1.94 (m, 2H), 1.85 - 1.65 (m, 8H), 1.55 (br d, J = 12.4 Hz, 2H), 1.36 - 1.18 (m, 2H), 1.03 - 0.79 (m, 7H)

[0395] LC-MS (ESI): m / z = 992.6 [M+H]+ PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0396] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0397] Step 1: Compound 116a

[0398] 5 To a solution of INT-5 (5.0 mg, 7.7 pmol, 1 equiv.) in DMF (500 pL) was added 1-(1- methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3J7)-dione, 2trifluoroacetic acid (7.5 mg, 12 pmol, 1.5 equiv. DIEA (6.0 mg, 8.0 pL, 46 pmol, 6.0 equiv.). andHATU (3.5 mg, 9.2 pmol, 1.2 equiv.). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was filtered and purified by prep-

[0399] 10 HPLC and lyophilized to give Compound 116a (3 mg) as a white solid.

[0400] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.56 (s, 1H), 10.11 - 9.89 (m, 1H), 8.73 - 8.56 (m, 1H), 8.17 - 7.99 (m, 1H), 7.81 (br s, 1H), 7.65 - 7.50 (m, 4H), 7.49 - 7.36 (m, 4H), 7.30 (t, J = 8.6 Hz, 1H), 7.15 (br d, J = 9.1 Hz, 1H), 7.11 (br s, 1H), 7.05 (br d, J = 8.6 Hz, 1H), 6.53 (s, 1H), 4.93 (t, J = 5.3 Hz, 1H), 4.36 (br d, J = 13.8 Hz, 1H), 4.16 - 4.05 (m, 2H), 3.98 (s, 3H), 3.91 (br t, J = 6.6 Hz, 4H), 3.71 (q, J = 4.7 Hz, 2H), 3.66 - 3.51 (m, 2H), 3.22 (q, J = 7.0 Hz, 1H), 3.15 - 2.87 (m, 6H), 2.76 (t, J = 6.6 Hz, 2H), 2.57 (br d, J = 2.9 Hz, 1H), 2.31 - 2.08 (m, 3H), 2.07 - 1.63 (m, 8H), 1.55 - 1.21 (m, 4H), 1.19 - 0.91 (m, 5H)

[0401] LC-MS (ESI): m / z = 1021.8 [M+H]+

[0402] 20 Example 8: Synthesis of Compound 121a PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0403] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0404] Compound 121a

[0405] Step 1: tert-butyl 2-(4-(3-(2.4-dioxotetraliydrop rimidin-l (2 / / )-yl)-l -methyl- 1 / / - indazol-6-yl)piperidin-l-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0406] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine-

[0407] 5 2,4(17 / ,3J7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv. in tetrahydrofuran (2.0 mL) and DMF (0.50 mL) was added tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (30 mg, 0.12 mmol, 1.1 equiv.) and potassium acetate (56 mg, 0.57 mmol, 5 equiv.). The reaction mixture was stirred at ambient temperature for 45 minutes. To the reaction mixture was then added sodium triacetoxyborohydride (48 mg, 0.23 mmol, 2 equiv), and the resulting mixture was stirred for 18 hours. The volatile organics were removed under reduced pressure to give a white solid. The solid was taken up in DMSO, filtered, and purified by prep-HPLC to give tertbutyl 2-(4-(3 -(2, 4-dioxotetrahydropyrimidin-l(2J7)-yl)-l -methyl- 1 J / -indazol-6-yl)piperi din- l-yl)-7-azaspiro[3.5]nonane-7-carboxylate (50 mg) as a white solid.

[0408] LC-MS (ESI): m / z = 551.5 [M+H]+

[0409] 15

[0410] Step 2: l-(6-( l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-l-methyl-17 / -indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. 2trifluoroacetic acid

[0411] To a solution of ter / -butyl 2-(4-(3 -(2, 4-di oxotetrahydropyri midi n- l (27 / )-yl)- l -methyl - U / -indazol-6-yl)piperidin-l-yl)-7-azaspiro[3.5]nonane-7-carboxylate (50 mg, 91 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 500 pL, 6.49 mmol, 71 equiv). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give a colorless oil. The oil was taken up in acetonitrile, frozen, and lyophilized to give l-(6-(l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4- yl)-l -methyl- 17 / -indazol-3-yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione, 2trifluoroacetic acid (58

[0412] 25 mg) as a white solid. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0413] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO)

[0414] LC-MS (ESI): m / z = 451.3 [M+H]+

[0415] Step 3: Compound 121a

[0416] To a solution of INT-2 (5.0 mg, 7.2 pmol, 1 equiv.) in DMF (500 pL) was added l-(6-

[0417] 5 (l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-l-methyl-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3J7)-dione, 2trifluoroacetic acid (7.3 mg, 11 pmol, 1.5 equiv. DIEA (5.5 mg, 7.5 pL, 43 pmol, 6.0 equiv.). andHATU (3.3 mg, 8.6 pmol, 1.2 equiv.). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was filtered, purified by prep-HPLC, and lyophilized to give Compound 121a (3 mg) as a white solid.

[0418] ’H NMR (400 MHz, DMSO-t / ,) 8 = 10.54 (s, 1H), 7.63 - 7.56 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.43 - 7.38 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 3.93 - 3.86 (m, 5H), 3.25 - 3.19 (m, 3H), 3.17 - 3.08 (m, 2H), 2.92 (br d, J = 6.3 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.71 - 2.57 (m, 2H), 2.45 - 2.37 (m, 1H), 2.24 - 2.12 (m, 1H), 1.98 (br t, J = 8.0 Hz, 2H), 1.84

[0419] 15 - 1.69 (m, 8H), 1.60 - 1.48 (m, 5H), 1.43 (br d, J = 2.9 Hz, 2H), 1.38 - 1.31 (m, 1H), 1.30 - 1.19 (m, 3H), 1.01 - 0.80 (m, 6H)

[0420] LC-MS (ESI): m / z = 1017.7 [M+H]+

[0421] Example 9: Synthesis of Compound 135a

[0422] Compound 135a

[0423] Step 1: Compound 135a

[0424] To a solution of INT-5 (5.0 mg, 7.7 pmol, 1 equiv.) in DMF (500 pL) was added l-(6- (l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-l-methyl-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3J7)-dione, 2trifluoroacetic acid (7.8 mg, 12 pmol, 1.5 equiv.), DIEA (6.0 mg, 8.0 pL,

[0425] 25 46 pmol, 6.0 equiv.), andHATU (3.5 mg, 9.2 pmol, 1.2 equiv.). The reaction mixture was stirred PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0426] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) at ambient temperature for 18 hours. The reaction mixture was filtered and purified by prep- HPLC and lyophilized to give Compound 135a (3 mg) as a white solid.

[0427] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.54 (s, 1H), 7.59 (br s, 1H), 7.57 (br d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.44 - 7.39 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H),

[0428] 5 7.31 - 7.22 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.17 - 4.06 (m, 2H), 3.96 (s, 3H), 3.90 (t, J = 6.6 Hz, 2H), 3.72 (br t, J = 4.5 Hz, 2H), 3.25 - 3.19 (m, 3H), 3.18 - 3.10 (m, 2H), 2.93 (br d, J = 6.0 Hz, 3H), 2.75 (t, J = 6.8 Hz, 2H), 2.71 - 2.57 (m, 2H), 2.46 - 2.37 (m, 1H), 2.24 - 2.14 (m, 1H), 2.02 - 1.93 (m, 2H), 1.85 - 1.69 (m, 8H), 1.59 - 1.48 (m, 5H), 1.44 (br d, J = 0.8 Hz, 2H), 1.38 - 1.19 (m, 4H), 1.01 - 0.80 (m, 5H)

[0429] LC-MS (ESI): m / z = 1047.6 [M+H]+

[0430] Example 10: Synthesis of Compound 137a

[0431] Compound 137a

[0432] Step 1: 6-bromo-4,5,7-trifluoro- 1 -methyl- 1 H-indazol-3-amine

[0433] 15 A mixture of 4-bromo-2,3,5,6-tetrafluorobenzonitrile (200 mg, 787 pmol, 1 equiw . methylhydrazinesulfate (227 mg, 1.57 mmol, 2 equiw . and potassium carbonate (326 mg, 2.36 mmol, 3 equiv.) was treated with DMA (8 mL) and heated at 90 °C for 24 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with water (900 mL) and brine (300 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give an off-white solid, which was purified by flash chromatography (heptanes to 30% ethyl acetate) to give 6-bromo-4,5,7-trifluoro-l-methyl-U / - indazol-3 -amine (164 mg) as a white solid.

[0434] LC-MS (ESI): m / z = 279.9 [M+H]+

[0435] 25 Step 2: 3-((6-bromo-4,5,7-trifluoro-l-methyl-lH-indazol-3-yl)amino)propanoic acid PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0436] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0437] To a solution of 6-bromo-4,5,7-trifluoro-l-methyl-l / 7-indazol-3-amine (200 mg, 714 pmol, 1 equiv. and acrylic acid (77.2 mg, 73.4 pL, 1.07 mmol, 1.5 equiv.) in HC1 (0.1 g, 2 mL, 4 mmol, 2 M, 6 equiv.) was added tetrabutylammonium bromide (23.0 mg, 22.2 pL, 71.4 pmol, 0.1 equiv). The reaction was stirred at 100 °C for 16 hours. The reaction mixture was diluted

[0438] 5 with water and saturated aqueous sodium bicarbonate (to pH ~8) and then acidified with AcOH (to pH ~5), resulting in a voluminous precipitate that was collected by filtration and washed with water to afford 3-((6-bromo-4,5,7-trifluoro-l-methyl-l / 7-indazol-3-yl)amino)propanoic acid (249 mg) as a peach-colored solid.

[0439] LC-MS (ESI): m / z = 352.0 [M+H]+

[0440] 10

[0441] Step 3: 1 -(6-bromo-4, 5, 7-trifluoro-l -methyl- 1 J / -indazol-3-yl)dihydropyrimidine- 2,4( l / / .3 / / )-dione

[0442] To a suspension of 3-((6-bromo-4,5,7-trifhioro-l-methyl-l / 7-indazol-3- yl)amino)propanoic acid (0.245 g, 696 pmol, 1 equiv.) in AcOH (2.5 mL) was added sodium cyanate (94.2 mg, 49.9 pL, 96% wt, 1.39 mmol, 2 equiv), and the mixture was stirred at 60 °C for 22 hours, becoming a homogeneous solution after 15 minutes. After 22 hours, an aqueous solution of HC1 (0.1 g, 2 mL, 4 mmol, 2 M, 6 equiv.) was added, and the reaction was stirred at 60 °C for an additional 2 hours. The reaction was concentrated by rotary evaporation, dissolved / suspended in acetonitrile (10 mL), treated with p-TsOH (265 mg), and stirred at 80

[0443] 20 °C for 12 hours. The reaction was concentrated by rotary evaporation, dissolved in DCM, washed with saturated aqueous sodium bicarbonate and brine, and concentrated to give 177 mg of a peach-colored solid, which was purified by prep-HPLC and lyophilized to give l-(6- bromo-4, 5, 7-trifluoro-l -methyl- l / 7-indazol-3-yl)dihydropyrimidine-2, 4(1 / 7, 3Z7)-di one (63 mg) as a white solid.

[0444] LC-MS (ESI): m / z = 377.0 [M+H]+

[0445] Step 4: tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)-4,5,7-trifluoro-l- methyl-l / / -indazol-6-yl)-3.6-dihydropyridine-l(2 / / )-carboxylate

[0446] To a solution of l-(6-bromo-4,5,7-trifluoro-l-methyl-l / 7-indazol-3-

[0447] 30 yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione (60 mg, 0.16 mmol, 1 equiv.) in 1,4-dioxane (3.0 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine- l(2 / 7)-carboxylate (54 mg, 0.18 mmol, 1.1 equiv.), potassium carbonate (66 mg, 0.48 mmol, .(i equiv. ), Pd(dppf)C12 (12 mg, 16 pmol, 0.1 equiv.), and water (0.6 mL). The reaction mixture was heated to 80 °C for 15 hours. The reaction was cooled to room temperature, filtered through PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0448] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) a 0.45 pm syringe filter, diluted with ethyl acetate, washed with water, 5% aqueous citric acid, water, saturated aqueous sodium bicarbonate, and brine, then dried over magnesium sulfate, filtered, and concentrated to give a brown solid. The solid was purified by flash chromatography (heptanes to ethyl acetate) to give tert-butyl 4-(3-(2,4-

[0449] 5 dioxotetrahydropyrimidin-l(2rt)-yl)-4,5,7-trifluoro-l-methyl-lZ / -indazol-6-yl)-3,6- dihydropyridine-l(2J7)-carboxylate (47 mg) as a white solid.

[0450] LC-MS (ESI): m / z = 480.3 [M+H]+

[0451] Step 5: tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2ET)-yl)-4,5,7-trifluoro-l-

[0452] 10 iuethyl-l / / -indazol-6-yl)piperidine-l -carboxylate

[0453] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2rt)-yl)-4,5,7-trifluoro- 1 -methyl- l / / -indazol-6-yl)-3,6-dihydropyri dine- l(2rt)-carboxylate (45 mg, 94 pmol, 1 equiv. and palladium on carbon (10 mg, 10% wt, 9.4 pmol, 0.1 equiv. was stirred vigorously in 1 : 1 MeOH-THF (100 mL) under H2. The mixture was stirred for 3 hours. The reaction was diluted with DCM, filtered through celite, concentrated, and dried under high vacuum to give tert- butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)-4,5,7-trifluoro-l-methyl-l / / -indazol-6- yl)piperidine-l -carboxylate (46 mg) as a white solid, which was carried on without further purification.

[0454] LC-MS (ESI): m / z = 481.3 [M-H]-

[0455] 20

[0456] Step 6: l-(4,5,7-trifluoro-l-methyl-6-(piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. trifluoroacetic acid

[0457] A solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin- l (27 / )-yl)-4,5,7-trifluoro- 1 -methyl- l / / -indazol-6-yl)piperidine-l -carboxylate (46 mg, 96 pmol, 1 equiv. in DCM (2 mL) was treated with trifluoroacetic acid (3 g, 2 mL, 0.03 mol, 300 equiv.} and HC1 (7.0 mg, 48 pL, 0.19 mmol, 4 M, 2 equiv.) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with DCM, concentrated again, and dried under high vacuum to give l-(4,5,7-trifluoro-l-methyl-6-(piperidin-4-yl)-17 / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3rt)-dione (64 mg, TFA salt) as a colorless glass-like oil, which was carried on without

[0458] 30 further purification.

[0459] LC-MS (ESI): m / z = 382.3 [M+H]+

[0460] Step 7: tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4,5,7- trifluoro-l-methyl-lH-indazol-6-yl)piperidin-l-yl)methyl)piperidine-l-carboxylate PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0461] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0462] To a solution of l-(4,5,7-trifluoro-l-methyl-6-(piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione, trifluoroacetic acid (47 mg, 1 equiv., 95 pmol) in di chloroethane (1.00 mL) was added tert-butyl 4-formylpiperidine-l -carboxylate (31 mg, 1.5 equiv., 0.14 mmol). The reaction mixture was stirred at 70 °C for 30 min. The reaction was

[0463] 5 cooled to ambient temperature. Sodium triacetoxyborohydride (31 mg, 1.5 equiv., 0.14 mmol) was added, and the reaction was stirred at 70 °C for an additional 2 hours. The reaction was cooled to ambient temperature and was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated sodium bicarbonate, water, and brine. The organic layer was then dried over magnesium sulfate, filtered, and concentrated to

[0464] 10 give a colorless semi-solid. The material was dissolved in DMSO and purified by prep-HPLC to give tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4,5,7-trifluoro-l-methyl- lH-indazol-6-yl)piperidin-l-yl)methyl)piperidine-l-carboxylate (45 mg) as a white solid.

[0465] LC-MS (ESI): m / z = 579.4 [M+H]+

[0466] Step 8: l-(4,5,7-trifluoro-l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-lH- indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione, trifluoroacetic acid

[0467] To a solution of tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-4,5,7- trifluoro-l-methyl-lH-indazol-6-yl)piperidin-l-yl)methyl)piperidine-l-carboxylate (45 mg, 1 equiv., 78 pmol) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 0.500 mL, 83

[0468] 20 equiv., 6.49 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes. Volatile organics were removed under reduced pressure to give l-(4,5,7-trifluoro-l-methyl-6- (l-(piperidin-4-ylmethyl)piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- dione, trifluoroacetic acid (43 mg) as a white solid.

[0469] LC-MS (ESI): m / z = 479.3 [M+H]+

[0470] Step 9: Compound 137a

[0471] To a solution of INT-5 (5.0 mg, 7.7 pmol, 1 equiv.) in DMF (500 pL) was added 1- (4,5,7-trifluoro-l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-lrt-indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3rt)-dione, trifluoroacetic acid (6.8 mg, 12 pmol, 1.5 equiv),

[0472] 30 DIEA (6.0 mg, 8.0 pL, 46 pmol, 6.0 equiv.), and HATU (3.5 mg, 9.2 pmol, 1.2 equiv.). The reaction mixture was stirred at ambient temperature for 90 minutes, then filtered, purified by prep-HPLC, and lyophilized to give Compound 137a (3 mg) as a white solid.

[0473] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.68 (s, 1H), 7.60 (br s, 1H), 7.57 (br d, J = 8.8 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.31 - 7.23 (m, 2H), 7.11 (br s, 1H), 7.08 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0474] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0475] (d, J = 9.5 Hz, 1H), 4.40 - 4.31 (m, 1H), 4.18 - 4.05 (m, 5H), 3.92 - 3.79 (m, 3H), 3.72 (br d, J = 4.3 Hz, 2H), 3.27 - 3.20 (m, 2H), 3.19 - 3.09 (m, 2H), 3.07 - 2.88 (m, 4H), 2.76 (t, J = 6.8 Hz, 2H), 2.48 - 2.38 (m, 2H), 2.25 - 2.11 (m, 3H), 2.11 - 1.92 (m, 4H), 1.83 - 1.64 (m, 6H), 1.55 (br d, J = 11.8 Hz, 2H), 1.37 - 1.18 (m, 3H), 1.04 - 0.79 (m, 7H)

[0476] 5 LC-MS (ESI): m / z = 1075.7 [M+H]+

[0477] Example 11: Synthesis of Compound 143a

[0478] Compound 143a

[0479] Step 1: 4-(tert-butylamino)-2,3,5-trifluorobenzonitrile

[0480] 10 To a solution of 2,3,4,5-tetrafluorobenzonitrile (90 g, 514.04 mmol, 1 equiv. in DMF (900 mL) was added 2-methylpropan-2-amine (112.79 g, 1.54 mol, 162.05 mL, 3 equiv.) under a N2 atmosphere. The suspension was degassed and purged with N2 three times. The mixture was stirred under N2 (15 psi) at 40 °C for 2 hours. The reaction mixture was quenched by the addition of water (1000 mL) and extracted with ethyl acetate (2000 mL). The combined organic layers were washed with aqueous sodium chloride (2000 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-( / c77-butylamino)-2,3,5- trifluorobenzonitrile (118 g, crude) as a white solid.

[0481] LC-MS (ESI): m / z = 229.1 [M+H]+

[0482] ’H NMR (400 MHz, CDCh-tZ) d = 7.03 (ddd, J= 2.0, 5.6, 10.8 Hz, 1H), 4.42 - 3.99

[0483] 20 (m, 1H), 1.40 (s, 9H)

[0484] Step 2: 4-amino-2,3,5-trifluoro-benzonitrile

[0485] A solution of 4-( / c77-butylarnino)-2,3,5-trifluorobenzonitrile (98 g, 429.42 mmol, 1 equiv.) in MeOH (2000 mL) and HC1 (200 mL) was stirred at 70 °C for 2 hours. The reaction PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0486] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) mixture was concentrated under reduced pressure to give 4-amino-2,3,5-trifluoro-benzonitrile (74 g, crude) as a white solid.

[0487] Step 3: 4-bromo-2,3,5-trifluoro-benzonitrile

[0488] 5 To a solution of 4-amino-2,3,5-trifluoro-benzonitrile (61.7 g, 358.50 mmol, 1 equiv. in acetonitrile (650 mL) was added dropwise CuBr2 (120.11 g, 537.75 mmol, 25.18 mL, 1.5 equiv.) and tert-butyl nitrite (55.45 g, 537.75 mmol, 63.96 mL, 1.5 equiv.) at 0 °C. After the addition, the mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched by the addition of water (500 mL) and extracted with ethyl acetate (1400 mL). The combined

[0489] 10 organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 4-bromo-2,3,5-trifluoro-benzonitrile (64 g) as a white solid.

[0490] Step 4: 6-bromo-5,7-difluoro-l-methyl-indazol-3-amine

[0491] To a solution of 4-bromo-2,3,5-trifluoro-benzonitrile (64 g, 271.20 mmol, 1 equiv.) in DMA (640 mL) was added potassium carbonate (56.22 g, 406.80 mmol, 1.5 equiv.) and methylhydrazine (93.71 g, 813.60 mmol, 107.10 mL, 40% purity, 3 equiv.). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched by the addition of water

[0492] 20 (1000 mL) and filtered to obtain 6-bromo-5,7-difluoro-l-methyl-indazol-3-amine (45.8 g, crude) as an off-white solid.

[0493] LC-MS (ESI): m / z = 263.9 [M+H]+

[0494] Step 5: 6-bromo-5,7-difluoro-3-iodo-l-methyl-indazole

[0495] To a solution of 6-bromo-5,7-difluoro-l-methyl-indazol-3-amine (64 g, 244.22 mmol, 1 equiv.) in 6 M sulfuric acid (407.04 mL, 10 equiv.) was added a solution of sodium nitrite (25.28 g, 366.34 mmol, 1.5 equiv.) in water (200 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. Acetonitrile (500 mL) was then added, followed by a solution of KI (121.63 g, 732.67 mmol, 3 equiv.) in water (200 mL). The resulting mixture was stirred at 25

[0496] 30 °C for 1 hour. The reaction mixture was quenched by the addition of sodium sulfite (100 mL) and extracted with ethyl acetate (150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was triturated with methyl tert-butyl ethe / cyclohexane (1 : 1) (250 mL) to obtain 6-bromo-5,7- difluoro-3-iodo-l-methyl-indazole (60 g) as a brown solid. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0497] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0498] ’H NMR (400 MHz, DMSO-t / 6) 6 = 7.27 (dd, J= 1.2, 8.0 Hz, 1H), 4.16 (d, J= 1.2 Hz, 3H)

[0499] Step 6: l-(6-bromo-5,7-difluoro-l-methyl-l / / -indazol-3-yl)-3-(4-

[0500] 5 inethoxybenzyl)dihydropyrimidine-2.4( 1 / / .3 / / )-dione

[0501] A mixture of 3 -[(4-methoxyphenyl)methyl]hexahydropyrimidine-2, 4-dione (2.83 g, 12.09 mmol, 1.1 equiw). 6-bromo-5,7-difluoro-3-iodo-l-methyl-indazole (4.1 g, 10.99 mmol, 1 eqniv.\ Cui (418.76 mg, 2.20 mmol, 0.2 equiv.\ cesium carbonate (10.75 g, 32.98 mmol, 3 equiv.\ and (lA,2A)-Al,A2-dimethylcyclohexane-l,2-diamine (312.76 mg, 2.20 mmol, 0.2

[0502] 10 equiv.) in dioxane (42 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C for 12 hours under a N2 atmosphere. The reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (90 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain l-(6-bromo-5,7-difhioro-l-methyl-lrt-indazol-3-yl)-3-(4- methoxybenzyl)dihydropyrimidine-2,4(U / ,3J7)-dione (3.5 g) as a white solid.

[0503] LC-MS (ESI): m / z = 481.0 [M+H]+

[0504] ’H NMR (400 MHz, DMSO-t / 6) d = 7.45 (dd, J= 0.8, 8.4 Hz, 1H), 7.24 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 4.85 (s, 2H), 4.13 - 4.07 (m, 3H), 3.96 - 3.88 (m, 2H), 3.72 (s,

[0505] 20 3H), 2.96 (t, J= 6.8 Hz, 2H)

[0506] Step 7: tert-butyl 4-[5,7-difluoro-3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin-l-yl]-l -met hylindazol-6-yl] -3, 6-dihydro-2Z / - pyridine- 1 -carboxylate

[0507] A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2Z7-pyridine- 1 -carboxylate (2.32 g, 7.51 mmol, \.2 equiv.\ 1 -(6-bromo-5,7-difluoro-l -methyl - U / -indazol-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione (3 g, 6.26 mmol, 1 equiw). cesium carbonate (6.12 g, 18.78 mmol, 3 equiv.), and Pd(dppf)C12 (458.01 mg, 625.95 pmol, 0.1 equiv.) in dioxane (30 mL) and water (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 2 hours under a N2 atmosphere. The reaction

[0508] 30 mixture was quenched by the addition of water (40 mL) and extracted with ethyl acetate (60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain tert-butyl 4-[5,7-difluoro-3-[3-[(4- methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-l-yl]-l-methylindazol-6-yl]-3,6- PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0509] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) dihydro-2 / 7-pyridine-l -carboxylate (1.8 g) as a white solid.

[0510] LC-MS (ESI): m / z = 582.2 [M+H]+

[0511] Step 8: tert-butyl 4-(5,7-difluoro-3-(3-(4-methoxybenzyl)-2,4-

[0512] 5 dioxotetrahydropyrimidin-1 (2 / / )-yl)-l -methyl- l / / -indazol-6-yl)piperidine-l -carboxylate

[0513] To a solution of tert-butyl 4-[5,7-difluoro-3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo- hexahydropyrimidin- 1 -y 1 ] - 1 -methylindazol-6-yl]-3 ,6-dihydro-2J / -pyridine- 1 -carboxylate (1.8 g, 3.09 mmol, 1 equiv.} in CF3CH2OH (20 mL) was added Pd on carbon (988.07 mg, 928.46 pmol, 10 wt%, 0.3 equiv. and Pd(OH)2 on carbon (651.94 mg, 928.46 pmol, 20 wt%, 0.3

[0514] 10 equiv. under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-(5,7-difluoro-3-(3-(4- methoxybenzyl)-2,4-dioxotetrahydropyrimidin- 1 (27 / )-yl )- 1 -methyl- 1 JT-indazol-6- yl)piperidine-l -carboxylate (1.5 g, crude) as a white solid.

[0515] LC-MS (ESI): m / z: 528.1 [M-54]+

[0516] Step 9: l-(5,7-difluoro-l-methyl-6-(piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione

[0517] A solution of tert-butyl 4-(5,7-difluoro-3-(3-(4-methoxybenzyl)-2,4-

[0518] 20 dioxotetrahydropyrimi din- l (27 / )-yl)- l -methyl- IT / -indazol-6-yl)piperi dine- 1 -carboxylate (0.7 g, 1.20 mmol, 1 equiv.} in trifluoroacetic acid (10 mL) and triflic acid (1 mL) was stirred at 70 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to obtain l-(5,7-difhioro-l-methyl-6- (piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine-2,4(U / ,3J7)-dione (0.4 g) as a white solid.

[0519] LC-MS (ESI): m / z = 363.9 [M+H]+

[0520] ’H NMR (400 MHz, DMSO-t / 6) d = 10.76 - 10.31 (m, 1H), 8.35 (s, 1H), 7.31 (d, J = 10.8 Hz, 1H), 4.10 (s, 3H), 3.89 (t, J= 6.8 Hz, 2H), 3.33 (d, J= 8.0 Hz, 3H), 2.96 (t, J= 11.6 Hz, 2H), 2.75 (t, J= 6.8 Hz, 2H), 2.23 - 2.06 (m, 2H), 1.83 (d, J= 12.8 Hz, 2H)

[0521] 30 Step 10: tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2ET)-yl)-5,7-difluoro- 1 -methyl- l / / -indazol-6-yl)piperidin-l-yl)-7-azaspiro|3.5|nonane-7-carboxylate

[0522] To a solution of l-(5,7-difhioro-l-methyl-6-(piperidin-4-yl)-l / / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione (40 mg, 68 pmol, 1 equiv.} in methanol (2.0 mL) was added tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (49 mg, 0.20 mmol, 3.0 equiv.} PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0523] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) and sodium acetate (33 mg, 0.41 mmol, 6.0 equiv.). The reaction mixture was stirred at 40 °C for 45 minutes. NaBH(OAc)3 (8.5 mg, 0.14 mmol, 2.0 equiv.) was then added, and the resulting mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure to give a yellow oil, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert¬

[0524] 5 butyl 2-(4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2J7)-yl)-5,7-difluoro- 1 -methyl- 1 JT-indazol-6- yl)piperidin-l-yl)-7-azaspiro[3.5]nonane-7-carboxylate (28 mg) as a white solid.

[0525] LC-MS (ESI): m / z = 587.4 [M+H]+

[0526] Step 11: l-(6-(l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-5,7-difluoro-l-methyl-

[0527] 10 l / / -indazol-3-yl)dihydropyrimidine-2.4( l / / .3 / / )-dione. trifluoroacetic acid

[0528] To a solution of tert-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)-5,7- difluoro- 1 -methyl- 1 J / -indazol-6-yl)piperidin- 1 -yl)-7-azaspiro[3.5]nonane-7-carboxylate (28 mg, 48 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 142 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give l-(6-(l-(7-azaspiro[3.5]nonan- 2-yl)piperidin-4-yl)-5,7-difluoro-l-methyl-lJ / -indazol-3-yl)dihydropyrimidine-2,4(lJ / ,3J7)- dione, trifluoroacetic acid (31 mg) as a white solid.

[0529] LC-MS (ESI): m / z = 487.3 [M+H]+

[0530] 20 Step 12: Compound 143a

[0531] To a solution of INT-5 (5.0 mg, 7.7 pmol, 1 equiv.) in DMF (500 pL) was added l-(6- (l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-5,7-difluoro-l-methyl-U / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione, trifluoroacetic acid (8.2 mg, 12 pmol, 1.5 equiv), DIEA (6.0 mg, 46 pmol, 8.0 pL, 6.0 equiv.), and HATU (3.5 mg, 9.2 pmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was filtered and purified by prep-HPLC to obtain Compound 143a (2.9 mg) as a white solid.

[0532] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.59 (s, 1H), 7.64 - 7.53 (m, 2H), 7.45 - 7.38 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.31 - 7.23 (m, 3H), 7.11 (br s, 1H), 7.07 (d, J = 9.6 Hz, 1H), 4.93 (br s, 1H), 4.18 - 4.05 (m, 5H), 3.89 (t, J = 6.7 Hz, 2H), 3.72 (br d, J = 4.0 Hz, 2H), 3.26 - 3.20

[0533] 30 (m, 2H), 3.19 - 3.09 (m, 2H), 3.06 - 2.97 (m, 1H), 2.96 - 2.89 (m, 2H), 2.81 - 2.63 (m, 3H), 2.43 (br d, J = 3.4 Hz, 1H), 2.19 (br t, J = 10.8 Hz, 1H), 2.11 - 1.92 (m, 4H), 1.83 - 1.64 (m, 6H), 1.62 - 1.18 (m, 10H), 1.02 - 0.77 (m, 5H)

[0534] LC-MS (ESI): m / z = 1083.6 [M+H]+ PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0535] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0536] Example 12: Synthesis of Compound 131a

[0537] Compound 131a

[0538] Step 1: tert-butyl 4-(3-(2.4-dioxotetr:ihydropyrimidin-l (2 / / )-yl)-l -methyl- 1 / / - indazol-6-yl)-[l,4'-bipiperidine]-l'-carboxylate

[0539] 5 To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(17 / ,3J7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv.) in DCE (2.0 mL) was added tert-butyl 4-oxopiperidine-l -carboxylate (25 mg, 0.12 mmol, 1.1 equiv.} and acetic acid (3.4 mg, 3.2 pL, 57 pmol, 0.5 equiv.}. The reaction mixture was stirred at 70 °C for 30 minutes. Sodium triacetoxyborohydride (36 mg, 0.17 mmol, 1.5 equiv.} was then added, and the resulting mixture was stirred for 2 hours. The reaction was cooled to ambient temperature and stirred overnight. The volatile organics were removed under reduced pressure to give a yellow solid, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl 4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (27 / )-yl )- 1 -methyl- 1 J / -indazol-6-yl)-[ 1 ,4'-bipiperidine]- l'-carboxylate (9 mg) as a white solid.

[0540] 15 LC-MS (ESI): m / z = 511.4 [M+H]+

[0541] Step 2: l-(6-(|1.4'-bipiperidin|-4-yl)-l-niethyl-l / / -ind:izol-3- yl)dihydropyriniidine-2.4( l / / .3 / / )-dione. 2trifluoroacetic acid

[0542] To a solution of tert-butyl 4-(3 -(2, 4-dioxotetrahydropyrimidin-l(2J7)-yl)-l -methyl- \H- indazol-6-yl)-[l,4'-bipiperidine]-l'-carboxylate (9 mg, 0.02 mmol, 1 equiv.} in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 400 equiv.}. The reaction mixture was stirred at ambient temperature for 1 hour. The volatile organics were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain l-(6-([l,4'- bipiperidin]-4-yl)-l -methyl- lJ / -indazol-3-yl)dihydropyrimidine-2, 4(1 H,3H}-di one,

[0543] 25 2trifluoroacetic acid (11 mg) as a light yellow solid.

[0544] LC-MS (ESI): m / z = 411.4 [M+H]+ PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0545] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0546] Step 3: Compound 131a

[0547] To a solution of INT-2 (5.0 mg, 8.5 pmol, 1 equiv.} in DMF (0.500 mL) was added 1- (6-([l, 4'-bipiperidin]-4-yl)-l-methyl-U / -indazol-3-yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-di one,

[0548] 5 2Trifluoroacetic acid (8.2 mg, 13 pmol, 1.5 equiv.}, DIEA (6.6 mg, 51 pmol, 8.9 pL, 6 equiv.}, and HATU (3.9 mg, 10 pmol, 1.2 equiv. . The reaction mixture was stirred at ambient temperature for 18 hours, then filtered and purified by prep-HPLC to obtain Compound 131a (3 mg) as a white solid.

[0549] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.53 (s, 1H), 7.60 (br d, J = 8.5 Hz, 2H), 7.53 (d,

[0550] 10 J = 8.5 Hz, 1H), 7.46 - 7.38 (m, 3H), 7.33 (t, J = 7.6 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.5 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.48 - 4.33 (m, 1H), 3.95 (s, 3H), 3.92 - 3.85 (m, 5H), 3.27 - 3.19 (m, 3H), 3.18 - 3.09 (m, 2H), 2.96 (br d, J = 10.0 Hz, 3H), 2.74 (t, J = 6.6 Hz, 2H), 2.65 - 2.55 (m, 1H), 2.47 - 2.40 (m, 1H), 2.27 (br t, J = 10.9 Hz, 2H), 2.19 (br t, J = 10.8 Hz, 1H), 1.86 - 1.64 (m, 8H), 1.62 - 1.50 (m, 2H), 1.40 - 1.14 (m, 4H), 1.02 - 0.80 (m, 5H)

[0551] LC-MS (ESI): m / z = 977.6 [M+H]+

[0552] Example 13: Synthesis of Compound 127a

[0553] 20 Step 1: tert-butyl 3-((4-(3-(2.4-dioxotetrahydropyriniidin-l(2 / / )-yl)-l-niethyl-l / / - indazol-6-yl)piperidin-l-yl)methyl)azetidine-l-carboxylate

[0554] To a solution of l-(l-methyl-6-(piperidin-4-yl)-l / 7-indazol-3-yl)dihydropyrimidine- 2,4(l / 7,3 / 7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv. in tetrahydrofuran (2.0 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0555] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) mL) and DMF (0.50 mL) was added tert-butyl 3 -formylazetidine- 1 -carboxylate (23 mg, 0.12 mmol, 1.1 equiv. and potassium acetate (56 mg, 0.57 mmol, 5 equiv.). The reaction mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol, 2 equiv.) was then added, and stirring continued for 18 hours. Volatile organics were

[0556] 5 removed under reduced pressure to give a white solid, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin- l (27 / )- yl)-l -methyl- U / -indazol-6-yl)piperi din- l-yl)methyl)azeti dine- 1 -carboxylate (50 mg) as a white solid.

[0557] LC-MS (ESI): m / z = 497.4 [M+H]+

[0558] 10

[0559] Step 2: 1 -(6-( 1 -(azet id in-3-y 1 ni el Iiy 1 )piperid in-4-y 1 )- 1 -in et hy 1- 1 / / -indazol-3- yl)dihydropyriinidine-2.4( l / / .3 / / )-dione. trifluoroacetic acid

[0560] To a solution of tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin- l (27 / )-yl)- l -methyl- U / -indazol-6-yl)piperidin-l-yl)methyl)azetidine-l-carboxylate (50 mg, 0.10 mmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 64 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain 1 -(6- (l-(azeti din-3 -ylmethyl)piperidin-4-yl)-l -methyl- U / -indazol-3 -yl)dihy dropyrimidine- 2,4(U / ,3J7)-dione, trifluoroacetic acid (51 mg) as a white solid.

[0561] 20 LC-MS (ESI): m / z = 397.4. [M+H]+

[0562] Step 3: Compound 127a

[0563] To a solution of INT-2 (5.0 mg, 8.5 pmol, 1 equiv.) in DMF (0.500 mL) was added 1- (6-(l-(azeti din-3 -ylmethyl)piperidin-4-yl)-l -methyl- U / -indazol-3 -yl)dihy dropyrimidine- 2,4(U / ,3J7)-dione, trifluoroacetic acid (6.5 mg, 13 pmol, 1.5 equiv.), DIEA (6.6 mg, 51 pmol, 8.9 pL, 6 equiv.), and HATU (3.9 mg, 10 pmol, 1.2 equiv.). The reaction mixture was stirred at ambient temperature for 18 hours, then filtered and purified by prep-HPLC to obtain Compound 127a (3 mg) as a white solid.

[0564] ’H NMR (400 MHz, DMSO-t / ,) 8 = 10.54 (s, 1H), 7.65 - 7.57 (m, 2H), 7.54 (d, J = 8.5

[0565] 30 Hz, 1H), 7.46 - 7.38 (m, 3H), 7.36 - 7.23 (m, 4H), 7.11 (br s, 1H), 7.07 (d, J = 9.8 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.17 (br t, J = 8.3 Hz, 1H), 3.96 (s, 3H), 3.93 - 3.82 (m, 5H), 3.73 (br dd, J = 5.9, 7.6 Hz, 1H), 3.43 (br dd, J = 5.5, 9.5 Hz, 2H), 3.27 - 3.19 (m, 3H), 3.18 - 3.08 (m, 2H), 2.99 - 2.87 (m, 2H), 2.83 - 2.70 (m, 3H), 2.66 - 2.56 (m, 1H), 2.22 - 2.11 (m, 1H), 2.10 - 1.98 (m, 3H), 1.82 - 1.66 (m, 5H), 1.63 - 1.50 (m, 2H), 1.30 - 1.14 (m, 2H), 0.99 - 0.73 (m, 5H) PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0566] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO)

[0567] LC-MS (ESI): m / z = 963.6 [M+H]+

[0568] Example 14: Synthesis of Compound 128a

[0569] Compound 128a

[0570] 5 Step 1: tert-butyl 4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2ET)-yl)-l-methyl- l / / -indazol-6-yl)piperidin-l-yl)ethyl)piperidine-l -carboxylate

[0571] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(17 / ,3J7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv.) in tetrahydrofuran (2.0 mL) and DMF (0.50 mL) was added tert-butyl 4-(2-oxoethyl)piperidine-l -carboxylate (28 mg, 0.12 mmol, 1.1 equiv.) and potassium acetate (56 mg, 0.57 mmol, 5 equiv). The reaction mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol, 2 equiv.) was then added, and stirring continued for 18 hours. Volatile organics were removed under reduced pressure to give a white solid, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl 4-(2-(4-(3-(2,4-

[0572] 15 dioxotetrahydropyrimi din- l(2J7)-yl)-l -methyl- 177-indazol-6-yl)piperi din- 1- yl)ethyl)piperidine-l -carboxylate (43 mg) as a white solid.

[0573] LC-MS (ESI): m / z = 539.4[M+H]+

[0574] Step 2: 1 -( 1 -nielhyl-6-( 1 -(2-( piperidin-4-yI )et Iiyl )piperidin-4-yI )- 1 / / -indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. 2Trifluoroacetic acid

[0575] To a solution of tert-butyl 4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)-l- m ethyl- 1 J / -indazol-6-yl)piperi din- l-yl)ethyl)piperidine-l -carboxylate (43 mg, 80 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 81 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics

[0576] 25 were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0577] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) l -( l -methyl-6-( l -(2-(piperidin-4-yl)ethyl)piperidin-4-yl)- l / / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione, 2trifluoroacetic acid (50 mg) as a white solid.

[0578] LC-MS (ESI): m / z = 439.4 [M+H]+

[0579] 5 Step 3: Compound 128a

[0580] To a solution of INT-2 (5.0 mg, 8.5 pmol, 1 equiv) in DMF (0.500 mL) was added 1- (l-methyl-6-(l-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-17 / -indazol-3-yl)dihydropyrimidine- 2,4(17 / ,3J7)-dione, 2trifluoroacetic acid (8.5 mg, 13 pmol, 1.5 equiv), DIEA (6.6 mg, 51 pmol, 8.9 pL, 6 equiv.), and HATU (3.9 mg, 10 pmol, 1.2 equiv.). The reaction mixture was stirred at

[0581] 10 ambient temperature for 18 hours, then filtered and purified by prep-HPLC to obtain Compound 128a (3 mg) as a white solid.

[0582] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.54 (s, 1H), 7.59 (br dd, J = 1.1, 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 - 7.38 (m, 3H), 7.36 - 7.30 (m, 2H), 7.30 - 7.23 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.34 (br d, J = 12.8 Hz, 1H), 3.96 (s, 3H), 3.93 - 3.80 (m, 6H), 3.26 - 3.19 (m, 3H), 3.17 - 3.09 (m, 2H), 3.03 - 2.88 (m, 3H), 2.75 (t, J = 6.8 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.47 - 2.38 (m, 2H), 2.33 (br t, J = 7.1 Hz, 2H), 2.25 - 2.13 (m, 1H), 2.03 - 1.92 (m, 2H), 1.84 - 1.62 (m, 7H), 1.55 (br d, J = 12.8 Hz, 3H), 1.44 - 1.34 (m, 2H), 1.33 - 1.19 (m, 2H), 1.07 - 0.79 (m, 7H)

[0583] LC-MS (ESI): m / z = 1005.7 [M+H]+

[0584] 20

[0585] Example 15: Synthesis of Compound 146a

[0586] O

[0587] Compound 146a

[0588] Step 1: tert-butyl 7-(4-(3-(2.4-dioxotetr:ihydropyrimidin-l (2 / / )-yl)-l -methyl- 1 / / - indazol-6-yl)piperidin-l-yl)-2-azaspiro[3.5]nonane-2-carboxylate PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0589] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0590] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3rt)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv.) in tetrahydrofuran (2.0 mL) and DMF (0.50 mL) was added tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (30 mg, 0.12 mmol, 1.1 equiv.) and potassium acetate (56 mg, 0.57 mmol, 5 equiv.). The reaction

[0591] 5 mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol, 2 equiv.) was then added, and stirring continued for 18 hours. Volatile organics were removed under reduced pressure to give a white solid, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl 7-(4-(3-(2,4- dioxotetrahydropyrimi din- l(2rt)-yl)-l -methyl- lrt-indazol-6-yl)piperi din- 1 -yl)-2-

[0592] 10 azaspiro[3.5]nonane-2-carboxylate (18 mg) as a white solid.

[0593] LC-MS (ESI): m / z = 551.5 [M+H]+

[0594] Step 2: 1 -( 6-( 1 -(2-azas piro |3.5 ] nona n-7-y 1 )piperid in-4-y 1 )- 1 -in el hy 1- 1 / / -indazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. trifluoroacetic acid

[0595] To a solution of tert-butyl 7-(4-(3-(2,4-dioxotetrahydropyrimidin- l (27 / )-yl)- l -methyl- U / -indazol-6-yl)piperidin-l-yl)-2-azaspiro[3.5]nonane-2-carboxylate (18 mg, 33 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 200 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain

[0596] 20 l-(6-(l-(2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-l-methyl-U / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3rt)-dione, trifluoroacetic acid (22 mg) as a white solid.

[0597] LC-MS (ESI): m / z = 451.2 [M+H]+

[0598] Step 3: Compound 146a

[0599] To a solution of INT-2 (5.0 mg, 8.0 pmol, 1 equiv.) in DMF (500 pL) was added l-(6- (l-(2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-l-methyl-U / -indazol-3-yl)dihydropyrimidine- 2,4(lZ7,3rt)-dione, trifluoroacetic acid (6.8 mg, 12 pmol, 1.5 equiv.), DIEA (6.2 mg, 48 pmol, 8.4 pL, 6.0 equiv.), and HATU (3.7 mg, 9.7 pmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 18 hours, then filtered and purified by prep-HPLC to obtain

[0600] 30 Compound 146a (3.8 mg) as a white solid.

[0601] ’H NMR (400 MHz, DMSO-t / ,) 8 = 10.54 (s, 1H), 7.65 - 7.56 (m, 2H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 - 7.38 (m, 3H), 7.33 (t, J = 7.5 Hz, 2H), 7.30 - 7.23 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.6 Hz, 1H), 7.02 (br d, J = 8.6 Hz, 1H), 3.96 (d, J = 1.1 Hz, 3H), 3.93 - 3.85 (m, 5H), 3.78 (s, 1H), 3.70 (s, 1H), 3.17 - 3.08 (m, 3H), 2.98 - 2.88 (m, 2H), 2.75 (t, J = 6.6 Hz, 2H), PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0602] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOI / OIWO)

[0603] 2.63 - 2.54 (m, 1H), 2.34 - 2.22 (m, 3H), 2.21 - 2.12 (m, 1H), 2.10 - 1.97 (m, 1H), 1.90 - 1.62 (m, 9H), 1.57 (br d, J = 7.6 Hz, 2H), 1.47 - 1.35 (m, 2H), 1.34 - 1.12 (m, 5H), 1.00 - 0.74 (m, 5H)

[0604] LC-MS (ESI): m / z = 1017.6 [M+H]+

[0605] 5

[0606] Example 16: Synthesis of Compound 147a

[0607] Compound 147a

[0608] Step 1: tert-butyl 6-(4-(3-(2.4-dioxotetrahydrop riniidin-l (2 / / )-yl)-l -methyl- 1 / / - indazol-6-yl)piperidin-l-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0609] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(17 / ,3J7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv.) in tetrahydrofuran (2.0 mL) andDMF (0.50 mL) was added tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (26 mg, 0.12 mmol, 1.1 equiv.) and potassium acetate (56 mg, 0.57 mmol, 5 equiv.). The reaction mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (48

[0610] 15 mg, 0.23 mmol, 2 equiv. ) was then added, and stirring continued for 18 hours. Volatile organics were removed under reduced pressure to give a white solid, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl 6-(4-(3-(2,4- dioxotetrahydropyrimi din- l(2J7)-yl)-l -methyl- 177-indazol-6-yl)piperi din- 1 -yl)-2- azaspiro[3.3]heptane-2-carboxylate (44 mg) as a white solid.

[0611] LC-MS (ESI): m / z = 523.4 [M+H]+

[0612] Step 2: l-(6-( l-(2-azaspiro|3.3|heptan-6-yl)piperidin-4-yl)-l -methyl- l / / -indazol- 3-yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. trifluoroacetic acid

[0613] To a solution of tert-butyl 6-(4-(3 -(2, 4-di oxotetrahydropyri midi n- l (27 / )-yl)- l -methyl -

[0614] 25 U / -indazol-6-yl)piperidin-l-yl)-2-azaspiro[3.3]heptane-2-carboxylate (44 mg, 84 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 77 PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0615] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO) equiv. The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain l-(6-(l-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-methyl-l / / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione, trifluoroacetic acid (48 mg) as a white solid.

[0616] 5 LC-MS (ESI): m / z = 423.3 [M+H]+

[0617] Step 3: Compound 147a

[0618] To a solution of INT-2 (5.0 mg, 8.0 pmol, 1 equiv) in DMF (500 pL) was added l-(6- (l-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-l-methyl-U / -indazol-3-yl)dihydropyrimidine-

[0619] 10 2,4(17 / ,3J7)-dione, trifluoroacetic acid (6.5 mg, 12 pmol, 1.5 equiv.), DIEA (6.2 mg, 48 pmol, 8.4 pL, 6.0 equiv.), and HATU (3.7 mg, 9.7 pmol, 1.2 equiv.). The reaction mixture was stirred at ambient temperature for 18 hours, then filtered and purified by prep-HPLC to obtain Compound 147a (5.5 mg) as a white solid.

[0620] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.47 (s, 1H), 7.55 (br s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.26 (t, J = 7.6 Hz, 2H), 7.23 - 7.16 (m, 2H), 7.04 (br s, 1H), 7.00 (d, J = 9.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.05 (s, 1H), 3.89 (s, 3H), 3.86 - 3.78 (m, 5H), 3.74 (s, 1H), 3.62 (s, 1H), 3.10 - 3.01 (m, 3H), 2.82 (br d, J = 9.5 Hz, 2H), 2.68 (t, J = 6.7 Hz, 2H), 2.59 - 2.47 (m, 2H), 2.25 - 2.15 (m, 2H), 2.09 (br t, J = 10.9 Hz, 1H), 1.98 - 1.81 (m, 3H), 1.80 - 1.55 (m, 8H), 1.54 - 1.42 (m, 2H), 1.24 - 1.05 (m, 3H), 0.93 - 0.64

[0621] 20 (m, 5H)

[0622] LC-MS (ESI): m / z = 989.6 [M+H]+

[0623] Example 17: Synthesis of Compound 161a

[0624] Compound 161a PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0625] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0626] Step 1: tert-butyl (7?)-3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / T)-yl)-l-methyl- l / / -indazol-6-yl)piperidin-l-yl)methyl)pyrrolidine-l -carboxylate

[0627] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3J7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv.) in tetrahydrofuran (2.0

[0628] 5 mL) and DMF (0.50 mL) was added tert-butyl (5)-3-formylpyrrolidine-l -carboxylate (25 mg, 0.12 mmol, 1.1 equiv.) and potassium acetate (56 mg, 0.57 mmol, 5 equiv). The reaction mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol, 2 equiv.) was then added, and stirring continued for 18 hours. Volatile organics were removed under reduced pressure to give a white solid, which was taken up in DMSO,

[0629] 10 filtered, and purified by prep-HPLC to obtain tert-butyl (A)-3-((4-(3-(2,4- dioxotetrahydropyrimi din- l(2J7)-yl)-l -methyl- U7-indazol-6-yl)piperi din- 1- yl)methyl)pyrrolidine-l -carboxylate (24 mg) as a white solid.

[0630] LC-MS (ESI): m / z = 511.4 [M+H]+

[0631] Step 2: (S)-l-( 1 -niethyl-6-( l-(pyrrolidiii-3-ylniethyl)piperidiii-4-yl)-l / / -iiidazol-3- yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. trifluoroacetic acid

[0632] To a solution of tert-butyl (A>)-3-((4-(3-(2,4-dioxotetrahydropyrimidin- l (27 / )-yl)- l - methyl-U / -indazol-6-yl)piperidin-l-yl)methyl)pyrrolidine-l-carboxylate (23 mg, 45 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 142

[0633] 20 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain (5)- 1 -(1 -methyl-6-( 1 -(pyrrolidin-3 -ylmethyl)piperidin-4-yl)- 1 JT-indazol-3 - yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione, trifluoroacetic acid (24 mg) as a white solid.

[0634] LC-MS (ESI): m / z = 411.4 [M+H]+

[0635] Step 3: Compound 161a

[0636] To a solution of INT-2 (5.0 mg, 8.5 pmol, 1 equiv.) in DMF (500 pL) was added (5)-l- (l-methyl-6-(l -(pyrrolidin-3 -ylmethyl)piperi din-4-yl)- l / Z-indazol-3 -yl)dihy dropyrimidine- 2,4(17 / ,3J7)-dione, trifluoroacetic acid (6.7 mg, 13 pmol, 1.5 equiv.), DIEA (6.6 mg, 51 pmol,

[0637] 30 8.9 pL, 6.0 equiv.), and HATU (3.9 mg, 10 pmol, 1.2 equiv). The reaction mixture was stirred at ambient temperature for 90 minutes, then filtered and purified by prep-HPLC to obtain Compound 161a (5.5 mg) as a white solid.

[0638] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.54 (d, J = 3.9 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.54 (dd, J = 3.8, 8.4 Hz, 1H), 7.45 (d, J = 5.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.33 (t, J = 7.5 Hz, PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0639] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0640] 2H), 7.30 - 7.22 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.6 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 3.93 - 3.85 (m, 5H), 3.62 - 3.48 (m, 2H), 3.25 - 3.08 (m, 6H), 3.03 (br t, J = 9.6 Hz, 1H), 2.99 - 2.88 (m, 2H), 2.75 (dt, J = 2.8, 6.6 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.41 - 2.13 (m, 4H), 2.11 - 1.94 (m, 2H), 1.93 - 1.84 (m, 1H), 1.77 (br s, 6H), 1.67 - 1.55 (m, 2H), 1.55 -

[0641] 5 1.43 (m, 1H), 1.36 - 1.17 (m, 2H), 1.00 - 0.75 (m, 5H)

[0642] LC-MS (ESI): m / z = 977.6 [M+H]+

[0643] Compound 161b

[0644] Step 1: tert-butyl (5)-3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2ET)-yl)-l-methyl- l / / -indazol-6-yl)piperidin-l-yl)methyl)pyrrolidine-l -carboxylate

[0645] To a solution of l-(l-methyl-6-(piperidin-4-yl)-U / -indazol-3-yl)dihydropyrimidine- 2,4(U / ,3J7)-dione, trifluoroacetic acid (50 mg, 0.11 mmol, 1 equiv. in tetrahydrofuran (2.0 mL) and DMF (0.50 mL) was added tert-butyl ( / ?)-3 -formyl pyrrol i di ne- l -carboxylate (25 mg,

[0646] 15 0.12 mmol, 1.1 equiv.) and potassium acetate (56 mg, 0.57 mmol, 5 equiv). The reaction mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol, 2 equiv.) was then added, and stirring continued for 18 hours. Volatile organics were removed under reduced pressure to give a white solid, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl (S)-3-((4-(3-(2,4- dioxotetrahydropyrimi din- l (27 / )-yl)- l -methyl- U7-indazol-6-yl)piperi din- 1- yl)methyl)pyrrolidine-l -carboxylate (17 mg) as a white solid.

[0647] LC-MS (ESI): m / z = 511.4 [M+H]+

[0648] Step 2: ( / ?)-!-( 1 -niethyl-6-( l-(pyrrolidiii-3-yliiietliyl)piperidin-4-yl)-l / / -indazol-3-

[0649] 25 yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. trifluoroacetic acid PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0650] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0651] To a solution of tert-butyl (5)-3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2J7)-yl)-l- methyl-U / -indazol-6-yl)piperidin-l-yl)methyl)pyrrolidine-l-carboxylate (16 mg, 31 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 210 equiv.). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics

[0652] 5 were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain (A)-l-(l-methyl-6-(l-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-U / -indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3J7)-dione, trifluoroacetic acid (17 mg) as a white solid.

[0653] LC-MS (ESI): m / z = 411.3 [M+H]+

[0654] Step 3: Compound 161b

[0655] To a solution of INT-2 (5.0 mg, 8.5 pmol, 1 equiv.) in DMF (500 pL) was added (R)-l- (l-methyl-6-(l-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-lZ7-indazol-3-yl)dihydropyrimidine- 2,4(17 / ,3J7)-dione, trifluoroacetic acid (6.7 mg, 13 pmol, 1.5 equiv. , DIEA (6.6 mg, 51 pmol, 8.9 pL, 6.0 equiv.), and HATU (3.9 mg, 10 pmol, 1.2 equiv). The reaction mixture was stirred

[0656] 15 at ambient temperature for 90 minutes, then filtered and purified by prep-HPLC to obtain Compound 161b (4.1 mg) as a white solid.

[0657] ’H NMR (400 MHz, DMSO-t / 6) 8 = 10.54 (d, J = 3.9 Hz, 1H), 7.64 - 7.57 (m, 2H),

[0658] 7.54 (dd, J = 3.8, 8.4 Hz, 1H), 7.45 (d, J = 5.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.30 - 7.22 (m, 2H), 7.11 (br s, 1H), 7.07 (d, J = 9.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.96 (s, 3H), 3.93 - 3.85 (m, 5H), 3.61 - 3.49 (m, 1H), 3.19 - 3.08 (m, 3H), 3.03 (br t, J = 9.6 Hz, 1H), 2.98 - 2.90 (m, 2H), 2.75 (dt, J = 2.8, 6.6 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.41 - 2.34 (m, 1H), 2.32 - 2.15 (m, 4H), 2.10 - 1.93 (m, 3H), 1.93 - 1.84 (m, 1H), 1.77 (br s, 6H), 1.67 -

[0659] 1.55 (m, 3H), 1.55 - 1.44 (m, 1H), 1.35 - 1.18 (m, 3H), 1.01 - 0.78 (m, 5H)

[0660] LC-MS (ESI): m / z = 977.6 [M+H]+

[0661] 25

[0662] PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0663] Docket No. TRLN-024-003W01 / 37998-02015 / WO (TBIO-OOl / OIWO)

[0664] Example 19: Synthesis of Compound 162a

[0665] Compound 162a

[0666] Step 1: tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / f)-yl)-5,7-difluoro- 1 -methyl- LH-indazol-6-yl)piperidin-l-yl)methyl)azetidine-l -carboxylate

[0667] 5 To a solution of l-(5,7-difluoro-l-methyl-6-(piperidin-4-yl)-l / 7-indazol-3- yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione (50 mg, 85 pmol, 1 equiv. in tetrahydrofuran (2.0 mL) and DMF (0.50 mL) was added tert-butyl 3 -formylazetidine- 1 -carboxylate (17 mg, 93 pmol, 1.1 equiv.) and potassium acetate (41 mg, 0.42 mmol, 5 equiv). The reaction mixture was stirred at ambient temperature for 45 minutes. Sodium triacetoxyborohydride (36 mg, 0.17 mmol, 2 equiv.) was then added, and stirring continued for 18 hours. Volatile organics were removed under reduced pressure to give a yellow oil, which was taken up in DMSO, filtered, and purified by prep-HPLC to obtain tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)- yl)-5,7-difluoro-l-methyl-l / 7-indazol-6-yl)piperidin-l-yl)methyl)azetidine-l-carboxylate (34 mg) as a white solid.

[0668] 15 LC-MS (ESI): m / z = 533.3 [M+H]+

[0669] Step 2: l-(6-(l-(azetidin-3-ylmethyl)piperidin-4-yl)-5,7-difluoro-l-methyl-lH- indazol-3-yl)dihydropyrimidine-2,4( l / / .3 / / )-dione. trifluoroacetic acid

[0670] To a solution of tert-butyl 3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2 / 7)-yl)-5,7- difluoro-l-m ethyl- l / 7-indazol-6-yl)piperi din- l-yl)methyl)azeti dine- 1 -carboxylate (34 mg, 64 pmol, 1 equiv.) in DCM (2.0 mL) was added trifluoroacetic acid (740 mg, 6.49 mmol, 0.500 mL, 100 equiv). The reaction mixture was stirred at ambient temperature for 1 hour. Volatile organics were removed under reduced pressure to give a colorless oil, which was lyophilized to obtain l-(6-(l-(azetidin-3-ylmethyl)piperidin-4-yl)-5,7-difluoro-l-methyl-l / 7-indazol-3-

[0671] 25 yl)dihydropyrimidine-2, 4(1 / 7, 3 / 7)-dione, trifluoroacetic acid (37 mg) as a white solid. PCT / US25 / 43376 25 August 2025 (25.08.2025)

[0672] Docket No. TRLN-02...

Claims

Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) WHAT IS CLAIMED IS:

1. A compound of Formula (AA): 5or a pharmaceutically acceptable salt thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; R2is selected from the group consisting of: H and methyl; 10 R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3alkyl optionally substituted with 1-3 F; X1is selected from the group consisting of: N, CH, and CR6; R7is C1-3 alkoxy optionally substituted with 1-3 Rc; 15 R6is H, or R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; R9is selected from the group consisting of: H and C(=O)OR10; 20 R10is selected from the group consisting of: (a) C1-6 alkyl optionally substituted with 1-3 Rc; (b) –(C0-2 alkylene)-phenyl optionally substituted with 1-3 Rd; L0is selected from the group consisting of: 25 (a) Cy; 854Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and (c) straight-chain C1-4alkylene optionally substituted with 1-3 Ra; Cy is selected from the group consisting of: phenylene, C3-10 cycloalkylene, and 4-10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; 5 L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), and - C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1; Ring A1 is selected from the group consisting of: C3-8 cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; 10 L2is selected from the group consisting of: a bond, O, C(=O), and a straight-chain C1-3 alkylene, wherein the straight-chain C1-3 alkylene is optionally substituted with 1-3 Ra; Ring A2 is a 4-12 membered heterocyclylene optionally substituted with 1-3 Ra; Ring C is selected from the group consisting of:, , 15, wherein cc represents the point of attachment to Ring A2; Y is N or CH; RY1is selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 F; and (b) –(C0-2 alkylene)-(C3-6 cycloalkyl); 20 Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; R11is H or C1-3 alkyl; each Rais independently selected from the group consisting of: halo, CN, OH, C1-325 alkoxy, and C1-3alkyl, wherein the C1-3alkyl is optionally substituted with 1-3 F; each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 3 alkoxy; 855Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, N(RN)2, and C1-3 alkyl optionally substituted with 1-3 Re; each Reis independently selected from the group consisting of: halo, CN, C1-3 alkoxy, OH, and N(RN)2; and 5 each RNis independently selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F.

2. A compound of Formula (AA): 10or a pharmaceutically acceptable salt thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; 15 R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F; X1is selected from the group consisting of: N, CH, and CR6; 20 R7is C1-3alkoxy optionally substituted with 1-3 Rc; R6is H, or R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 Ra; R8is selected from the group consisting of: H and halo; 25 R9is selected from the group consisting of: H and C(=O)OR10; 856Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) R10is selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) –(C0-2 alkylene)-phenyl optionally substituted with 1-3 Rd; 5 L0is selected from the group consisting of: (a) Cy; (b) –CH2-Cy-*, wherein * represents the point of attachment to L1; and (c) straight-chain C1-4alkylene optionally substituted with 1-3 Ra; Cy is selected from the group consisting of: phenylene, C3-10cycloalkylene, and 4-10 10 membered heterocyclene, each of which is optionally substituted with 1-3 Ra; L1is selected from the group consisting of: a bond, C(=O), CH2, CH(Ra), and - C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1; Ring A1 is selected from the group consisting of: C3-8 cycloalkylene and 4-12 15 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, O, C(=O), and a straight-chain C1-3alkylene, wherein the straight-chain C1-3alkylene is optionally substituted with 1-3 Ra; Ring A2 is a 4-12 membered heterocyclylene optionally substituted with 1-3 Ra; 20 Ring C is selected from the group consisting of:, wherein cc represents the point of attachment to Ring A2; Y is N or CH; RY1is selected from the group consisting of: (a) C1-3 alkyl optionally substituted with 1-3 F; and 25 (b) –(C0-2alkylene)-(C3-6cycloalkyl); 857Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Y1, Y2, and Y3are each independently selected from the group consisting of: CH and CRY2, wherein each RY2is an independently selected halo; R11is H or C1-3 alkyl; each Rais independently selected from the group consisting of: halo, CN, OH, C1-35 alkoxy, and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with 1-3 F; each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 3 alkoxy; each Rdis independently selected from the group consisting of: halo, CN, OH, C1-3alkoxy, N(RN)2, and C1-3 alkyl optionally substituted with 1-3 Re; 10 each Reis independently selected from the group consisting of: halo, CN, C1-3 alkoxy, OH, and N(RN)2; and each RNis independently selected from the group consisting of: H and C1-3 alkyl optionally substituted with 1-3 F.

3. The compound of claim 1 or 2, wherein Ring. 15 4. The compound of claim 1 or 2, wherein Ring.

5. The compound of any one of claims 1-4, wherein Y is N. 20 6. The compound of any one of claims 1-5, wherein RY1is C1-3 alkyl (e.g., methyl, ethyl, or isopropyl). 25 7. The compound of any one of claims 1-6, wherein RY1is methyl. 858Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 8. The compound of any one of claims 1-5, wherein RY1is C1-3alkyl substituted with 1-3 -F (e.g., -CH2CF3).

9. The compound of any one of claims 1-5, wherein RY1is C3-6cycloalkyl (e.g., 5 cyclopropyl).

10. The compound of any one of claims 1-9, wherein at least one of Y1, Y2, and Y3is CRY2. 10 11. The compound of any one of claims 1-10, wherein two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2.

12. The compound of any one of claims 1-11, wherein Y1and Y2are each CF; and Y3is CH. 15 13. The compound of any one of claims 1-11, wherein Y1, Y2, and Y3are each CF.

14. The compound of any one of claims 1-9, wherein Y1, Y2, and Y3are each CH. 20 15. The compound of any one of claims 1-10, wherein Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH.

16. The compound of any one of claims 1-15, wherein Ring A2 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. 25 17. The compound of any one of claims 1-16, wherein Ring A2 is selected from the group consisting of: piperidinylene, tetrahydropyridylene, piperazinylene, pyrrolidinylene, and azetidinylene, each of which is optionally substituted with 1-2 Ra. 30 18. The compound of any one of claims 1-17, wherein Ring A2 is selected from the group consisting859Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) , and, each of which is optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2.

19. The compound of any one of claims 1-18, wherein Ring5 optionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2.

20. The compound of any one of claims 1-19, wherein Ring A2 is, wherein bb represents the point of attachment to L2. 10 21. The compound of any one of claims 1-18, wherein Ring A2 is.

22. The compound of any one of claims 1-21, wherein L2is selected from the group consisting of: a bond, CH2, CH2CH2, and -C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2. 15 23. The compound of any one of claims 1-22, wherein L2is CH2.

24. The compound of any one of claims 1-22, wherein L2is CH2CH2 or - C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2; or wherein L2is 20 CH(Me).

25. The compound of any one of claims 1-22, wherein L2is a bond.

26. The compound of any one of claims 1-25, wherein Ring A1 is a 4-6 membered 25 nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. 860Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 27. The compound of any one of claims 1-26, wherein Ring A1 is selected from the group consisting of: piperidinylene, pyrrolidinylene, azabicyclo[3.1.0]hexanylene, and azetidinylene, each optionally substituted with 1-2 Ra. 5 28. The compound of any one of claims 1-27, wherein Ring A1 is selected from the10 aa represents the point of attachment to L2.

29. The compound of any one of claims 1-25, wherein Ring A1 is a 7-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-2 Ra. 15 30. The compound of any one of claims 1-25 or 29, wherein Ring A1 is a 7-12 membered nitrogen-containing spirocyclic heterocyclylene.

31. The compound of any one of claims 1-25 or 29-30, wherein Ring A1 is selected, 20point of attachment to L2. 861Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 32. The compound of any one of claims 1-25 or 29, wherein Ring A1 is selected from the group consisting of:, , , wherein aa represents the point of attachment to L2. 5 33. The compound of any one of claims 1-25, wherein Ring A1 is a C3-8cycloalkylene optionally substituted with 1-3 Ra.

34. The compound of any one of claims 1-25 or 33, wherein Ring A1 is selected from the group consisting of:, , , , 10.

35. The compound of any one of claims 1-34, wherein L1is C(=O).

36. The compound of any one of claims 1-34, wherein L1is CH2. 15 37. The compound of any one of claims 1-34, wherein L1is -C(=O)N(H)-#, wherein the # presents the point of attachment to Ring A1.

38. The compound of any one of claims 1-37, wherein L0is Cy. 20 39. The compound of claim 38, wherein Cy is a C4-6monocyclic cycloalkylene optionally substituted with 1-3 Ra.

40. The compound of claim 38 or 39, wherein Cy is selected from the group 25 consisting of:, each of which is optionally 862Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) substituted with 1-3 substituents independently selected from the group consisting of: F and C1-3 alkyl optionally substituted with 1-3 F.

41. The compound of any one of claims 38-40, wherein Cy is selected from the 5 group consisting of:, wherein dd represents the point of attachment to L1.

42. The compound of claim 38, wherein Cy is a C6-10 bridged bicyclic cycloalkylene. 10 43. The compound of claim 38 or 42, wherein Cy is selected from the group15 44. The compound of claim 38, wherein Cy is a 4-6 membered heterocyclylene optionally substituted with 1-3 Ra., wherein dd represents the point of attachment to L1. 20 46. The compound of any one of claims 1-37, wherein L0is Cy; and Cy is, wherein X2is selected from the group consisting of: CH, CRa(e.g., CMe), and N; and dd represents the point of attachment to L1. 25 47. The compound of any one of claims 1-37, wherein L0is a straight-chain C1-4 alkylene optionally substituted with 1-3 Ra. 863Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 48. The compound of any one of claims 1-37 or 47, wherein L0is a straight-chain C2-4 alkylene. 5 49. The compound of any one of claims 1-34, wherein L1is C(=O); L0is Cy, wherein Cy is, wherein X2is selected from the group consisting of: CH and CRa(e.g., CMe); and dd represents the point of attachment to L1.

50. The compound of any one of claims 1-34, wherein L1is C(=O); and L0is Cy, 10 wherein Cy is a C6-10 bridged bicyclic cycloalkylene (e.g.,, ,51. The compound of any one of claims 1-34, wherein L1is CH2or C(=O); and L0is a straight-chain C2-4alkylene. 15 52. The compound of any one of claims 1-51, wherein R9is H.

53. The compound of any one of claims 1-52, wherein R1is phenyl. 20 54. The compound of any one of claims 1-53, wherein R2is methyl.

55. The compound of any one of claims 1-54, wherein R3and R4are each an independently selected halo. 25 56. The compound of any one of claims 1-55, wherein R3is Cl; and R4is F.

57. The compound of any one of claims 1-56, wherein R5is H.

58. The compound of any one of claims 1-57, wherein R8is F. 864Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 59. The compound of any one of claims 1-58, wherein X1is CH.

60. The compound of any one of claims 1-59, wherein R7is C2-3alkoxy substituted 5 with 1-3 Rc, wherein each Rcis independently selected from the group consisting of: F, CN, OH, and C1-3 alkoxy.

61. The compound of any one of claims 1-60, wherein R7is.

62. The compound of any one of claims 1-60, wherein R7is selected from the group 10 consisting of:

63. The compound of any one of claims 1-59, wherein R7is C1-3 alkoxy (e.g., methoxy). 15 64. The compound of any one of claims 1-58, wherein X1is CR6; and R6and R7, taken together with the two ring carbon atoms connecting them, form a 5-6 membered heterocyclyl ring optionally substituted with 1-2 Ra; optionally R6and R7, taken together with the two ring carbon atoms connecting them, form. 20 65. The compound of any one of claims 1-58 or 60-63, wherein X1is N.

66. The compound of any one of claims 1-65, wherein R11is H.

67. The compound of claim 1, wherein the compound of Formula (AA) is a 25 compound of Formula (A1), (A2), or (A3): 865Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 5Formula (A3) or a pharmaceutically acceptable salt thereof, wherein: 10 X2is CH, CRa, or N (e.g., CH or CMe); 866Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) Cy is a C6-10bridged bicyclic cycloalkylene; L0is a straight-chain C2-4 alkylene; L1is selected from the group consisting of: C(=O) and CH2; and L2is selected from the group consisting of: a bond, CH2, CH2CH2, and -C(Me)2CH2-*, 5 wherein the * represents point of attachment to Ring A2.

68. The compound of claim 1 or 67, wherein the compound of Formula (AA) is a compound of Formula (I) or (II): 10Formula (II) or a pharmaceutically acceptable salt thereof, wherein: R1is phenyl optionally substituted with 1-3 Ra; 15 R2is selected from the group consisting of: H and methyl; R3and R4are independently selected from the group consisting of: H and halo; R5is selected from the group consisting of: H and C1-3alkyl optionally substituted with 867Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) R7is C1-3alkoxy optionally substituted with 1-3 Rc; R8is selected from the group consisting of: H and halo; X1is N or CH; 5 X2is N or CH; L1is C(=O) or CH2; Ring A1 is selected from the group consisting of: C3-8cycloalkylene and 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; L2is selected from the group consisting of: a bond, CH2, CH2CH2, O, and C(=O); 10 Ring A2 is a 4-10 membered heterocyclylene optionally substituted with 1-3 Ra; Y is N or CH; RY1is C1-3 alkyl; Y1, Y2, and Y3are each independently selected from the group consisting of: CH and 15 CRY2, wherein each RY2is an independently selected halo; each Rais independently selected from the group consisting of: halo, CN, OH, and C1-3alkyl optionally substituted with 1-3 F; and each Rcis independently selected from the group consisting of: halo, CN, OH, and C1- 203alkoxy.

69. The compound of claim 68, wherein the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. 25 70. The compound of claim 68, wherein the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

71. The compound of any one of claims 67-70, wherein Y is N. 30 72. The compound of any one of claims 67-70, wherein RY1is methyl.

73. The compound of any one of claims 67-72, wherein at least one of Y1, Y2, and Y3is CRY2. 868Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 74. The compound of any one of claims 67-73, wherein two or three (e.g., two) of Y1, Y2, and Y3are independently selected CRY2.

75. The compound of any one of claims 67-74, wherein Y1and Y2are each CF; and 5 Y3is CH.

76. The compound of any one of claims 67-74, wherein Y1, Y2, and Y3are each CF.

77. The compound of any one of claims 67-72, wherein Y1, Y2, and Y3are each 10 CH.

78. The compound of any one of claims 67-72, wherein Y3is CH; one of Y1and Y2is CF; and the other of Y1and Y2is CH. 15 79. The compound of any one of claims 67-78, wherein Ring A2 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra.

80. The compound of any one of claims 67-79, wherein Ring A2 is selected from the group consisting of: piperidinylene, tetrahydropyridylene, piperazinylene, 20 pyrrolidinylene, and azetidinylene, each of which is optionally substituted with 1-2 Ra.

81. The compound of any one of claims 67-80, wherein Ring A2 is selected from the group consisting of:,, , each of which is optionally substituted with 1-2 Ra; 25 wherein bb represents the point of attachment to L2. 869Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 82. The compound of any one of claims 67-81, wherein Ringoptionally substituted with 1-2 Ra, wherein bb represents the point of attachment to L2.

83. The compound of any one of claims 67-82, wherein Ring5, wherein bb represents the point of attachment to L2.

84. The compound of any one of claims 67-81, wherein Ring A2 is.

85. The compound of any one of claims 67-84, wherein L2is selected from the 10 group consisting of: a bond, CH2, and CH2CH2.

86. The compound of any one of claims 67-85, wherein L2is CH2.

87. The compound of any one of claims 67-86, wherein L2is a bond. 15 88. The compound of any one of claims 67 or 71-84, wherein L2is CH2CH2 or - C(Me)2CH2-*, wherein the * represents point of attachment to Ring A2.

89. The compound of any one of claims 67-88, wherein Ring A1 is a 4-6 membered 20 nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra.

90. The compound of any one of claims 67-89, wherein Ring A1 is selected from the group consisting of: piperidinylene, pyrrolidinylene, and azetidinylene, each optionally substituted with 1-2 Ra. 25 870Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 91. The compound of any one of claims 67-90, wherein Ring A1 is selected from the group consisting of:, , , wherein aa represents the point of attachment to L2. 5 92. The compound of any one of claims 67-88, wherein Ring A1 is a 7-12 membered nitrogen-containing bicyclic heterocyclylene optionally substituted with 1-2 Ra.

93. The compound of any one of claims 67-88 or 92, wherein Ring A1 is a 7-12 membered nitrogen-containing spirocyclic bicyclic heterocyclylene. 10 94. The compound of any one of claims 67-88 or 92-93, wherein Ring A1 is selected from the group consisting of:, ,. 15 95. The compound of any one of claims 67-88, wherein Ring A1 is a C3-8 cycloalkylene (96. The compound of any one of claims 67-95, wherein L1is C(=O). 20 97. The compound of any one of claims 67-96, wherein X2is CH.

98. The compound of any one of claims 67 or 71-96, wherein X2is CMe. 25 99. The compound of any one of claims 67-71, wherein: 871Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) X1is CH; L1is C(=O); L2is selected from the group consisting of: a bond and CH2; andRing A2 is optionally substituted with 1-2 Ra, wherein bb represents the 5 point of attachment to L2.

100. The compound of claim 99, wherein Ring A1 is a 4-6 membered nitrogen- containing heterocyclylene optionally substituted with 1-3 Ra. 10 101. The compound of claim 99, wherein Ring A1 is a 7-12 membered nitrogen- containing spirocyclic bicyclic heterocyclylene.

102. The compound of any one of claims 67-101, wherein R1is phenyl. 15 103. The compound of any one of claims 67-102, wherein R2is methyl.

104. The compound of any one of claims 67-103, wherein R3and R4are independently selected halo. 20 105. The compound of any one of claims 67-104, wherein R3is Cl; and R4is F.

106. The compound of any one of claims 67-105, wherein R5is H.

107. The compound of any one of claims 67-106, wherein X1is CH. 25 108. The compound of any one of claims 67-107, wherein R8is F.

109. The compound of any one of claims 67-108, wherein R7is C2-3 alkoxy substituted with OH. 30 110. The compound of any one of claims 67-109, wherein R7is . 872Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 111. The compound of any one of claims 67-108, wherein R7is C1-3 alkoxy.

112. The compound of any one of claims 67-108 or 111, wherein R7is methoxy. 5 113. The compound of claim 68 or 69, wherein the compound of Formula (I) is a compound of Formula (I-a):Formula (I-a) 10 or a pharmaceutically acceptable salt thereof, wherein: R7is C1-3alkoxy optionally substituted with F or OH; and Y1, Y2, and Y3are independently selected from the group consisting of: CH and CF.

114. The compound of claim 68 or 70, wherein the compound of Formula (II) is a 15 compound of Formula (II-a):Formula (II-a) or a pharmaceutically acceptable salt thereof, wherein: 873Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) R7is C1-3alkoxy optionally substituted with F or OH; and Y1, Y2, and Y3are independently selected from the group consisting of: CH and CF.

115. The compound of claim 113 or 114, wherein Ring A2 is a 4-6 membered 5 nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra; and L2is selected from the group consisting of: a bond, CH2, and CH2CH2.

116. The compound of any one of claims 113-115, wherein Ring A2 isoptionally substituted with 1-2 Ra, wherein bb represents the point of 10 attachment to L2; and L2is selected from the group consisting of: a bond and CH2.

117. The compound of any one of claims 113-116, wherein Ring A2 is, wherein bb represents the point of attachment to L2. 15 118. The compound of any one of claims 113-117, wherein L2is CH2.

119. The compound of any one of claims 113-118, wherein Ring A1 is a 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. 20 120. The compound of any one of claims 113-119, wherein Ring A1 is selected from the group consisting of:, , , wherein aa represents the point of attachment to L2. 25 121. The compound of any one of claims 113-118, wherein Ring A1 is a 7-12 membered nitrogen-containing spirocyclic bicyclic heterocyclylene. 874Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) 122. The compound of any one of claims 113-118 or 121, wherein Ring A1 is selected from the group consisting of:,wherein aa represents the point of attachment to L2. 5 123. The compound of any one of claims 113-122, wherein R7is.

124. The compound of any one of claims 113-123, wherein Y is N. 10 125. The compound of any one of claims 113-124, wherein Y1and Y2are each CF; and Y3is CH.

126. The compound of any one of claims 113-125, wherein RY1is methyl. 15 127. The compound of claim 1, wherein the compound of Formula (AA) is selected from the group consisting of the compounds depicted in Table C1, or a pharmaceutically acceptable salt thereof.

128. A pharmaceutical composition comprising a compound of any one of claims 1- 20 127, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

129. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-127, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 25 according to claim 128.

130. A method of treating cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a cancer having a Hippo pathway dysregulation 875Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) a therapeutically effective amount of a compound of any one of claims 1-127 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 128. 5 131. A method of treating cancer in a subject, the method comprising: (a) determining that the cancer in the subject has a Hippo pathway dysregulation; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-127 or a pharmaceutically acceptable salt thereof, or a pharmaceutical 10 composition according to claim 128.

132. The method of claim 131, wherein the step of determining that the cancer in the subject has a Hippo pathway dysregulation comprises consulting the subject’s medical record. 15 133. The method of claim 131, wherein the step of determining that the cancer in the subject has a Hippo pathway dysregulation includes performing an assay to detect the Hippo pathway dysregulation in a tumor sample from the subject.

134. The method of claim 133, wherein the method comprises obtaining a tumor 20 sample from the subject.

135. The method of claim 134, wherein the tumor sample is a biopsy sample.

136. The method of any one of claims 133-135, wherein the assay is selected from 25 the group consisting of sequencing, immunohistochemistry, and enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

137. The method of claim 136, wherein the sequencing is pyrosequencing or next generation sequencing. 30 138. The method of any one of claims 129-137, wherein the cancer is selected from the group consisting of: bladder cancer (e.g., bladder urothelial carcinoma), breast cancer, colorectal cancer (e.g., colon cancer or rectal cancer), cervical cancer (e.g., cervical squamous cell carcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), epithelioid 876Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) hemangioendothelioma, gastric cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., kidney renal papillary cell carcinoma), lung cancer (e.g., mesothelioma or lung squamous cell carcinoma), liver cancer, prostate cancer, sarcoma, and a combination thereof. 5 139. The method of claim 138, wherein the cancer is mesothelioma.

140. The method of claim 139, wherein the cancer is pleural mesothelioma. 10 141. The method of any one of claims 129-137, wherein the cancer is a squamous cell-involved cancer.

142. The method of claim 141, wherein the squamous cell-involved cancer is selected from the group consisting of: bladder urothelial carcinoma, cervical squamous cell 15 carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and a combination thereof.

143. The method of any one of claims 139-142, wherein the method comprises administering an additional therapy or therapeutic agent to the subject. 20 144. A method for a method for modulating TEAD protein activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-127, or a pharmaceutically acceptable salt thereof. 25 145. The method of claim 144, wherein the contacting occurs in vivo.

146. The method of claim 144, wherein the contacting occurs in vitro.

147. The method of claim 144, wherein the contacting occurs ex vivo. 30 148. The method of any one of claims 144-147, wherein the mammalian cell is a mammalian cancer cell.

149. A ternary complex comprising a TEAD protein, a compound of any one of 877Docket No. TRLN-024-003WO1 / 37998-02015 / WO (TBIO-001 / 01WO) claims 1-127, or a pharmaceutically acceptable salt thereof, and a CRBN protein. 878

Images