Compounds and methods of use

Abstract

Provided are compounds of Formula (I): (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions, processes of preparing and methods of use thereof; wherein Ring B, RA, RB, R3, R3' m and n are as defined in any of the embodiments described herein.

Description

Docket No. TGO-035WOCOMPOUNDS AND METHODS OF USEField

[0001] Provided herein are compounds, and compositions and methods thereof. In some embodiments, provided are compounds for inactivating HBS1 like translational GTPase (HBS1L). In some embodiments, provided are methods for treatment of diseases or disorders, such as cancer.Reference to a Sequence Listing

[0002] This application contains a Sequence Listing which has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. Said XML file, created on December 30, 2025, is named TGO-035WO and is 2,824 bytes in size.Background

[0003] Cell proliferation is controlled by the balance between proteins that stimulate growth (oncogenes) and proteins that limit growth (tumor suppressors). In cancer, genes encoding tumor suppressors are often inactivated, resulting in uncontrolled cell proliferation. One method to treat cancers characterized by inactivation of a tumor suppressor gene is to employ the concept of synthetic lethality. Synthetic lethality describes a relationship between two genes (or their protein products) where inactivation of either gene / protein alone is tolerated, but combined inactivation of both factors is lethal (Huang, A., et al., Nature Reviews Drug Discovery 2020, 19, 23-38; Kaelin, W. G. K. Jr. Nature Reviews Cancer 2005, 5 (9), 689-698).

[0004] Inactivation of a tumor suppressor gene can create specific dependencies in tumor cells that do not exist in non-tumor cells, where the tumor suppressor gene is intact. These tumor-specific dependencies can be targets for selective inhibition of tumor cells without damaging the healthy tissue.

[0005] One w ell-described tumor suppressor gene that is commonly inactivated in cancer is CDKN2A. This gene is often inactivated by chromosomal deletion, which can co-delete nearby genes as collateral damage. MTAP is a gene adjacent to CDKN2A on chromosome 9p that is often co-deleted with CDKN2A. Cells that lack MTAP are hyperdependent on theDocket No. TGO-035WOPRMT5 protein, exemplifying a synthetic lethal relationship between MTAP and PRMT5 (Mavrakis, K. J.; et al.. Science 2016, 351 (6278), 1208-1213; Marjon. K et al., Cell Reports 2016, 15 (3), 574-587; Kryukov, G. V. et al.. Science 2016, 351 (6278), 1214-1218).

[0006] Individually, loss of MTAP or PRMT5 are each tolerated. However, dual inactivation of MTAP and PRMT5 is lethal. Accordingly, the growth of tumor cells that have inactivated thegene can be inhibited by inactivating PRMT5 in this context, while cells that have MTAP intact can tolerate PRMT5 inactivation.

[0007] Similarly to MTAP, the FOCAD gene is also found on chromosome 9p and is frequently co-deleted with CDKN2A and MTAP. Functionally, the FOCAD protein works with mammalian superkiller (SKI) complex proteins to promote the degradation of aberrant mRNAs and thus plays a role in ribosome quality control and ribosome rescue.

[0008] There is a need in the art to identify a synthetic lethal counterpart to FOCAD and then to create inactivators (e.g., inhibitors or degraders) of that protein. The present invention addresses these (and other) needs.Summary

[0009] Applicants have found, surprisingly and advantageously, that FOCAD deleted cancer cells are hyper-dependent for their survival on the HBS1L protein, and that dual inactivation of FOCAD and HBS1L is synthetic lethal. More generally. Applicants have found that cancers with impaired mRNA quality control involving the loss or impairment of the SKI complex function (e.g., by the deletion or deficiency of FOCAD or other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L) are likely to be hyper-dependent for their survival on the function of the HBS1L / PELO complex, and that inactivation of HBS1L can promote the death of such cancer cells while being tolerated by normal cells.

[0010] The present invention provides small molecule degraders of HBS1L, pharmaceutical compositions thereof, and methods for their use to treat FOCAD-deficient cancers as well as cancers deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L and cancers that are PELO-dependent.

[0011] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:Docket No. TGO-035WORing B is selected from the group consisting of 6-14 membered aryl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 member heteroaryl containing 1-3 heteroatoms selected from N, O and S;R3and R3are each independently selected from the group consisting of H, -C1-C3 alkyl and -C1-C3 haloalkyl or are taken together with the carbon to which they are attached to form a C3-C9 cycloalkyl or a 4-7 membered heterocyclyl containing 1 heteroatom selected from N, O and S, provided that R3and R3are not both H;each RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl. -C3-C9 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered ary l), -(C1-C2 alkyl)(6-10 membered heteroary l), -ORA2, -N(RA2)2, -C(=O)RA1, -C(=O)ORA2, -NRA2C(=O)RA1, -NRA2C(=O)ORA1, -C(=O)N(RA2)2, -C(=O)N(ORA2)(RA2), -OC(=O)N(RA2)2, -S(=O)RA1, -S(=O)2RA1, -SRA2, -S(=O)(=NRA2)RA1, -NRA2S(=O)2RA1and -S(=O)2N(RA2)2;each RBis independently selected from the group consisting of -D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 heteroalkyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl). -(C1-C2 alkyl)(6-10 membered heteroaryl), -ORB2, -N(RB2)2. -C(=O)RB1, -C(=O)ORB2, -NRB2C(=O)RB1, -NRB2C(=O)ORB1, -C(=O)N(RB2)2, -C(=O)N(ORB2)(RB2), -OC(=O)N(RB2)2, -S(=O)RB1, -S(=O)2RB1, -SRB2, -S(=O)(=NRB2)RB1, -NRB2S(=O)2RB1and -S(=O)2N(RB2)2wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1. 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of-OMe or -OH;Docket No. TGO-035WOeach R4is independently selected from -D, =O, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -Ci-Ce hydroxyalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2;each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl);each RB2is independently selected from –H, –D, –C1-C6 alkyl, –C1-C6 alkenyl, –C1-C6 haloalkyl, –C1-C6 haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, –(C1-C2 alkyl)(C3-C9 cycloalkyl), –(C1-C2 alkyl)(4-10 member heterocyclyl), –(C1-C2 alkyl)(6-10 membered aryl), –(C1-C2 alkyl)(6-10 membered heteroaryl), wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1 or 2 instances of C1-C6 alkyl, OH or halo;n is 0, 1, 2 or 3; andm is 0, 1, 2 or 3.

[0012] In some embodiments, provided is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent.

[0013] In some embodiments, provided is a method of treating an HBS1L-sensitive disease (e.g., cancer) in a subject in need thereof by administering to the subject an effective amount (e.g., a therapeutically effective amount) of compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein or a pharmaceutically acceptable composition thereof. In some embodiments, the compound or composition is administered in combination with a second therapeutic agent. In some embodiments, provided is a method of treating a FOCAD-deficient disease (e.g., a FOCAD-defi cient cancer) in a subject in need thereof by administering to the subject an effective amount (e.g., a therapeutically effective amount) of compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments describedDocket No. TGO-035WOherein or a pharmaceutically acceptable composition thereof. In some embodiments, the compound or composition is administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is a PRMT5 inhibitor. In some embodiments, the second therapeutic agent is a MAT2A inhibitor.

[0014] In some embodiments, provided is a method of treating a cancer in a subject in need thereof comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from said subject, wherein the FOCAD level can be assessed directly (e.g., by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC);b) comparing the test sample with a reference, wherein FOCAD deficiency in said test sample compared to the reference indicates the cancer in said subject will respond to therapeutic treatment with an HBS1L degrader; andc) administering an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (I) as defined herein or a pharmaceutical composition thereof to the subject identified in step b).

[0015] In some embodiments, provided is a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, or of a pharmaceutically acceptable composition as described herein for treating a FOCAD-deficient disease (e.g., a FOCAD-deficient cancer) in a subject in need thereof. In some embodiments, the compound or composition is configured to be administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is a PRMT5 inhibitor.

[0016] In some embodiments, provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, or a pharmaceutically acceptable composition as described herein for treating a FOCAD-deficient disease (e.g., a FOCAD-deficient cancer) in a subject in need thereof In some embodiments, the compound or composition is configured to be administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is a PRMT5 inhibitor. In some embodiments, the second therapeutic agent is a MAT2A inhibitor.

[0017] In some embodiments, provided is a use of a compound of compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, or of a pharmaceutically acceptable composition as described herein in theDocket No. TGO-035WOmanufacturing of a medicament for treating a FOCAD-deficient disease (e.g., a FOCAD-defi cient cancer) in a subject in need thereof. In some embodiments, the medicament is configured to be administered in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent is a PRMT5 inhibitor.Brief Description of the FiguresFIG. 1 FOCAD-deleted cancer cells are dependent on HBS1L, whereas FOCAD intact cancer cells are not. Doxycycline-inducible sgRNA was used to edit the HBS1L locus (+DOX row) and cell growth was assessed by staining colonies with crystal violet as described in Example 2.FIG. 2 Schematic representation of ribosome rescue by the SKI complex and HBS1L / PELO complex. Image generated with BioRender®.FIG. 3 Depicts the results of an in-vivo CDX mouse experiment using a FOCAD-null HBS1L knockout MIAPACA2 xenograft in which HBS1L expression can be turned on through Doxycycline-inducible expression of HBS1L cDNA (+DOX) showing that tumor grow th is suppressed in the absence of HBS1L (-DOX) and is rescued by sustained expression of HBS1L.Detailed Description

[0018] The disclosure herein sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0019] As generally described herein, provided are compounds (e.g., compounds of Formula (I) or compounds of Table 1, or pharmaceutically acceptable salts thereof) that are HBS1L degraders useful for treating proliferating disorders (e.g., cancers) associated with FOCAD deficiencies. In some embodiments, the compounds are useful in treating proliferating disorders (e.g., cancers) deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the compounds are useful in treating proliferating disorders (e.g., cancers) that are sensitive to HBS1L inactivation because they are PELO-dependent.

[0020] As generally described herein, provided is a method for treating an HBS1L-sensitive proliferating disease (e.g., cancer) by administering to a patient in need thereof a compoundDocket No. TGO-035WOthat can inactivate HBS1L (e.g., an HBS1L degrader). The HBS1L-sensitive disease can be a disease associated with FOCAD deficiencies, a disease associated with deficiencies in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L, or a disease that is PELO-dependent.Definitions

[0021] As used in the present disclosure, the following words and phrases are generally intended to have the meanings as set forth below unless expressly indicated otherwise or the context in which they are used indicates otherwise.FOCAD

[0022] "‘FOCAD-’ as used herein refers to focadhesin, a focal adhesion protein, also known as KIAA1797 encoded by the FOCAD gene (KIAA1797 gene) External IDs:OMIM: 614606; MGI: 2676921; HomoloGene: 9842; GeneCards: FOCAD.RefSeq (mRNA): NM_017794; NM_001375567; NM_001375568;NM_001375570; RefSeq (protein) NP_060264; NP_001362496; NP_001362497;NP 001362499. Location: Chr 9: 20.66 - 21 Mb. By “wild-type” FOCAD is meant that encoded by any or all of NM_017794; NM_001375567; NM_001375568; NM_001375570 or having the same amino acid sequence (NP_060264; NP_001362496; NP_001362497;NP_001362499).

[0023] As used herein, “inactivation” of a target protein in a tissue (e.g., in a tumor) can be a result of copy number loss, low expression at the mRNA and / or protein level, loss of function mutation, epigenetic silencing, hypomorphs, or any other aberration that reduces activity of the target. Inactivation of a target protein can be achieved through treatment with a compound that is an “inactivator” of that target, which refers to any compound capable of inhibiting the production, level, activity, expression, or presence of the target. These include, as non-limiting examples, any compound inhibiting the transcription of the gene, the maturation of RNA, the translation of mRNA, the posttranslational modification of the protein, the enzymatic activity of the protein, the interaction of the protein with a substrate, or compounds that degrade the protein. The term also refers to any agent that inhibits the cellular function of the protein, either by inhibition of the active site, allosteric modulation of the protein structure, disruption of protein-protein interactions, or by inhibiting the transcription, translation, post-translational modification, or stability of the protein.Docket No. TGO-035WO

[0024] As used herein, the terms “FOCAD-deficient”, “FOCAD-deficiency”, “FOCAD-null”, FOCAD-deleted" and the like refer to cells (including, but not limited to, cancer cells, cell lines, tissues, tissue types, tumors, etc.) that have a significant reduction in post-translational modification, production, expression, level, stability and / or activity of FOCAD relative to that in a control, e.g., reference or normal or non-cancerous cells. The reduction can be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the reduction is at least 20%. In some embodiments, the reduction is at least 50%. The term “FOCAD-deficient” and the like, regarding a cell or cells, etc., indicate that the cell or cells, etc., are deficient in FOCAD. FOCAD-deficient cells include those wherein the FOCAD gene has been mutated, deleted, or transcriptionally silenced. As a non-limiting example, FOCAD-deficient cells can have a homozygous deletion. In some embodiments, FOCAD-deficient cells can have a heterozygous deletion. In some embodiments, the FOCAD-deficient cells are also CDKN2A-deficient. In some embodiments, the FOCAD-deficient cells are also MTAP-deficient. The FOCAD deficiency can be detected using any reagent or technique known in the art, for example: immunohistochemistry utilizing an antibody to FOCAD. and / or genomic sequencing, and / or nucleic acid hybridization and / or amplification utilizing at least one probe or primer, for example a probe or primer comprising a sequence of at least 12 contiguous nucleotides (nt) of the sequence of FOCAD, wherein the primer is no longer than about 30 nt.

[0025] A “FOCAD-deficiency -related” or “FOCAD deficient” disease (for example, a proliferating disease, e.g., a cancer) or a disease (for example, a proliferating disease, e.g, a cancer) “associated with FOCAD deficiency” or a disease (for example, a proliferating disease, e.g., a cancer) “characterized by FOCAD deficiency” and the like refer to an ailment (for example, a proliferating disease, e.g, a cancer) wherein a significant number of cells are FOCAD-deficient. For example, in a FOCAD-deficiency-related disease, one or more disease cells can have a significantly reduced post-translational modification, production, expression, level, stability and / or activity of FOCAD. Examples of FOCAD-deficiency-related diseases include, but are not limited to, cancers (e.g, FOCAD-deficient cancers), including but not limited to: bladder cancer (e.g., urothelial carcinoma), skin cancer (e.g., cutaneous melanoma), non-small cell lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g, head and neck squamous cell carcinoma), prostate cancer (e.g, prostateDocket No. TGO-035WOadenocarcinoma), esophagogastric cancer (e.g., esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g., colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g., ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g, clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma. In some embodiments, the FOCAD-deficiency-related disease is a histology agnostic FOCAD-deficient cancer.

[0026] In a patient afflicted with a FOCAD-deficiency-related disease, it is possible that some disease cells (e.g, cancer cells) can be FOCAD-deficient while others are not. Thus, the present disclosure encompasses methods of treatment involving diseases of these tissues, or any other tissues, wherein the proliferation of FOCAD-deficient cells can be inhibited by administration of an HBS1L degrader.

[0027] Some cancer cells which are FOCAD-deficient are also deficient in CDKN2A; the post-translational modification, production, expression, level, stability, and / or activity of the CDKN2A gene or its product are decreased in these cells. The genes for FOCAD and CDKN2A are in close proximity on chromosome 9p21; FOCAD is located approximately 970 kb telomeric to CDKN2A. Many cancer cell types harbor CDKN2A / FOCAD loss (loss of both genes). Thus, in some embodiments, a FOCAD-deficient cell is also deficient in CDKN2A.

[0028] Some cancer cells which are FOCAD-deficient are also deficient in MTAP; the post-translational modification, production, expression, level, stability, and / or activity of the MTAP gene or its product are decreased in these cells. The genes for FOCAD and MTAP are in close proximity on chromosome 9p21; FOCAD is located approximately 800 kb telomeric to MTAP. Many cancer cell types harbor MTAP / FOCAD loss (loss of both genes). Thus, in some embodiments, a FOCAD-deficient cell is also deficient in MTAP.HBS1L

[0029] " HBS1L" as used herein is the gene or protein HBS1 like translational GTPase, also known as ERFS; HBS1; KIAA1038, EF-la; eRF3c; HSPC276.

[0030] External IDs: HGNC: 4834; NCBI Gene: 10767; Ensembl: ENSG00000112339; OMIM: 612450; MGI: 1891704; HomoloGene: 68525; GeneCards: HBS1L.Docket No. TGO-035WO

[0031] RefSeq (mRNA): NM_001145158: NM_001145207; NM_006620;NM_001363686. The mouse homologs are NM_001042593; NM_019702; NM_001145209. RefSeq (protein): NP_001138630; NP_001138679; NP_006611; NP_001350615. Mouse homologs NP_001036058; NP_062676; NP_001138681.

[0032] HBS1L is the GTPase component of the Pelota-HBS1L (PELO-HBS1L) complex, a complex that recognizes ribosomes stalled at the 3' end of an mRNA and engages stalled ribosomes by destabilizing mRNA in the mRNA channel, triggering the No-Go Decay (NGD) and Non-Stop Mediated Decay pathways (Pisareva VP, et al., “Dissociation by Pelota, Hbsl and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes'’ EMBO J. 2011 May 4;30(9): 1804-17: Saito S, HosodaN, Eloshino S. “The Hbsl-Dom34 protein complex functions in non-stop mRNA decay in mammalian cells” J Biol Chem. 2013 Jun 14:288(24): 17832-43; Shao S, et al., “Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes” Cell. 2016 Nov 17;167(5):1229-1240). Following mRNA extraction from stalled ribosomes by the SKI complex and degradation by FOCAD, the Pelota-HBS1L complex promotes recruitment of ABCE1, which drives the disassembly of stalled ribosomes, followed by degradation of damaged mRNAs as part of the NGD pathway (Pisareva; Zinoviev A, et al., “Extraction of mRNA from Stalled Ribosomes by the Ski Complex. Mol Cell. 2020 Mar 19;77(6): 1340-1349”).

[0033] The terms “HBS1L inhibitor” “HBSIL-inactivating compound” and “HBS1L inactivator” refer to any compound capable of inhibiting the production, level, activity, expression, or presence of HBS1L. These include, as non-limiting examples, any compound inhibiting the transcription of the gene, the maturation of RNA, the translation of mRNA, the posttranslational modification of the protein, the enzymatic activity of the protein, the interaction of the protein with a substrate, or compounds that degrade or facilitate the degradation of the protein (e.g, HBS1L degraders, e.g., PROTACs, molecular glues) etc. The term also refers to any agent that inhibits the cellular function of the HBS1L protein, either by inhibition of the active site, allosteric modulation of the protein structure, disruption of protein-protein interactions, or by inhibiting the transcription, translation, post-translational modification, or stability of HBS1L protein.

[0034] The term “HBS IL degrader” refers to any compound capable of eliminating or reducing the amount of HBS1L in a cell (<?.g, a tumor cell) by using a cell’s natural system for eliminating misfolded or spent proteins. An HBS IL degrader induces the degradation of HBS IL by forming a ternary complex with an E3 ubiquitin ligase and HBS IL. In someDocket No. TGO-035WOembodiments, an HBS1L degrader is a PROTAC. In some embodiments, an HBS1L degrader is a molecular glue.

[0035] As described further herein, a disease, a cancer cell, a cancer type, or a subject with cancer, is “HBS1L inactivator sensitive,” “sensitive to treatment with HBS1L inactivators,” “sensitive to HBS1L therapeutic inactivation,” “HBSIL-sensitive” or described in similar terms if it is amenable to treatment with an HBS1L inactivator (e.g., an HBS IL degrader)(e.g., due to the loss or impairment of the SKI complex function, e.g.. due to its FOCAD deficiency, due to a deficiency in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L, or due to PELO dependency). In some embodiments, the disease (e.g., cancer) is HBS1L sensitive (e.g., sensitive to an HBS1L degrader) because it is FOCAD-deficient. In some embodiments, the disease (e.g, cancer) is HBSIL-sensitive (e.g., sensitive to an HBS IL degrader) because it is dependent on PELO and PELO levels are decreased upon HBS IL depletion. In some embodiments, the disease (e.g., cancer) is HBSIL-sensitive (e.g, sensitive to an HBS1L degrader) because it is TTC37-defi cient. AVEN-deficient, WDR61 -deficient, or SKIV2L-deficient.Chemical Definitions

[0036] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell. Organic Chemistry, University Science Books, Sausalito. 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0037] It is to be understood that descriptions of compound structures, including possible substitutions, are limited to those which are chemically possible.

[0038] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers,Docket No. TGO-035WOincluding racemic mixtures and mixtures enriched in one or more stereoisomer. References to compounds that are racemic mixtures are meant to also include the individual enantiomers contained in the mixture. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemales and Resolutions (Wiley Interscience. New York. 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). Additionally encompassed are compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0039] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds with an (or) designation are single enantiomers wherein the absolute stereochemistry’ yvas arbitrarily assigned (e.g, based on chiral SFC elution). Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted (i.e., have no bold or hashed wedge stereochemistry depictions) are mixtures of enantiomers at that center. Compounds that are marked with (abs) or have bold or hashed wedge depictions with no additional flags at a stereogenic center are single enantiomers wherein the absolute stereochemistry is as indicated. Absolute stereochemistry for a compound can be determined and / or confirmed by methods known to a person of skill in the art, for example by obtaining a single crystal X-ray structure, by preparing the compound from a starting material of known stereochemistry, or by structure-activity relationship correlation with compounds with known stereochemistry.

[0040] The '‘enantiomeric excess” (“e.e.”) or “% enantiomeric excess” (“%e.e.”) of a composition as used herein refers to an excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition can contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer, e.e. = (90-10) / 100 = 80%.

[0041] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.The ‘'diastereomeric excess” (“d e.”) or “% diastereomeric excess” (“%d.e.”) of a composition as used herein refers to an excess of one diastereomer relative to one or moreDocket No. TGO-035WOdifferent diastereomers present in the composition. For example, a composition can contain 90% of one diastereomer, and 10% of one or more different diastereomers.d.e. = (90-10) / 100 = 80%.

[0042] Thus, a composition containing 90% of one diastereomers and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.

[0043] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In some embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%. at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0044] In a formula, — is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified.

[0045] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-6 alkyd” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-6, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0046] It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term ‘“substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (z.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0047] The term “unsaturated bond” refers to a double or triple bond.

[0048] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0049] The term “saturated” refers to a moiety that does not contain a double or triple bond, z.e., the moiety only contains single bonds.Docket No. TGO-035WO

[0050] Affixing the suffix "-ene" to a group indicates the group is a divalent moiety, e.g, alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0051] The term “azido” refers to the radical -N3.

[0052] “Aliphatic” refers to an alkyd, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0053] “Cycloalky lalkyl” refers to an alkyl radical in which the alky l group is substituted with a cycloalkyl group. In some embodiments, a cycloalkylalkyl is a-(Ci-C2 alkyl)(cycloalkyl) (e.g, a C1-C2 alkyl(C3-C9 cycloalkyl). Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl. cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0054] “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group (e.g, a 3-10 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O, S, and oxidized forms thereof). In some embodiments, a heterocyclylalkyl is a (Ci-C2alkyl)-(heterocyclyl), e.g, a (C1-C2 alkyl)(4-10 membered heterocyclyl) (e.g, –CH2-heterocyclyl, –CH2CH2-heterocyclyl, –CH(CH3)-heterocyclyl). In some embodiments, a heterocyclylalkyl is a –CH2-heterocyclyl. Typical heterocyclylalkyl groups include, but are not limited to, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0055] “Aralkyl” or “arylalkyl” is a subset of alkyl and aryl, as defined herein, and refers to an alkyl group substituted by an aryl group (e.g., a Ce-Cio ary l group). In some embodiments, arylalkyl is a C1-C2 alkyl-aryl, e.g., a (C1-C2 alkyl)(6-10 membered aryl)(e.g., -CFh-aryl, -CftyC ty-aryl, -CH(CH3)-aryl). In some embodiments, arylalkyl is a –CH2-aryl (e.g., –CH2-phenyl, –CH2-naphthyl).

[0056] “Alkyd” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl” or “C1-C20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alkyl”). In some embodiments,Docket No. TGO-035WOan alkyl group has 1 to 10 carbon atoms (“Ci-io alkyl"’). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C i-7 alkyd”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C i-6 alkyd”, also referred to herein as “lower alkyl”). In some embodiments, an alkyd group has 1 to 5 carbon atoms (“C1-5 alkyl"’). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci^ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyd”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-buty l (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Cg). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is unsubstituted C1–10 alkyl (e.g., –CH3). In some embodiments, the alkyl group is substituted Ci-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3),!Pr (-CH(CH3)2), " Pr (-CH2CH2CH3). " Bu (-CH2CH2CH2CH3), or 'Bu (-CH2CH(CH3)2).

[0057] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-). butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (–CH2CH2CH2CH2CH2CH2–), and the like. Exemplary substituted alkylene groups, e.g, substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (–CH(CH3)–, (–C(CH3)2–), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-. -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-),and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.Docket No. TGO-035WO

[0058] ‘‘Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1- 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (‘‘C2-20 alkenyl”). In some embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (”€’2 4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (‘‘C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2 4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4). and the like. Examples of C2-6 alkenyl groups include the aforementioned C2 1 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Cs), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e.. unsubstituted (an "unsubstituted alkenyl”) or substituted (a ‘'substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In some embodiments, the alkenyl group is substituted C2-10 alkenyl.

[0059] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In some embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”).Docket No. TGO-035WOIn some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2 4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3). 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2 4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alky nyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents: e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In some embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0060] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e.. between the point of attachment. In some embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-10 alk 1”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-8 alky l”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1 4 alky l”). In some embodiments, a heteroalky 1 group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi-3 alkyl”). In some embodiments, a heteroalkylDocket No. TGO-035WOgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In some embodiments, the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In some embodiments, the heteroalkyl group is a substituted heteroCuo alkyl.Exemplary heteroalkyl groups include: –CH2OH, –CH2OCH3, –CH2NH2, –CH2NH(CH3), -CH2N(CH3)2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NH2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2.

[0061] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g, naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designates the number of carbon atoms in the entire fused ring system. Particularly aryl groups include phenyl, naphthalenyl, indenyl, dihydroindenyl, dihydrophenanthrenyl, tetrahydronaphthalenyl, dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 6H-benzo[c]chromen-3-yl and 5,6-dihydrophenanthridinyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted Ce-i4 aryl. In some embodiments, the ary l group is substituted Ce-14 aryl.

[0062] In some embodiments, an aryl group is substituted with one or more of groups selected from halo, Ci-Cs alkyl, Ci-Cs haloalkyl, cyano, hydroxy, Ci-Cs alkoxy, and amino.

[0063] Examples of representative substituted aryls include the followingDocket No. TGO-035WOR56R57 andR57wherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-Cs alky l, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, -NR58COR59, -NR58SOR59. -NR58SO2R59, -COOalkyl, -COOaryl, -CONR58R59, -CONR58OR59, -NR58R59, -SO2NR58R59, -S-alkyl, -SOalkyl, –SO2alkyl, –Saryl, –SOaryl, –SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, or S. R58and R59are independently hydrogen, -Ci-Cs alkyl, -C1-C4 haloalkyl, -C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0064] “Fused ar l" refers to an ary 1 having two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0065] “Heteroaryr refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring. In such instances, unless otherwise specified, the number of ring members designates the total number of ring members in the fused (heteroaryl / carbocyclyl or heteroaryl / heterocyclyl) ring system. “Heteroary l” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).Docket No. TGO-035WO

[0066] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. In some embodiments, a heteroaryl group is a bicyclic 8-12 membered aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“8-12 membered bicyclic heteroaryl”). In some embodiments, a heteroaryl group is an 8-10 membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“8-10 membered bicyclic heteroaryl”). In some embodiments, a heteroaryl group is a 9-10 membered bicyclic aromatic ring system having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“9-10 membered bicyclic heteroaryl”). Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroary l group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.Docket No. TGO-035WO

[0067] Exemplary' 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyL Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary' 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyL and thiepinyl. Exemplary' 5,6-bicyclic heteroary l groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0068] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, -Ci-Cs alky l, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, and 5-10 membered heteroary l.Docket No. TGO-035WO

[0069] In the structures described herein, a substituent attached to a polycyclic (e.g., bicyclic or tricyclic) cycloalkyl, heterocyclyl, aryl or heteroaryl with a bond that spans two or more rings is understood to mean that the substituent can be attached at any position in each of the rings.

[0070] “Heteroaralky or “heteroarylalkyl” is a subset of “alky l” and refers to an alkyd group substituted by a heteroaryl group (e.g., a 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof), wherein the point of attachment is on the alkyl moiety. In some embodiments, a heteroarylalkyl is a (C1-C2 alkyl)-(heteroaryl)e.g, a (C1-C2 alkyl)(5-10 membered heteroaryl) (e.g.. -Ctty-heteroaryl. -CH2CH2-heteroaryl, -CH(CH3)-heteroaryl). In some embodiments, a heteroarylalky l is a-CH2-heteroaryl. Typical heteroarylalkyl groups include, but are not limited to, pyridinylmethyl, pyrimidinylmethyl, furanylmethyl, thiophenylmethyl, pyrrolylmethyl, pyrazolylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyridinylethyl, pyrimidinylethyl, furanylethyl, thiophenylethyl, pyrrolylethyl, pyrazolylethyl, imidazolylethyl, thiazolylethyl, oxazolylethyl. thiazolylethyl and the like.

[0071] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic monocyclic, bicyclic, or tricyclic or polycyclic hydrocarbon ring system having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Carbocyclyl groups include fully saturated ring systems (e.g, cycloalky ls), and partially saturated ring systems. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3). cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5). cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Cs), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10Docket No. TGO-035WOcarbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-IH-indenyl (C9), decahydronaphthalenyl (C 10), spiro[4.5]decanyl (C10), and the like.

[0072] As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocy clic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more ar l or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocy clyl group is an unsubstituted C3-14 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0073] The term “cycloalkyl” as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 14 carbons containing the indicated number of rings and carbon atoms (for example a C3-C14 monocyclic, C4-C14 bicyclic, C5 C 14 tricyclic, or C6-C14 polycyclic cycloalkyl). In some embodiments “cycloalkyl” is a monocyclic cycloalkyl. In some embodiments, a monocyclic cycloalkyl has 3-14 ring carbon atoms. (“C3-14 monocyclic cycloalkyl”). In some embodiments, a monocyclic cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 monocyclic cycloalky l”). In some embodiments, a monocyclic cycloalky l group has 3 to 8 ring carbon atoms (“C3-8 monocyclic cycloalkyl”). In some embodiments, a monocyclic cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 monocyclic cycloalkyl”). In some embodiments, a monocyclic cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 monocyclic cycloalkyl”). In some embodiments, a monocyclic cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 monocyclic cycloalky l”). In some embodiments, a monocyclic cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 monocyclic cycloalkyl”). Examples of monocyclic C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalky l groups as well as cyclopropyl (C3) and cy clobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs).Docket No. TGO-035WO

[0074] In some embodiments “cycloalkyl” is a bicyclic cycloalkyl. In some embodiments, a bicyclic cycloalkyl has 4-14 ring carbon atoms. (“C4-14 bicyclic cycloalkyl”). In some embodiments, a bicyclic cycloalkyl group has 4 to 12 ring carbon atoms (“C4-12 bicyclic cycloalkyl”). In some embodiments, a bicyclic cycloalkyl group has 4 to 10 ring carbon atoms (“C4-10 bicyclic cycloalky l”). In some embodiments, a bicyclic cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 bicyclic cycloalkyl”). In some embodiments, a bicyclic cycloalkyl group has 6 to 10 ring carbon atoms (“Ce-io bicyclic cycloalkyl”). In some embodiments, a bicyclic cycloalkyd group has 8 to 10 ring carbon atoms (“Cs-io bicyclic cycloalkyl”). In some embodiments, a bicyclic cycloalkyd group has 7 to 9 ring carbon atoms (“C7-9 bicyclic cycloalkyl”). Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo [1.1.1] pentane (C5). spiro[2.2] pentane (C5), bicyclo[2.1.0]pentane (C5). bicyclo[2.1.1]hexane (Ce), bicyclo[3.1.0]hexane (Ce), spiro[2.3] hexane (Cs), bicyclo[2.2.1]heptane (norbomane) (C7), bicyclo[3.2.0]heptane (C7), bicyclo[3.1.1]heptane (C7), bicyclo [3.1.1] heptane (C7), bicyclo[4.1.0]heptane (C7), spiro[2.4] heptane (C7), spiro [3.3] heptane (C7), bicyclo[2.2.2]octane (Cs), bicyclo[4.1.1]octane (C8)octahydropentalene (Cs), bicyclo[3.2. l]octane (Cs), bicyclo[4.2.0]octane (Cs), spiro[2.5]octane (Cs), spiro [3.4] octane (Cs), bicyclo[3.3. l]nonane (C9), octahydro- IH-indene (C9), bicyclo[4.2.1]nonane (C9), spiro[3.5]nonane (C9), spiro[4.4]nonane (C9), bicyclo[3.3.2]decane (C10), bicyclo[4.3. l]decane (C10), spiro[4.5]decane (C10), bicyclo[3.3.3]undecane (Cn), decahydronaphthalene (C10), bicyclo[4.3.2]undecane (Cn), spiro [5.5] undecane (Cn) and bicyclo[4.3.3]dodecane (C12).In some embodiments '‘cycloalkyl” is a tricyclic cycloalkyl. In some embodiments, a tricyclic cycloalky l has 6-14 ring carbon atoms. (“Ce-14 tricyclic cycloalkyl”). In some embodiments, a tricyclic cycloalkyl group has 8 to 12 ring carbon atoms (“Cs-12 tricyclic cycloalkyl”). In some embodiments, a tricyclic cycloalkyd group has 10 to 12 ring carbon atoms (" C 10-12 tricyclic cycloalkyl. Examples of tricyclic cycloalkyds include adamantine (C12).

[0075] Unless otherw ise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.

[0076] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, andDocket No. TGO-035WOsilicon (“3-10 membered heterocyclyl”). In some embodiments, the heterocyclyl is a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1. 2 or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, including oxidized forms thereof In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl’') or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members designates the total number of atoms in the fused ring system. Unless otherw ise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In some embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

[0077] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0078] Exemplary' 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclylDocket No. TGO-035WOgroups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, -dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl. oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl. oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary' 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl. dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary' 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary' 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C, aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl. tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl. chromenyl, lH-benzo[e][l,4]diazepinyl, 1.4.5.7-tetrahydropyrano|3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4EI-thieno[2,3-c]pyranyl, 2,3-dihydro-lEI-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4.5.6.7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2, 3, 4-tetrahydro-1.6-naphthyridinyl. and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0079] ‘‘Nitrogen-containing heterocyclyl” group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation.Docket No. TGO-035WOmorpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl). azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0080] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0081] “Acyl” refers to a radical -C(=O)R20, where R20is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted ary l, or substituted or unsubstitued heteroaryl, as defined herein. “Alkanoyl” is an acyl group wherein R20is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (–C(=O)CH₃), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), — C(=O)-Ci-Cs alkyl, C(=O)-(CH2)t(Ce Cio aryl), -C(=O)-(CH2)t(5-10 membered heteroaryl), - C(=0)-(CH2)t(C3-Cio cycloalkyl), and -C(=O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In some embodiments, R20is Ci-Cs alkyl, substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted Ci-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0082] The term aminoalkyd refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an -NH2 group.

[0083] The term hydroxyalky 1 refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an -OH group.

[0084] The terms “alkylamino” and “dialkylamino” refer to -NH(alkyl) and~N(alkyl)2 radicals respectively. In some embodiments the alkylamino is a-NH(Ci-C4 alkyl). In some embodiments the alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n-buty lamino, iso-but 'lamino, sec-butylamino, or te / 7-buty lamino. In some embodiments the dialkylamino is -N(Ci-Ce alkyl)2. In some embodiments the dialkylamino is aDocket No. TGO-035WOdimethylamino, a methylethylamino, a diethylamino, a methylpropyl amino, a methylisopropylamino, a methylbulylamino. a methylisobutylamino or a methyltertbutylamino.

[0085] The term “aryloxy” refers to an -O-ary I radical. In some embodiments the aryloxy group is phenoxy.

[0086] The term “haloalkoxy” refers to alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the term “fluoroalkoxy” includes haloalkoxy groups, in which the halo is fluorine. In some embodiments haloalkoxy groups are difluoromethoxy and trifluoromethoxy.

[0087] “Alkoxy” refers to the group -OR29where R29is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl. substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy,.scc-butoxy. n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0088] In some embodiments, R29is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino. Ce-Cio aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary' ‘substituted alkoxy’ groups include, but are not limited to, -0-(CH2)t(Ce-Cio aryl), -O-(CH2)t(5-10 membered heteroaryl), -0-(CH2)t(C3-Cio cycloalkyl), and -O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyd, halo, unsubstituted C1-C4 alkoxy, unsubstituted Ci-C4 haloalky 1, unsubstituted C1-C4 hydroxy alkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy' groups are -OCF3, -OCH2CF3. -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2N(CH3)2.

[0089] “Amino” refers to the radical -NH2.

[0090] “Oxo group” refers to -C(=O)-.Docket No. TGO-035WO

[0091] ‘‘Substituted amino'’ refers to an amino group of the formula -N(R38)2 wherein R38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38is not a hydrogen. In some embodiments, each R38is independently selected from hydrogen, -Ci-Cs alkyl, -Cs-Cs alkenyl, -C3-C8 alkynyl, Cg-Cio aryl. 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or Ci-Cs alkyl, substituted with halo or hydroxy; C3-C8 alkenyl, substituted with halo or hydroxy; C3-C8 alky nyl, substituted with halo or hydroxy, or -(CH2XC6-C 10 aryl), -(CH2)t(5-10 membered he ternary I). -(CH2)t(C3-Cio cycloalkyl), or -(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alky l, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

[0092] Exemplary “substituted amino” groups include, but are not limited to, -NR39-CI-CS alkyl, -NR39-(CH2)t(Cg-Cio aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39-(CH2)t(C.3-Cio cycloalkyl), and -NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents H or Ci-Cs alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted C1-C4 haloalky l, unsubstituted C 1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino' includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylammo, arylamino. substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0093] In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, SO2RCC, SO2ORCC, SORaa, C(=S)N(RCC)2, C(=O)SRCC, C(=S)SRCC, C1-10 alkyl (e g., aralkyl, heteroaralkyl). -C2-10 alkenyl, -C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl,Docket No. TGO-035WOheteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis. T. W. Greene, and P. G. M. Wuts, 3rdedition, John Wiley & Sons. 1999. incorporated herein by reference.each instance of Raais, independently, selected from -C1-10 alkyl, -Ci-10 perhaloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rbbis. independently, selected from hydrogen, -OH. -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2. -CO2Raa. -SO2Raa, -C(=NRcc)ORaa. -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, -Ci-io alkyl, -C1-10 perhaloalkyl, -C2-10 alkenyl, -C2-10 alky nyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl. Ce-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, ary l, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X is a counterion.each instance of Rccis, independently, selected from hydrogen, -C1-10 alkyl, -Ci-io perhaloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 ary l, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alky nyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rddis, independently, selected from halogen, -CN, -NO2, N3. -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)?+X, -N(ORee)Rff, -SH, -SRee, -SSRee,Docket No. TGO-035WOC(=O)Ree, CO2H, CO2Ree, OC(=O)Ree, OCO2Ree, C(=O)N(Rff)2, OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2. -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(-S)N(R“)2. -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, -C1-6alkyl, -C1-6perhaloalkyl, -C2-6alkenyl, -C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S; wherein X is a counterion;each instance of Reeis, independently, selected from -C1-6alkyl, -C1-6perhaloalkyl, -C2-6alkenyl, -C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl. wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rffis, independently, selected from hydrogen, -C1-6alkyl, -C1-6perhaloalkyl, -C2-6alkenyl, -C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alky nyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, ary l, and heteroary l is independently substituted with 0, 1. 2, 3, 4, or 5 Rgggroups; andeach instance of Rggis, independently, halogen, -CN, -NO2, -Ns, -SO2H, -SO3H, -OH, -OCi-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3+X’, -NH(CI-6alkyl)2+X’, -NH2(CI-6alkyl) X, -NH3X. -N(OCI-6alkyl)(Ci-6alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH. -SCi-6 alkyl. -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl). -CO2H, -CO2(Ci-6alkyl).-OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)(C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6Docket No. TGO-035WOalkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(=NH)NH(C1-6alkyl), -OC(=NH)NH2, -NHC(=NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2, -C(=S)NH(C1-6alkyl), -C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)(OC1-6alkyl)2, -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2, -C1-6alkyl, -C1-6perhaloalkyl, -C2-6alkenyl, -C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0094] For example, nitrogen protecting groups such as amide groups (e.g.. -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxy acetamide, acetoacetamide. (N’-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

[0095] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2, 7-di-t-buty 1- [9-(l 0.10-dioxo- 10, 10, 10.10-tetrahy drothioxanthyl)]methy 1 carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropy lallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc). 8-quinolylDocket No. TGO-035WOcarbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthryl methyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)] methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2.4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc). 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cy anoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate. 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl)methyl carbamate, r-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N. N-dimethylcarboxamido)benzy 1 carbamate, 1, 1 -dimethyl-3-(N, N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobomyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1 -methylcyclobutyl carbamate. 1-methylcyclohexyl carbamate, 1 -methyl- 1 -cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, l-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1 -phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte). 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’-Docket No. TGO-035WOdimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0096] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)-acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole. N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE). 5-substituted l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1 -substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary’ ammonium salts, N-benzylamine. N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fem), N-2-picolylamino N′-oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-di phenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’, N’-dimethylaminomethylene)amine, N, N’-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0097] In some embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an ‘‘hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SRaa, -C(=O)Raa, CO2Raa, C(=O)N(Rbb)2, C(=NRbb)Raa, C(=NRbb)ORaa, C(=NRbb)N(Rbb)2, S(=O)Raa, -SO2Raa. -Si(Raa)3, -P(RCC)2, -P(RCC)3+X, -P(ORCC)2. -P(ORCC)3+X, -P(=O)(Raa)2,Docket No. TGO-035WO-P(=O)(ORcc)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein.Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene, and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0098] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM). / -butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM). benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), / -butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR). tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-di oxide, 1 -[(2-chloro-4-methyl)pheny 1] -4-methoxypiperidin-4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4.7-methanobenzofuran-2-yl. 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzy l (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl. o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2.6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl. tri(p-methoxyphenyl)methyl, 4-(4’-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4”-tris(benzoy loxyphenyl)methyl, 3-(imidazol- 1 -yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxido. trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, / -buty ldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,Docket No. TGO-035WOacetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxy acetate, phenoxyacetate, p-chlorophenoxyacetate. 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec). 2-(triphenylphosphonio) ethyl carbonate (Peoc). isobutyl carbonate, vinyl carbonate, allyl carbonate, / -butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzy l carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methy l dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-( 1, 1,3,3-tetramethylbuty l)phenoxy acetate, 2,4-bi s( 1, 1 -dimethylpropy l)phenoxy acetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N, N, N’, N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alky l 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0099] In some embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, C(=O)SRaa, C(=O)Raa, -CO2Raa, C(=O)N(Rbb)2, -C(=NRbb)Raa. -C(=NRbb)ORaa. -C(=NRbb)N(Rbb)2, -S(=O)Raa, -SO2Raa, -Si(Raa)3.-P(RCC)2, -P(RCC)3+X, -P(ORCC)2, -P(ORcc)3+X−, -P(=O)(Raa)2, -P(=O)(OR“)2, and -P(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene, and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0100] The term “leaving group” is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. Examples of suitable leaving groups include, but are not limited to, halogen (such as F, -Cl, -Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,Docket No. TGO-035WOalkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is halogen, alkanesulfonyloxy, arenesulfonyloxy, diazonium, alkyl diazenes, aryl diazenes, alkyl triazenes, aryl triazenes, nitro, alkyl nitrate, aryl nitrate, alkyl phosphate, ary l phosphate, alkyl carbonyloxy, aryl carbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, ammonia, alkyl amines, aryl amines, hydroxyl group, alkyloxy group, or aryloxy. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), / >-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g, formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0101] “Carboxy” refers to the radical -C(=O)OH.

[0102] “Cyano” refers to the radical -CN.

[0103] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In some embodiments, the halo group is either fluoro or chloro.

[0104] “Haloalky 1” refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (-CF3), difluoromethyl (-CHF2), fluoromethyl (-CH2F), chloromethyl (-CH2CI), dichloromethy l (-CHCh), tribromomethyl (-CH2Br), and the like.

[0105] “Hydroxy” refers to the radical -OH.

[0106] “Nitro” refers to the radical -NO2.

[0107] “Thioketo” refers to the group =S.

[0108] Alkyl, alkenyl, alkynyl. carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g, “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). InDocket No. TGO-035WOgeneral, the term “substituted’', whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g.. a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. Any and all such combinations are contemplated in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0109] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2. -N3, -SO2H. -SO3H. -OH, -ORaa. -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X−, -N(ORcc)Rbb. -SH, -SRaa, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, C(=O)N(Rbb)2, OC(=O)N(Rbb)2, NRbbC(=O)Raa, NRbbCO2Raa, NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -S(=O)(=NRbb)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)2Raa, -OP(=O)2Raa, -P(=O)(Raa)2, -OP(=O)(Raa)2. -OP(=O)(ORCC)2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2. -P(=O)(NRbb)2, -OP(=O)(NRbb)2, -NRbbP(=O)(OR“)2, -NRbbP(=O)(NRbb)2, -P(R“)2, -P(RCC)3, -OP(RCC)2, -OP(RCC)3, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), -Ci-io alkyl, -Ci-io haloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl. aryl, and heteroaryl is independently substituted with 0. 1, 2, 3, 4. or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from C1-10alkyl, -C1-10haloalkyl, -C2-10alkenyl, -C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14Docket No. TGO-035WOmembered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa. -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC. -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(RCC)2, -P(=O)(NRCC)2, -C1-10alkyl, -C1-10haloalkyl, -C2-10alkenyl, -C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alky nyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rccis, independently, selected from hydrogen, -C1-10alkyl, -C1-10haloalkyl, -C2-10alkenyl, -C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rddis. independently, selected from halogen. -CN. -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2,-NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, --C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, -C1-6alkyl, -C1-6haloalkyl, -C2-6alkenyl, -C2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =0 or =S;each instance of Reeis, independently, selected from C1-6alkyl, -C1-6haloalkyl, -C2-6alkenyl, -C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10Docket No. TGO-035WOmembered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, ary l, and heteroaryl is independently substituted with 0, 1, 2, 3. 4, or 5 Rgggroups;each instance of Rffis, independently, selected from hydrogen, -Ci-6 alkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl. aryl, and heteroaryl is independently substituted with 0. 1, 2, 3, 4. or 5 Rgggroups; andeach instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3+X−, -NH(C1-6alkyl)2+X−, -NH2(C1-6alkyl)+X−, -NH3+X−, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, -OC(=O)NH(C1-6alkyl), -NHC(=O)(C1-6alkyl), -N(C1-6alkyl)C(=O)(C1-6alkyl), -NHCO2(C1-6alkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1-6alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, -OC(=NH)NH(C1-6alkyl), -OC(=NH)NH2, -NHC(=NH)N(C1-6alkyl)2, -NHC(=NH)NH2, -NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(C1-6alkyl), -SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2, -C(=S)NH(C1-6alkyl), -C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)2(C1-6alkyl), -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(=O)(OC1-6alkyl)2, -C1-6alkyl, -C1-6haloalkyl, -C2-6alkenyl, -C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0110] A “counterion” or “anionic counterion” is a negatively7charged group associated with a cationic quaternary7amino group in order to maintain electronic neutrality7. Exemplary' counterions include halide ions (e.g., F, Cl", Br, I"), NO3, CIO4. OH, H2POr. HSO4. S OF2sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthal ene-2-sulfonate, naphthal ene-1 -sulfonic acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).Docket No. TGO-035WO

[0111] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=O)Raa, -C(=O)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, -SO2ORCC, -SORaa, -C(=S)N(RCC)2, -C(=O)SRCC, -C(=S)SRCC. -P(=O)2Raa, -P(=O)(Raa)2. -P(=O)2N(Rcc)2, -P(=O)(NRcc)2, -Ci-io alkyl, -Ci-io haloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, C3-10 carbocyclyl. 3-14 membered heterocyclyl, Ce- 14 aryl, and 5-14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, and, and heteroaryl is independently substituted with 0, 1.2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0112] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.Other definitions

[0113] As used herein, the term -’salt" refers to any and all salts and encompasses pharmaceutically acceptable salts.

[0114] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate,Docket No. TGO-035WOdodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate. lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci 4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0115] A “subject” to which administration is contemplated includes, but is not limited to, humans (z.e., a male or female of any age group, e.g, a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomologus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is anon-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.Disease, disorder, and condition are used interchangeably herein.

[0116] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (‘therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”). In some embodiments, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorderDocket No. TGO-035WOor condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

[0117] In general, the “effective amounf ’ of a compound refers to an amount sufficient to elicit the desired biological response e.g., to treat a disease or disorder described herein. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment (i. e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount”).

[0118] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated w ith the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the therapeutic treatment of the disease, disorder, or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of disease or condition, enhances the therapeutic efficacy of another therapeutic agent, or allows for a reduction in the dose of another therapeutic agent needed to achieve maximum efficacy.

[0119] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0120] As used herein, the term "selective" refers to a compound that is at least about 3-fold more potent (e.g., 3-fold, 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000-fold) against one target compared to other targets. For example, an HBS1L degrader that is selective over GSPT1 is at least 10-fold (e.g., 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold. 1000-fold) more potent against HBS1L than against GSPT1. In some embodiments,Docket No. TGO-035WOa selective HBS1L degrader is 10-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS1L degrader is 20-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS IL degrader is 30-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS1L degrader is 50-fold more potent against HBS IL than against GSPT1. In some embodiments, a selective HBS IL degrader is 100-fold more potent against HBS IL than against GSPT1. In some embodiments, a selective HBS IL degrader is 500-fold more potent against HBS IL than against GSPT1. In some embodiments, a selective HBS 1 L degrader is 1 OOO-fold more potent against HBS IL than against GSPT1. The difference in potency can be determined, for example, by comparing the DC50 values against different targets.Compounds

[0121] Provided herein are compounds of Formula (I). Unless the context requires otherwise, reference throughout this specification to “a compound of Formula (I)7’ or “compounds of Formula (I)” refers to all embodiments of Formula (I) including, for example, compounds of Formula (I), (F), (I”), (II), (IF), (II ”), (II-l), (II-l ’), (11-1 ”), as well as the compounds of Table 1.

[0122] The compounds of the present disclosure are degraders of HBS1L. In some embodiments, the compounds selectively degrade HBS IL over GSPT1.

[0123] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 member heteroaryl containing 1-3 heteroatoms selected from N, O and S;R3and R3are each independently selected from the group consisting of H, -C1-C3 alkyl and -C1-C3 haloalkyl or are taken together with the carbon to which they are attached toDocket No. TGO-035WOform a C3-C9 cycloalky l or a 4-7 membered heterocyclyl containing 1 heteroatom selected from N, O and S. provided that R3and R3are not both H;each RAis independently selected from the group consisting of -D, halo, -CN, -SF5, -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -C3-C9 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9 cycloalkyl). -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -C(=O)ORA2, -NRA2C(=O)RA1, -NRA2C(=O)ORA1, -C(=O)N(RA2)2, -C(=O)N(ORA2)(RA2), -OC(=O)N(RA2)2, -S(=O)RA1, -S(=O)2RA1, -SRA2, -S(=O)(=NRA2)RA1, -NRA2S(=O)2RA1and -S(=O)2N(RA2)2;each RBis independently selected from the group consisting of -D, halo, -CN, =O, -SF5, -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl,-Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl), -ORB2, -N(RB2)2, -C(=O)RB1, -C(=O)ORB2, -NRB2C(=O)RB1, -NRB2C(=O)ORB1, -C(=O)N(RB2)2, -C(=O)N(ORB2)(RB2), -OC(=O)N(RB2)2, -S(=O)RB1, -S(=O)2RB1, -SRB2, -S(=O)(=NRB2)RB1, -NRB2S(=O)2RB1and -S(=O)2N(RB2)2wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of -OMe or -OH;each R4is independently selected from -D, =O, halo, -OH, -NH2, -CN, -Ci-Ce alkyl, -Ci-C6haloalkyl, -Ci-C6hydroxyalkyl, -OC1-C6alkyl, -OCi-C6haloalkyl, -NH(C1-C6alkyl), -N(C1-C6alkyl)2;each RB1is independently selected from -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9 cy cloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl);each RB2is independently selected from –H, -D, -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce haloalkyl. -Ci-Ce haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 memberedDocket No. TGO-035WOheterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl), wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1 or 2 instances of C1-C6alkyl, OH or halo;n is 0, 1, 2 or 3; andm is 0, 1, 2 or 3.

[0124] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:(I); and whereinRing B, RA, RB, R3, R3', m and n are as defined in any of the embodiments described herein.

[0125] In some embodiments, the compound is of Formula (I’),(I') wherein Ring B, RA, RB, R3, m and n are as defined in any of the embodiments described herein.

[0126] In some embodiments, the compound is of Formula (1”),(I”) wherein Ring B, RA, RB, R3, R3, m and n are as defined in any of the embodiments described herein.Docket No. TGO-035WOOthe attachment point to H H

[0128] As generally defined herein, each RAis independently selected from the group consisting of -D, halo, -CN, -SF5, -Ci-Ce alkyl, -Ci-Ce alkenyl, -C1-C6heteroalkyl, -C1-C6haloalkyl, -C3-C9 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered ary l, 6-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6- 10 membered aryl), -(C1-C2 alkyl)(6- 10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -C(=O)ORA2, -NRA2C(=O)RA1, -NRA2C(=O)ORA1, -C(=O)N(RA2)2, -C(=O)N(ORA2)(RA2), -OC(=O)N(RA2)2, -S(=O)RA1, -S(=O)2RA1, -SRA2, -S(=O)(=NRA2)RA1, -NRA2S(=O)2RA1and -S(=O)2N(RA2)2

[0129] In some embodiments, each RAis independently selected from the group consisting of halo, -Ci-Ce alkyl, -Ci-Ce alkenyl, and -ORA2.

[0130] In some embodiments, each RAis independently' selected from the group consisting of -F, -Cl, -Me, -Et, -zPr, - / Bu. -vinyl, and -OCH3.

[0131] In some embodiments, each RAis independently selected from the group consisting of –F, –Cl, –Me, -Et, -vinyl, and -OCH3.

[0132] In some embodiments, RAis -D.

[0133] In some embodiments, RAis halo (e.g, fluoro, chloro, bromo, iodo). In some embodiments, RAis -Cl. In some embodiments, RAis -F. In some embodiments, RAis -Br. In some embodiments. RAis -I.

[0134] In some embodiments, RAis -CN.

[0135] In some embodiments, RAis -SF5.

[0136] In some embodiments, RAis –C1–C6alkyl (e.g., –Me, –Et, –nPr –iPr, –tBu) In some embodiments, RAis -Me. In some embodiments, RAis -Et. In some embodiments RAis –nPr or –iPr.Docket No. TGO-035WO

[0137] In some embodiments, RAis -Ci-Ce alkenyl (e.g., -vinyl, isopropenyl). In some embodiments, RAis -vinyl. In some embodiments, RAis -isopropenyl.

[0138] In some embodiments, RAis -Ci-Ce heteroalkyl (e.g., methoxy methyl, methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl). In some embodiments, RAis methoxymethyl (-CH2OCH3). In some embodiments, RAis aminomethyl (e.g.,-CH2NH2, -CH2NHCH3, -CH2N(CH3)2.

[0139] In some embodiments, RAis -Ci-Ce haloalkyl (e.g.. -CHF2. -CH2F, -CF3, -CH2CF3). In some embodiments, RAis trifluoromethyl (-CF3). In some embodiments, RAis difluoromethyl (-CHF2).

[0140] In some embodiments, RAis C3-C9cycloalkyl (e.g, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, RAis cyclopropyl. In some embodiments RAis cyclobutyl. In some embodiments, RAis cyclopentyl. In some embodiments, RAis cyclohexyl.

[0141] In some embodiments, RAis 4-10 membered heterocyclyl. In some embodiments, RAis 4-7 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pipendinyl, piperazinyl, morpholinyl, azepanyl). In some embodiments, RAis oxetanyl. In some embodiments, RAis tetrahydropyranyl. In some embodiments, RAis tetrahydrofuranyl. In some embodiments, RAis azetidinyl. In some embodiments, RAis pyrrolidinyl. In some embodiments, RAis piperidinyl. In some embodiments, RAis piperazinyl. In some embodiments. RAis morpholinyl. In some embodiments, RAis azepanyl.

[0142] In some embodiments, RAis 6-10 membered aryl (e.g., phenyl, naphthyl, dihydrobenzofuranyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, wherein the attachment point is on the phenyl ring). In some embodiments, RAis phenyl.

[0143] In some embodiments, RAis a 5-10 membered heteroaryl. In some embodiments, RAis a 5-6 membered monocyclic heteroaryl (e.g, furanyl, pyrrolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, oxathiazolyl). In some embodiments, RAis an 8-10 membered bicyclic heteroaryl (e.g., indolyl, benzofuranyl, benzothiophenyl, IH-indazolyl. 2-H-indazolyl. benzothiazolyl. benzimidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl).

[0144] In some embodiments RAis -(C1-C2 alkyl)(C3-C9 cycloalkyl), (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,cycloheptylmethyl).Docket No. TGO-035WO

[0145] In some embodiments, RAis -(C1-C2 alkyl)(4- 10 member heterocyclyl) (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl. pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0146] In some embodiments, RAis -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, RAis benzyl.

[0147] In some embodiments, RAis -(C1-C2 alkyl)(6-10 membered heteroaryl), (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0148] In some embodiments, RAis -ORA2wherein RA2is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy). In some embodiments, RAis hydroxy. In some embodiments, RAis methoxy. In some embodiments, RAis ethoxy. In some embodiments, RAis propoxy. In some embodiments, RAis isopropoxy. In some embodiments, RAis -Ci-Ce haloalkoxy. In some embodiments, RAis trifluoromethoxy (-OCF3). In some embodiments, RAis difluoromethoxy (-OCHF2).

[0149] In some embodiments, RAis -N(RA2)2 wherein each RA2is independently as defined in any of the embodiments described herein (e.g., –NH2, –NHRA2, –N(CH3)RA2). In some embodiments, RAis -NH2. In some embodiments, RAis –NHRA2(e.g., –NHCH3, - NHCH2CH3, -NHPr, -NH'Pr, -NHcyclopropyl, -NHcyclobutyl). In some embodiments, RAis -N(CH3)RA2(e.g.. -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH2CH2CH3, -N(CH3)Pr, -N(CH3)cyclopropyl, -N(CH3)cyclobutyl).

[0150] In some embodiments, RAis -C(=O)RA1or -C(=O)ORA2wherein RA1and RA2are independently as defined in any of the embodiments described herein. In some embodiments, RAis -C(=O)RA1wherein RA1is as defined in any of the embodiments described herein. In some embodiments, RAis -C(=O)(C1-C8alkyl). RAis -C(=O)(C3-C9cycloalkyl). In some embodiments, RAis -C(=O)CH3, -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O)zBu, -C(=O)iPr, -C(=O)CH2CH2CH3 or-C(=O)OCH3. In some embodiments, RAis acetyl (-C(=O)CH3). In some embodiments, RAis -C(=O)ORA2. In some embodiments, RAis -COOH. In some embodiments, RAis –COOCH3.

[0151] In some embodiments, RAis -NRA2C(=O)RA1wherein RA1and RA2are independently as defined in any of the embodiments described herein. In some embodiments, RAis -NHC(=O)RA1(e.g., -NHC(=O)CH3, -NHC(=O)CH2CH3, -NHC(=O)CH2CH2CH3, -NHC(=O)‘Pr, -NHC(=O)Bu, -NHC(=O)‘Bu, -NHC(=O)Cyclopropyl, -Docket No. TGO-035WONHC(=O)Cyclobutyl). In some embodiments, RAis -N(CH3)C(=O)RA1(e.g., -N(CH3)C(=O)CH3. -N(CH3)C(=O)CH2CH3, -N(CH3)C(=O)CH2CH2CH3, -N(CH3)C(=O)‘Pr, -N(CH3)C(=O)Bu, -N(CH3)C(=O)1BU, -N(CH3)C(=O)Cyclopropyl, -N(CH3)C(=O)Cyclobutyl).

[0152] In some embodiments, RAis -NRA2C(=O)ORA1wherein RA1and RA2are independently as defined in any of the embodiments described herein. In some embodiments, RAis -NHC(=O)ORA1(e.g.. -NHC(=O)OCH3, -NHC(=O)OCH2CH3, -NHC(=O)OCH2CH2CH3, -NHC(=O)O‘Pr, -NHC(=O)OBu, -NHC(=O)OlBu, -NHC(=O)OCyclopropyl, -NHC(=O)OCyclobutyl). In some embodiments, RAis -N(CH3)C(=O)ORA2(e.g, -N(CH3)C(=O)OCH3, -N(CH3)C(=O)OCH2CH3, -N(CH3)C(=O)OCH2CH2CH3, -N(CH3)C(=O)O‘Pr, -N(CH?)C(=O)OBu, -N(CH3)C(=O)OtBu, -N(CH3)C(=O)OCyclopropyl, -N(CH3)C(=O)OCyclobutyl).

[0153] In some embodiments, RAis -C(=O)N(RA2)2wherein RA2is as defined in any of the embodiments described herein (e.g., -C(=O)NH2, -C(=O)NHRA2, -C(=O)N(CH3)RA2). In some embodiments, RAis -C(=O)NH2. In some embodiments, RAis -C(=O)NHRA2(e.g, -C(=O)NHCH3. -C(=O)NHCH2CH3. -C(=O)NHPr, -C(=O)NH'Pr, -C(=O)NHBu, -C(=O)NHfBu, -C(=O)NHCyclopropyl, -C(=O)NHCyclobutyl). In some embodiments, RAis -C(=O)N(CH3)RA2(e.g., -C(=O)N(CH3)2, -C(=O)N(CH3)CH2CH3, -C(=O)N(CH3)CH2CH2CH3, -C(=O)N(CH3)'Pr, -C(=O)N(CH3)Bu, -C(=O)N(CH3)Bu, -C(=O)N(CH3)Cyclopropyl, -C(=O)N(CH3)Cyclobutyl).

[0154] In some embodiments, RAis -C(=O)N(ORA2)(RA2) wherein RA2is as defined in any of the embodiments described herein. In some embodiments, RAis -C(=O)NH(ORA2) (e.g., -C(=O)NHOH, -C(=O)NHOCH3). In some embodiments, RAis -C(=O)NHOH.

[0155] In some embodiments, RAis -OC(=O)N(RA2)2wherein RA2is as defined in any of the embodiments described herein. In some embodiments, RAis -OC(=O)NHRA2(e.g., -OC(=O)NHCH3, -OC(=O)NHCH2CH3, -OC(=O)NHPr, -OC(=O)NH'Pr. -OC(=O)NHBu, -OC(=O)NHBu, -OC(=O)NHCyclopropyl, -OC(=O)NHCyclobutyl). In some embodiments, RAis -OC(=O)N(CH3)RA2(e.g, -OC(=O)N(CH3)2. -OC(=O)N(CH3)CH2CH3. -OC(=O)N(CH3)CH2CH2CH3, -OC(=O)N(CH3)'Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3)Cyclopropyl, -OC(=O)N(CH3)Cyclobutyl).

[0156] In some embodiments, RAis -S(=O)RA1wherein RA1is as defined in any of the embodiments described herein. In some embodiments, RAis -S(=O)alkyl (e.g., -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH2CH3, -S(=O)Pr). In some embodiments, RAis -Docket No. TGO-035WOS(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=0)cyclohexyl).

[0157] In some embodiments, RAis -S(=O)2RA1wherein RA1is as defined in any of the embodiments described herein. In some embodiments, RAis -S(=O)2alkyl (e.g., -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2Pr, -S(=O)2iPr). In some embodiments, RAis -S(=O)2Cycloalkyl (e.g., -S(=O)2cyclopropyl, -S(=O)2cyclobutyl, -S(=O)2cyclopentyl, -S(=O)2cyclohexyl). In some embodiments, RAis S(=0)2aryl (e.g., -S(=O)2phenyl).

[0158] In some embodiments, RAis -SRA2wherein RA2is as defined in any of the embodiments described herein. In some embodiments, RAis -Salkyl (e.g., -SCH3, -SCH2CH3, -SPr, -S'Pr). In some embodiments, RAis -Scycloalkyl (e.g, -Scyclopropyl, -Scyclobutyl, -S cyclopentyl, -Scyclohexyl). In some embodiments, RAis -Saryl (e.g., -Sphenyl).

[0159] In some embodiments, RAis -S(=O)(=NRA2)RA1wherein RA1and RA2are independently as defined in any of the embodiments described herein. In some embodiments, RAis -S(=O)(=NH)RA1(e.g., -S(=O)(=NH)CH3, -S(=O)(=NH)CH2CH3. -S(=O)(=NH)CH2CH2CH3. -S(=O)(=NH)iPr, -S(=O)(=NH)Bu, -S(=O)(=NH)lBu, -S(=O)(=NH)Cyclopropyl, -S(=O)(=NH)Cyclobutyl). In some embodiments, RAis -S(=O)(=NCH3)RA1(e g., S(=O)(=NCH3)CH3, S(=O)(=NCH3)CH2CH3, S(=O)(=NCH3)CH2CH2CH3, -S(=O)(=NCH3)'Pr, -S(=O)(=NCH3)Bu, -S(=O)(=NCH3)‘BU, -S(=0)(=NCH3)CyclopropyL -S(=O)(=NCH3)Cyclobutyl).

[0160] In some embodiments, RAis -NRA2S(=O)2RA1wherein RA1and RA2are independently as defined in any of the embodiments described herein. In some embodiments, RAis -NHS(=O)2alkyl (e.g, -NHS(=O)2CH3, -NHS(=O)2CH2CH3, -NHS(=O)2Pr, -NHS(=O)2iPr). In some embodiments, RAis -NHS(=O)2Cycloalkyl (e.g., -NHS(=O)2Cyclopropyl, -NHS(=O)2Cyclobutyl, -NHS(=O)2Cyclopentyl, -NHS(=O)2cyclohexyl). In some embodiments, RAis -N(CH3)S(=O)2alkyl (e.g., -N(CH3)S(=O)2CH3, N(CH3)S(=O)2CH2CH3, N(CH3)S(=O)2Pr, N(CH3)S(=O)2iPr). In some embodiments,RAis -N(CH3)S(=O)2cycloalkyl (e.g., -N(CH3)S(=O)2cyclopropyl, -N(CH3)S(=O)2Cyclobutyl, -N(CH3)S(=O)2Cyclopentyl, -N(CH3)S(=O)2Cyclohexyl).

[0161] In some embodiments, RAis -S(=O)2N(RA2)2 wherein RA2is as defined in any of the embodiments described herein, (e.g., -S(=O)2NH2, -S(=O)2NHRA2, -S(=O)2N(CH3)RA2). In some embodiments, RAis -S(=O)2NH2. In some embodiments, RAis -S(=O)2NHRA2(e.g., -S(=O)2NHCH3, -S(=O)2NHCH2CH3, -S(=O)2NHPr, -S(=O)2NH'Pr, -S(=O)2NHcyclopropyl,Docket No. TGO-035WO-S(=O)2NHcyclobutyl). In some embodiments, RAis -S(=O)2N(CH3)RA2(e.g., -S(=O)2N(CH3)2, -S(=O)2N(CH3)CH2CH3, -S(=O)2N(CH3)CH2CH2CH3, -S(=O)2N(CH3)iPr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0162] As generally defined herein, R3and R3'are each independently selected from the group consisting of H, -C1-C3 alkyl and -C1-C3 haloalkyl or are taken together with the carbon to which they are attached to form a C3-C9 cycloalkyl or a 4-7 membered heterocyclyl containing 1 heteroatom selected from N, O and S, provided that R3and R3'are not both H;

[0163] In some embodiments, R3and R3'are each independently selected from H, -C1-C3 alkyl and -C1-C3 haloalkyl or are taken together with the carbon to which they are attached to form a C3-C6 cycloalkyl or a 4-7 membered heterocyclyl containing 1 oxygen atom, provided that R3and R3'are not both H.

[0164] In some embodiments, R3and R3'are each independently -C1-C3 alkyl.

[0165] In some embodiments, R3and R3'are each independently selected from H, -Me, -Et, -iPr and -CF3or are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl ring, provided that R3and R3'are not both H.

[0166] In some embodiments, R3and R3'are each independently selected from H, -Me and -Et.

[0167] In some embodiments, R3and R3'are both -Me.

[0168] As generally defined herein, Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof, and 5-14 member heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0169] In some embodiments, Ring B is selected from 6-14 membered aryl, C3-C9 cycloalkyl and 5-14 member heteroaryl containing 1-3 heteroatoms selected fromN, O and S.

[0170] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 member bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C4-C9 fused bicyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 member tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0171] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 member bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9Docket No. TGO-035WObridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 member tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0172] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 member bicyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl. 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0173] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3-dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo [4.2.0]octanyl, octahydro- IH-indenyl, decahydronaphthalenyl, bicyclo [l.l.l]pentanyl, bicyclo[1.2.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl. oxetanyl, azepanyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2-H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0174] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1, 2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl. isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-Docket No. TGO-035WObenzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo [4.2.0]octanyl, octahydro- IH-indenyl, decahydronaphthalenyl, bicyclo[1.1.1]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptan-yl, bicyclo[2.2.2]octanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl. thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl. benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2-H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0175] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl. pyrimidinyl, benzo[d]isothiazolyl. indolyl, benzofuranyl, IH-indazolyl, 2-H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl. thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0176] In some embodiments, Ring B is selected from the group consisting ofDocket No. TGO-035WO

[0177] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthal enyl, 1, 2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.

[0178] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, naphthalenyl, 9. 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.

[0179] In some embodiments, Ring B is 6-14 member ary l. In some embodiments, Ring B is phenyl, 9-10 member bicyclic aryl or 13-14 membered tricyclic aryl. In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.

[0180] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, naphthalenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl. In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-inden-5-yl, 2, 3-dihydrobenzofuran-6-yl, benzo[d][l,3]dioxol-5-yl, naphthalen-2-yl, 9,10-dihydrophenanthren-2-yl, 6H-benzo[c]chromen-3-yl, 6H -benzofc] chromen-8-yl and 5,6-dihydrophenanthridin-3-yl.

[0181] In some embodiments, Ring B is selected from phenyl or 9-10 member bicyclic aryl. In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-IH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl.Docket No. TGO-035WOindolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1.2, 3, 4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl and 9-H fluorenyl.

[0182] In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro- IH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl and naphthal enyl. In some embodiments, Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-inden-5-yl. 2, 3-dihydrobenzofuran-6-yl, benzo[d][l,3]dioxol-5-yl and naphthalen-2-yl.

[0183] In some embodiments, Ring B is phenyl.

[0184] In some embodiments, the moiety' represented as

[0185] As generally defined herein, each RBis independently selected from the group consisting of -D, halo, -CN, =0, -SF5, -C1-C6alkyl, -C1-C6alkenyl, -C1-C6heteroalkyl, -C1-C6haloalkyl, -C1-C6haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, –(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroary 1), -ORB2, -N(RB2)2, -C(=O)RB1, -C(=O)ORB2, -NRB2C(=O)RB1, -NRB2C(=O)ORB1, -C(=O)N(RB2)2, -C(=O)N(ORB2)(RB2), -OC(=O)N(RB2)2. -S(=O)RB1, -S(=O)2RB1, -SRB2. -S(=O)(=NRB2)RB1, -NRB2S(=O)2RB1and -S(=O)2N(RB2)2 wherein each ary l, cycloalky l, cycloalkenyl, heterocyclyl and heteroary l is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkeny l, haloalkyl and haloalkeny l is substituted with 0 or 1 instances of-OMe or -OH. and wherein each R4, RB1and RB2is independently as defined in any of the embodiments described herein.

[0186] In some embodiments, each RBis independently selected from the group consisting of-D, halo, =0, -CN, -SF5, -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce haloalkyl, -Ci-CgDocket No. TGO-035WOhaloalkenyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof. 6-10 membered aryl. 5-6 member heteroaryl containing 1-3 heteroatoms selected fromN, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(6-10 membered aryl), -ORB2, -N(RB2)2, -C(=O)RB1and — NRB2S(=O)2RB1wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of-OMe or -OH, wherein each R4is as defined in any of the embodiments described herein.

[0187] In some embodiments, each RBis independently selected from the group consisting of-D, halo, -CN, SF5, -Ci-Ce alkyl, -Ci-Ce alkenyl, -C1-C6haloalkyl, -Ci-Ce haloalkenyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl containing 1-2 heteroatoms selected fromN, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-2 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(6-10 membered ary l), -ORB2, -N(RB2)2, -C(=O)RB1and — NRI!2S(=O)2RI>’1wherein each ary l, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of -OMe or -OH, and wherein each R4is selected from -F, -C1,=O, -OH,-OMe, -CN, -Me, - / Bu. -CF3, -OCF3, -CHF2and CH2CH2OH; RB1is phenyl, and each RB2is independently selected from -Me, -Et, -CF3, –CH(CH3)oxetan-3-yl, imidazol-2-yl and phenyl.

[0188] In some embodiments, each RBis independently selected from the group consisting of-D, halo, -Ci-Ce alkyl, -Ci-Ce haloalkyl, C3-C9 cycloalkyl and 6-10 membered aryl wherein each ary l and cycloalkyl is substituted with 0, 1, 2 or 3 instances of R4, and each alky l is substituted with 0 or 1 instances of -OH and wherein each R4is selected from -F, - / Bu and -CF3.

[0189] In some embodiments, each RBis independently selected from the group consisting of -F, -Cl, -Br, -CN, -Me, -Et,-iPr, -tBu, 3,3-dimethy lbutan-2-yl, vinyl, isopropenyl, -OMe, -OCF3, -O(l-(oxetan-3-yl)ethyl), -Ocyclopropyl, -cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentan-1-yl, spiro[2.2]pentanyl, -ODcyclopropyl, -SF5, -CHF2, -C(F)(CH3)2, -CF3, -CF2CH3, -C(=CF2)CH2CH2CH3, -CH(CF3)CH3. -C(CF3)(CH3)2, -CH2CF3, -C(=CH2)CF3, phenyl, -N(CH3)2, -N(CH3CH2)2, furan-3-yl, pyridin-2-yl, 4-oxo-4H-chromen-3-yl, pyrrolidin-l-yl, piperidin-l-y 1, morpholin-4-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, azetidin-l-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, piperazin-1-yl, tetrahydrofuran-3-yl, 8-oxabicyclo[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]oct-2-en-3-yl,Docket No. TGO-035WO2,3-dihydro-l,4-dioxin-5-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-4-yl, -NH-imidazol-2-yl, NH-phenyl, benzyl, -C(=O)phenyl, -OPhenyl, N(CH3)S(=O)2phenyl, wherein each -Me,- Et,-iPr, -tBu, 3,3-dimethylbutan-2-yl, -CHF2, -C(F)(CH3)2, -CF3, -CF2CH3, -C(=CF2)CH2CH2CH3, -CH(CF3)CH3, -CH2CF3and -C(CF3)(CH3)2is substituted with 0 or 1 instances of-OMe or -OH and each cyclopropyl, cyclobutyl, cyclohexyl, bicy clo [ 1.1.1] pentan- 1-yl, spiro[2.2]pentanyl. phenyl, oxetan-3-yl, furan-3-yl, pyridin-2-yl, 4-oxo-4H-chromen-3-yl, pyrrolidin-l-yl, piperidin-l-yl, morpholin-4-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, azetidin-l-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, piperazin- 1-yl, tetrahydrofuran-3-yl, 8-oxabicyclo[3.2. l]octan-3-yl, 8-oxabicyclo[3.2. l]oct-2-en-3-yl, 2,3-dihydro-l,4-dioxin-5-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-4-yl, imidazol-2-yl is substituted at available positions with 0, 1 or 2 instances of R4wherein each R4is as defined in any of the embodiments described herein.

[0190] In some embodiments, each R4is selected from -F, -C1,=O, -OH,-OMe, -OCF3, -CN, -Me, -tBu, -CHF2, -CF3. -CH2CH2OH.

[0191] In some embodiments, each RBis independently selected from the group consisting of -Cl, -tBu, 3,3-dimethylbutan-2-yl, -cyclopropyl, -CHF2, -CF3and -phenyl wherein each - / Bu and 3,3-dimethylbutan-2-yl is substituted with 0 or 1 instances of -OH, and wherein each -cyclopropyl and phenyl is substituted at available positions with 0, 1 or 2 instances of R4wherein each R4is as defined in any of the embodiments described herein. In some embodiments, each R4is selected from -F, -tBu and -CF3.

[0192] In some embodiments, each RBis independently selected from the group consisting of:HO-F, -Cl,-Br, -CN, -Me, -Et, -iPr, -tBu,, -CH=CH2, -C(=CH2)CH3, -SF5, -CHF2,-C(F)(CH3)2. -CF3, -CF2CH3,F^F, -CH(CF3)CH3,CF3, -C(CF3)(CH3)2, -. CNCH2CF3, -C(=CH2)CF3Docket No. TGO-035WO

[0193] In some embodiments, each RBis independently selected from the group consisting of:Docket No. TGO-035WO

[0194] In some embodiments, each RBis independently selected from the group consisting of:

[0195] In some embodiments, each RBis independently selected from the group consisting of:

[0196] In some embodiments, RBis =O,

[0197] In some embodiments, RBis -D.

[0198] In some embodiments, RBis halo (e.g., fluoro, chloro, bromo, iodo). In some embodiments each RBis independently selected from -F and -Cl. In some embodiments. RBis -Cl. In some embodiments, RBis -F. In some embodiments, RBis -Br. In some embodiments, RBis -I.

[0199] In some embodiments, RBis -CN.

[0200] In some embodiments, RBis -SF5.

[0201] In some embodiments, RBis -Ci-Ce alkyl. In some embodiments. RBis selected from the group consisting of -Me, -Et, -nPr, -iPr, -tBu, 3,3-dimethylbutan-2-yl, each substituted with 0 or 1 instances of -OH or -OMe.

[0202] In some embodiments, RBis selected from the group consisting of -Me, -Et, -nPr, -iPr. -tBu, 3,3-dimethylbutan-2-yl, each substituted with 0 or 1 instances of -OH.

[0203] In some embodiments, RBis selected from the group consisting of 3,3-dimethylbutan-2-yl and -tBu.

[0204] In some embodiments, RBis -Me. In some embodiments, RBis -Et. In some embodiments RBis -iPr. In some embodiments RBis -tBu. In some embodiments RBis 3,3-dimethyl-2-hydroxybutan-2-yl. In some embodiments, RBis selected from the group consisting of 3,3-dimethylbutan-2-yl and -tBu each substituted with 0 or 1 instances of -OH.Docket No. TGO-035WO

[0205] In some embodiments, RBis -Ci-Ce alkenyl. In some embodiments, RBis selected from the group consisting of -vinyl and isopropen-2-yl. In some embodiments, RBis -vinyl. In some embodiments, RBis isopropen-2-yl.

[0206] In some embodiments, RBis -Ci-Ce heteroalkyl. In some embodiments, RBis methoxymethyl (-CH2OCH3). In some embodiments, RBis hydroxymethyl (-CH2OH). In some embodiments, RBis aminomethyl (e.g.,-CH2NH2, -CH2NHCH3, -CH2N(CH3)2.

[0207] In some embodiments, RBis -Ci-Ce haloalkyl or -Ci-Ce haloalkenyl.

[0208] In some embodiments, RBis selected from the group consisting -CHF2, -C(F)(CH3)2, -CF2CH3, -C(=CF2)CH2CH2CH3, -CF3, -CH(CF3)CH3, -C(CF3)(CH3)2, -CH2CF3, -C(=CH2)CF3, each substituted with 0 or 1 instances of -OH or -OMe (e.g, substituted with 0 or 1 instance of OMe).

[0209] In some embodiments, RBis selected from the group consisting of –CHF2, and –CF3.

[0210] In some embodiments, RBis trifluoromethyl (–CF3). In some embodiments, RBis difluoromethyl (–CHF2).

[0211] In some embodiments, RBis C3-C9 cycloalkyl wherein the cycloalkyl is substituted with 0, 1. 2 or 3 instances of R4.

[0212] In some embodiments, RBis selected from the group consisting of C3-C7 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl). C4-C9 fused bicyclic cycloalkyl (e.g, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo [4.2.0]octanyl, octahydro- IH-indenyl, decahydronaphthalenyl), C5-C9 bridged cycloalkyl (e.g, bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl) and C5-C9 spiro cycloalkyl (e.g, spiro [2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl), each substituted with 0, 1, 2 or 3 instances of R4wherein each R4is as defined in any of the embodiments described herein.

[0213] In some embodiments, RBis selected from the group consisting of C3-C7 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C5-C9 bridged cycloalkyl (e.g, bicyclo [l.l.l]pentanyl, bicyclo[1.2.1]hexanyl,bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl) and C5-C9 spiro cycloalkyl (e.g. spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl), each substituted with 0, 1, 2 or 3 instances of R4wherein each R4is as defined in any of the embodiments described herein.Docket No. TGO-035WO

[0214] In some embodiments, RBis selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, bicyclo [l.l.l]pentanyl and spiro[2.2]pentanyl, each substituted with 0, or 1 instances of R4wherein each R4is as defined in any of the embodiments described herein. In some embodiments, each R4is independently selected from the group consisting of -Me, -rBu, -OCF3, -CF3 and -CN. In some embodiments, R4is independently selected from the group consisting of- / Bu, and -CF3.

[0215] In some embodiments, RBis selected from the group consisting of,

[0216] In some embodiments, RBis C3-C7 monocyclic cycloalkyl substituted with 0, or 1 instances of R4wherein each R4is as defined in any of the embodiments described herein.

[0217] In some embodiments, RBis selected from the group consisting of cyclopropyl, cyclobutyl and cyclohexyl, each substituted with 0 or 1 instances of R4wherein each R4is as defined in any of the embodiments described herein.

[0218] In some embodiments, RBis cyclopropyl substituted with 0 or 1 instances of R4wherein each R4is as defined in any of the embodiments described herein.

[0219] In some embodiments, R4is selected from the group consisting of - / Bu. and -CF3.

[0220] In some embodiments, RBis selected from the group consisting ofand F Z V^F / \F

[0221] In some embodiments, RBisF7 l^F

[0222] In some embodiments, Rn is t— AF

[0223] In some embodiments, RBis -(C1-C2 alkyl)(C3-C9 cycloalkyl) wherein the cycloalkyl is substituted with 0, 1, 2 or 3 instances of R4.

[0224] In some embodiments, RBis -(C1-C2 alkyl)(C3-C9 cycloalkyl) wherein the cycloalkyl is substituted with 0 or 1 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, R4is -Me.Docket No. TGO-035WO

[0225] In some embodiments,RBis.

[0226] In some embodiments, RBis 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof, wherein the heterocyclyl is substituted with 0, 1, 2 or 3 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, RBis selected from the group consisting of 4-oxo-4H-chromenyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, piperazinyl, tetrahydrofuranyl, 8-oxabicyclo[3.2. l]octanyl, 8-oxabicyclo[3.2. l]oct-2-enyl, tetrahydropyranyl, 3,4-dihydro-2H-pyranyl, 2,3-dihydro-l,4-dioxinyl and 3.6-dihydro-2H-pyranyl, each substituted with 0 or 1 instances of R4wherein each R4is as defined in any of the embodiments described herein.substituted with 0, 1, 2 or 3 instances of R4wherein each R4is as defined in any of the embodiments described herein. In some embodiments, each R4is selected from the group consisting of =0,-F, -Me, -OH, -CH2CH2OH, -OMe and -CHF2

[0228] In some embodiments, RBis 6-10 membered aryl wherein the aryl is substituted with 0, 1, 2 or 3 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, RBis phenyl substituted with 0, 1 or 2 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, RBis phenyl substituted with 0 or 1 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, each R4is independently selected from -F, -Cl and -Me. In some embodiments, each RBis independently selected fromDocket No. TGO-035WO

[0229] In some embodiments, RBis 5-6 member heteroarvl containing 1-3 heteroatoms selected fromN, O and S (e.g., furanyl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl), wherein the heteroaryl is substituted with 0, 1, 2 or 3 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, R4is selected from -Me. -F. -Cl, -OMe and -CF3.

[0230] In some embodiments RBis -(C1-C2 alkyl)(6-10 membered cycloalkyl) (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0231] In some embodiments, RBis -(C1-C2 alkyl)(6-10 membered heterocyclyl)(e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0232] In some embodiments, RBis -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, RBis benzyl.

[0233] In some embodiments, RBis -(C1-C2 alkyl)(6-10 membered heteroaryl) (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0234] In some embodiments, RBis -ORB2wherein RB2is as defined in any of the embodiments described herein (e.g., hydroxy (-OH), methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, phenoxy, -OCH(CH?)oxetan-yl, -OCF3).

[0235] In some embodiments, RBis -N(RB2)2 wherein RB2is as defined in any of the embodiments described herein (e.g, -NH2, -NHRB2, -N(CH3)RB2). In some embodiments, RBis -NH2. In some embodiments, RBis -NHRB2(e.g., -NHCH3, -NHCH2CH3, -NHPr, -NH'Pr, -NHcyclopropyl. -NHcyclobutyl, NHphenyl, NH imidazol-2-yl). In some embodiments, RBis -N(CH3)RB2(e.g., -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH2CH2CH3, -N(CHs)'Pr, -N(CH3)cyclopropyl, -N(CHs)cyclobutyl).Docket No. TGO-035WO

[0236] In some embodiments, RBis -C(=O)RB1or -C(=O)ORB1wherein RB1is as defined in any of the embodiments described herein. In some embodiments. RBis -C(=O)RB1wherein RB1is as defined in any of the embodiments described herein. In some embodiments, RBis -C(=O)alkyl. In some embodiments, RBis -C(=O)CH3, -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O)'Bu. -C(=O)'Pr, -C(=O)CH2CH2CH3or-C(=O)OCH3. In some embodiments, RBis acetyl (-C(=O)CH3). In some embodiments, RBis -C(=O)phenyl. In some embodiments, RBis -C(=O)ORB2. In some embodiments. RBis -COOH. In some embodiments, RBis COOCH3.

[0237] In some embodiments, RBis -NRB2C(=O)RB1wherein RB1is as defined in any of the embodiments described herein. In some embodiments, RBis -NHC(=O)RB1(e.g., -NHC(=O)CH3. -NHC(=O)CH2CH3. -NHC(=O)CH2CH2CH3, -NHC(=O)‘Pr, -NHC(=O)Bu. -NHC(=O)lBu, -NHC(=O)CyclopropyL -NHC(=O)Cyclobutyl). In some embodiments, RBis -N(CH3)C(=O)RB1(e.g, -N(CH3)C(=O)CH3, -N(CH3)C(=O)CH2CH3, -N(CH3)C(=O)CH2CH2CH3, -N(CH3)C(=O)‘Pr, -N(CH3)C(=O)Bu, -N(CH3)C(=O)lBu, -N(CH3)C(=O)Cyclopropyl, -N(CH3)C(=O)Cyclobutyl).

[0238] In some embodiments, RBis -NRB2C(=O)ORB1wherein RB2and RB1are as defined in any of the embodiments described herein. In some embodiments, RBis -NHC(=O)ORB1(e.g, NHC(=O)OCH3, NHC(=O)OCH2CH3, NHC(=O)OCH2CH2CH3, NHC(=O)O‘Pr, NHC(=O)OBu, -NHC(=O)O‘Bu, -NHC(=O)OCyclopropyl, -NHC(=O)OCyclobutyl). In some embodiments, RBis -N(CH3)C(=O)ORB1(e.g, -N(CH3)C(=O)OCH3, -N(CH3)C(=O)OCH2CH3, -N(CH3)C(=O)OCH2CH2CH3, -N(CH3)C(=O)O‘Pr, -N(CH3)C(=O)OBU, -N(CH3)C(=O)O1BU, -N(CH3)C(=O)OCyclopropyl, -N(CH3)C(=O)OCyclobutyl).

[0239] In some embodiments, RBis -C(=O)N(RB2)2wherein RB2is as defined in any of the embodiments described herein (e.g., -C(=O)NH2, -C(=O)NHRB2, -C(=O)N(CH3)RB2). In some embodiments, RBis -C(=O)NH2. In some embodiments, RBis -C(=O)NHRB2(e.g, -C(=O)NHCH3. C(=O)NHCH2CH3, C(=O)NHPr, C(=O)NH'Pr, C( O)NHBu.C(=O)NH'Bu. -C(=O)NHCyclopropyl, -C(=O)NHCyclobutyl). In some embodiments, RBis -C(=O)N(CH3)RB2(e.g. -C(=O)N(CH3)2, -C(=O)N(CH3)CH2CH3, -C(=O)N(CH3)CH2CH2CH3, -C(=O)N(CH3)'Pr, -C(=O)N(CH3)Bu, -C(=O)N(CH3)fBu, -C(=O)N(CH3)Cyclopropyl, -C(=O)N(CH3)Cyclobutyl).Docket No. TGO-035WO

[0240] In some embodiments, RBis -C(=O)N(ORB2)(RB2) wherein RB2is as defined in any of the embodiments described herein. In some embodiments, RBis -C(=O)NH(ORB2) (e.g, -C(=O)NHOH, -C(=O)NHOCH3). In some embodiments, RBis -C(=O)NHOH.

[0241] In some embodiments, RBis -OC(=O)N(RB2)2 wherein RB2is as defined in any of the embodiments described herein. In some embodiments, RBis -OC(=O)NHRB2(e.g., -OC(=O)NHCH3, -OC(=O)NHCH2CH3, -OC(=O)NHPr, -OC(=O)NH'Pr, -OC(=O)NHBu, -OC(=O)NHBu, -OC(=O)NHCyclopropyl, -OC(=O)NHCyclobutyl). In some embodiments. RBis -OC(=O)N(CH3)RB2(e g, -OC(=O)N(CH3)2, -OC(=O)N(CH3)CH2CH3, -OC(=O)N(CH3)CH2CH2CH3, -OC(=O)N(CH3)'Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3)tBu, -OC(=O)N(CH3)Cyclopropyl, -OC(=O)N(CH3)Cyclobutyl).

[0242] In some embodiments, RBis -S(=O)RB1wherein RB1is as defined in any of the embodiments described herein. In some embodiments, RBis -S(=O)alkyl (e.g, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH2CH2CH3, -S(=O)'Pr). In some embodiments, RBis -S(=O)cycloalkyl (e.g, -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl. -S(=0)cyclohexyl).

[0243] In some embodiments, RBis -S(=O)2RB1wherein RB1is as defined in any of the embodiments described herein. In some embodiments, RBis -S(=O)2alkyl (e.g., -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2Pr, S(=O)2'Pr). In some embodiments, RBis -S(=O)2cycloalkyl (e.g., -S(=O)2cyclopropyl, -S(=O)2cyclobutyl, -S(=O)2cyclopentyl, -S(=O)2cyclohexyl). In some embodiments, RBis S(=O)2aryl (e.g, -S(=O)2phenyl).

[0244] In some embodiments, RBis -SRB2wherein RB2is as defined in any of the embodiments described herein. In some embodiments, RBis -Salkyl (e.g, -SCH3, -SCH2CH3, -SPr, -S'Pr). In some embodiments, RBis -Scycloalkyl (e.g., -S cyclopropyl, -Scyclobutyl, -S cyclopentyl, -Scyclohexyl). In some embodiments, RBis -Saryl (e.g, -Sphenyl).

[0245] In some embodiments, RBis -S(=O)(=NRB2)RB1wherein RB2and RB1are as defined in any of the embodiments described herein. In some embodiments, RBis S(=O)(=NH)RB1(e.g, -S(=O)(=NH)CH3, -S(=O)(=NH)CH2CH3, -S(=O)(=NH)CH2CH2CH3. -S(=O)(=NH)iPr, -S(=O)(=NH)Bu. -S(=O)(=NH)‘Bu, -S(=O)(=NH)Cyclopropyl, -S(=O)(=NH)Cyclobutyl). In some embodiments, RBis -S(=O)(=NCH3)RB1(e.g., -S(=O)(=NCH3)CH3, -S(=O)(=NCH3)CH2CH3, -S(=O)(=NCH3)CH2CH2CH3, -S(=O)(=NCH3)iPr, -S(=O)(=NCH3)BU, -S(=O)(=NCH3)tBu, -S(=O)(=NCH3)Cyclopropyl, -S(=O)(=NCH3)Cyclobutyl).Docket No. TGO-035WO

[0246] In some embodiments, RBis -NRB2S(=O)2RB1wherein RB2and RB1are as defined in any of the embodiments described herein. In some embodiments, RBis -NHS(=O)2alkyl (e.g, -NHS(=O)2CH3, -NHS(=O)2CH2CH3, -NHS(=O)2Pr, -NHS(=O)2'Pr). In some embodiments,RBis -NHS(=O)2cycloalkyl (e.g, -NHS(=O)2cyclopropyl, -NHS(=O)2cyclobutyl, -NHS(=O)2cyclopentyl, -NHS(=O)2cyclohexyl). In some embodiments, RBis -NHS(=O)2aiyl (e.g, -NHS(=O)2phenyl). In some embodiments, RBis -N(CH3)S(=O)2alkyl (e.g, -N(CH3)S(=O)2CH3, -N(CH3)S(=O)2CH2CH3. -N(CH3)S(=O)2Pr, -N(CH3)S(=O)2iPr). In some embodiments, RBis -N(CH3)S(=O)2cycloalkyl (e.g, -N(CH3)S(=O)2cyclopropyl, -N(CH3)S(=O)2cyclobutyl. -N(CH3)S(=O)2cyclopentyl. -N(CH3)S(=O)2Cyclohexyl). In some embodiments, RBis -N(CH3)S(=O)2aryl (e.g., -N(CH3)S(=O)2phenyl).

[0247] In some embodiments, RBis -S(=O)2N(RB2)2wherein RB2is as defined in any of the embodiments described herein, (e.g., -S(=O)2NH2, -S(=O)2NHRB2, -S(=O)2N(CH3)RB2). In some embodiments, RBis -S(=O)2NH2. In some embodiments, RBis -S(=O)2NHRB2(e.g, -S(=O)2NHCH3, -S(=O)2NHCH2CH3, -S(=O)2NHPr, -S(=O)2NH'Pr, -S(=O)2NHcyclopropyl, -S(=O)2NHcyclobutyl). In some embodiments, RBis -S(=O)2N(CH3)RB2(e.g, -S(=O)2N(CH3)2, -S(=O)2N(CH3)CH2CH3, -S(=O)2N(CH3)CH2CH2CH3, -S(=O)2N(CH3)iPr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0248] As generally defined herein, each R4is independently selected from -D, =O, halo, -OH, -NH2. -CN. -Ci-Ce alkyl, -C1-C6haloalkyl, -Ci-Ce hydroxy alkyl, -OCi-Ce alkyl, -OCi-Cg haloalkyl, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2.

[0249] In some embodiments, each R4is independently selected from =0, halo, -OH, -CN, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -OCi-Ce alkyl, OCi-Ce haloalkyl and -Ci-Ce hydroxyalkyl.

[0250] In some embodiments, each R4is independently selected from the group consisting of-F, -Cl, =0, -OH,-OMe, -CN, -Me, -rBu, -CF3, -OCF3, -CH2CH2OH and -CHF2.

[0251] In some embodiments, each R4is independently selected from the group consisting of-F, / Bu and CF3.

[0252] In some embodiments, each R4is independently -D.

[0253] In some embodiments, each R4is independently =O,

[0254] In some embodiments, each R4is independently halo (e g, -F, -Cl, -Br, -I). In some embodiments, each R4is independently selected from -F and -Cl. In some embodiments, each R4is independently -F. In some embodiments, each R4is independently -Cl.Docket No. TGO-035WO

[0255] In some embodiments, each R4is independently -OH.

[0256] In some embodiments, each R4is independently. -OCi-Ce alkyl (e.g, methoxy, ethoxy, propoxy, isopropoxy). In some embodiments, each R4is independently -OMe (methoxy). In some embodiments, each R4is independently, -OCi-Ce haloalkyl (e.g., trifluoromethoxy). In some embodiments, each R4is independently -OCF3 (trifluoromethoxy).

[0257] In some embodiments, each R4is independently -CN.

[0258] In some embodiments, each R4is independently -Ci-Ce alkyl (e.g, -Me, -Et, -nPr, -iPr, / B u) In some embodiments, each R4is independently selected from -Me- and - / Bu In some embodiments, each R4is independently -Me. In some embodiments, each R4is independently - / Bu.

[0259] In some embodiments, each R4is independently -Ci-Ce haloalkyl (e.g, -CF3, -CHF2, -CH2F, -CH2CF3). In some embodiments, each R4is independently -CF3.

[0260] In some embodiments, each R4is independently -Ci-Ce hydroxyalkyl (e.g., -CH2CH2OH).Docket No. TGO-035WODocket No. TGO-035WODocket No. TGO-035WODocket No. TGO-035WODocket No. TGO-035WODocket No. TGO-035WO

[0270] As generally defined herein, each RA1is independently selected from -Ci-Ce alkyl, - Ci-Ce alkenyl, -Ci-Ce haloalkyl. -Ci-Ce haloalkenyl, C3-C9 cycloalkyl. C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S orDocket No. TGO-035WOoxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, –(C1-C2 alkyl)(C3-C9 cycloalkyl), –(C1-C2 alkyl)(4-10 member heterocyclyl), –(C1-C2 alkyl)(6-10 membered aryl), –(C1-C2 alkyl)(6-10 membered heteroaryl).

[0271] In some embodiments, each RA1is independently selected from the group consisting of–C1–C6alkyl, –C1–C6haloalkyl, C3–C9cycloalkyl, and 4-10 membered heterocyclyl.

[0272] In some embodiments, each RA1is independently selected from the group consisting of -Ci-Ce alkyl, (e.g, -Me, -Et, -Pr, -Pr, - ec-Bu, -Hu) and -Ci-Ce haloalkyl (e.g., -CF3, -CHF2, -CH2CF3).

[0273] In some embodiments, each RA1is independently selected from the group consisting of -Me, -Et, -Pr, -'Pr, -sec-Bu, - / Bu. -CF3, -CHF2and -CH2CF3.

[0274] In some embodiments, each RA1is independently -Ci-Ce alkyl (e.g., -Me, -Et, -Pr, -'Pr,-”Bu, -Hu, -sec-Bu. -zso-Bu). In some embodiments, each RA1is independently -Me. In some embodiments, each RA1is independently -Et. In some embodiments, each RA1is independently -Pr or -zPr.

[0275] In some embodiments, each RA1is independently -Ci-Ce haloalkyl. In some embodiments, each RA1is independently trifluoromethyl (–CF3). In some embodiments, each RA1is independently difluoromethyl (-CHF2).

[0276] In some embodiments, each RA1is independently C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each RA1is independently cyclopropyl. In some embodiments each RA1is independently cyclobutyl. In some embodiments, each RA1is independently cyclopentyl. In some embodiments, each RA1is independently cyclohexyl.

[0277] In some embodiments, each RA1is independently 4-10 membered heterocyclyl (e.g, oxetanyl, tetrahydropyranyL tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0278] In some embodiments, RA1is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O. N and S, a 6-membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, RA1is independently a 5-membered monocyclic heteroaryl (e.g., pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, RA1is independently thiophenyl (e., thiophen-2-yl, thiophen-3-yl). In some embodiments,Docket No. TGO-035WORA1is independently pyrazolyl (e.g, pyrazol-l-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, RA1is independently thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, RA1is independently a 6-membered monocyclic heteroaryl (.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, RA1is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, RA1is independently pyrimidinyl (e.g., pyrimidin-2-yl. pyrimidin-4-yl, pyrimidin-5-yl).

[0279] In some embodiments, RA1is independently 6-10 membered aryl. In some embodiments, RA1is independently 6-10 membered mono or bicyclic aryl. In some embodiments, RA1is independently phenyl.

[0280] In some embodiments, each RA1is independently -(C1-C2 alkyl)(C3-C9 cycloalkyl) (e.g, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0281] In some embodiments, each RA1is independently -(C1-C2 alkyl)(4-10 member heterocyclyl) (e.g, oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0282] In some embodiments, each RA1is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RA1is independently benzyl.

[0283] In some embodiments, each RA1is independently -(C1-C2 alkyl)(6-10 membered heteroaryl)(e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0284] As generally defined herein, each RA2is independently selected from -H, -D, -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from O, N, S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl).

[0285] In some embodiments, each RA2is independently selected from the group consisting of H. D, -Ci-Ce alkyl. -Ci-Ce haloalkyl, C3-C9 cycloalkyl, and 4-10 membered heterocyclyl.

[0286] In some embodiments, each RA2is independently selected from the group consisting of H, D, -Ci-Ce alkyl, (e.g., -Me, -Et, -Pr, -Pr, -sec-Bu. -'Bu) and -Ci-Ce haloalkyl (e.g, -CF3, -CHF2, -CH2CF3).Docket No. TGO-035WO

[0287] In some embodiments, each RA2is independently selected from the group consisting of H, D, -Me, -Et, -Pr, -'Pr. - ec-Bu, -®u. -CF3, -CHF2and -CH2CF3.

[0288] In some embodiments, each RA2is independently H. In some embodiments, each RA2is independently D.

[0289] In some embodiments, each RA2is independently –C1–C6alkyl (e.g, -Me, -Et, -Pr, -'Pr,-”Bu, -'Bu. -sec-Bu. -zso-Bu). In some embodiments, each RA2is independently -Me. In some embodiments, each RA2is independently -Et. In some embodiments, each RA2is independently -Pr or -zPr.

[0290] In some embodiments, each RA2is independently -Ci-Ce haloalkyl. In some embodiments, each RA2is independently trifluoromethyl (–CF3). In some embodiments, each RA2is independently difluoromethyl (–CHF2).

[0291] In some embodiments, each RA2is independently C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each RA2is independently cyclopropyl. In some embodiments each RA2is independently cyclobutyl. In some embodiments, each RA2is independently cyclopentyl.

[0292] In some embodiments, each RA2is independently 4-10 membered heterocyclyl (e.g, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0293] In some embodiments, RA2is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, a 6-membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, RA2is independently a 5-membered monocyclic heteroaryl (e.g, pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, RA2is independently thiophenyl (e.g, thiophen-2-yl, thiophen-3-yl). In some embodiments, RA2is independently pyrazolyl (e g., pyrazol-l-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, RA2is independently thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, RA2is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments. RA2is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, RA2is independently pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl).Docket No. TGO-035WO

[0294] In some embodiments, RA2is independently 6-10 membered aryl. In some embodiments, RA2is independently 6-10 membered mono or bicyclic aryl. In some embodiments, RA2is independently phenyl.

[0295] In some embodiments, each RA2is independently –(C1-C2 alkyl)(C3-C9 cycloalkyl) (e.g, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0296] In some embodiments, each RA2is independently -(C1-C2 alkyl)(4-10 member heterocyclyl) (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0297] In some embodiments, each RA2is independently -(C1-C2 alkyl)(6- 10 membered aryl). In some embodiments, each RA2is independently benzyl.

[0298] In some embodiments, each RA2is independently -(C1-C2 alkyl)(6-10 membered heteroaryl)(e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0299] As generally defined herein, each RB1is independently selected from -Ci-Cg alkyl, -Ci-Cg alkenyl, -Ci-Cg haloalkyl, -Ci-Cg haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, –(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl).

[0300] In some embodiments, each RB1is independently selected from the group consisting of-Ci-Ce alkyl, -Ci-Ce haloalkyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl and 6-10 membered aryl.

[0301] In some embodiments, each RB1is independently selected from the group consisting of –C1–C6alkyl, (e.g, -Me, -Et, -Pr, -Pr, -sec-Bu, -'Bu). -Ci-Cg haloalkyl (e.g., –CF3, –CHF2, –CH2CF3) and phenyl.

[0302] In some embodiments, each RB1is independently selected from the group consisting of -Me, -Et, -Pr, -'Pr. -se -Bu. - / Bu. -CF3, –CHF2, –CH2CF3and phenyl.

[0303] In some embodiments, each RB1is independently -Ci-Ce alkyl (e.g., -Me, -Et, -Pr, -Pr,-”Bu, -'Bu. -sec-Bu. -Ao-Bu). In some embodiments, each RB1is independently -Me. In some embodiments, each RB1is independently -Et. In some embodiments, each RB1is independently -Pr or -zPr.Docket No. TGO-035WO

[0304] In some embodiments, each RB1is independently -Ci-Cs haloalkyl. In some embodiments, each RB1is independently trifluoromethyl (–CF3). In some embodiments, each RB1is independently difluoromethyl (–CHF2).

[0305] In some embodiments, each RB1is independently C3-C9 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopenty l, cyclohexyl). In some embodiments, each RB1is independently cyclopropyl. In some embodiments each RB1is independently cyclobutyl. In some embodiments, each RB1is independently cyclopentyl. In some embodiments, each RB1is independently cyclohexyl.

[0306] In some embodiments, each RB1is independently 4-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0307] In some embodiments, RB1is independently a 5-6 membered monocyclic heteroaryl (e.g., a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, a 6-membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, RB1is independently a 5-membered monocyclic heteroaryl (e.g, pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, RB1is independently thiophenyl (e.g., thiophen-2-yl, thiophen-3-yl). In some embodiments, RB1is independently pyrazolyl (e.g., pyrazol-l-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, RB1is independently thiazolyl (e.g, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, RB1is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, RB1is independently pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, RB1is independently pyrimidinyl (e.g., pyrimidin-2-yl. pyrimidin-4-yl, pyrimidin-5-yl).

[0308] In some embodiments, RB1is independently 6-10 membered aryl. In some embodiments, RB1is independently 6-10 membered mono or bicyclic aryl. In some embodiments, RB1is independently phenyl.

[0309] In some embodiments, each RB1is independently -(C1-C2 alkyl)(C3-C9 cycloalkyl) (e.g, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0310] In some embodiments, each RB1is independently -(C1-C2 alkyl)(4-10 member heterocyclyl) (e.g, oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl,Docket No. TGO-035WOpyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0311] In some embodiments, each RB1is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RB1is independently benzyl.

[0312] In some embodiments, each RB1is independently -(C1-C2 alkyl)(6-10 membered heteroaryl)(e.g, pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0313] As generally defined herein, each RB2is independently selected from -H, -D. -Ci-Cg alkyl, -Ci-Cg alkenyl, -Ci-Cg haloalkyl, -Ci-Cg haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), –(C1-C2 alkyl)(6-10 membered aryl), –(C1-C2 alkyl)(6-10 membered heteroaryl), wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1 or 2 instances of Ci-Cg alky l, OH or halo;

[0314] In some embodiments, each RB2is independently selected from the group consisting of H, D, -Ci-Cg alkyl, -Ci-Cg haloalkyl, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S and -(C1-C2 alkyl)(4-10 member heterocyclyl).

[0315] In some embodiments, each RB2is independently selected from the group consisting of-H, -D,-Me, -Et, -CF3, -CH(CH3)oxetan-3-yl. imidazol-2-yl and phenyl.

[0316] In some embodiments, each RB2is independently-Me.

[0317] In some embodiments, each RB2is independently -Ci-Cg alkyl (e.g., -Me, -Et, -Pr, -Pr,-”Bu, -'Bu. -scc-Bu. -zso-Bu). In some embodiments, each RB2is independently selected from the group consisting of -Me and-Et. In some embodiments, each RB2is independently -Me. In some embodiments, each RB2is independently -Et. In some embodiments, each RB2is independently -Pr or -zPr.

[0318] In some embodiments, each RB2is independently -Ci-Cg haloalkyl. In some embodiments, each RB2is independently trifluoromethyl (–CF3). In some embodiments, each RB2is independently difluoromethyl (–CHF2).

[0319] In some embodiments, each RB2is independently C3-C9cycloalkyl (e.g, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each RB2is independently cyclopropyl. In some embodiments each RB2is independently cyclobutyl. InDocket No. TGO-035WOsome embodiments, each RB2is independently cyclopentyl. In some embodiments, each RB2is independently cyclohexyl.

[0320] In some embodiments, each RB2is independently 4-10 membered heterocyclyl (e.g, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0321] In some embodiments, RB2is independently a 5-6 membered monocyclic heteroaryl (e.g. a 5-membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N and S, a 6-membered monocyclic heteroaryl containing 1-3 N heteroatoms). In some embodiments, RB2is independently a 5-membered monocyclic heteroaryl (e.g, pyrazolyl, pyrrolyl, thiophenyl, furyl, thiazolyl, isothiazolyl, oxazolyl. isoxazolyl, imidazolyl, triazolyl, thiadiazolyl, oxadiazolyl). In some embodiments, RB2is independently thiophenyl (e.g, thiophen-2-yl, thiophen-3-yl). In some embodiments, RB2is independently pyrazolyl (e.g., pyrazol-l-yl, pyrazol-3-yl, pyrazol-5-yl). In some embodiments, RB2is independently thiazolyl (e.g, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl). In some embodiments, RB2is independently imidazolyl (e.g, imidazol-2-yl). In some embodiments, RB2is independently a 6-membered monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl). In some embodiments, RB2is independently pyridinyl (e.g, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl). In some embodiments, RB2is independently pyrimidinyl (e.g, pyrimidin-2-yl. pyrimidin-4-yl, pyrimidin-5-yl).

[0322] In some embodiments, RB2is independently 6-10 membered aryl. In some embodiments, RB2is independently 6-10 membered mono or bicyclic aryl. In some embodiments, RB2is independently phenyl.

[0323] In some embodiments, each RB2is independently -(C1-C2 alkyl)(C3-C9 cycloalkyl) (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0324] In some embodiments, each RB2is independently -(C1-C2 alkyl)(4-10 member heterocyclyl) (e.g, oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0325] In some embodiments, each RB2is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RB2is independently benzyl.

[0326] In some embodiments, each RB2is independently -(C1-C2 alkyl)(6-10 membered heteroaryl)(e.g, pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).Docket No. TGO-035WO

[0327] As generally defined herein, n is 0, 1, 2 or 3. In some embodiments, n is 0, 1 or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0328] As generally defined herein, m is 0, 1, 2 or 3. In some embodiments, m is 0, 1 or 2. In some embodiments, m is 1, 2 or 3. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.O o

[0329] In some embodiments, the moiety represented aso is o. Insome embodiments, the moiety represented aso is o

[0330] In some embodiments, the compound of Formula (I) is of Formula (I’):(I’) wherein Ring B, RA, RB, R3, R3', m and n are as defined in any of the embodiments described herein.

[0331] In some embodiments, the compound of Formula (I) is of Formula (I”):(RA)nO R3R3’N^N (RB)mN-0 H H(I’’) wherein Ring B, RA, RB, RA, RB, R3, R3', m and n are as defined in any of the embodiments described herein.

[0332] In some embodiments, the compound of Formula (I) is of Formula (II)Docket No. TGO-035WOdefined in any of the embodiments described herein.

[0333] In some embodiments, the compound of Formula (I) is of Formula (IF)defined in any of the embodiments described herein.

[0334] In some embodiments, the compound of Formula (I) is of Formula (II”):defined in any of the embodiments described herein.

[0335] In some embodiments, the compound of Formula (I) is of Formula (II-l ):(II-l) wherein Ring B, RBand m are as defined in anv of the embodiments described herein.

[0336] In some embodiments, the compound of Formula (I) is of Formula (II-l ’):(II- 1’) wherein Ring B, RBand m are as defined in any of the embodiments described herein.

[0337] In some embodiments, the compound of Formula (I) is of Formula (II-l”):Docket No. TGO-035WO(II- 1”) wherein Ring B, RBand m are as defined in any of the embodiments described herein.

[0338] In some embodiments, provided is a compound selected from the compounds of Table 1, or pharmaceutically acceptable salts thereof.

[0339] Compounds described herein (e.g., a compound of Formula (I) to (II- 1 ”) or a compound of Table 1, or pharmaceutically acceptable salts thereof) are useful as degraders of HBS1L.

[0340] Table 1 indicates DC50 values for the degradation of HBS1L and GSPT1 proteins in a pair of HEK293 (LgBiT) cell lines expressing CRISPR knock-in HiBiT tagged HBS1L (“HBSIL-HiBiT cells”) and CRISPR knock-in HiBiT-tagged GSPT1 (“GSPTl-HiBiT cells”), respectively (columns 3 and 4) measured as described in Example 5. In Table 1, columns 4 and 5, “a” indicates a DC50 of < 100 nM, “b” indicates a DC50 equal to or greater than 100 nM but less than 500 nM, “c” indicates an DC50 equal to or greater than 500 nM but less than 5pM and “d” indicates an DC 50 equal to or greater than 5pM in the HBSIL-HiBiT and GSPTl-HiBiT cells, respectively. In column 6, “A” indicates aDCso ratio greater than or equal to 100 fold between the DC50 in the GSPTl-HiBiT cells and the HBSIL-HiBiT cells; “B” indicates a DC50 ratio greater than or equal to 30 fold but lower than 100 fold between the between the DC50 in the GSPTl-HiBiT cells and the HBSIL-HiBiT cells; “C” indicates a DC50 ratio greater than or equal to 10 fold but lower than 30 fold between the between the DC50 in the GSPTl-HiBiT cells and the HBSIL-HiBiT cells; “D” indicates aDCso ratio of less than 10 fold between the between the DC50 in the GSPTl-HiBiT cells and the HBSIL-HiBiT cells. Compounds with a ratio equal to or greater than 10-fold are considered selective degraders of HBS1L over GSPT1.

[0341] Table 1 additionally indicates EC50 values in a ternary complex formation assay as described in Example 6 between His-tagged Recombinant Human CUL4A / RBX1 / DDB1 / CRBN Complex Protein (“E3 complex”), tested compound and HBS1L (column 7) and GSPT1 (column 8) respectively. In Table 1, columns 7 and 8, “a*” indicates an EC50 of < 100 nM, “b*” indicates an EC50 equal to or greater than 100 nM but less than 500 nM, “c*” indicates an EC50 equal to or greater than 500 nM but less than 5pMDocket No. TGO-035WOand “d*” indicates an EC50 equal to or greater than 5pM for the ternary complex formation with HBS1L and GSPT1, respectively.Table 1-Exemplary compounds with selected biological activity dataHBS1L GSPT HBS1L GSPT1 Hibit 1 Hibit Hibit Ternary Ternary DC50 DC50 Selectivity EC50 EC50 Nr. [uM] [uM] (G / H) [uM] [uM]0 \ / F. pC.. HN-(\ 1MHN )1 b d A a* d* cT / X'AXX 9.•X N-0 Is!<j N 0 Hn (1 / Os 2 b d A b* d* FZ^NV X. 9.CZ C Fl jL O N-0 HN hYZ\HXsX.3 a d A b* d*H A XT1 XNYNM X \Zo~O H / XX'^N-^oHH ryuF4 d d D d* d*H f 7 O. NX\X Ji \ / Ou-Z 1" N0 N-oHH p < 7rCi5 b d B c* d* H XH / fXnCXN ON 0 HH6 d d D d* d*O Docket No. TGO-035WO ) IZ6fTA z\ 1 \ / ^ 1\^ o / O _ / \^ O\^^^yy 7 b d B b* d* IZ IZ IZ X XooXo IZ zzZZo ~JTl / — 8 d d Dd* d*zo Tl9 c d B c* d*H n^YNvM 1 V1 XnN-0 H NA-XO^N 0 ( J^A^F 10 b d A b* d* F™ VYP-N-4 zx V0^N 0 H(^QHAT\ F\=A J^F2\ F 11 b d B c* d* 5 'xz / ( o=4 z—o *xo^j -0 HF^\AFF12 b d A a* d* A13 a b Db* d*HN v0AN~° H14 a d A b* d* HO \Docket No. TGO-035WO15 b d B b* d*Alternative Embodiments

[0342] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In some embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%. at least 20%. at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.Pharmaceutical Compositions

[0343] In another embodiment, provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof.

[0344] The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound provided herewith, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0345] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions provided herewith include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d–α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids,Docket No. TGO-035WOwater, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat. Cyclodextrins such as a-, 0-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2 and 3 hydroxypropyl-P-cyclodextrins. or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0346] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0347] In some embodiments, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0348] Also provided is a compound described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use as a pharmaceutical or a medicament (e.g., a medicament for the treatment of an HBS1L-sensitive disease in a subject in need thereof. In some embodiments, the disease is a FOCAD-deficient disease. In some embodiments, the disease is deficient in other SKI complex members including, but not limited to TTC37. AVEN, WDR61 and SKIV2L. In some embodiments, the disease is sensitive to HBS1L inactivation because it is PELO-dependent. In some embodiments, the disease is a proliferating disease. In some embodiments, the disease is a cancer. In a further embodiment, the disease is a FOCAD-deficient cancer. In some embodiments, the disease is a cancer deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is a cancer sensitive to HBS1L inactivation because it is PELO-dependent.

[0349] In some embodiments, the cancer is histology agnostic (e.g., is a FOCAD-deficient, TTC37, AVEN, WDR61 or SKIV2L deficient cancer or a PELO-dependent cancer of any histology). In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g., urothelial carcinoma), skin cancer (e.g., cutaneous melanoma), non-small cell lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g., lower grade glioma)), head and neck cancer (e.g, head and neck squamous cellDocket No. TGO-035WOcarcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g., colon adenocarcinoma), mesothelioma (e.g., pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g., liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g., diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0350] Also provided is a compound described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use in the treatment of an HBS IL-sensitive disease in a subject in need thereof. In some embodiments, the disease is a FOCAD-defi cient disease. In some embodiments, the disease is deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is sensitive to HBS1L inactivation because it is PELO-dependent. In some embodiments, the disease is a proliferating disease. In some embodiments, the disease is a cancer. In a further embodiment, the disease is a FOCAD-deficient cancer. In some embodiments, the disease is a cancer deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is a cancer sensitive to HBS IL inactivation because it is PELO-dependent.

[0351] In some embodiments, the cancer is histology agnostic (e.g., is a FOCAD-deficient, TTC37, AVEN, WDR61 or SKIV2L deficient cancer or a PELO-dependent cancer of any histology). In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g., lower grade glioma)), head and neck cancer (e.g, head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g. colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g., liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancerDocket No. TGO-035WO(e.g., pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma. Also provided is a compound described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use in the manufacturing of a medicament (e.g., a medicament for the treatment of an HBS 1L-sensitive disease in a subject in need thereof. In some embodiments, the disease is a FOCAD-deficient disease. In some embodiments, the disease is deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is sensitive to HBS1L inactivation because it is PELO-dependent. In some embodiments, the disease is a proliferating disease. In some embodiments, the disease is a cancer. In a further embodiment, the disease is a FOCAD-deficient cancer. In some embodiments, the disease is a cancer deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is a cancer sensitive to HBS IL inactivation because it is PELO-dependent.

[0352] In some embodiments, the cancer is histology agnostic (e.g., is a FOCAD-deficient, TTC37, AVEN, WDR61 or SKIV2L deficient cancer or a PELO-dependent cancer of any histology). In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g., urothelial carcinoma), skin cancer (e.g., cutaneous melanoma), non-small cell lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g., lower grade glioma)), head and neck cancer (e.g., head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g., esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g., colon adenocarcinoma), mesothelioma (e.g., pleural mesothelioma), ovarian cancer (e.g., ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g., liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g., pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g., diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0353] Generally, the compounds provided herein are administered in an effective amount (e.g., a therapeutically effective amount). The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compoundDocket No. TGO-035WOadministered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0354] The pharmaceutical compositions provided herewith may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions provided herewith may contain any conventional nontoxic pharmaceutically acceptable carriers, adjuvants, or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0355] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0356] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0357] Injectable compositions are ty pically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the activeDocket No. TGO-035WOcompound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3–butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0358] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.Docket No. TGO-035WO

[0359] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0360] The pharmaceutical compositions provided herewith may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound provided herewith with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0361] The pharmaceutical compositions provided herewith may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0362] The above-described components for orally administrable, injectable, or topically administrable, rectally administrable, and nasally administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0363] The compounds described herein can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington ’s Pharmaceutical Sciences.

[0364] When the compositions provided herewith comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably betw een about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds provided herewith.Alternatively, those agents may be part of a single dosage form, mixed together with the compounds provided herewith in a single composition.

[0365] Also provided is the pharmaceutically acceptable acid addition salt of a compound described herein (e.g., compound of Formula (I)).Docket No. TGO-035WO

[0366] The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0367] The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg of body weight, alternatively dosages between 1 mg and 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions provided herewith will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. In some embodiments, the compound is administered less frequently than daily. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w).Alternatively, such preparations contain from about 20% to about 80% active compound.

[0368] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0369] Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination provided herewith may be administered, if necessary.Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.Docket No. TGO-035WOMethods o f Treatment and UseTreatment of FOCAD-deficient proliferation disorders

[0370] FOCAD-deletion is a common genetic event in human cancer.

[0371] Applicants have found, surprisingly and advantageously, that cells that lack FOCAD are hyper-dependent for their survival on the HBS1L protein, exemplifying a synthetic lethal relationship between FOCAD and HBS1L. Publicly available databases such as DepMap reveal that loss of FOCAD or HBS1L are each generally tolerated individually. However, Applicants have found that dual inactivation of FOCAD and HBS1L is lethal. Accordingly, applicants have shown that the growth of tumor cells that have inactivated the FOCAD gene can be inhibited by inactivating HBS1L in this context, while cells that have FOCAD intact can tolerate HBS1L inactivation (FIG. 1). Similarly, genetic inactivation of HBS IL causes tumor growth inhibition in a mouse CDX model of MIAPACA2 FOCAD-null tumors, and tumor growth is sustained with continuous expression of HBS1L (FIG. 3). Therefore, compounds that reduce or eliminate the function of the HBS IL protein may have activity in limiting the growth of FOCAD-inactivated tumor cells. The utility of HBS IL inactivating compounds is agnostic to histology and disease indication, as FOCAD is inactivated in cell lines across a variety of lineages and in patients across a variety of disease indications.

[0372] Functionally, the FOCAD protein works with mammalian superkiller (SKI) complex proteins to promote the degradation of mRNA. The HBS1L / PELO complex is also involved in ribosome release and provides a means for ribosome recycling (FIG. 2). Without being bound by theory, it appears that inactivation of FOCAD leads to increased reliance on the HBS1L / PELO complex for ribosome recycling. Similarly to FOCAD, inactivation of SKI complex proteins (including but not limited to SKIV2L, TTC37, AVEN, and WDR61) can confer hyperdependence on HBS IL. Inactivation of FOCAD and other SKI complex proteins can encompass copy number loss, low expression of mRNA and / or protein level, loss of function mutation, epigenetic silencing, hypomorphs, or any other aberration that reduces activity. Another context in which HBS IL is a dependency is microsatellite instability (MSI-high). Microsatellite repeats can lead to aberrant mRNAs which can lead to ribosome stalling during translation, requiring ribosome rescue by HBS1L and / or mRNA degradation facilitated by FOCAD and / or the SKI complex. Microsatellite repeats can also lead to altered expression of proteins in which microsatellites are present, which could include FOCAD or members of the SKI complex. Publicly available data in DepMap demonstrate that MSI-high cancer cell lines are hyperdependent on the ribosome quality control pathway, which includesDocket No. TGO-035WOthe SKI complex (See, e.g, gygi.hms.harvard.edu / publications / ccle.html) HBS1L and its binding partner PELO have been shown to regulate each other’s protein stability (O'Connell AE, et al., PLoS Genet. 2019 Feb 1; 15(2)). Depletion of HBS1L leads to a decrease in PELO protein level. Therefore, inactivation of HBS1L could be an indirect method of targeting PELO and would be beneficial in diseases that could be treated or ameliorated by decreases in PELO levels.

[0373] As FOCAD is more distal to CDKN2A compared to MTAP, most cells that have FOCAD inactivated as collateral damage to CDKN2A loss also have MTAP loss. Therefore, patients having loss of both FOCAD and MTAP would be expected to be responsive to the combination of HBS1L inactivating compounds and PRMT5 inactivating compounds.

[0374] FOCAD deletion frequency in a subset of human cancers is observed as annotated in The Cancer Genome Atlas (portal. gdc.cancer.gov / genes / ENSGOOOOOl 88352 ). Cancers with high FOCAD deletion frequencies are glioblastoma multiforme (GBM), mesothelioma (e.g., pleural mesothelioma), bladder cancer, pancreatic cancer, melanoma, non small-cell lung cancer (NSCLC), esophagogastric cancer, mature B-cell neoplasms, head and neck cancer, neuroepithelial cancer, glioma, cholangiocarcinoma, sarcoma, adrenocortical cancer, ovarian epithelial cancer, breast cancer, renal non-clear cell cancer, thymic epithelial cancer, hepatobiliary cancer, pheochromocytoma, prostate cancer, thyroid cancer, cervical cancer, colorectal carcinoma, endometrial cancer, and clear-cell renal-cell carcinoma. FOCAD deletion in cells is one of the mechanisms that leads to FOCAD-deficiency. and confers enhanced dependency on the HBS1L in cancer cells. Other mechanisms leading to FOCAD deficiency include, inter alia, FOCAD translocations and FOCAD epigenetic silencing which could also lead to FOCAD-null and / or FOCAD deficient tumors.

[0375] The compounds of the instant disclosure (e.g., compounds of Formula (I)) are HBS1L degraders useful in the treatment of cancers sensitive to HBS1L inactivation (e.g., FOCAD-deficient (e.g., FOCAD-deleted) cancers, and cancers deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L, PELO -dependent cancers, etc.). In some embodiments, the compounds of the instant disclosure are selective degraders of HBS1L over GSPT1.

[0376] GSPT1 is a GTPase involved in mRNA maturation by its processing of stop codons. It shares some homology to HBS1L but is not synthetic lethal with FOCAD, and thus serves as an anti-target for HBS1L targeting compounds intended to take advantage of the synthetic lethal relationship between HBS1L and FOCAD.Docket No. TGO-035WO

[0377] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an HBS1L-sensitive disease (e.g., HBS1L-sensitive cancer) comprising administering to the subject in need thereof a therapeutically effective amount of an HBS1L-inactivating compound (e.g., an HBS1L degrader). In some embodiments, the HBS1L-sensitive disease (e.g., HBS1L-sensitive cancer) is a FOCAD-deficient (e.g., FOCAD-deleted) cancer. In some embodiments, the disease (e.g, cancer) is deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease (e.g, cancer) is sensitive to HBS1L inactivation because it is PELO-dependent. In some embodiments, the disease is a proliferating disease. In some embodiments, the disease is a cancer. In a further embodiment, the disease is a FOCAD-deficient cancer. In some embodiments, the disease is a cancer deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is a cancer sensitive to HBS1L inactivation because it is PELO-dependent.

[0378] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an HBSIL-sensitive disease (e.g, HBSIL-sensitive cancer) comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof.

[0379] In some embodiments, provided is a compound of the present disclosure (e.g, a compound of Formula (I)), or a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure for use in a method of treating human or animal subjects having or having been diagnosed with an HBSIL-sensitive disease (e.g., HBSIL-sensitive cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0380] In some embodiments, provided is a compound of the present disclosure (e.g., a compound of Formula (I)), or a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure for use in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with an HBSIL-sensitive disease (e.g., HBSIL-sensitive cancer)). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0381] In some embodiments, provided is a use of a compound of the present disclosure (e.g, a compound of Formula (I)), or of a pharmaceutical composition comprising aDocket No. TGO-035WOcompound of Formula (I) of the present disclosure in a method of treating human or animal subjects having or having been diagnosed with an HBSIL-sensitive disease (e.g. HBS1L-sensitive cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0382] In some embodiments, provided is use of a compound of the present disclosure (e.g., a compound of Formula (I)), or of a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with an HBSIL-sensitive disease (e.g, HBSIL-sensitive cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0383] In some embodiments, provided are methods for treating an HBS IL-sensitive disease (e.g, HBSIL-sensitive cancer) in a subject in need thereof comprising administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g., compound of Formula (I)) or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an HBSIL-sensitive disease (e.g., HBSIL-sensitive cancer) comprising administering to the subject in need thereof a therapeutically effective amount of pharmaceutical composition of the present disclosure (e.g., a composition comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier). In some embodiments, the compound or composition is administered in combination with a second therapeutic agent.

[0385] In some embodiments, provided are methods of treating an HBSIL-sensitive disease (e.g, HBSIL-sensitive cancer) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of pharmaceutical composition of the present disclosure (e.g, a composition comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier). In some embodiments, the compound or composition is administered in combination with a second therapeutic agent. In some embodiments, the subject is human.

[0386] In some embodiments, the disease is a FOCAD-deficient disease (e.g, a FOCAD-deleted disease). In some embodiments, the disease is deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L. In some embodiments, the disease is sensitive to HBS1L inactivation because it is PELO-dependent.Docket No. TGO-035WOIn some embodiments, the disease is a proliferating disease. In some embodiments, the disease is a cancer. In a further embodiment, the disease is a FOCAD-deficient cancer (e.g, a FOCAD-deleted cancer). In some embodiments, the disease is a cancer deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKTV2L. In some embodiments, the disease is a cancer sensitive to HBS1L inactivation because it is PELO -dependent. In some embodiments, the cancer is histology agnostic (e.g, is a FOCAD-deficient. TTC37, AVEN, WDR61 or SKIV2L deficient cancer or a PELO-dependent cancer of any histology). In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), nonsmall cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g, head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g., esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g, colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g, clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0387] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with a FOCAD-deficient disease (e.g, FOCAD-deficient cancer) comprising administering to the subject in need thereof a therapeutically effective amount of an HBSIL-inactivating compound (e.g, an HBS1L degrader).

[0388] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with a FOCAD-deleted disease (e.g, FOCAD-deleted cancer) comprising administering to the subject in need thereof a therapeutically effective amount of an HBSIL-inactivating compound (e.g, an HBS1L degrader).

[0389] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with a SKI complex member-deficient disease (e.g, SKI complex member-deficient cancer) comprising administering to the subject in need thereof a therapeutically effective amount of an HBSIL-inactivating compound (e.g., an HBS1L degrader). In some embodiments, the SKI complex member-deficient disease is TTC37,Docket No. TGO-035WOAVEN. WDR61 or SKIV2L deficient). In some embodiments, the SKI complex member-deleted disease is TTC37, AVEN, WDR61 or SKIV2L deleted).

[0390] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with a FOCAD-deficient disease (e.g, a FOCAD-deficient cancer) comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g, a compound of Formula (I)) or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, provided is a compound of the present disclosure (e.g, a compound of Formula (I)), or a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure for use in a method of treating human or animal subjects having or having been diagnosed with a FOCAD-deficient disease (e.g., a FOCAD-deficient cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0392] In some embodiments, provided is a compound of the present disclosure (e.g, a compound of Formula (I)), or a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure for use in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with a FOCAD-deficient disease (e.g, a FOCAD-deficient cancer)). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0393] In some embodiments, provided is a use of a compound of the present disclosure (e.g, a compound of Formula (I)), or of a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure in a method of treating human or animal subjects having or having been diagnosed with a FOCAD-deficient (e.g., a FOCAD-deficient cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0394] In some embodiments, provided is use of a compound of the present disclosure (e.g, a compound of Formula (I)), or of a pharmaceutical composition comprising a compound of Formula (I) of the present disclosure in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with a FOCAD-deficient disease (e.g, a FOCAD-deficient cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0395] In some embodiments, provided are methods for treating a FOCAD-deficient disease (e.g., a FOCAD-deficient cancer) in a subject in need thereof comprisingDocket No. TGO-035WOadministering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g., compound of Formula (I)) or a pharmaceutically acceptable salt thereof.

[0396] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with a FOCAD-deficient disease (e.g., a FOCAD-deficient cancer) comprising administering to the subject in need thereof a therapeutically effective amount of pharmaceutical composition of the present disclosure (e.g, a composition comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier). In some embodiments, the compound or composition is administered in combination with a second therapeutic agent.

[0397] In some embodiments, provided are methods of treating a FOCAD-deficient disease (e.g., a FOCAD-deficient cancer) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of pharmaceutical composition of the present disclosure (e.g., a composition comprising a compound of Formula (I), or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier). In some embodiments, the compound or composition is administered in combination with a second therapeutic agent. In some embodiments, the subject is human.

[0398] In some embodiments, the cancer is a FOCAD-deficient cancer selected from the group consisting of bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g, glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g., head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g, colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g, clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g. diffuse large B-cell lymphoma (DLBCL)) and sarcoma.Docket No. TGO-035WO

[0399] In some embodiments of any of the embodiments described herein, the FOCAD-deficient disease is a FOCAD-deleted disease. In some embodiments of any of the embodiments described herein, the FOCAD-deficient cancer is a FOCAD-deleted cancer.

[0400] The HBS1L degraders (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) described herein can be used in a method of inhibiting proliferation of FOCAD-deficient cells in vivo or in vitro.

[0401] The HBS1L degraders (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) described herein can be used in a method of inhibiting proliferation of HBS1L-sensitive cells (e.g., FOCAD-deficient cells, cells deficient in other SKI complex members including, but not limited to TTC37, AVEN, WDR61 and SKIV2L, or cells that are PELO-dependent) in a subject in need thereof, the method comprising the step of administering to the subject an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) in an amount that is effective to inhibit proliferation of the HBS1L-sensitive cells. In some embodiments, the subject in need thereof suffers from an HBS1L-sensitive cancer (e.g., a FOCAD-deficient cancer, TTC37, AVEN, WDR61 or SKIV2L deficient cancer or a PELO-dependent cancer) of any histology. In some embodiments, the subject in need thereof suffers from an HBSIL-sensitive cancer selected from the group consisting of bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g., cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g. glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g, head and neck squamous cell carcinoma), prostate cancer (e.g, prostate adenocarcinoma), esophagogastric cancer (e.g., esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g, colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g, clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0402] In some embodiments, the cancer has previously been treated with a PRMT5 inhibitor.Docket No. TGO-035WO

[0403] In some embodiments, the cancer is resistant or refractory to treatment with a PRMT5 inhibitor.

[0404] In some embodiments, the cancer has relapsed after treatment with a PRMT5 inhibitor.Combination therapies

[0405] In some embodiments, provided are methods of treatment of FOCAD-deficient proliferative disorders and other HBS IL-sensitive proliferative disorders as described herein (e.g., cancers) with an HBS1L degrader (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) in combination with one or more therapeutic agents.

[0406] In some embodiments, provided are methods of treatment of FOCAD-deficient proliferative disorders and other HBS1L-sensitive proliferative disorders as described herein (e.g., cancers) with an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) in combination with a second therapeutic agent. In some embodiments, provided are methods of treatment of FOCAD-deficient proliferative disorders and other HBS1L-sensitive proliferative disorders as described herein (e.g., cancers) with an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) in combination with a second therapeutic agent and a third therapeutic agent. In some embodiments, provided are methods of treatment of FOCAD-deficient proliferative disorders and other HBS1L-sensitive proliferative disorders as described herein (e.g., cancers) with HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0407] The term "‘Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “coagent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect. In some embodiments, the combination is additive. In some embodiments, the combination is synergistic. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-Docket No. TGO-035WOadministration"’ or “combined administration’" or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and nonfixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g., HBS1L degraders described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g, an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g, the administration of three or more therapeutic agent.

[0408] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.

[0409] In some embodiments, HBS1L degraders described herein are combined with other therapeutic agents, including, but not limited to. other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

[0410] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, toDocket No. TGO-035WOa patient in need thereof an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a general chemotherapeutic agents selected from anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® orNeosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®). 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®). my lotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hy camptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0411] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g. a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an EGFR-inhibitor (e.g, cetuximab, panitumimab, erlotinib, gefitinib and EGFRi NOS). In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a MAPK-pathway inhibitor (e.g, BRAFi, panRAFi, MEKi, ERKi). In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), orDocket No. TGO-035WOpharmaceutically acceptable salts thereof) and a PI3K-mTOR pathway inhibitor (e.g., alpha-specific PI3Ki, pan-class I PI3Ki and mTOR / PI3Ki, particularly everolimus and analogues thereof).

[0412] FOCAD-deletion can co-occur with MTAP deletion, which renders the cells sensitive to PRMT5 inhibition. In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS IL degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), and a PRMT5 inhibitor (e.g., TNG-908, TNG-462 (Tango Therapeutics), AMG193 (Amgen), MRTX1719 (BMS / Mirati), AZD3470 (AstraZeneca), BGB-58067 (BeiGene), PH020, GTA182 (Aperion), BN 105 BioNova, ATG-042 (Antengene), GH56 (Genhouse), ABSK131 (Abbisco), RVU305 (RYVU Therapeutics), HSK41959-2 (Havsco)). In some embodiments, the PRMT5 inhibitor is an MTA-cooperative PRMT5 inhibitor.

[0413] FOCAD-deletion can co-occur with mutations in the KRAS gene (e.g., KRASG12C). In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof), and a KRAS inhibitor (e.g, apan-KRAS or a specific G12C, G12D, e.g., RM-036, G13C inhibitor, e.g., adagrasib, sotorasib, LY3537982, RMC-6236, RMC-6291, RMC-9805, RMC-8839). In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), and a Spliceosome inhibitor (e.g., SF3bl inhibitors; eg, E7107).

[0414] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an HDAC inhibitor or DNA methyltransferase inhibitor. In some embodiments, the HDAC inhibitor is a non-selective HDAC inhibitor (e.g, Belinostat (Spectrum), Romidepsin (Celgene / BMS), Vorinostat (Merck), Panobinostat (Novartis), Remetinostat (Medivir), Pracinostat (MEI), Quisinostat (Janssen), Fimepinostat (Curis), Abexinostat (Xynomic), Ivaltinostat (CG)). In some embodiments, the HDAC inhibitor is HDAC6-selective (e.g, Ricolinostat (Regenacy),Docket No. TGO-035WOCitarinostat (BMS / Acetylon), KA2507 (Karus)). In some embodiments, the HD AC inhibitor is a CoRest inhibitor (e.g., TNG-260 (Tango Therapeutics), ALKS-1140 (Alkermes). JBI-802 (Jubilant), BEA- 17 (Beactica). In some embodiments the HD AC inhibitor is a class I HD AC inhibitor (e.g., Merck60 (Merck), Tucidinostat / Chidamide (HUYABIO), Entinostat (Syndax), Mocetinostat (Mirati / BMS), GS-443023 (Gilead), Zabadinostat (ingenOX), Bocodepsin (OnKure), Domatinostat (4SC), Nanatinostat (Viracta).

[0415] In some embodiments, the DNA methyltransferase inhibitor is 5 -azacytidine. In some embodiments, the HD AC inhibitor is TNG-260.

[0416] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g. a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is selected from the group consisting of S095033 (Servier), S095035 (Servier), ISM3412 (Insilico), SYH2039 (CSPC ZhongQi) and HM100760.

[0417] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an inhibitor of a protein which interacts with or is required for HBS1L function, including, but not limited to, PELO or ABCE1.

[0418] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an HDM2 inhibitor and / or 5-FU or other purine analogues (e.g, 6-thioguanine, 6-mercaptopurine).

[0419] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a CDK4 inhibitor, including, but not limited to, LEE011 or a CDK4 / 6 inhibitor (e.g., palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio ®).

[0420] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, toDocket No. TGO-035WOa patient in need thereof an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a targeted treatment contingent on the dependency of individual target tumors on relevant pathways as determined by suitable predictive markers, including but not limited to: inhibitors of HDM2i, PI3K / mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi.

[0421] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and immunotherapy.

[0422] in some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an immunotherapeutic agent.

[0423] in some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g, ipilimumab, tremelimumab).

[0424] In some embodiments, the immunotherapeutic agent is an anti-PD-1 or anti-PD-Ll agent (e.g., an antibody). In some embodiments, the immunotherapeutic agent is an anti-PD-1 agent (e.g, an anti-PD-1 antibody, e.g., nivolumab (z.e., MDX-1106, BMS-936558, ONO-4538); CT-011; AMP-224; pembrolizumab (MK-3475); pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab. sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab). In some embodiments, the immunotherapeutic agent is an anti-PD-Ll agent (e.g, an anti-PD-Ll antibody, e.g., BMS936559 (z.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C); envafolimab; cosibelimab; sugemalimab. AUNP-12 or atezolizumab (MPDL-3280A) or an anti-PD-Ll small molecule (e.g, CA-170)).

[0425] In some embodiments, the immunotherapeutic agent is a checkpoint blocking antibody (e.g, anti-TIM3, anti-LAG3, anti-TIGIT including IMP321 and MGA271).In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0426] In some embodiments, the immunotherapeutic agent is a co-stimulatory antibody (e.g, anti-4-lBB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).In some embodiments, the immunotherapeutic agent is a cancer vaccine such as a neoantigen. These vaccines can be developed using peptides or RNA (e.g, mRNA).Docket No. TGO-035WO

[0427] In some embodiments, the immunotherapeutic agent is an oncolytic virus.In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0428] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g.. a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a disease-specific huMAB (e.g., an anti-HER3 huMAB).

[0429] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g. a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an ADC / ADCC contingent on the expression of relevant surface targets on target tumors of interest.

[0430] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g. a compound of Formula (I), or pharmaceutically acceptable salts thereof) and one or more DNA damage pathway inhibitor. In some embodiments, a DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g, AZD1775). and a Chkl inhibitor (e.g, AZD7762). In some embodiments, a DNA damage pathway inhibitor is a DNA alkylating agent.

[0431] In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g. a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a PARP inhibitor. In some embodiments, a PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, E7016, iniparib, and 3-aminobenzamide.

[0432] Some patients may experience allergic reactions to the HBS1L degraders described herein and / or other anti-cancer agent(s) during or after administration; therefore, anti-allergic agents are often administered to minimize the risk of an allergic reaction. In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in needDocket No. TGO-035WOthereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an anti-allergic agent (e.g, a corticosteroid, including, but not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®). prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®); an antihistamine, such as diphenhydramine (e.g., Benadryl®), hydroxyzine, and cyproheptadine; a bronchodilator, such as the beta-adrenergic receptor agonists, albuterol (e.g., Proventil®), and terbutaline (Brethine®)).

[0433] Some patients may experience nausea during and after administration of the HBS IL degraders described herein and / or other anti-cancer agent(s); therefore, anti-emetics are used in preventing nausea (upper stomach) and vomiting. In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an anti-emetic (e.g., aprepitant (Emend®), ondansetron (Zofran®). granisetron HC1 (Kytril®), lorazepam (Ativan®), dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof).

[0434] Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable. In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and an analgesic (e.g., an over-the-counter analgesic (e.g., Tylenol®), an opioid analgesic (e.g., hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g, Astramorph® or Avinza®), oxycodone (e.g, OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), fentanyl (e.g, Duragesic®))).Docket No. TGO-035WO

[0435] In an effort to protect normal cells from treatment toxicity and to limit organ toxicities, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy. In some embodiments, provided is a method of treating a disease or disorder as described herein (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS1L degrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a cytoprotective agent (e.g., Amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid)).

[0436] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium '‘The Merck Index’’ or from databases, e.g., Patents International (e.g., IMS World Publications).

[0437] The above-mentioned compounds, which can be used in combination with an HBS1L degrader as described herein, can be prepared, and administered as described in the art. including, but not limited to. in the documents cited above.

[0438] In some embodiments, provided are pharmaceutical compositions comprising at least one compound of the present disclosure (e.g., an HBS1L degrader, e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anti-cancer agents.

[0439] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with a FOCAD-deficient proliferative disorder or another HBSIL-sensitive proliferative disorder as described herein (e.g., cancer) comprising administering to the subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof in combination with one or more therapeutic agents as described herein.

[0440] In some embodiments, provided are methods of treating a FOCAD-deficient proliferative disorder or another HBSIL-sensitive proliferative disorder as described herein (e.g., cancer) in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound of the present disclosure (e.g., a compound of Formula (I)) or aDocket No. TGO-035WOpharmaceutically acceptable salt thereof in combination with one or more therapeutic agents as described herein.

[0441] In particular, compositions will either be formulated together as a combination therapeutic or administered separately.

[0442] In combination therapy, an HBS IL degrader as described herein and other anticancer agent(s) may be administered either simultaneously, concurrently, or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.

[0443] In a preferred embodiment, the compound of the present disclosure (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and the other anticancer agent(s) is generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The HBS IL degrader as described herein and other anticancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.

[0444] In another embodiment, provided are kits that include one or more HBS IL degrader(s) as described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and a second therapeutic agent as disclosed herein are provided. Representative kits include (a) an HBS IL degrader as described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), (b) at least one other therapeutic agent, e.g, as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration.

[0445] An HBS IL degrader as described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) may also be used in combination with known therapeutic processes, for example, the administration of hormones or especially radiation. A compound of the present disclosure may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof an HBS ILDocket No. TGO-035WOdegrader described herein (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) and radiation.Patient Selection and Monitoring

[0446] In some embodiments, provided is a method of determining if a subject having or having been diagnosed with a cancer (e.g, a cancer patient) will respond to therapeutic treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), comprising the steps of:a) contacting a test sample obtained from said subject with a reagent capable of detecting human cancer cells that have FOCAD deficiency; andb) comparing the test sample with a reference (e.g, a reference sample taken from anon-cancerous or normal control subject),wherein the presence of FOCAD deficiency in said test sample indicates that the subject will respond to therapeutic treatment with an HBS1L degrader (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof).

[0447] In some embodiments, provided is a method of determining if a cancer will respond to therapeutic treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), comprising the steps of:a) contacting a test sample obtained from a subject having or having been diagnosed with said cancer with a reagent capable of detecting human cancer cells that have FOCAD deficiency; andb) comparing the test sample with a reference (e.g, a reference sample taken from anon-cancerous or normal control subject),wherein the presence of FOCAD deficiency in said test sample indicates that the cancer will respond to therapeutic treatment with an HBS IL degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof). In some embodiments, the cancer is bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g, glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g., head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g. colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarianDocket No. TGO-035WOepithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g., pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma. In some embodiments, the method further comprises the step of determining the level of HBS1L in the cancer cells. The level of expression of HBS1L can be considered when determining the therapeutically effective dosage of an HBS1L degrader.

[0448] In some embodiments, provided is a method of determining the sensitivity of a cancer cell to HBS1L inactivation (e.g, inactivation with an HBS1L degrader, e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), comprising the steps of:a) assaying the production, level, activity, expression, or presence of FOCAD, in said cancer cell;b) comparing the production, level, activity, expression, or presence of FOCAD in the cancer cell with the production, level, activity, expression, or presence of FOCAD, respectively, in a non-cancerous or normal control cell,wherein a decreased level, activity or expression in the cancer cell indicates FOCAD deficiency and wherein FOCAD deficiency indicates that said cancer cell is sensitive to the HBS1L degrader.

[0449] In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g., urothelial carcinoma), skin cancer (e.g., cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g, glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g, head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g., colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g, clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.Docket No. TGO-035WO

[0450] In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g, glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g., head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g. colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0451] In some embodiments provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer (e g, a cancer associated with FOCAD deficiency) comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human FOCAD- deficient cancer cells in a test sample obtained from said subj ect), wherein the FOCAD level can be assessed directly (e.g, by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g, by protein ELISA or IHC);b) comparing the test sample with a reference (e.g, a reference sample taken from a non-cancerous or normal control subject), wherein FOCAD deficiency in said test sample indicates said subject will respond to therapeutic treatment with anHBS1L degrader; andc) administering a therapeutically effective amount ofHBSIL degrader (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0452] In some embodiments provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer (e.g, a cancer associated with a SKI complex member deficiency) comprising the steps of:a) assessing the level of a SKI complex member protein (e.g., TTC37, AVEN, WDR61, or SKIV2L) in a test sample obtained from said subject (e.g, byDocket No. TGO-035WOcontacting the sample with a reagent capable of detecting human SKI complex member protein-deficient cancer cells in a test sample obtained from said subject), wherein the SKI complex member protein level can be assessed directly (e.g., by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC); b) comparing the test sample with a reference (e.g., a reference sample taken from anon-cancerous or normal control subject), wherein SKI complex member protein deficiency in said test sample indicates said subject will respond to therapeutic treatment with an HBS1L degrader; andc) administering a therapeutically effective amount ofHBSIL degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0453] In some embodiments provided is a therapeutic method of treating a cancer (e.g., a cancer associated with FOCAD deficiency) in a subject in need thereof comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human FOCAD- deficient cancer cells), wherein the FOCAD level can be assessed directly (e.g., by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC); b) comparing the test sample with a reference (e.g., a reference sample taken from anon-cancerous or normal control subject), wherein FOCAD deficiency in said test sample indicates said cancer will respond to therapeutic treatment with an HBS1L degrader; andc) administering a therapeutically effective amount of HBS IL degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0454] In some embodiments provided is a therapeutic method of treating a cancer (e.g., a cancer associated with a SKI complex member deficiency) in a subject in need thereof comprising the steps of:a) assessing the level of a SKI complex member protein (e.g., TTC37, AVEN, WDR61, or SKIV2L) in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human SKI complex member protein-deficient cancer cells in a test sample obtained from said subject),Docket No. TGO-035WOwherein the SKI complex member protein level can be assessed directly (e.g., by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC); b) comparing the test sample with a reference (e.g, a reference sample taken from anon-cancerous or normal control subject), wherein SKI complex member protein deficiency in said test sample indicates said subject will respond to therapeutic treatment with an HBS1L degrader; andc) administering a therapeutically effective amount of HBS IL degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0455] In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g, urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g., lower grade glioma)), head and neck cancer (e.g., head and neck squamous cell carcinoma), prostate cancer (e.g, prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g. colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g., ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0456] In some embodiments, the method further comprises the step of determining the level of HBS1L in the cancer cells. In some embodiments provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer associated with FOCAD deficiency comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human FOCAD- deficient cancer cells), wherein the FOCAD level can be assessed directly (e.g., by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC); b) comparing the test sample with a reference sample (e.g, a reference sample taken from a non-cancerous or normal control subject), wherein FOCADDocket No. TGO-035WOdeficiency in said test sample indicates said cancer will respond to therapeutic treatment with an HBS1L degrader, andc) administering a therapeutically effective amount of a composition comprising an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0457] In some embodiments provided is a therapeutic method of treating cancer associated with FOCAD deficiency in a subject in need thereof comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human FOCAD- deficient cancer cells), wherein the FOCAD level can be assessed directly (e.g, by ELISA. LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC); b) comparing the test sample with a reference sample (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein FOCAD deficiency in said test sample indicates said cancer will respond to therapeutic treatment with an HBS1L degrader, andc) administering a therapeutically effective amount of a composition comprising an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0458] In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g., urothelial carcinoma), skin cancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e.g., head and neck squamous cell carcinoma), prostate cancer (e.g, prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g, colon adenocarcinoma), mesothelioma (e.g, pleural mesothelioma), ovarian cancer (e.g., ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g, liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

[0459] In some embodiments, the method further comprises the step of determining the level of HBS1L in the cancer cells.Docket No. TGO-035WO

[0460] In some embodiments provided is a method of determining if a subj ect having or having been diagnosed with a cancer associated with FOCAD deficiency will respond to treatment with an HBS1L degrader (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human FOCAD- deficient cancer cells), wherein the FOCAD level can be assessed directly (e.g. by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by SDMA-modified protein ELISA or IHC);b) comparing the test sample with a reference (e.g., a reference sample taken from anon-cancerous or normal control subject), wherein FOCAD deficiency in said test sample indicates said subject will respond to therapeutic treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0461] In some embodiments provided is a method of determining if a cancer associated with FOCAD deficiency will respond to treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) comprising the steps of:a) assessing the level of FOCAD in a test sample obtained from a subject having or having been diagnosed with said cancer (e.g., by contacting the sample with a reagent capable of detecting human FOCAD-deficient cancer cells), wherein the FOCAD level can be assessed directly (e.g, by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g., by protein ELISA or IHC);b) comparing the test sample with a reference (e.g., a reference sample taken from anon-cancerous or normal control subject), wherein FOCAD deficiency in said test sample indicates said cancer will respond to therapeutic treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject identified in step b).

[0462] In some embodiments, the cancer is selected from the group consisting of bladder cancer (e.g., urothelial carcinoma), skin cancer (e.g., cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), breast cancer, brain cancer (e.g., glioblastoma multiforme, glioma (e.g, lower grade glioma)), head and neck cancer (e g, head and neck squamous cellDocket No. TGO-035WOcarcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g, esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g., colon adenocarcinoma), mesothelioma (e.g., pleural mesothelioma), ovarian cancer (e.g, ovarian epithelial adenocarcinoma), hepatobiliary cancer (e.g., liver hepatocellular carcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal carcinoma, non-clear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g., diffuse large B-cell lymphoma (DLBCL)) and sarcoma. In some embodiments, the method further comprises the step of determining the level of HBS1L in the cancer cells.Sample preparation

[0463] Further provided are assays for the detection of FOCAD deficiency. They can include detecting a mutation related to FOCAD deficiency, e.g., in a body fluid such as blood (e.g., serum or plasma), bone marrow, cerebral spinal fluid, peritoneal / pleural fluid, lymph fluid, ascites, serous fluid, sputum, lacrimal fluid, stool, or urine, or in a tissue such as a tumor tissue. The tumor tissue can be fresh tissue or preserved tissue (e.g, formalin fixed tissue, paraffin-embedded tissue).

[0464] Body fluid samples can be obtained from a subject using any of the methods known in the art. Methods for extracting cellular DNA from body fluid samples are well known in the art. Typically, cells are lysed with detergents. After cell lysis, proteins are removed from DNA using various proteases. DNA is then extracted with phenol, precipitated in alcohol, and dissolved in an aqueous solution. Methods for extracting acellular DNA from body fluid samples are also known in the art. Commonly, a cellular DNA in a body fluid sample is separated from cells, precipitated in alcohol, and dissolved in an aqueous solution.Detection of HBS1L sensitivity

[0465] Samples, once prepared, can be tested for FOCAD deficiency, which indicates that the sample is sensitive to treatment with an HBS1L degrader. The detection of FOCAD deficiency can be done by any number of ways, for example: DNA sequencing, PCR based methods, including RT-PCR, microarray analysis. Southern blotting, Northern blotting, Next Generation Sequencing, and dip stick analysis. In some embodiments, FOCAD deficiency is evaluated by any technique known in the art, for example, immunohistochemistry utilizing an anti-FOCAD antibody or derivative thereof, and / or genomic sequencing, or nucleic acid hybridization, or amplification utilizing at least one probe or primer, for example a probe orDocket No. TGO-035WOprimer comprising a sequence of at least 12 contiguous nucleotides (nt) of the sequence of FOCAD wherein the primer is no longer than about 30 nt.

[0466] The polymerase chain reaction (PCR) can be used to amplify nucleic acid sequences and identify FOCAD deficiency from either genomic DNA or RNA extracted from tumor tissue. PCR is well known in the art and is described in detail in Saiki et al., Science 1988, 239:487.

[0467] Methods of detecting FOCAD deficiency by hybridization are provided. The method comprises identifying FOCAD deficiency in a sample by its inability to hybridize to FOCAD nucleic acid sequence. The nucleic acid probe is detectably labeled with a label such as a radioisotope, a fluorescent agent, or a chromogenic agent. Radioisotopes can include without limitation; 3H, 32P, 33P and 35S etc. Fluorescent agents can include without limitation: FITC, texas red, rhodamine, etc.

[0468] The probe used in detection that is capable of hybridizing to FOCAD nucleic acid sequence can be from about 8 nucleotides to about 100 nucleotides, from about 10 nucleotides to about 75 nucleotides, from about 15 nucleotides to about 50 nucleotides, or about 20 to about 30 nucleotides. The kit can also provide instructions for analysis of patient cancer samples, wherein the presence or absence of FOCAD deficiency indicates if the subject is sensitive or insensitive to treatment with an HBS1L degrader.

[0469] Single stranded conformational polymorphism (SSCP) can also be used to detect FOCAD deficiency. This technique is well described in Orita et al., PNAS 1989, 86:2766-2770.Measurement of Gene Expression

[0470] Evaluation of FOCAD deficiency and measurement of FOCAD gene expression, and measurement of HBS1L gene expression can be performed using any method or reagent known in the art.

[0471] Detection of gene expression can be by any appropriate method, including for example, detecting the quantity of mRNA transcribed from the gene or the quantity of cDNA produced from the reverse transcription of the mRNA transcribed from the gene or the quantity of the polypeptide or protein encoded by the gene. These methods can be performed on a sample by sample basis or modified for high throughput analysis. For example, using Affymetrix™ U133 microarray chips.

[0472] In some embodiments, gene expression is detected and quantitated by hybridization to a probe that specifically hybridizes to the appropriate probe for that biomarker. The probesDocket No. TGO-035WOalso can be attached to a solid support for use in high throughput screening assays using methods known in the art.

[0473] In some embodiments, the expression level of a gene is determined through exposure of a nucleic acid sample to the probe-modified chip. Extracted nucleic acid is labeled, for example, with a fluorescent tag, preferably during an amplification step.

[0474] Hybridization of the labeled sample is performed at an appropriate stringency level. The degree of probe-nucleic acid hybridization is quantitatively measured using a detection device.

[0475] Alternatively, any one of gene copy number, transcription, or translation can be determined using known techniques. For example, an amplification method such as PCR may be useful. General procedures for PCR are taught in MacPherson et al., PCR: A Practical Approach, (IRL Press at Oxford University Press (1991)). However, PCR conditions used for each application reaction are empirically determined. A number of parameters influence the success of a reaction. Among them are annealing temperature and time, extension time, Mg2+ and / or ATP concentration, pH, and the relative concentration of primers, templates, and deoxyribonucleotides. After amplification, the resulting DNA fragments can be detected by agarose gel electrophoresis followed by visualization with ethidium bromide staining and ultraviolet illumination. In some embodiments, the hybridized nucleic acids are detected by detecting one or more labels attached to the sample nucleic acids. The labels can be incorporated by any of a number of means well known to those of skill in the art. However, in some embodiments, the label is simultaneously incorporated during the amplification step in the preparation of the sample nucleic acid. Thus, for example, polymerase chain reaction (PCR) with labeled primers or labeled nucleotides will provide a labeled amplification product. In a separate embodiment, transcription amplification, as described above, using a labeled nucleotide (e.g, fluorescein-labeled UTP and / or CTP) incorporates a label into the transcribed nucleic acids.

[0476] Alternatively, a label may be added directly to the original nucleic acid sample (e.g., mRNA, poly A, mRNA, cDNA, etc.) or to the amplification product after the amplification is completed. Means of attaching labels to nucleic acids are well known to those of skill in the art and include, for example nick translation or end-labeling (e.g., with a labeled RNA) by kinasing of the nucleic acid and subsequent attachment (ligation) of a nucleic acid linker joining the sample nucleic acid to a label (e.g., a fluorophore).Docket No. TGO-035WOIn one example, the gene expression can be measured through an in-situ hybridization protocol that can detect RNA molecules on a slide containing tissue sections or cells (e.g., through RNAscope®).

[0477] Detectable labels suitable for use in the methods disclosed herein include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. Useful labels include biotin for staining with labeled streptavidin conjugate, magnetic beads (e.g, Dynabeads™), fluorescent dyes (e.g., fluorescein, texas red, rhodamine, green fluorescent protein, and the like), radiolabels (e.g., 3H, 125I, 35S, 14C, or 32P), enzymes (e.g, horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and colorimetric labels such as colloidal gold or colored glass or plastic (e.g. polystyrene, polypropylene, latex, etc.) beads.

[0478] Detection of labels is well known to those of skill in the art. Thus, for example, radiolabels may be detected using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted light. Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label. The detectable label may be added to the target (sample) nucleic acid(s) prior to, or after the hybridization, such as described in WO 97 / 10365. These detectable labels are directly attached to or incorporated into the target (sample) nucleic acid prior to hybridization. In contrast, “indirect labels” are joined to the hybrid duplex after hybridization. Generally, the indirect label is attached to a binding moiety that has been attached to the target nucleic acid prior to the hybridization. For example, the target nucleic acid may be biotinylated before the hybridization. After hybridization, an avidin-conjugated fluorophore will bind the biotin bearing hybrid duplexes providing a label that is easily detected. For a detailed review of methods of labeling nucleic acids and detecting labeled hybridized nucleic acids see Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 24: Hybridization with Nucleic Acid Probes, P. Tijssen, ed.Elsevier, N. Y. (1993).Detection of polypeptides

[0479] Protein levels of FOCAD can be determined by examining protein expression or the protein product. Determining the protein level involves measuring the amount of any immunospecific binding that occurs between an antibody that selectively recognizes andDocket No. TGO-035WObinds to the polypeptide of the biomarker in a sample obtained from a subject and comparing this to the amount of immunospecific binding of at least one biomarker in a control sample.

[0480] A variety of techniques are available in the art for protein analysis. They include but are not limited to radioimmunoassays, ELISA (enzyme linked immunosorbent assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays (using e.g., colloidal gold, enzyme or radioisotope labels), Western blot analysis, immunoprecipitation assays, immunofluorescent assays, flow cytometry, immunohistochemistry, HPLC, mass spectrometry, confocal microscopy, enzymatic assays, surface plasmon resonance and SDS-PAGE.Adjacent biomarkers

[0481] Near or adjacent to FOCAD on chromosome 9 are several other biomarkers.CDKN2A is often, if not usually, deleted along with FOCAD. Additional genes or pseudogenes in this region include: MLLT3, MIR4474, FOCAD-AS1, RPL7AP48, MIR491, SNORA30B, IFNB1, HACD3, KLHL9, and MTAP.

[0482] In some embodiments of the methods, the cell that is FOCAD-deficient is also deficient in CDKN2A. In some embodiments, the cell that is FOCAD-deficient is also deficient in one or more of: CDKN2A, MLLT3, MIR4474, FOCAD-AS1, RPL7AP48, MIR491, SNORA30B, IFNB1, HACD3, KLHL9, and MTAP.

[0483] In some embodiments of the methods, the cell that is FOCAD-deficient is also deficient in MTAP. In some embodiments, the cell that is FOCAD-deficient is also deficient in one or more of: MTAP, CDKN2A, MLLT3, MIR4474, FOCAD-AS1, RPL7AP48, MIR491, SNORA30B, IFNB1, HACD3, and KLHL9.

[0484] Thus, in various methods involving a step of evaluating a cell for FOCAD deficiency or determining if a cell is FOCAD-deficient, this step can comprise the step of determining if the cell is deficient for one or more of these markers: CDKN2A. MLLT3, MIR4474, FOCAD-AS1, RPL7AP48, MIR491, SNORA30B, IFNB1, HACD3, KLHL9, and MTAP.

[0485] Thus, in some embodiments, the disclosure encompasses: A method of determining if a subject having or having been diagnosed with a cancer will respond to therapeutic treatment with an HBS1L degrader, comprising the steps of:

[0486] a) evaluating a test sample obtained from said subject for FOCAD deficiency, and evaluating a reference sample from a non-cancerous or normal control subject for FOCAD deficiency, wherein FOCAD deficiency in the test sample relative to the reference sampleDocket No. TGO-035WOindicates that the subject will respond to therapeutic treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof); wherein FOCAD deficiency is evaluated by evaluating the deficiency of one or more of the following biomarkers: CDKN2A, MLLT3, MIR4474, FOCAD-AS1, RPL7AP48, MIR491, SNORA30B, IFNB1, HACD3, KLHL9, and MTAP, and wherein the method can further comprise the following steps:b) determining the level of FOCAD in the subject, wherein steps a) and b) can be performed in any order;c) administering a therapeutically effective amount of an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject; andd) determining the level of HBS1L activity in the subject following step c), wherein a decrease in the level of HBS1L or its activity is correlated with the inhibition of the proliferation of the cancer, and wherein steps c) and d) are performed after steps a) and b).

[0487] In some embodiments, the disclosure encompasses: A method of determining if a cancer will respond to therapeutic treatment with an HBS1L degrader, comprising the steps of:

[0488] a) evaluating a test sample obtained from a subject having or having been diagnosed with said cancer for FOCAD deficiency, and evaluating a reference sample from a non-cancerous or normal control subject for FOCAD deficiency, wherein FOCAD deficiency in the test sample relative to the reference sample indicates that the cancer will respond to therapeutic treatment with an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof); wherein FOCAD deficiency is evaluated by evaluating the deficiency of one or more of the following biomarkers: CDKN2A, MLLT3, MIR4474, FOCAD-AS1, RPL7AP48, MIR491, SNORA30B, IFNB1, HACD3, KLHL9, and MTAP, and wherein the method can further comprise the following steps:b) determining the level of FOCAD in the subject, wherein steps a) and b) can be performed in any order;c) administering a therapeutically effective amount of an HBS1L degrader (e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof) to the subject; andDocket No. TGO-035WOd) determining the level of HBS1L activity in the subject following step c), wherein a decrease in the level of HBS1L or its activity is correlated with the inhibition of the proliferation of the cancer, and wherein steps c) and d) are performed after steps a) and b).Assaying for biomarkers and HBS1L degrader treatment

[0489] A number of patient stratification strategies could be employed to find patients likely to be sensitive to HBS1L inactivation with an HBS1L degrader (e.g.. an HBS1L degrader of the present disclosure, e.g., a compound of Formula (I), or pharmaceutically acceptable salts thereof), including but not limited to, testing for FOCAD deficiency.

[0490] Once a patient has been assayed for FOCAD deficiency and predicted to be sensitive to treatment with an HBS1L degrader, administration of any HBS1L degrader (e.g, a compound of Formula (I), or pharmaceutically acceptable salts thereof) to a patient can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents may be empirically adjusted.Kits

[0491] In some embodiments provided are kits related to methods of use described herein.

[0492] In some embodiments, provided is a kit for predicting the sensitivity of a subject having or having been diagnosed with a FOCAD-deficiency-related cancer for treatment with an HBS1L degrader is provided. The kit comprises: i) reagents capable of detecting human FOCAD-deficient cancer cells; and ii) instructions for how to use said kit.Examples

[0493] In order that the invention(s) described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any w ay as limiting their scope. In theDocket No. TGO-035WOsynthetic examples below, the descriptions of experimental procedures within a reaction sequence are listed in numerical order.

[0494] In the synthetic schemes below, when the stereochemistry indicator (e.g, rac-, rel-) in the computer-generated name conflicts with the stereochemical indicators in the compound structure as depicted in the scheme, the stereochemical indicators in the scheme take precedence.

[0495] Exemplary syntheses utilizing racemic starting materials to provide racemic mixtures of products can be readily adapted to provide enantiopure final products by either utilizing an enantiopure starting material or by chiral separation of the final compound using methods known in the art.AbbreviationsGeneralADDP 1, 1 '-(azodicarbonyl)dipiperidineanhy. anhydrousaq.aqueoussatd. saturatedmin(s) minute(s)hr(s) hour(s)s secondsmL millilitermmol millimole(s)mM millimolarpM micromolarnM nanomolarmol mole(s)MS mass spectrometryNMR nuclear magnetic resonanceTLC thin layer chromatographyHPLC high-performance liquid chromatographyMe methyli-Pr iso-propylt-Bu tert-butyl‘BuXPhos 2-di- / e / 7-butylphosphino-2 ',4',6' -triisopropylbiphenylDocket No. TGO-035WOPh phenylEt ethylBz benzoylRuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenylSpectrumHz hertz5 chemical shiftJ coupling constants singletd doublett tripletq quartetm multipletbr broadqd quartet of doubletsdquin doublet of quintetsdd doublet of doubletsdt doublet of tripletsSolvents and ReagentsDAST DiethylaminosulfurtrifluorideCHCI3 chloroformDCM dichloromethaneDMF dimethylformamideEt2O diethyl etherEtOH ethyl alcoholEtOAc ethyl acetateMeOH methyl alcoholMeCN acetonitrilePE petroleum etherTHF tetrahydrofuranDMSO dimethyl sulfoxidet-BuOK potassium / m-butoxide9-BBN 9-borabicyclo[3.3.1]nonaneDocket No. TGO-035WOAcOH acetic acidHC1 hydrochloric acidH2SO4 sulfuric acidNH4CI ammonium chlorideKOH potassium hydroxideNaOH sodium hydroxideK2CO3 potassium carbonateNa2CO3 sodium carbonateTFA trifluoroacetic acidNa2SO4 sodium sulfateNaBH4 sodium borohydrideNaHCO3 sodium bicarbonateLiHMDS lithium hexamethyldisilylamideEt3N triethylaminePy pyridinePCC pyridinium chlorochromateDMAP 4-(dimethylamino)pyridineDIPEA N, N-diisopropylethylamineBINAP 2,2’-bis(diphenylphosphanyl)-l,l '-binaphthyldppf 1,1′-bis(diphenylphosphino)ferrocenePEP Phospho(enol)pyruvic acidLDH Lactate DehydrogenaseDTT DL-DithiothreitolBSA Bovine Serum AlbuminNADH P-Nicotinamide adenine dinucleotide, reducedPd(tBu3P)2 bis(tri-tert-butylphosphine)palladium(0)AcCl acetyl chloridez-PrMgCl Isopropylmagnesium chlorideTBSC1 ter / -Butyl(chloro)dimethylsilane(z-PrO)4Ti titanium tetraisopropoxideBHT 2,6-di-t-butyl-4-methylphenoxideBzCl benzoyl chlorideCsF cesium fluorideDocket No. TGO-035WODCC dicyclohexylcarbodiimideDMP Dess-Martin periodinaneEtMgBr ethylmagnesium bromideTEA tri ethyl amineAlaOH alanineTBAF tetra-n-butylammonium fluorideTBS t-butyldimethylsilylTMS tri methyl silylTMSCF3 (Trifluoromethyl)trimethylsilaneTs p-toluenesulfonylBu butylTi(OPr)4 tetraisopropoxytitaniumLAH Lithium Aluminium HydrideLDA lithium diisopropylamideLiOH. H2O lithium hydroxide hydratesMAD methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide)NBS N-bromosuccinimideNa2S2O3 sodium thiosulfateBoc t-butoxycarbonylMTBE methyl tert-butyl etherDIAD diisopropyl azodicarboxylateGeneral experimental notes:

[0496] In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company), and used without further purification.

[0497] Spots were visualized by UV light (254 and 220 nm). Purification by column and flash chromatography was carried out using silica gel (100-200 mesh). Solvent systems are reported as the ratio of solvents.

[0498] NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer.1H chemical shifts are reported in 5 values in ppm with tetramethylsilane (TMS, = 0.00 ppm) as the internal standard. See, e.g., the data provided in Table 2.

[0499] LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with ESI (+) ionization mode. See, e.g., the data provided in Table 2.Docket No. TGO-035WOScheme 1- General procedure for the synthesis of Compounds of Formula IIn Scheme 1, Ring B, RA, RB, R Ry, m and n are as described in any of the embodiments described herein.

[0500] To a mixture of Amine M (1 eq) in a suitable solvent (e.g., THF) was added (4-nitrophenyl) carbonochloridate (~1.5 eq) and base (e.g., pyridine) (-5 eq), then the mixture was stirred at 15°C for 0.5 hrs. The reaction mixture was concentrated to give the Intermediate B, which was used for next step directly without purification.

[0501] To a mixture of Intermediate N (1 eq) in a suitable solvent e.g., DMF) (200 mL) was added amine C (~leq) and a base e.g., DIEA) (-5 eq), then the mixture was stirred at 15°C for 12 hrs. The crude product was purified by / i / 'c / i-f IPLC (exemplary conditions;NH4HCO3 column: Welch Xtimate C18250*150mm# lOum; mobile phase: [A: FEOQOmM NEUHCCE B: ACN]; B%: 40.00%-70.00%, 18. OOmin) to give the final compound of Formula (I). Optionally, to obtain enantiomerically enriched compounds, the racemic mixture can be separated by methods known to one of skill in the art, such as, for example, chiral SFC (exemplary conditions: column: ChiralPak IH, 250*30mm, 10um;mobile phase: [A: CO2; B: IPA]; B%: 50.00%-50.00%,8.00 min)Example 1. Compounds prepared as described in Scheme 1

[0502] Compound of the invention (e.g., compounds depicted in Table 1 and Table 2) were prepared by methods similar to those described in Scheme 1 from the intermediates described in the ‘“Intermediates” section.Docket No. TGO-035WOTable 2 Exemplary compounds and characterization dataCompo MS MSStructure ’ll NMR Data (400 MHz)und Nr Calc. found‘H NMR (400 MHz, DMSO-Y) 5 ppm 10.89 (s, HI), 8.68 (s, III), 8.05 (d, J = 7.8 IIz, III), 7.40 - 7.27 (m, 6H), 7.17 - 7.05 (m, 2H), 4.63 (s, 1H), 4.57 14 522.3 522.2(ddd, 7 = 6 1, 8 1, 11.6 Hz, 1H), 290 - 277 (m, 1H), 2.62 - 2.55 (m, 1H), 2.26 - 2.11 (m, 2H), 1.62 (s, 6H), 1.45 (s, 3H), 0.83 (s, 9H).‘H NMR (400 MHz, DMSO-Y) 8 ppm 10.89 (s, 1H), 8.66 (s, 1H), 8.05 (d, 7 = 7.5 Hz, 1H), 7.38 - 7.27 (m, 4H), 7.24 - 7.19 (m, 2H), 7.13 - 7.05 (m, 13 HN M 5183 5182 2H), 457 (ddd, 7 = 59, 83, 11 5 Hz, 1H), 289 - 2.79 (m, 1H), 2.68 - 2.59 (m, 1H), 2.25 - 2.11 (m, 2H), 1.60 (s, 6H), 0.86 - 0.83 (m, 2H), 0.81 (s, 9H), 0.53 - 0.45 (m, 2H);‘H NMR (DMSO-rfs, 400 MHz) 8 (ppm)10.89 (s, 1H), 865 (s, 1H), 805 (br d, J = 78 Hz, 1H), 743 - 3 477.2 478.2 7.25 (m, 6H), 7.21 - 7.01 (m, 2H), 4.65 - 4.50 (m,1H), 2.96 - 2.75 (m, 1H), 2.59 (br d, J = 17.4 Hz, 1H), 2.29 - 2.07 (m, 2H), 1.60 (s, 6H), 1.26 (s, 9H)> H NMR (400 MHz, DMSO-Y) 8 ppm 1.64 (s, 6 H) 2.13 - 2.26 (m, 2 H) 2.55 - 2.63 (m, 1 H) 2.78 - 2.89 (m, 1 H) 4.48 - 4.68 (m, 1 H) 7.08 (t, J=7.87 Hz, 1 2 515.2 516.2 H) 722 - 7.30 (m, 3 H) 7.35 (dd, J=12.93, 805 Hz,2 H) 7.48 (d, J=8.34 Hz, 2 H) 7.54 - 7.61 (m, 2 H) 7.68 (dd, J=8.70, 5.48 Hz, 2 H) 7.99 - 8.10 (m, 1 H) 8.63 - 8.74 (m, 1 H) 1090 (s, 1 H)‘H NMR (DMSO-76, 400 MHz) 8 (ppm)10.95 - 10.82 (m, 1H), 8.70 - 865 (m, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.43 (br s, 4H), 7.35 (dd, J = 8.1, 13.6 Hz, 1 M AN529.2 530.2 2H), 7.20 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 457 (ddd, J = 6.1, 8.1, 11.6 Hz, 1H), 2.89 - 2.79 (m, 1H), 2.63 - 2.54 (m, 1H), 2.24 - 2.08 (m, 2H), 1.60 (s, 6H), 1.33 - 1.28 (m, 2H), 1 09 (br s, 2H)Docket No. TGO-035WOCompo MS MSStructure ‘H NMR Data (400 MHz)und Nr Calc. found‘H NMR (DMSO-rfe, 400 MHz) 8 (ppm)10.89 (s, 1H), 8.67 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.42 - 7.31 (m, 611), 7.20 (s, HI), 7.08 (t, J = 7.9 Hz, HI), 12 529.2 530.2 4.62 - 4.53 (m, 1H), 2.82 (br d, J = 11.7 Hz, 1H),2.63 - 2.54 (m, 1H), 2.18 (br dd, J = 4.1, 11.7 Hz, 2H), 1.60 (s, 6H), 1.33 - 1.28 (m, 2H), 1.09 (br s, 2H)‘H NMR (400 MHz, DMSO-Y) <5 ppm 10.89 (s, 1H), 8.69 (s, 1H), 8.05 (dd, J= 0.7, 7.9 Hz, 1H), 7.67 - 7.57 (m, 4H), 7.53 - ...

Claims

Docket No. TGO-035WOClaims1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 member heteroaryl containing 1-3 heteroatoms selected from N, O and S;R3and R3are each independently selected from the group consisting of H, -C1-C3 alky l and -C1-C3 haloalky 1 or are taken together with the carbon to which they are attached to form a C3-C9 cycloalkyl or a 4-7 membered heterocyclyl containing 1 heteroatom selected from N, O and S, provided that R3and R3are not both H;each RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -C3-C9 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, –(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6- 10 membered ary l), -(C1-C2 alkyl)(6-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -C(=O)ORA2, -NRA2C(=O)RA1, -NRA2C(=O)ORA1, -C(=O)N(RA2)2, -C(=O)N(ORA2)(RA2), -OC(=O)N(RA2)2. -S(=O)RA1, -S(=O)2RA1, -SRA2, -S(=O)(=NRA2)RA1. -NRA2S(=O)2RA1and -S(=O)2N(RA2)2;each RBis independently selected from the group consisting of-D, halo. -CN, =0, -SF5, -Ci-Cs alkyl, -Ci-Ce alkenyl. -Ci-Ce heteroalky 1,-Ci-Cs haloalkyl, -Ci-Ce haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl). -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-l 0 membered heteroaryl), -ORB2, -N(RB2)2, -C(=O)RB1, -Docket No. TGO-035WOC(=O)ORB2, -NRB2C(=O)RB1, -NRB2C(=O)ORB1, -C(=O)N(RB2)2, -C(=O)N(ORB2)(RB2), -OC(=O)N(RB2)2. -S(=O)RB1, -S(=O)2RB1, -SRB2. -S(=O)(=NRB2)RB1, -NRB2S(=O)2RB1and -S(=O)2N(RB2)2wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of-OMe or -OH;each R4is independently selected from -D, =O, halo, -OH, -NH2, -CN, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Cg haloalkyl, -NH(Ci-C6alkyl), -N(CI-C6alkyl)2;each RB1is independently selected from -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce haloalkyl, -Ci-Cs haloalkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected fromN, O and S, — (Ci-C2alkyl)(C3-C9 cycloalkyl). -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6- 10 membered aryl), -(C1-C2 alkyl)(6- 10 membered heteroaryl);each RB2is independently selected from -H, -D, -Ci-Ce alkyl, -Ci-Ce alkenyl, -Ci-Ce haloalkyl. -Ci-Ce haloalkenyl, C3-C9 cycloalkyl. C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected fromN, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S, — (Ci-C2alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(4-10 member heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(6-10 membered heteroaryl), wherein each cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is substituted with 0, 1 or 2 instances of Ci-Ce alkyl, OH or halo;n is 0, 1, 2 or 3; andm is 0, 1, 2 or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (T):Docket No. TGO-035WO3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I”):

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3and R3are each independently selected from H, -C1-C3 alkyl and -C1-C3 haloalkyl or are taken together with the carbon to which they are attached to form a C -C6 cycloalkyl or a 4-7 membered heterocyclyl containing 1 oxygen atom, provided that R3and R3are not both H.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3and R3are each independently -C1-C3 alkyl.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3and R3are each independently selected from H, -Me, -Et, -zPr and -CF3 or are taken together with the carbon to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl ring, provided that R3and R3are not both H.

7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3and R3are each independently selected from H, -Me and -Et.

8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R3and R3are both -Me.Docket No. TGO-035WO9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, the compound is of Formula (II)10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof. wherein, the compound is of Formula (IT)11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein, the compound is of Formula (II”):

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of halo, -Ci-Ce alkyl, -Ci-Ce alkenyl, and -ORA2.

13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of-F, -Cl, -Me, -Et, - / Pr. -tBu, -vinyl, and -OCH3.Docket No. TGO-035WO14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of-F, -Cl, -Me, -Et. -vinyl, and -OCH3.

15. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein n is 0.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein n is 1.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein n is 2.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein n is 3.

19. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof,O20. The compound of claim 1. or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II- 1):

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II- 1 ’):Docket No. TGO-035WO(II-l ).

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, the compound is of Formula (II- 1”):

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 6-14 membered ary l, C3-C9 cycloalkyl and 5-14 member heteroaryl containing 1-3 heteroatoms selected fromN, O and S.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 9-10 member bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C4-C9 fused bicyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 member tricy clic heteroaryl containing 1-3 heteroatoms selected fromN, O and S.

25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 9-10 member bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 member tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 9-10 member bicyclic aryl,Docket No. TGO-035WOC3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected fromN. O and S and 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

27. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is 6-14 membered aryl.

28. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl or 9-10 member bicyclic aryl.

29. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-14 member heteroaryl containing 1-3 heteroatoms selected from N, O and S.

30. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of 5-6 member monocyclic heteroaryl containing 1-3 heteroatoms selected fromN, O and S, 8-10 member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 member tricyclic heteroaryl containing 1-3 heteroatoms selected fromN, O and S.

31. The compound of any one of claims 1 -22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3-dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl. bicyclo[2.1.0]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo [4.2.0]octanyl, octahydro-lH-indenyl, decahydronaphthalenyl, bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl, oxetanyl, azepanyl. piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2-H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl,Docket No. TGO-035WObenzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo [3, 4-b] pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

32. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1.2.3.4-tetrahydroquinolinyl. chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl. 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo [4.2.0]octanyl, octahydro-lH-indenyl, decahydronaphthal enyl, bicyclo [1.1.1]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.

2. l]heptan-yl, bicyclo[2.2.2]octanyl. spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d] isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2-H-indazolyl, benzo [b] thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

33. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl. 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1.2.3.4-tetrahydroquinolinyl, chromanyl, isochromanyl, 9-H fluorenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl. thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d]isothiazolyl,Docket No. TGO-035WOindolyl, benzofuranyl, IH-indazolyl, 2-H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [1,2,4]triazolo[4,3-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), 1H-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

34. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, 1,3 dihydroisobenzofuranyl, indolinyl, isoindolinyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl. chromanyl, isochromanyl. 9-H fluorenyl, 9. 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl. thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, and pyrimidinyl.

35. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo|d][l,3]dioxolyl, naphthalenyl, 9, 10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, thiophenyl, pyridinyl, indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]thiazolyl and phenanthridinyl.

36. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, naphthalenyl, cyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl. thiophenyl, and pyridinyl.

37. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting ofDocket No. TGO-035WOand 38. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.

39. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein Ring Bis40. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety represented as41. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety represented asis42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-D, halo. =0, -CN, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9 cycloalkyl.4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected fromN, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(6-10Docket No. TGO-035WOmembered aryl), -ORB2, -N(RB2)2, -C(=O)RB1and — NRB2S(=O)2RB1wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of -OMe or -OH.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-D, halo, -CN, SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl containing 1-2 heteroatoms selected fromN, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 member heteroaryl containing 1-2 heteroatoms selected fromN, O and S, -(C1-C2 alkyl)(C3-C9 cycloalkyl), -(C1-C2 alkyl)(6-10 membered aryl), -ORB2, -N(RB2)2, -C(=O)RB1and — NRB2S(=O)2RB1wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroary l is substituted with 0, 1, 2 or 3 instances of R4and each alkyl, alkenyl, haloalkyl and haloalkenyl is substituted with 0 or 1 instances of -OMe or -OH. and wherein each R4is selected from -F, -Cl, =O, -OH, -OMe, -CN, -Me, -tBu, -CF3, -OCF3, -CHF2and -CH2CH2OH; RB1is phenyl, and each RB2is independently selected from -Me, -Et, -CF3, –CH(CH3)oxetan-3-yl, imidazol-2-yl and phenyl.

44. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-D, halo, -Ci-Ce alkyl, -Ci-Ce haloalkyl, C3-C9 cycloalkyl and 6-10 membered ary l wherein each aryl and cycloalkyl is substituted with 0, 1, 2 or 3 instances of R4, and each alkyl is substituted with 0 or 1 instances of -OH and wherein each R4is selected from -F, - / Bu and -CF3.

45. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of -F, -Cl, -Br, -CN, - Me, -Et,-iPr, -tBu, 3,3-dimethylbutan-2-yl, vinyl, isopropenyl, -OMe, -OCF3, -0(1-(oxetan-3-yl)ethyl), -Ocyclopropyl, -cyclopropyl, cyclobutyl, cyclohexyl,bicyclo[1.1.1]pentan-1-yl, spiro[2.2]pentanyl, -CH2Cyclopropyl, -SF5, -CHF2, -C(F)(CH3)2, -CFs, -CF2CH3, -C(=CF2)CH2CH2CH3, -CH(CF3)CH3, -C(CF3)(CH3)2, -CH2CF3, -C(=CH2)CF3, phenyl, -N(CH3)2, -N(CH3CH2)2, furan-3-yl, pyridin-2-yl, 4-oxo-4H-chromen-3-yl, pyrrolidin-l-yl, piperidin-1-yl, morpholin-4-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, azetidin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, piperazin-1-yl, tetrahydrofuran-3-yl, 8-oxabicyclo[3.

2. l]octan-3-yl, 8-oxabicyclo[3.

2. l]oct-2-en-3-yl, 2,3-dihydro-l,4-dioxin-5-yl,Docket No. TGO-035WOtetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-4-yl. -NH-imidazol-2-yl, NH-phenyl. benzyl. -C(=O)phenyl, -OPhenyl.N(CH3)S(=O)2phenyl, wherein each -Me -Et,-iPr, -tBu, 3,3-dimethylbutan-2-yl, -CHF2, -C(F)(CH3)2, -CF3, -CF2CH3, -C(=CF2)CH2CH2CH3,-CH(CF3)CH3, -CH2CF3and-C(CF3)(CH3)2is substituted with 0 or 1 instances of-OMe or -OH and each cyclopropyl, cyclobutyl, cy clohexyl, bicyclo[l.1.1] pentan- 1-yl. spiro[2.2]pentanyl, phenyl, oxetan-3-yl, furan-3-yl, pyridin-2-yl, 4-oxo-4H-chromen-3-yl, pyrrolidin-l-yl. piperidin-l-yl. morpholin-4-yl, 3-oxa-6-azabicyclo[3.1.1 ]heptan-6-yl, azetidin-l-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, piperazin- 1-yl, tetrahydrofuran-3-yl, 8-oxabicyclo[3.

2. l]octan-3-yl, 8-oxabicyclo[3.

2. l]oct-2-en-3-yl, 2,3-dihydro-l,4-dioxin-5-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-4-yl. imidazol-2-yl is substituted at available positions with 0, 1 or 2 instances of R4.

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein each R4is selected from -F. -Cl =0, -OH,-OMe, -OCF3, -CN, -Me, -tBu, -CHF2, -CF3, -CH2CH2OH.

47. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of -Cl, -tBu, 3,3-dimethylbutan-2-yl, -cyclopropyl, -CHF2, -CF3and -phenyl wherein each -tBu and 3,3-dimethylbutan-2-yl is substituted with 0 or 1 instances of -OH, and wherein each -cyclopropyl and phenyl is substituted at available positions with 0, 1 or 2 instances of R448. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein each R4is selected from -F, -tBu and -CF3.

49. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of:HO-F, -Cl, -Br, -CN, -Me, -Et, -iPr, -tBu, -CH=CH2, -C(=CH2)CH3, -SF5, -CHF2.-C(F)(CH3)2, CF3, CF2CH3, CF3, CH(CF3)CH3, CF3, C(CF3)(CH3)2,Docket No. TGO-035WO50. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of:Docket No. TGO-035WO51. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of:

52. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of:

53. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis halo (e.g., fluoro, chloro, bromo, iodo).

54. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein each RBis independently -Cl.

55. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis -Ci-Ce alkyl.

56. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of -Me, -Et, -nPr, -iPr. -tBu, and 3,3-dimethylbutan-2-yl, each substituted with 0 or 1 instances of -OH or-OMe.

57. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of 3.3-dimethylbutan-2-yl and -tBu each substituted with 0 or 1 instances of -OH.

58. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,wherein RBisDocket No. TGO-035WO59. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis - / Bu.

60. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis -Ci-Ce haloalkyl.

61. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting -CHF2, -C(F)(CH3)2, -CF2CH3, -CF3, -CH(CF3)CH3, -C(CF3)(CH3)2, and -CH2CF3, each substituted with 0 or 1 instances of -OH or -OMe (e.g., substituted with 0 or 1 instance of OMe).

62. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of –CHF2, and –CF3.

63. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis difluoromethyl (–CHF2).

64. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis trifluoromethyl (–CF3).

65. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis C3-C9 cycloalkyl wherein the cycloalkyl is substituted with 0, 1, 2 or 3 instances of R466. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of C3-C7 monocyclic cycloalkyl (e.g.. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C4-C9 fused bicyclic cycloalkyl (e.g., bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentanyL bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo [4.2.0]octanyl, octahydro- IH-indenyl, decahydronaphthalenyl), C5-C9 bridged cycloalkyl (e.g., bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.

2. l]heptanyl. bicyclo[2.2.2]octanyl) and C5-C9 spiro cycloalkyl (e.g., spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl), each substituted with 0, 1, 2 or 3 instances of R4.

67. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of C3-C7 monocyclic cycloalkyl (e.g..Docket No. TGO-035WOcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C5-C9 bridged cycloalkyl e.g., bicyclo [l.l.l]pentanyl, bicyclo [1.2.1]hexanyl, bicyclo[2.2.1]heptanyl. bicyclo[2.2.2]octanyl) and C5-C9 spiro cycloalkyl (e.g, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl), each substituted with 0, 1, 2 or 3 instances of R468. The compound of any one of claims 1-41. or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, bicyclo [l.l.l]pentanyl and spiro[2.2]pentanyl, each substituted with 0, or 1 instances of R4.

69. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from the group consisting of -Me, - / Bu. -OCF3, -CF3 and -CN.

70. The compound of claim 68, or a pharmaceutically acceptable salt thereof, wherein R4is independently selected from the group consisting of-rBu, and -CF3.

71. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,Fwherein RBis selected from the group consisting of72. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis C3-C7 monocyclic cycloalkyl substituted with 0, or 1 instances of R4.

73. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis selected from the group consisting of cyclopropyl, cyclobutyl and cyclohexyl, each substituted with 0 or 1 instances of R4.

74. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis cyclopropyl substituted with 0 or 1 instances of R4.

75. The compound of claim 74, or a pharmaceutically acceptable salt thereof, wherein R4is selected from the group consisting of - / Bu. and -CF3.Docket No. TGO-035WO76. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,wherein RBis selected from the group consisting of77. The compound of any one of claims 1-41. or a pharmaceutically acceptable salt thereof,wherein RBis78. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,wherein RBis79. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis 6-10 membered aryl wherein the aryl is substituted with 0, 1. 2 or 3 instances ofR480. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein RBis phenyl substituted with 0, 1, or 2 instances of R4.

81. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,82. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,wherein RBis83. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof,wherein each RBis84. The compound of any one of claims 1-42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from =0,Docket No. TGO-035WOhalo, -OH, -CN, -Ci-Ce alkyl, -C1-C6haloalkyl, -OCi-Ce alkyl, OCi-Ce haloalkyl and -Ci-Ce hydroxyalkyl.

85. The compound of any one of claims 1-42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from the group consisting of-F, -Cl, =0, -OH -OMe, -CN, -Me, - / Bu. -CF3, -OCF3, -CH2CH2OH and -CHF2.

86. The compound of any one of claims 1-42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from the group consisting of-F, - / Bu and -CF3.

87. The compound of any one of claims 1-42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halo (e.g., -F, -Cl, -Br).

88. The compound of any one of claims 1-42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently-F.

89. The compound of any one of claims 1-42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -Ci-Ce alkyl (e.g., -Me, -Et, -nPr, -zPr, - / Bu).

90. The compound of any one of claims 1 -42, 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently - / Bu91. The compound of any one of claims 1-42.

45. 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -Ci-Ce haloalkyl (e.g., -CHF2, -C(F)(CH3)2, -CF3, -CH(CF3)CH3,).

92. The compound of any one of claims 1-42. 45, 47, 65-68, 72-74 and 79-80, or a pharmaceutically acceptable salt thereof, wherein each R4is independently -CF3.

93. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety represented asis selected from the group consisting ofDocket No. TGO-035WODocket No. TGO-035WODocket No. TGO-035WOFDocket No. TGO-035WODocket No. TGO-035WO94. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,B )wherein the moiety represented asis selected from the group consisting ofDocket No. TGO-035WO 95. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,96. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,97. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety representedas98. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof.wherein the moiety representedasDocket No. TGO-035WO99. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety representedas100. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety representedas101. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety representedas F102. The compound of any one of claims 1-12, 16-18 and 23-101, or a pharmaceutically acceptable salt thereof, wherein each RA1is independently selected from the group consisting of–C1–C6alkyl, –C1–C6haloalkyl, C3–C9cycloalkyl, and 4-10 membered heterocyclyl.

103. The compound of any one of claims 1-12, 16-18 and 23-101, or a pharmaceutically acceptable salt thereof, wherein each RA1is independently selected from the group consisting of –C₁–C₆ alkyl, (e.g., –Me, –Et, –Pr, –ⁱPr, –sec-Bu, –ⁱBu) and –C₁–C₆ haloalkyl (e.g., –CF₃, –CHF₂, –CH₂CF₃).

104. The compound of any one of claims 1-12, 16-18 and 23-103, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, D, –C1–C6alkyl, –C1–C6haloalkyl, C3–C9cycloalkyl, and 4-10 membered heterocyclyl.

105. The compound of any one of claims 1-12, 16-18 and 23-103, or a pharmaceutically acceptable salt thereof, wherein each R2is independently selected from the group consisting of H, D, -Ci-Ce alkyl, (e.g., -Me, -Et, -Pr, -'Pr, -sec-Bu, -ᵗBu) and -Ci-Ce haloalkyl (e.g, -CF3, -CHF2, -CH2CF3).Docket No. TGO-035WO106. The compound of any one of claims 1-43, 84-92 and 102-105, or a pharmaceutically acceptable salt thereof, wherein each RB1is independently selected from the group consisting of-Ci-Ce alkyl, -Ci-Ce haloalkyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl and 6-10 membered aryl.

107. The compound of any one of claims 1-43, 84-92 and 102-105, or a pharmaceutically acceptable salt thereof, wherein each RB1is independently selected from the group consisting of -Ci-Ce alkyd, (e.g, -Me, -Et, -Pr, -'Pr, -sec-Bu, -zBu), -Ci-Ce haloalkyl (e.g., –CF3, –CHF2, –CH2CF3) and phenyl.

108. The compound of any one of claims 1-43, 84-92 and 102-105, or a pharmaceutically acceptable salt thereof, wherein each RB1is independently selected from the group consisting of –Me, –Et, –Pr, –ⁱPr, –sec-Bu, –tBu, –CF₃, –CHF₂, –CH₂CF₃ and phenyl.

109. The compound of any one of claims 1-43. 84-92 and 102-108, or a pharmaceutically acceptable salt thereof, wherein each RB2is independently selected from the group consisting of H, D, -Ci-Ce alkyl, -Ci-Ce haloalkyl, 6-10 membered aryl, 5-6 member heteroaryl containing 1-3 heteroatoms selected from N, O and S and-(Ci-C2 alkyl)(4-10 member heterocyclyl).

110. The compound of any one of claims 1-43, 84-92 and 102-108, or a pharmaceutically acceptable salt thereof, wherein each RB2is independently selected from the group consisting of –H, –D, –Me, –Et, –CF₃, -CH(CH₃)oxetan-3-yl, imidazol-2-yl and phenyl.

111. The compound of any one of claims 1-43, 84-92 and 102-108, or a pharmaceutically acceptable salt thereof, wherein each RB2is independently selected from the group consisting of -Me and -CF3.

112. The compound of any one of claims 1-111 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds of Table 1.

113. A pharmaceutical composition comprising a compound of any one of claims 1-112 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

114. The pharmaceutical composition of claim 113, further comprising a second therapeutic agent.Docket No. TGO-035WO115. An HBSIL-inactivating compound (e.g., an HBSIL degrader) for use in a method of treating an HBSIL-sensitive cancer in a subject in need thereof.

116. A compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of claim 113, for use in treating an HBSIL-sensitive cancer in a subject in need thereof.

117. The compound or composition for use of claim 115 or 116, wherein the cancer is a FOCAD-deficient cancer.

118. The compound or composition for use of claim 117, wherein the FOCAD-deficient cancer is a FOCAD-deleted cancer.

119. The compound or composition for use of claim 115 or 116, wherein the cancer is deficient in one or more of TTC37, AVEN, WDR61 and SK1V2L.

120. The compound or composition for use of claim 115 or 116, wherein the cancer is PELO -dependent.

121. A compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of claim 113, for use in treating a FOCAD-deficient cancer in a subject in need thereof.

122. The compound or composition for use of any one of claims 115-121, wherein the compound, or a pharmaceutically acceptable salt thereof, or composition is for use in combination with a second therapeutic agent.

123. A pharmaceutically acceptable composition of claim 114 for use in treating a FOCAD-deficient cancer in a subject in need thereof.

124. The compound or composition for use of claim 122 or 123 wherein the second therapeutic agent is a PRMT5 inhibitor (e.g., an MTA-cooperative PRMT5 inhibitor).

125. The compound or composition for use of claim 122 or 123 wherein the second therapeutic agent is a MAT2A inhibitor.

126. The compound or composition for use of any one of claims 115-125, wherein the cancer selected from the group consisting of bladder cancer (e.g., urothelial carcinoma), skinDocket No. TGO-035WOcancer (e.g, cutaneous melanoma), non-small cell lung cancer (e.g, lung squamous cell carcinoma, lung adenocarcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), breast cancer, brain cancer (e.g, glioblastoma multiforme, glioma), head and neck cancer (e.g, head and neck squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), esophagogastric cancer (e.g., esophageal carcinoma, stomach adenocarcinoma), colorectal cancer (e.g., colon adenocarcinoma), glioma (e.g, lower grade glioma), mesothelioma (e.g. pleural mesothelioma), ovarian cancer (e.g. ovarian epithelial adenocarcinoma), hepatobiliary cancer (e g, liver hepatocellularcarcinoma, cholangiocarcinoma), kidney cancer (e.g., clear cell renal cell carcinoma, nonclear cell renal carcinoma), cervical cancer, endometrial cancer, thyroid cancer, adrenal gland cancer (e.g, pheochromocytoma, adrenocortical cancer), thymic cancer, neuroepithelial cancers, mature B cell neoplasms (e.g, diffuse large B-cell lymphoma (DLBCL)) and sarcoma.

127. A compound of any one of claims 1-112, or a pharmaceutically acceptable salt thereof, or composition of claim 113 or 114, for use in treating a cancer in a subject in need thereof, wherein:a) the level of FOCAD in a test sample obtained from said subject has been assessed, wherein the FOCAD level can be assessed directly (e.g, by ELISA, LC-MS / MS, or qPCR) or indirectly (e.g. by protein ELISA or IHC);b) the test sample has been compared with a reference, wherein FOCAD deficiency in said test sample compared to the reference indicates the cancer in said subject will respond to therapeutic treatment with an HBS1L degrader; andc) an effective amount (e.g, a therapeutically effective amount) of the compound or composition is administered to the subject identified in step b).

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