Heterocyclic HBS1l degraders

Abstract

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

Description

Docket No. TGO-030WOCOMPOUNDS 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 October 23, 2025, is named TGO-030WO and is 4,176 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. 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 well -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 the PRMT5 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., Cell1IPTS / 200159134.1Docket No. TGO-030WOReports 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 the MTAP gene 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 on the function of the HBS1L / PELO complex for their survival, 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 (X) or a pharmaceutically acceptable salt thereof, wherein:2IPTS / 200159134.1Docket No. TGO-030WORing A is selected from the group consistingX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;X7is CH or N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10IPTS / 200159134.1Docket No. TGO-030WOmembered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl; or R5and one instance of RAcan be taken together with the atoms to which they are attached to form a 4-7 membered carbocyclic ring;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O4IPTS / 200159134.1Docket No. TGO-030WOand S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0012]

[0013] In some embodiments, provided is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Y is N or CR5;IPTS / 200159134.1Docket No. TGO-030WORing B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;6IPTS / 200159134.1Docket No. TGO-030WOR5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl; or R5and one instance of RAcan be taken together with the atoms to which they are attached to form a 4-7 membered carbocyclic ring;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0014] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:7IPTS / 200159134.1Docket No. TGO-030WOX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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), - 8IPTS / 200159134.1Docket No. TGO-030WOOC(=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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, — (Ci-C2alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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;9IPTS / 200159134.1Docket No. TGO-030WOn is 0, 1, 2 or 3; andm is 0, 1, 2 or 3.

[0015] In an embodiment, Ring

[0016] In some embodiments, provided is a compound of Formula (B) or a pharmaceutically acceptable salt thereof, wherein:Y is N or CR5;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -10IPTS / 200159134.1Docket No. TGO-030WOeach RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N,11IPTS / 200159134.1Docket No. TGO-030WOO and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0017] In some embodiments, provided is a pharmaceutical composition comprising a compound of Formula (X), 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.

[0018] In some embodiments, provided is a method of treating an HBSIL-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 a compound of Formula (X), 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-deficient cancer) in a subject in need thereof by administering to the subject an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (X), 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, the second therapeutic agent is a PRMT5 inhibitor. In some embodiments, the second therapeutic agent is a MAT2A inhibitor.

[0019] In some embodiments, provided is a method of treating a cancer in a subject in need thereof comprising the steps of:12IPTS / 200159134.1Docket No. TGO-030WOa) 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 (X) as defined herein or a pharmaceutical composition thereof to the subject identified in step b).

[0020] In some embodiments, provided is a use of a compound of Formula (X), 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.

[0021] In some embodiments, provided is a compound of Formula (X), 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.

[0022] In some embodiments, provided is a use of a compound of Formula (X), 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 the manufacturing of a medicament for treating a FOCAD-deficient disease (e.g., a FOCAD-deficient 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 Figures13IPTS / 200159134.1Docket No. TGO-030WOFIG. 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 HBS IL knockout MIAPACA2 xenograft in which HBS IL expression can be turned on through Doxycycline-inducible expression of HBS IL cDNA (+DOX) showing that tumor growth is suppressed in the absence of HBS IL (-DOX) and is rescued by sustained expression of HBS IL.FIG. 4 Shows tumor volume over time in MIAPACA2 pancreatic cancer xenograft model following oral administration of an exemplary HBS IL degrader at doses of 2, 6, 20, or 60 mg / kg BID compared to vehicle control.FIG. 5 Shows tumor volume over time in RS411 blood cancer xenograft model following oral administration of an exemplary HBS IL degrader at doses of 2, 6, 20, or 60 mg / kg BID compared to vehicle control.FIG. 6 Shows tumor volume over time in NCIH838 lung cancer xenograft model following oral administration of an exemplary HBS IL degrader at doses of 2, 6, 20, or 60 mg / kg BID compared to vehicle control.Detailed Description

[0023] 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.

[0024] As generally described herein, provided are compounds (e.g., compounds of Formula (X) or compounds of Table 1, or pharmaceutically acceptable salts thereof) that are HBS IL 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 HBS IL inactivation because they are PELO-dependent.14IPTS / 200159134.1Docket No. TGO-030WO

[0025] As generally described herein, provided is a method for treating an HBSIL-sensitive proliferating disease (e.g., cancer) by administering to a patient in need thereof a compound that can inactivate HBS1L (e.g., an HBS1L degrader). The HBSIL-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

[0026] 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

[0027] “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).

[0028] 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 15IPTS / 200159134.1Docket No. TGO-030WOthe protein structure, disruption of protein-protein interactions, or by inhibiting the transcription, translation, post-translational modification, or stability of the protein.

[0029] 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-defi cient. 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.

[0030] 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, brain16IPTS / 200159134.1Docket No. TGO-030WOcancer 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. In some embodiments, the FOCAD-deficiency-related disease is a histology agnostic FOCAD-deficient cancer.

[0031] 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.

[0032] 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.

[0033] 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

[0034] " HBS1L" as used herein is the gene or protein HBS1 like translational GTPase, also known as ERFS; HBS1; KIAA1038, EF-la; eRF3c; HSPC276.17IPTS / 200159134.1Docket No. TGO-030WO

[0035] External IDs: HGNC: 4834; NCBI Gene: 10767; Ensembl: ENSG00000112339; OMIM: 612450; MGI: 1891704; HomoloGene: 68525; GeneCards: HBS1L.

[0036] 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.

[0037] HBS1L is the GTPase component of the Pelota-HBSIL (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 Pel ota, Hbsl and ABCE1 of mammalian vacant 80S ribosomes and stalled elongation complexes” EMBO J. 2011 May 4;30(9): 1804-17; Saito S, HosodaN, Hoshino 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-HBSIL 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”).

[0038] 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.

[0039] The term “HBS1L degrader” refers to any compound capable of eliminating or reducing the amount of HBS1L in a cell (e.g., a tumor cell) by using a cell’s natural system18IPTS / 200159134.1Docket No. TGO-030WOfor eliminating misfolded or spent proteins. An HBS1L degrader induces the degradation of HBS1L by forming a ternary complex with an E3 ubiquitin ligase and HBS1L. In some embodiments, an HBS1L degrader is a PROTAC. In some embodiments, an HBS1L degrader is a molecular glue.

[0040] 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 a HBS1L inactivator (e.g., an HBS1L 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 HBS1L degrader) because it is dependent on PELO and PELO levels are decreased upon HBS1L depletion. In some embodiments, the disease (e.g., cancer) is HBSIL-sensitive (e.g., sensitive to an HBS1L degrader) because it is TTC37-deficient, AVEN-deficient, WDR61 -deficient, or SKIV2L-deficient.Chemical Definitions

[0041] 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.

[0042] It is to be understood that descriptions of compound structures, including possible substitutions, are limited to those which are chemically possible.

[0043] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For19IPTS / 200159134.1Docket No. TGO-030WOexample, 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, including 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 etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 332 25 (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.

[0044] Unless otherwise indicated, the absolute stereochemistry of all chiral atoms is as depicted. Compounds with an (or) designation in the stereochemistry column in Table 1 or at a chiral atom in Table 2 are single enantiomers wherein the absolute stereochemistry was arbitrarily assigned (e.g., based on chiral SFC elution as described in the Examples section). 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.

[0045] 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%.20IPTS / 200159134.1Docket No. TGO-030WO

[0046] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

[0047] 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 more different 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%.

[0048] 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%.

[0049] 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.

[0050] In a formula, — is a single bond where the stereochemistry of the moieties immediately attached thereto is not specified.

[0051] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, Cs^i, C4-6, C4-5, and C5-6 alkyl.

[0052] 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 (i.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.

[0053] The term “unsaturated bond” refers to a double or triple bond.21IPTS / 200159134.1Docket No. TGO-030WO

[0054] The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.

[0055] The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0056] 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, heteroalkenyl ene 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.

[0057] The term “azido” refers to the radical -N3.

[0058] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0059] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. In some embodiments, a cycloalkylalkyl is a -(C1-C2 alkyl)(cycloalkyl) (e.g., a C1-C2 alkyl(C3-C9cycloalkyl). 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.

[0060] “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 (C1-C2 alkyl)-(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.

[0061] “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 C6-C10 aryl group). In some embodiments, arylalkyl is a C1-C2 alkyl-aryl, e.g., a (C1-C2 alkyl)(6-10 membered aryl)(e.g., –CH2-aryl, –22IPTS / 200159134.1Docket No. TGO-030WOCH2CH2-aryl, -CH(CH3)-aryl). In some embodiments, arylalkyl is a -CH2-aryl e.g., -CH2-phenyl, -CH2-naphthyl).

[0062] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“Ci-20 alkyl” or “C1-C20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-10 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 (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 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 (“Ci alkyl”). 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-butyl (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 (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) 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 Ci-10 alkyl (e.g., -CH3). In some embodiments, the alkyl group is substituted Ci-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (–CH(CH3)2), nPr (–CH2CH2CH3), nBu (–CH2CH2CH2CH3), or tBu (–CH2CH(CH3)2).

[0063] “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-, -23IPTS / 200159134.1Docket No. TGO-030WOCH2CH(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.

[0064] “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) (“C2–20alkenyl”). 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 (“C2–9alkenyl”). 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 (“C2–4alkenyl”). 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 (“C2alkenyl”). 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 C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), 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, / .<?., 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.

[0065] “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) (“C2–20alkynyl”). In some embodiments, alkynyl24IPTS / 200159134.1Docket No. TGO-030WOdoes 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”). In 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 alkynyl group is independently optionally substituted, / .<?., 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.

[0066] 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, / .<?., 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 (“heteroCi-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-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 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms25IPTS / 200159134.1Docket No. TGO-030WO(“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group 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 heteroCi-io alkyl.Exemplary heteroalkyl groups include: -CH₂OH, -CH₂OCH3, -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, -CH2CH₂OH, -CH2CH₂OCH3, -CH2CH2NH2, -CH2CH2NH(CH3), -CH2CH2N(CH3)2.

[0067] “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 14π 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 (“Cuaryl”; 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, / .<?., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted Ce-14 aryl. In some embodiments, the aryl group is substituted Ce-14 aryl.26IPTS / 200159134.1Docket No. TGO-030WO

[0068] 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.

[0069] Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-Cs alkyl, 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.

[0070] “Fused aryl” refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0071] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π 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. “Heteroaryl” 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 27IPTS / 200159134.1Docket No. TGO-030WOgroups 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).

[0072] 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”)28IPTS / 200159134.1Docket No. TGO-030WOor substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0073] 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 heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinol inyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0074] Examples of representative heteroaryls include the following:IPTS / 200159134.1Docket No. TGO-030WOwherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, -Ci-Cs alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, and 5-10 membered heteroaryl.

[0075] 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.

[0076] “Heteroaralkyl” or “heteroarylalkyl” is a subset of “alkyl” and refers to an alkyl 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 (Ci-C2alkyl)-(heteroaryl)e.g., a (C1-C2 alkyl)(5-10 membered heteroaryl) (e.g., –CH2-heteroaryl, –CH2CH2-heteroaryl, -CH(CH3)-heteroaryl). In some embodiments, a heteroarylalkyl is a -CH2-heteroaryl. Typical heteroarylalkyl groups include, but are not limited to, pyridinylmethyl, pyrimidinylmethyl, furanylmethyl, thiophenylmethyl, pyrrolylmethyl, pyrazolyl methyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyridinylethyl, pyrimidinylethyl, furanylethyl, thiophenyl ethyl, pyrrolyl ethyl, pyrazolyl ethyl, imidazolylethyl, thiazolyl ethyl, oxazolyl ethyl, thiazolyl ethyl and the like.

[0077] 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., cycloalkyls), 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 (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the30IPTS / 200159134.1Docket No. TGO-030WOaforementioned 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 C3-10 carbocyclyl 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 (C10), spiro[4.5]decanyl (C10), and the like.

[0078] As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic 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 aryl 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 carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl.

[0079] 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-C14 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 cycloalkyl”). In some embodiments, a monocyclic cycloalkyl 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 cycloalkyl”). 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 C5-31IPTS / 200159134.1Docket No. TGO-030WO6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs).

[0080] 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 cycloalkyl”). 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 cycloalkyl group has 8 to 10 ring carbon atoms (“Cs-io bicyclic cycloalkyl”). In some embodiments, a bicyclic cycloalkyl group has 7 to 9 ring carbon atoms (“C7-9 bicyclic cycloalkyl”). Examples of bicyclic cycloalkyls include bicyclo[1.1.0]butane (C4), bicyclo[l.l.l]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 (Ce), 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[3.2.1]octane (Cs), bicyclo[4.2.0]octane (Cs), spiro[2.5]octane (Cs), spiro[3.4]octane (Cs), bicyclo[3.3.1]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[4.3.1]decane (C10), spiro[4.5]decane (C10), bicyclo[3.3.3]undecane (C11), decahydronaphthalene (C10), bicyclo[4.3.2]undecane (C11), spiro[5.5]undecane (C11) and bicyclo[4.3.3]dodecane (C12).In some embodiments “cycloalkyl” is a tricyclic cycloalkyl. In some embodiments, a tricyclic cycloalkyl 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 cycloalkyl group has 10 to 12 ring carbon atoms (“C10-12 tricyclic cycloalkyl. Examples of tricyclic cycloalkyls include adamantine (C12).

[0081] Unless otherwise 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.32IPTS / 200159134.1Docket No. TGO-030WO

[0082] “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, and silicon (“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 otherwise 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.

[0083] 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 1-233IPTS / 200159134.1Docket No. TGO-030WOring 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.

[0084] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups 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, 5-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 Ce 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- 1,8-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-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-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-l,6-naphthyridinyl, and the like. Exemplary 6-membered heterocyclyl groups34IPTS / 200159134.1Docket No. TGO-030WOfused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0085] “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, morpholine, 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.

[0086] “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.

[0087] “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 aryl, 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), cyclohexyl carbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzyl carbonyl (-C(=O)CH2Ph), — C(=O)-Ci-Cs alkyl, -C(=0)-(CH2)t(C6-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.

[0088] The term aminoalkyl refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an -NH2 group.

[0089] The term hydroxyalkyl refers to a substituted alkyl group wherein one or more of the hydrogen atoms are independently replaced by an -OH group.35IPTS / 200159134.1Docket No. TGO-030WO

[0090] The terms “alkylamino” and “dialkylamino” refer to -NH(alkyl) and-N(alkyl)? radicals respectively. In some embodiments the alkylamino is a-NH(Ci-C4 alkyl). In some embodiments the alkylamino is methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, / .w-butylamino, ec-butylamino, or / c / V-butylamino. In some embodiments the dialkylamino is -N(Ci-Ce alkyl)?. In some embodiments the dialkylamino is a dimethylamino, a methylethylamino, a diethylamino, a methylpropylamino, a methylisopropylamino, a methylbutylamino, a methylisobutylamino or a methyltertbutylamino.

[0091] The term “aryloxy” refers to an -O-aryl radical. In some embodiments the aryloxy group is phenoxy.

[0092] 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.

[0093] “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, Zc / V-butoxy, ec-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.

[0094] 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)?-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, -0-(CH2)t(C6-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 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or36IPTS / 200159134.1Docket No. TGO-030WOhydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH₂OH, and -OCH2CH2N(CH3)2.

[0095] “Amino” refers to the radical -NH2.

[0096] “ Oxo group” refers to -C(=O)-.

[0097] “ 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, -C3-C8 alkenyl, -C3-C8 alkynyl, Ce-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 alkynyl, substituted with halo or hydroxy, or -(CH2XC6-C10 aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2XC3-C10 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 alkyl, 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.

[0098] Exemplary “substituted amino” groups include, but are not limited to, -NR39-CI-C8 alkyl, -NR39-(CH2)t(C6-Cio aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39-(CH2XC3-C10 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 haloalkyl, unsubstituted C1-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 alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0099] 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 protecting37IPTS / 200159134.1Docket No. TGO-030WOgroups 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, -Ci-io alkyl (e.g., aralkyl, heteroaralkyl), -C2-10 alkenyl, -C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 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, -C1-10 perhaloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, 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 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-10 alkyl, -Ci-10 perhaloalkyl, -C2-10 alkenyl, -C2-10 alkynyl, heteroC 1-10 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, aryl, 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, -Ci-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, Ce-14 aryl, 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, heteroalkyl, heteroalkenyl,38IPTS / 200159134.1Docket No. TGO-030WOheteroalkynyl, 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, “Ns, -SO2H, -SO3H, -OH, -ORee, -0N(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)(ORee)2, -P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, -C1-6 alkyl, -C1-6 perhaloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroCi-ealkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-io carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 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 -C1-6 alkyl, -C1-6 perhaloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroCi-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-io carbocyclyl, Ce-io aryl, 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, -C1-6 alkyl, -C1-6 perhaloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroCi-ealkyl, heteroC2-6alkenyl, heteroC2-ealkynyl, C3-io carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl 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, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, 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, -OC1-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6alkyl)2, -N(CI-6alkyl)3X, -NH(CI-6alkyl)2X, -NH2(CI-6alkyl) X, -NH3X, -N(OCI-6alkyl)(Ci-6alkyl), -N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6alkyl), -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl),39IPTS / 200159134.1Docket No. TGO-030WO-OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)(CI-6alkyl), -N(CI-6alkyl)C(=O)(Ci-6alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, -NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -C(=NH)O(CI-6alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6alkyl)2, -OC(NH)NH(Ci-6 alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(CI-6alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2, -SO2C1-6 alkyl, -SO2OC1-6 alkyl, -OSO2Ci-6alkyl, -SOCi-6 alkyl, -Si(Ci-6alkyl)3, -OSi(Ci-6alkyl)3-C(=S)N(CI-6alkyl)2, -C(=S)NH(CI-6alkyl), -C(=S)NH2, -C(=O)S(Ci-6alkyl), -C(=S)SCi-6alkyl, -SC(=S)SCi-6alkyl, -P(=O)(OCi-6alkyl)2, -P(=O)(Ci-6alkyl)2, -OP(=O)(Ci-6alkyl)2, -OP(=O)(OCi-6alkyl)2, -Ci-6 alkyl, -Ci-6 perhaloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, heteroCi-ealkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-io carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0100] For example, nitrogen protecting groups such as amide groups (e.g., -C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, tri chloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridyl carb oxami de, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, 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-(b enzoy 1 oxym ethyl )b enzami de.

[0101] 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- / -butyl-[9-(l 0, 10-dioxo- 10, 10, 10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB- / -BOC), l,l-dimethyl-2, 2, 2 -tri chloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di- / -butylphenyl)-l-40IPTS / 200159134.1Docket No. TGO-030WOmethylethyl carbamate (Z-Bumeoc), 2-(2’- and 4’-pyridyl)ethyl carbamate (Pyoc), 2-(N, N-dicyclohexylcarboxamido)ethyl carbamate, / -butyl carbamate (BOC orBoc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1 -isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfmylbenzyl carbamate (Msz), 9-anthrylmethyl 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-cyanoethyl 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, / -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)benzyl carbamate, 1, l-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, 1 -methyl- l-(p-phenylazophenyl)ethyl carbamate, 1-m ethyl- 1 -phenylethyl carbamate, 1 -methyl- l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri- / -butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0102] 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), 2,4,6-41IPTS / 200159134.1Docket No. TGO-030WOtrimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMB S), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0103] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)-acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’ -phenylaminothioacyl derivative, N-benzoylphenyl alanyl 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- 1,1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, 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 (pentaacyl chromium- 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).

[0104] In some embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen42IPTS / 200159134.1Docket No. TGO-030WOprotecting 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)(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.

[0105] 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), guaiacolmethyl (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 -methoxy cyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, l-[(2-chloro-4-methyl)phenyl]-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 -ethoxy ethyl, 1-(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxy ethyl, 1 -methyl- 1 -benzyloxy ethyl, 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, benzyl (Bn), p-m ethoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-di chlorobenzyl, 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(benzoyloxyphenyl)methyl, 3-(imidazol-l-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, trimethyl silyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropyl silyl (IPDMS),43IPTS / 200159134.1Docket No. TGO-030WOdiethylisopropylsilyl (DEIPS), dimethylthexyl silyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethyl silyl (DPMS), t-butylmethoxyphenyl silyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, di chloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, 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-(phenyl sulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, Ebutyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl 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 -tetramethylbutyl)phenoxy acetate, 2,4-bi s( 1, 1 -dimethylpropyl)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, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0106] 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)(ORCC)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.44IPTS / 200159134.1Docket No. TGO-030WO

[0107] 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, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, 7V,( -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, aryl phosphate, alkylcarbonyloxy, arylcarbonyloxy, alkoxcarbonyloxy, aryoxcarbonyloxy 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), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (tritiate, -OTf). In some cases, the leaving group is a brosylate, such as / ?-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 moi eties, thioether moi eties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0108] “Carboxy” refers to the radical -C(=O)OH.

[0109] “Cyano” refers to the radical -CN.

[0110] “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.

[0111] “Haloalkyl” 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), dichloromethyl (-CHCI2), tribromomethyl (-CH2Br), and the like.

[0112] “Hydroxy” refers to the radical -OH.

[0113] “Nitro” refers to the radical -NO2.

[0114] “ Thioketo” refers to the group =S.45IPTS / 200159134.1Docket No. TGO-030WO

[0115] 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). In general, 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.

[0116] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -0N(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)(ORcc)2, -NRbbP(=O)(NRbb)2, -P(RCC)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-io carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,46IPTS / 200159134.1Docket No. TGO-030WOheterocyclyl, 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 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 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, -Ci-10 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 Rbbgroups 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 Rccis, independently, selected from hydrogen, -Ci-10 alkyl, -Ci-10 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 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, -0N(Rff)2, -N(Rff)2, -N(Rff)3+X, -N(0Ree)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(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -0C(=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, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6alkenyl, -C2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, 5-10 membered heteroaryl,47IPTS / 200159134.1Docket No. TGO-030WOwherein 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 Ci-6 alkyl, -Ci-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;each instance of Rffis, independently, selected from hydrogen, -C1-6 alkyl, -C1-6 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, -OC; alkyl, -ON(CI-6 alkyl)2, -N(CI-6 alkyl)2, -N(CI-6 alkyl)3+X, -NH(CI-6 alkyl)2+X, -NH2(CI-6alkyl) X, -NH3 X, -N(OCI-6 alkyl)(Ci-6 alkyl), -N(OH)(CI-6 alkyl), -NH(OH), -SH, -SC1-6 alkyl, -SS(Ci-6 alkyl), -C(=O)(Ci^ alkyl), -CO2H, -CO2(Ci 6 alkyl), -OC(=O)(Ci-6 alkyl), -OCO2(Ci^> alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, -OC(=O)NH(CI-6alkyl), -NHC(=O)(Ci^ alkyl), -N(CI-6 alkyl)C(=O)(Ci-6alkyl), -NHCO2(CI 6 alkyl), -NHC(=O)N(Ci 6 alkyl)2, -NHC(=O)NH(Ci6alkyl), -NHC(=0)NH2, -C(=NH)O(CI-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OCi6alkyl, -C(=NH)N(Ci^ alkyl)2, -C(=NH)NH(CI-6 alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6 alkyl)2, -OC(NH)NH(Ci 6 alkyl), -0C(NH)NH2, -NHC(NH)N(CI^> alkyl)2, -NHC(=NH)NH2, -NHSO2(CI^ alkyl), -SO2N(CI6alkyl)2, -SO2NH(CI6alkyl), -SO2NH2 -SO2C1-6 alkyl, -SO2OC16alkyl, -OSO2C1-6 alkyl, -SOC1-6 alkyl, -Si(Ci-6alkyl)3, -OSi(Ci6alkyl)3-C(=S)N(CI-6alkyl)2, -C(=S)NH(CI-6 alkyl), -C(=S)NH2, -C(=O)S(Ci6alkyl), -C(=S)SCi^ alkyl, -SC(=S)SC S alkyl, -P(=O)2(Ci-6 alkyl), -P(=O)(Ci-6 alkyl)2, -OP(=O)(Ci-6 alkyl)2, -OP(=O)(OCi-6 alkyl)2, -C1-6 alkyl, -C1-6 haloalkyl, -C2-6 alkenyl, -C2-6 alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =0 or =S; wherein X is a counterion.

[0117] A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F, Cl", Br", I"), NO3, CIO4, OH, H2PO4, HSO4,48IPTS / 200159134.1Docket No. TGO-030WOSO4’2sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthal ene-2-sulfonate, naphthal ene-l-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).

[0118] 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, -C1-10alkyl, -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, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0119] 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

[0120] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts.

[0121] 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,49IPTS / 200159134.1Docket No. TGO-030WOphosphoric 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, dodecyl sulfate, 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.

[0122] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.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 a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0123] Disease, disorder, and condition are used interchangeably herein.

[0124] 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 specified50IPTS / 200159134.1Docket No. TGO-030WOdisease, 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, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

[0125] In general, the “effective amount” 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”).

[0126] 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 with 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.

[0127] 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.51IPTS / 200159134.1Docket No. TGO-030WO

[0128] 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, a 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 HBS1L degrader is 30-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS1L degrader is 50-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS1L degrader is 100-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS1L degrader is 500-fold more potent against HBS1L than against GSPT1. In some embodiments, a selective HBS1L degrader is 1000-fold more potent against HBS1L than against GSPT1. The difference in potency can be determined, for example, by comparing the DC50 values against different targets.Compounds

[0129] Provided herein are compounds of Formula (X). Unless the context requires otherwise, reference throughout this specification to “a compound of Formula (X)” or “compounds of Formula (X)” refers to all embodiments of Formula (X) including, for example, compounds of Formula (X), (A), (B), (I), (I’), (I”), (II), (IF), (II”), (II- A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-A-1), (II-A-2), (II-A-3), (II-B-1), (II-B-2), (II-B-3), (II-B-4), (II-C-1), (II-C-2), (II-D-1), (II-E-1), (II-F-1), (II-G-1), (II-H-I), (II-I-I), (III), (III-A), (III-A1) as well as the compounds of Table 1 or Table 2.

[0130] The compounds of the present disclosure are degraders of HBS1L. In some embodiments, the compounds selectively degrade HBS1L over GSPT1.

[0131] In some embodiments, provided is a compound of Formula (X) or a pharmaceutically acceptable salt thereof, wherein:IPTS / 200159134.1Docket No. TGO-030WORing A is selected from the group consistingindicates the attachment point tX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;X7is CH or N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl,53IPTS / 200159134.1Docket No. TGO-030WOC3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl; or R5and one instance of RAcan be taken together with the atoms to which they are attached to form a 4-7 membered carbocyclic ring;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N,54IPTS / 200159134.1Docket No. TGO-030WOO and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0132] In some embodiments, provided is a compound of Formula (X) or a pharmaceutically acceptable salt thereof, wherein:whereinY, Ring A, Ring B, RA, RB, R3, R3, m and n are as defined in any of the embodiments described herein.

[0133] In an embodiment, Ringwherein X1, X2, X3, X4, X5, X6are as defined in any of the embodiments described herein.

[0134] In some embodiments, provided is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:55IPTS / 200159134.1Docket No. TGO-030WOX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Y is N or CR5;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORB2, -N(RB2)2, -C(=O)RB1, - 56IPTS / 200159134.1Docket No. TGO-030WOC(=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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl; or R5and one instance of RAcan be taken together with the atoms to which they are attached to form a 4-7 membered carbocyclic ring;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, — (Ci-C2alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N,57IPTS / 200159134.1Docket No. TGO-030WOO and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0135] In some embodiments, provided is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Y is N or CR5;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered 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-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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), -IPTS / 200159134.1Docket No. TGO-030WOeach RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, — (Ci-C2alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered59IPTS / 200159134.1Docket No. TGO-030WOheterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0136] In some embodiments, provided is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:whereinX1, X2, X3, X4, X5, X6, Y, Ring B, RA, RB, R3, R3, m and n are as defined in any of the embodiments described herein.

[0137] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:IPTS / 200159134.1Docket No. TGO-030WOX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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), - 61IPTS / 200159134.1Docket No. TGO-030WOOC(=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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, — (Ci-C2alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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;62IPTS / 200159134.1Docket No. TGO-030WOn is 0, 1, 2 or 3; andm is 0, 1, 2 or 3.

[0138] In some embodiments, provided herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof,wherein:X1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered 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-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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, 5-663IPTS / 200159134.1Docket No. TGO-030WOmembered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(CI-C6 alkyl), -N(CI-C6alkyl)2;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N,64IPTS / 200159134.1Docket No. TGO-030WOO and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0139] In some embodiments, provided herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof,wherein:whereinX1, X2, X3, X4, X5, X6, Y, Ring B, RA, RB, R3, R3, m and n are as defined in any of the embodiments described herein.

[0140] In some embodiments, the compound is of Formula (I’),wherein X1, X2, X3, X4, X5, X6, Y, Ring B, RA, RB, R3, R3, m and n are as defined in any of the embodiments described herein.

[0141] In some embodiments, the compound is of Formula (I”),wherein X1, X2, X3, X4, X5, X6, Y, Ring B, RA, RB, R3, R3, m and n are as defined in any of the embodiments described herein.IPTS / 200159134.1Docket No. TGO-030WO

[0142] In an embodiment, Ringwherein X7is as defined in any of the embodiments described herein.

[0143] In some embodiments, provided is a compound of Formula (B) or a pharmaceutically acceptable salt thereof, wherein:Y is N or CR5;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -66IPTS / 200159134.1Docket No. TGO-030WOeach RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N,67IPTS / 200159134.1Docket No. TGO-030WOO and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

[0144] In some embodiments, provided is a compound of Formula (B) or a pharmaceutically acceptable salt thereof, wherein:wherein X7, Y, Ring B, R3, R3, RA, RB, m and n are as defined in any of the embodiments described herein.

[0145] In some embodiments, the moiety representedIPTS / 200159134.1Docket No. TGO-030WO

[0146] In some embodiments, the moiety representedindicates the attachment point t

[0147] In some embodiments, the moiety representedwherein ' indicates the attachment point tindicates theattachment point t69IPTS / 200159134.1Docket No. TGO-030WO

[0148] In some embodiments, the moiety representedwherein indicates the attachment point tattachment point t

[0149] In some embodiments, the moiety representedwherein indicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0150] In some embodiments, the moiety representedwherein indicates the attachment point tattachment point t

[0151] In some embodiments, the moiety representedwherein indicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0152] In some embodiments, the moiety representedindicates the attachment point t

[0153] In some embodiments, the moiety representedwherein indicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0154] In some embodiments, the moiety represented

[0155] In some embodiments, the moiety representedIPTS / 200159134.1Docket No. TGO-030WO

[0156] In some embodiments, the moiety representedselected fromindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0158] In somethe group consistingwherein ' indicates the attachment point tindicates theattachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0159] In some embodiments, the moiety representedindicates the attachment point t

[0160] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0161] In some embodiments, the moiety representedindicates the attachment point t

[0162] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0163] In some embodiments, the moiety representedindicates the attachment point t

[0164] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0165] In some embodiments, the moiety representedindicates the attachment point t

[0166] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0167] In some embodiments, the moiety representedindicates the attachment point t

[0168] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0169] In some embodiments, the moiety representedindicates the attachment point t

[0170] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0171] In some embodiments, the moiety representedindicates the attachment point t

[0172] In some embodiments, the moiety representedindicates the attachment point tIPTS / 200159134.1Docket No. TGO-030WO

[0173] In some embodiments, the moiety representedindicates the attachment point t

[0174] In some embodiments, the moiety represented83IPTS / 200159134.1Docket No. TGO-030WO

[0175] In some embodiments, the moiety representedindicates the attachment point t

[0176] As generally defined herein, Y is selected from the group consisting of N and CR5, wherein R5is defined in any of the embodiments described herein.

[0177] In some embodiments, Y is selected from the group consisting of N, C-H, C-OH, and C-F.

[0178] In some embodiments, Y is N.

[0179] In some embodiments, Y is C-H.

[0180] In some embodiments, Y is C-OH.

[0181] In some embodiments, Y is C-F.

[0182] In some embodiments, the moiety represented

[0183] In some embodiments, the moiety represented

[0184] In some embodiments, the moiety represented

[0185] As generally defined herein, each RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci- 84IPTS / 200159134.1Docket No. TGO-030WOCe haloalkyl, -C3-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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

[0186] In some embodiments, each RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -C3-C9cycloalkyl, 4-10 membered heterocyclyl, -ORA2and -N(RA2)2.

[0187] In some embodiments, each RAis independently selected from the group consisting of-D, -F, -Cl, -CN, -SF5, -Me, -Et, -zzPr, -zPr, -tBu, -vinyl, isopropenyl, -CH₂OCH3, -CH2CH₂OCH3, -CF3, -CH2F, -CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, piperidinyl, pyrrolidinyl, morpholinyl, -OH, -OCH3, -NH2, -NHCH3 and -N(CH3)2.

[0188] In some embodiments, each RAis independently selected from the group consisting of-D, -F, -Cl, -CN, -SF5, -Me, -Et, -zPr, -tBu, -CF3, cyclopropyl, cyclobutyl, oxetanyl, -OH and -OCH3.

[0189] In some embodiments, each RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl and -Ci-Ce haloalkyl.

[0190] In some embodiments, each RAis independently selected from the group consisting of-D, -F, -Cl, -CN, -SF5, -Me, -Et, -zPr, -tBu, and -CF3.

[0191] In some embodiments, each RAis independently selected from the group consisting of halo and -C1-C6 alkyl.

[0192] In some embodiments, each RAis independently selected from the group consisting of-F, -Cl, -Me, -Et, -zPr and -tBu.

[0193] In some embodiments, each RAis independently selected from the group consisting of-F and -Me.

[0194] In some embodiments, RAis -D.

[0195] 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.

[0196] In some embodiments, RAis -CN.

[0197] In some embodiments, RAis -SF5.85IPTS / 200159134.1Docket No. TGO-030WO

[0198] In some embodiments, RAis -C1-C6 alkyl (e.g., -Me, -Et, -zzPr -zPr, -tBu). In some embodiments, RAis -Me. In some embodiments, RAis -Et. In some embodiments RAis -zzPr or -zPr.

[0199] In some embodiments, RAis -Ci-Ce alkenyl (e.g., -vinyl, isopropenyl). In some embodiments, RAis -vinyl. In some embodiments, RAis -isopropenyl.

[0200] In some embodiments, RAis -Ci-Ce heteroalkyl (e.g., methoxymethyl, methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl). In some embodiments, RAis methoxymethyl (-CH₂OCH3). In some embodiments, RAis aminomethyl (e.g.,-CH2NH2, -CH2NHCH3, -CH2N(CH3)2.

[0201] 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).

[0202] In some embodiments, RAis C3-C9 cycloalkyl (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.

[0203] In some embodiments, RAis 4-10 membered heterocyclyl. In some embodiments, RAis 4-7 membered heterocyclyl (e.g, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, 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.

[0204] 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.

[0205] 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, 2H-indazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl).86IPTS / 200159134.1Docket No. TGO-030WO

[0206] In some embodiments RAis -(C1-C2 alkyl)(C3-C9cycloalkyl), (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0207] In some embodiments, RAis -(C1-C2 alkyl)(4-10 membered heterocyclyl) (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0208] In some embodiments, RAis -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, RAis benzyl.

[0209] In some embodiments, RAis -(C1-C2 alkyl)(5-10 membered heteroaryl), (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0210] 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).

[0211] 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).

[0212] 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)(Ci-C6 alkyl). RAis -C(=O)(C3-C9cycloalkyl). In some embodiments, RAis -C(=O)CH3, -C(=O)cyclopropyl, -C(=O)cyclobutyl, -C(=O)zBu, -C(=O)'Pr, -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 COOCH3.87IPTS / 200159134.1Docket No. TGO-030WO

[0213] 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)tBu, -NHC(=O)Cyclopropyl, -NHC(=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)tBu, -N(CH3)C(=O)Cyclopropyl, -N(CH3)C(=O)Cyclobutyl).

[0214] 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)OtBu, -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(CH3)C(=O)OBu, -N(CH3)C(=O)OtBu, -N(CH3)C(=O)OCyclopropyl, -N(CH3)C(=O)OCyclobutyl).

[0215] 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)NHTr, -C(=O)NHBu, -C(=O)NHzBu, -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)Tr, -C(=O)N(CH3)Bu, -C(=O)N(CH3tBu, -C(=O)N(CH3)Cyclopropyl, -C(=O)N(CH3)Cyclobutyl).

[0216] 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.

[0217] 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)NHzBu, -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, -88IPTS / 200159134.1Docket No. TGO-030WOOC(=O)N(CH3)CH2CH2CH3, -OC(=O)N(CH3)'Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3)zBu, -OC(=O)N(CH3)Cyclopropyl, -OC(=O)N(CH3)Cyclobutyl).

[0218] 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)Tr). In some embodiments, RAis -S(=O)cycloalkyl (e.g., -S(=O)cyclopropyl, -S(=O)cyclobutyl, -S(=O)cyclopentyl, -S(=O)cyclohexyl).

[0219] 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)2'Pr). 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(=O)2aryl (e.g., -S(=O)2phenyl).

[0220] 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, -STr). In some embodiments, RAis -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In some embodiments, RAis -Saryl (e.g., -Sphenyl).

[0221] 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)tBu, -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)iPr, -S(=O)(=NCH3)Bu, -S(=O)(=NCH3)tBu, - S(=O)(=NCH3)Cyclopropyl, -S(=O)(=NCH3)Cyclobutyl).

[0222] 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)2'Pr). 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)2Tr). In89IPTS / 200159134.1Docket No. TGO-030WOsome 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).

[0223] 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)2NHTr, -S(=O)2NHcyclopropyl, -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).

[0224] As generally defined herein, R3and R3are each independently selected from H, -C1-C3 alkyl and -C1-C3 haloalkyl, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, 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 R3are not both H.

[0225] In some embodiments, 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-C9cycloalkyl or a 4-7 membered heterocyclyl containing 1 heteroatom selected from N, O and S, provided that R3and R3are not both H;

[0226] In some embodiments, R3and R3are each independently selected from H, -C1-C3 alkyl and -C1-C3 haloalkyl, wherein each hydrogen of the alkyl can be replaced by deuterium 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 R3are not both H.

[0227] In some embodiments, 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 C3-C6 cycloalkyl or a 4-7 membered heterocyclyl containing 1 oxygen atom, provided that R3and R3are not both H.

[0228] In some embodiments, R3and R3are each independently -C1-C3 alkyl, wherein each hydrogen of the alkyl can be replaced by deuterium.

[0229] In some embodiments, R3and R3are each independently -C1-C3 alkyl.

[0230] In some embodiments, R3and R3are each independently selected from H, -Me, -Et, -zPr and -CF3, wherein each hydrogen of the -Me, -Et and -zPr can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a90IPTS / 200159134.1Docket No. TGO-030WOcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl ring, provided that R3and R3are not both H.

[0231] In some embodiments, 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.

[0232] In some embodiments, R3and R3are each independently selected from H, -Me, -CD3 and -Et. In some embodiments, R3and R3are each independently selected from H, -Me and -Et.

[0233] In some embodiments, R3and R3are independently selected from -Me and -CD3.

[0234] In some embodiments, R3and R3are both -Me.

[0235] As generally defined herein, Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0236] In an embodiment, Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0237] 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, chromanyl, isochromanyl, 2H-chromenyl, 9H 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[1.1.1]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, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-91IPTS / 200159134.1Docket No. TGO-030WOnaphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzof ] oxazolyl, imidazo[2, 1 -b] [ 1,3,4]thiadiazolyl, [ 1,2,4]triazolo[4,3 -a]pyridinyl, imidazof 1,2-a]pyridinyl, imidazof l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0238] 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, chromanyl, isochromanyl, 9H 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[1.1.1]pentanyl, bicyclofl.2. l]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, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo [cl\ oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazof l,2-a]pyridinyl, imidazof l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0239] In some embodiments, Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, and 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S. In some embodiments, Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, and 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0240] 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, chromanyl, isochromanyl, 2H-chromenyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-92IPTS / 200159134.1Docket No. TGO-030WOdihydrophenanthridin-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, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo [ ] oxazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, 1H-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0241] 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, chromanyl, isochromanyl, 9H 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[1.1.1]pentanyl, bicyclofl.2. l]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, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzo [cl\ oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, 1H-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0242] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7monocyclic cycloalkyl, C4-C9fused bicyclic cycloalkyl, C5-C9bridged cycloalkyl, C5-C9spiro cycloalkyl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered93IPTS / 200159134.1Docket No. TGO-030WObicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0243] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7monocyclic cycloalkyl, C4-C9fused bicyclic cycloalkyl, C5-C9bridged cycloalkyl, C5-C9spiro cycloalkyl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0244] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0245] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, C5-C9 spiro cycloalkyl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0246] 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, chromanyl, isochromanyl, 2H-chromenyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentanyl, bicyclofl.2. l]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, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzo [ ] oxazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, [l,2,4]triazolo[4,3-a] pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl,94IPTS / 200159134.1Docket No. TGO-030WOlH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0247] 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, chromanyl, isochromanyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]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, benzofd] isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzo [cl\ oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, 1H-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0248] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0249] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, C3-C7 monocyclic cycloalkyl, C5-C9 bridged cycloalkyl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0250] 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, chromanyl, isochromanyl, 2H-chromenyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-95IPTS / 200159134.1Docket No. TGO-030WOdihydrophenanthridin-yl, bicyclo[1.1.1]pentanyl, cyclohexyl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d]isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo [ ] oxazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, 1H-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0251] 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, chromanyl, isochromanyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo[ ]oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0252] 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, 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.

[0253] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0254] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.96IPTS / 200159134.1Docket No. TGO-030WO

[0255] In some embodiments, Ring B is selected from 6-14 membered aryl and 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0256] In some embodiments, Ring B is selected from 6-14 membered aryl and 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0257] In some embodiments, Ring B is selected from the group consisting of phenyl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0258] In some embodiments, Ring B is selected from the group consisting of phenyl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0259] Ring B is selected from the group consisting of phenyl, 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, naphthalenyl, 2H-chromenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, thiophenyl, pyridinyl, indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]thiazolyl, benzo[d]oxazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, 2H-indazolyl and phenanthridinyl.

[0260] 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, 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.

[0261] In some embodiments, wherein Ring B is selected from the group consisting of phenyl, 2H-chromenyl, bicyclo[1.1.1]pentanyl, thiophenyl, indolyl, benzofuranyl, benzo[d]thiazolyl, benzo[d]oxazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, 2H-indazolyl, and b enzo [b ] thi opheny 1.

[0262] In some embodiments, Ring B is selected from the group consisting of phenyl, thiophenyl, indolyl, benzofuranyl, and benzo[b]thiophenyl.

[0263] In some embodiments, Ring B is selected from the group consisting of phenyl, thiophen-2-yl, benzo[b]thiophen-2-yl, benzofuran-2-yl, indole-2-yl.

[0264] In some embodiments, In some embodiments, Ring B is selected from the groupconsistingIPTS / 200159134.1Docket No. TGO-030WO5

[0265] In some embodiments, Ring B is selected from the group consisting ofIPTS / 200159134.1Docket No. TGO-030WO

[0267] In some embodiments, Ring B is selected from the group consisting ofIPTS / 200159134.1Docket No. TGO-030WO

[0268] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0269] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0270] 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, chromanyl, isochromanyl, 2H-chromenyl, 9H fluorenyl, thiophenyl, benzo[b]thiophenyl, benzo[d]thiazolyl, benzo[d]oxazolyl, benzofuranyl, indolyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.

[0271] In some embodiments, Ring B is

[0272] 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, chromanyl, isochromanyl, 9H fluorenyl, thiophenyl, benzo[b]thiophenyl, benzofuranyl, indolyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.

[0273] In some embodiments, Ring B is selected from the group consisting of thiophenyl, pyridinyl, benzo[b]thiophenyl, benzo[d]thiazolyl, phenanthridinyl, indolyl, and benzofuranyl.

[0274] In some embodiments, Ring B is selected from the group consisting of phenyl, thiophenyl, benzo[b]thiophenyl, benzofuranyl and indolyl.100IPTS / 200159134.1Docket No. TGO-030WO

[0275] In some embodiments, Ring B is selected from the group consisting of

[0277] In some embodiments, Ring B is C3-C7 cycloalkyl. In some embodiments, Ring B is 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[1.1.1]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).

[0278] In some embodiments, Ring B is selected from the group consisting of C3-C7 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C5-C9 bridged cycloalkyl (e.g., bicyclo[1.1.1]pentanyl, bicyclofl.2. l]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).

[0279] In some embodiments, Ring B is C3-C7 monocyclic cycloalkyl. In some embodiments, Ring B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In some embodiments, Ring B is cyclohexyl.101IPTS / 200159134.1Docket No. TGO-030WO

[0280] In some embodiments, Ring B is C4-C9 fused bicyclic cycloalkyl. In some embodiments, Ring B is selected from the group consisting of 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 and decahydronaphthal enyl.In some embodiments, Ring B is C5-C9 bridged cycloalkyl. In some embodiments, Ring B is selected from the group consisting of bicyclof 1.1.1 ]pentanyl, bicyclofl.2. l]hexanyl, bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl. In some embodiments, Ring B is selected from the group consisting of bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl. In some embodiments, Ring B is bicyclo[2.2.1]heptanyl. In some embodiments, Ring B is bicyclo[2.2.1]heptan-2-yl. In some embodiments, Ring B is bicyclo[2.2.2]octanyl (e.g., bicyclo[2.2.2]octan-l-yl, bicyclo[2.2.2]octan-2-yl. In some embodiments, Ring B is bicyclo[2.2.2]octan-l-yl. In some embodiments, Ring B is bicyclo[2.2.2]octan-2-yl. In someembodiments, Ring B is bicyclofl. l.l]pentanyl. In some embodiments, Ring B is.

[0281] In some embodiments, Ring B is C5-C9 spiro cycloalkyl. In some embodiments, Ring B is selected from the group consisting of spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl. In some embodiments, RingB is spiro[3.3]heptanyl. In some embodiments, Ring B is spiro[3.3]heptan-2-yl.

[0282] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0283] In some embodiments, Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0284] 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, chromanyl, isochromanyl, 9H102IPTS / 200159134.1Docket No. TGO-030WOfluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo[ ]oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0285] 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-benzo[c]chromen-8-yl, 5,6-dihy drophenanthri din-3 -yl, thi ophen-2 -yl, pyri din-3 -yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-2-yl, benzo[d]thiazol-5-yl, phenanthri din-3 -yl and phenanthridin-8-yl.

[0287] In some embodiments, Ring B is 6-14 membered aryl. In some embodiments, Ring B is phenyl, 9-10 membered 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, chromanyl, isochromanyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.103IPTS / 200159134.1Docket No. TGO-030WO

[0288] 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-benzo[c]chromen-8-yl and 5,6-dihydrophenanthri din-3 -yl.

[0289] In some embodiments, Ring B is selected from phenyl or 9-10 membered bicyclic 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, chromanyl, isochromanyl and 9H fluorenyl.

[0290] 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 and naphthalenyl. In some embodiments, Ring B is selected from the group consisting of phenyl, 2, 3 -dihydro- 1H-inden-5-yl, 2, 3-dihydrobenzofuran-6-yl, benzo[d][l,3]dioxol-5-yl and naphthalen-2-yl.

[0291] In some embodiments, Ring B is phenyl.

[0292] In some embodiments, Ring B is 9-10 membered bicyclic aryl. In some embodiments, Ring B is selected from the group consisting of 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, chromanyl, isochromanyl and 9H fluorenyl. In some embodiments, Ring B is selected from the group consisting of 2,3-dihydro-lH-indenyl, 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl and naphthalenyl. In some embodiments, Ring B is selected from the group consisting of 2,3-dihydro-lH-inden-5-yl, 2,3-dihydrobenzofuran-6-yl, benzo[d][l,3]dioxol-5-yl and naphthal en-2-yl. In some embodiments, Ring B is 2,3-dihydro-lH-indenyl. In some embodiments, Ring B is 2,3-dihydro-lH-inden-5-yl. In some embodiments, Ring B is 2,3-dihydrobenzofuranyl. In some embodiments, Ring B is 2,3-dihydrobenzofuran-6-yl. In some embodiments, Ring B is benzo[d][l,3]dioxolyl. In some embodiments, Ring B is benzo[d][l,3]dioxol-5-yl. In some embodiments, Ring B is naphthalenyl. In some embodiments, Ring B is naphthal en-2-yl.104IPTS / 200159134.1Docket No. TGO-030WO

[0293] In some embodiments, Ring B is 13-14 membered tricyclic aryl. In some embodiments, Ring B is selected from the group consisting of 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl. In some embodiments, Ring B is selected from the group consisting of 9,10-dihydrophenanthren-2-yl, 6H-benzo[c]chromen-3-yl, 6H-benzo[c]chromen-8-yl and 5,6-dihydrophenanthridin-3-yl. In some embodiments, Ring B is 9,10-dihydrophenanthrenyl. In some embodiments, Ring B is 9,10-dihydrophenanthren-2-yl. In some embodiments, Ring B is 6H-benzo[c]chromenyl. In some embodiments, Ring B is 6H-benzo[c]chromen-3-yl. In some embodiments, Ring B is 6H-benzo[c]chromen-8-yl. In some embodiments, RingB is 5,6-dihydrophenanthridin-yl. In some embodiments, Ring B is 5,6-dihydrophenanthridin-3-yl.

[0294] In some embodiments, Ring B is a 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S. In some embodiments, Ring B is selected from the group consisting of 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S. In some embodiments, Ring B is selected from the group consisting of 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0295] In some embodiments, Ring B is a 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S. In some embodiments, Ring B is selected from the group consisting of 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S. In some embodiments, Ring B is selected from the group consisting of 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S and 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0296] In some embodiments, Ring B is selected from the group consisting of thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzo[d] isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzo [ ] oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, 1H-105IPTS / 200159134.1Docket No. TGO-030WOpyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl, imidazo[2,l-b][l,3,4]thiadiazolyl and phenanthridinyl.

[0297] In some embodiments, Ring B is selected from the group consisting of thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzofd] isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzo [ ] oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, 1H-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

[0298] In some embodiments, Ring B is selected from the group consisting of thiophenyl, pyridinyl, benzo[b]thiophenyl, benzo[d]thiazolyl, benzo[d]oxazolyl, 2H-indazolyl, phenanthridinyl, indolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, and benzofuranyl.

[0299] In some embodiments, Ring B is selected from the group consisting of thiophenyl, pyridinyl, benzo[b]thiophenyl, benzo[t / ]thiazolyl, benzofuranyl, indolyl and phenanthridinyl.

[0300] In some embodiments, Ring B is selected from the group consisting of thiopheneyl, pyridin-3-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-2-yl, benzo[d]thiazol-5-yl, benzofuran-2-yl, indol-2-yl, phenanthri din-3 -yl and phenanthridin-8-yl.

[0301] In some embodiments, Ring B is selected from the group consisting of thiopheneyl, benzo[b]thiophen-2-yl, benzofuran-2-yl and indol-2-yl.106IPTS / 200159134.1Docket No. TGO-030WO

[0304] In some embodiments, Ring B is selected from the group consisting of:

[0306] In some embodiments, Ring B is a 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S. In some embodiments, Ring B is a 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S. In some embodiments, Ring B is selected from the group consisting of thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl and pyrimidinyl. In some embodiments, Ring B is selected from the group consisting of thiophenyl and pyridinyl. In some embodiments, Ring B is selected from the group consisting of thiophen-2-yl, pyridin-2-yl and pyridin-3-yl. In some embodiments, Ring B is selected from the group consisting of thiophen-2-yl and pyridin-3-yl. In some embodiments, Ring B is thiophenyl. In some embodiments, Ring B is107IPTS / 200159134.1Docket No. TGO-030WOthiophen-2-yl. In some embodiments, Ring B is pyridinyl. In some embodiments, Ring B is pyridin-2-yl. In some embodiments, Ring B is pyridin-3-yl.

[0307] In some embodiments, Ring B is 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0308] In some embodiments, Ring B is 8-10 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S.

[0309] In some embodiments, Ring B is selected from the group consisting of benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo[ ]oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, and thiazolo[5,4-b]pyridinyl.

[0310] In some embodiments, Ring B is selected from the group consisting of benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzo[ ]oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl and thiazolo[5,4-b]pyridinyl.

[0311] In some embodiments, B is selected from the group consisting of benzo[b]thiophenyl, indolyl, benzofuranyl, 2H-indazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, benzo[d]oxazolyl, and benzo[d]thiazolyl. In some embodiments, Ring B is selected from the group consisting of benzo [b]thiophenyl, indolyl, benzofuranyl and benzo[d]thiazolyl. In some embodiments, ring B is selected from the group consisting of benzo [b]thiophenyl, benzo[d]thiazolyl, indolyl, 2H-indazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, benzo[d]oxazolyl, and benzofuranyl.

[0312] In some embodiments, Ring B is selected from the group consisting of benzo[b]thiophenyl, indolyl and benzofuranyl.

[0313] In some embodiments, Ring B is selected from the group consisting of benzo[b]thiophen-2-yl, benzofuran -2 -yl and indol-2-yl.108IPTS / 200159134.1Docket No. TGO-030WO

[0314] In some embodiments, Ring B is selected from the group consisting ofIn some embodiments, Ring B is selected from the group consisting of

[0315] In some embodiments, Ring B is selected from the group consisting

[0316] In some embodiments, Ring B is benzo[b]thiophenyl. In some embodiments, Ring B is benzo[b]thiophen-6-yl. In some embodiments, Ring B is benzo[b]thiophen-5-yl. In some 109IPTS / 200159134.1Docket No. TGO-030WOembodiments, Ring B is benzo[b]thiophen-2-yl. In some embodiments, Ring B is benzo[d]thiazolyl. In some embodiments, Ring B is benzo[d]thiazol-5-yl. In some embodiments, Ring B is benzo[d]thiazol-2-yl. In some embodiments, Ring B is benzo[d]oxazolyl. In some embodiments, Ring B is benzo[d]oxazol-5-yl. In some embodiments, Ring B is benzo[d]oxazol-2-yl. In some embodiments, Ring B is benzofuranyl. In some embodiments, Ring B is benzofuran -2 -yl. In some embodiments, Ring B is indolyl. In some embodiments, Ring B is indol-2-yl. In some embodiments, Ring B is imidazo[2,l-b][l,3,4]thiadiazolyl. In some embodiments, RingB is imidazo[2,l-b][l,3,4]thiadiazol-2-yl. In some embodiments, Ring B is 2H-indazolyl. In some embodiments, Ring B is 2H-indazol-6-yl.

[0317] In some embodiments, Ring B is 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S. In some embodiments, Ring B is 11-14 membered tricyclic heteroaryl containing 1-3 heteroatoms selected from N, O and S. In some embodiments, Ring B is phenanthridinyl. In some embodiments, Ring B is selected from the group consisting of phenanthri din-3 -yl and phenanthridin-8-yl. In some embodiments, Ring B is phenanthridin-3-yl. In some embodiments, Ring B is phenanthri din-8-yl.

[0318] In some embodiments, Ring B is selected from the group consisting[,

[0320] In some embodiments, Ring B is

[0321] In someIPTS / 200159134.1Docket No. TGO-030WO

[0323] In some embodiments, Ring

[0324] In some embodiments, Ring B

[0325] In some

[0326] In some

[0327] In some

[0328] In some embodiments, the moiety represented

[0329] In some embodiments, the moiety represented

[0330] In some embodiments, the moiety represented

[0331] In some embodiments, the moiety represented

[0332] In some embodiments, the moiety represented111IPTS / 200159134.1Docket No. TGO-030WO

[0333] In some embodiments, the moiety represented

[0334] In some embodiments, the moiety represented

[0335] In some embodiments, the moiety represented

[0336] In some embodiments, the moiety represented as

[0337] In some embodiments, the moiety represented as

[0338] As generally defined herein, each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, - Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, and wherein each R4, RB1and RB2is independently as defined in any of the embodiments described herein.

[0339] In some embodiments, each RBis independently selected from the group consisting of-D, halo, =0, -CN, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 membered 112IPTS / 200159134.1Docket No. TGO-030WOheteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(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.

[0340] In some embodiments, each RBis independently selected from the group consisting of-D, halo, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 4-10 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(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, and wherein each R4is independently 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.

[0341] In some embodiments, each RBis independently selected from the group consisting of-D, halo,-C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 4-10 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl and -ORB2, wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4, and wherein each R4is independently selected from -F, -Cl, -Me and -CF3 and each RB2is -Me.

[0342] In some embodiments, 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, -O(l-(oxetan-3-yl)ethyl), -Ocyclopropyl, -cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentan-l-yl, spiro[2.2]pentanyl, -CH2cyclopropyl, -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-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[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]oct-2-en-3-yl, 2,3-dihydro-l,4-dioxin-5-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-113IPTS / 200159134.1Docket No. TGO-030WO5-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)CH2CH2CH3J-CH(CF3)CH3, -CH2CF3and -C(CF3)(CH3)2is substituted with 0 or 1 instances of -OMe or -OH and each cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[l.l.l]pentan-l-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[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]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.

[0343] In some embodiments, each R4is independently selected from -F, -C1,=O, -OH,-OMe, -OCF3, -CN, -Me, -tBu, -CHF2, -CF3, -CH2CH2OH.

[0344] In some embodiments, each RBis independently selected from the group consisting of-F, -Cl, -Me, -Et, -tBu, cyclopropyl, -CHF2, -CF3,-CH(CF3)CH3, --CH2CF3, -C(=CH2)CF3, phenyl, 8-oxabicyclo[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]oct-2-en-3-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-4-yl, wherein each cyclopropyl, phenyl, 8-oxabicyclo[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]oct-2-en-3-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-4-yl is substituted at available positions with 0, 1 or 2 instances of R4.

[0345] In some embodiments, each R4is independently selected from -F, -Cl, -Me and -CF3.

[0346] In some embodiments, each RBis independently selected from the group consisting of:114IPTS / 200159134.1Docket No. TGO-030WO

[0347] In some embodiments, each RBis independently selected from the group consisting of:115IPTS / 200159134.1Docket No. TGO-030WO-F, -Cl, -Me, -Et,-tBu, -CHF2, -CF3, -CF2CH3,-CH(CF3)CH3, -CH2CF3, -C(=CH2)CF3,

[0348] In some embodiments, each RBis independently selected from the group consisting of:-F, -Cl, -Me, -Et,-tBu, -CHF2, -CF3, -CF2CH3,-CH(CF3)CH3, -CH2CF3, -C(=CH2)CF3,and -OMe.

[0349] In some embodiments, RBis =0.

[0350] In some embodiments, RBis -D.

[0351] 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.

[0352] In some embodiments, RBis -CN.

[0353] In some embodiments, RBis -SF5.

[0354] In some embodiments, RBis -C1-C6 alkyl. In some embodiments, each RBis independently 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.

[0355] In some embodiments, each RBis independently 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.

[0356] In some embodiments, each RBis independently selected from the group consisting of -Me, -Et, and -tBu.116IPTS / 200159134.1Docket No. TGO-030WO

[0357] 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.

[0358] In some embodiments, RBis -Ci-Ce alkenyl. In some embodiments, each RBis independently selected from the group consisting of -vinyl and isopropen-2-yl. In some embodiments, RBis -vinyl. In some embodiments, RBis isopropen-2-yl.

[0359] 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.

[0360] In some embodiments, RBis -C1-C6 haloalkyl or -C1-C6 haloalkenyl.

[0361] In some embodiments, each RBis independently 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).

[0362] In some embodiments, each RBis independently selected from the group consisting of-CHF2, -CF3, -CF2CH3, -CH2CF3, -CH(CF3)CH3, and -C(=CH2)CF3.

[0363] In some embodiments, RBis trifluoromethyl (-CF3). In some embodiments, RBis difluoromethyl (-CHF2). In some embodiments, RBis -CH(CF3)CH3. In some embodiments,RBis CF3. In some embodiments, RBis -CH2CF3. In some embodiments, RBis -C(=CH2)CF3. In some embodiments, RBis -C(=CH2)CF3.

[0364] In some embodiments, RBis C3-C9cycloalkyl wherein the cycloalkyl 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, each RBis independently 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[1.1.1]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 R4, wherein R4is as defined in any of the embodiments described herein.117IPTS / 200159134.1Docket No. TGO-030WO

[0365] In some embodiments, each RBis independently selected from the group consisting of C3-C7 monocyclic cycloalkyl (e.g, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), C5-C9 bridged cycloalkyl (e.g, bicyclo[1.1.1]pentanyl, bicyclofl.2. l]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 R4, wherein R4is as defined in any of the embodiments described herein.

[0366] In some embodiments, each RBis independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl and spiro[2.2]pentanyl, each substituted with 0, or 1 instance of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, each R4is independently selected from the group consisting of -Me, tBu, -OCF3, -CF3 and -CN. In some embodiments, R4is independently selected from the group consisting of -Me, and -CF3.

[0367] In some embodiments, each RBis independently selected from the group consisting

[0368] In some embodiments, each RBis independently selected from the group consisting

[0369] In some embodiments, RBis C3-C7 monocyclic cycloalkyl substituted with 0, or 1 instance of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, each RBis independently selected from the group consisting of cyclopropyl, cyclobutyl and cyclohexyl. In some embodiments, RBis cyclopropyl substituted with 0 or 1 instances of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, R4is independently selected from the group consisting of -Me, and -CF3. In some embodiments, RBis cyclohexyl (e.g., unsubstituted cyclohexyl). In someembodiments, each RBis independently selected from the group consisting of118IPTS / 200159134.1Docket No. TGO-030WOIn some embodiments, each RBis independently selected from the group consisting of Fand. In some embodiments, RBis. In some embodiments, RBis.In some embodiments,

[0370] In some embodiments, RBis C4-C9 fused bicyclic cycloalkyl substituted with 0, or 1 instance of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, each RBis independently selected from the group consisting of 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 and decahydronaphthalenyl.

[0371] In some embodiments, RBis C5-C9 bridged cycloalkyl substituted with 0, or 1 instance of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, each RBis independently selected from the group consisting of bicyclo[1.1.1]pentanyl, bicyclofl.2. l]hexanyl, bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl. In some embodiments, RBis bicyclo[1.1.1]pentanyl (e.g., unsubstitutedbicyclof 1.1.1 ]pentanyl

[0372] In some embodiments, RBis C5-C9 spiro cycloalkyl substituted with 0, or 1 instance of R4, wherein R4is as defined in any of the embodiments described herein. In some embodiments, each RBis independently selected from the group consisting of spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[4.4]nonanyl. In some embodiments, RBis spiro[2.2]pentanyl (e.g., unsubstitutedspiro[2.2]pentanyl

[0373] In some embodiments, RBis -(C1-C2 alkyl)(C3-C9cycloalkyl) wherein the cycloalkyl is substituted with 0, 1, 2 or 3 instances of R4.

[0374] In some embodiments, RBis -(C1-C2 alkyl)(C3-C9cycloalkyl) 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.

[0375] In some embodiments,119IPTS / 200159134.1Docket No. TGO-030WO

[0376] In some embodiments, RBis 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, 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, each RBis independently 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[3.2.1]octanyl, 8-oxabicyclo[3.2.1]oct-2-enyl, tetrahydropyranyl, 3,4-dihydro-2H-pyranyl, 2,3-dihydro-l,4-dioxinyl and 3,6-dihydro-2H-pyranyl.

[0377] In some embodiments, each RBis independently selected from the group consisting, each substituted with 0, 1, 2 or 3 instances of R4, wherein each R4is independently as defined in any of the embodiments described herein. In some embodiments,each RBis independently selected from the group consisting of,each substituted with 0, 1 or 2 instances of R4, wherein each R4is independently as defined in any of the embodiments described herein. In some embodiments, each R4is independently selected from the group consisting of =O,-F, -Me, -OH, -CH2CH₂OH, -OMe and -CHF2. In some embodiments, each R4is-Me.

[0378] In some embodiments, RBis 3-6 membered monocyclic heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl) 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 5-6 membered monocyclic heterocyclyl containing one O heteroatom (e.g., tetrahydropyranyl (e.g., tetrahydropyran-3-yl, tetrahydropyran-2-yl), dihydropyranyl (3,4-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-4-yl), 2,3-dihydro-l,4-dioxinyl (e.g., 2,3-dihydro-l,4-dioxin-5-yl),120IPTS / 200159134.1Docket No. TGO-030WOtetrahydrofuranyl (e.g., tetrahydrofuran-3-yl)) 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 oxetanyl. In some embodiments, RBis tetrahydropyranyl (e.g., tetrahydropyran-3-yl, tetrahydropyran-2-yl). In some embodiments, RBis dihydropyranyl (3,4-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-4-yl). In some embodiments, RBis tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl). In some embodiments, RBis azetidinyl. In some embodiments, RBis pyrrolidinyl. In some embodiments, RBis piperidinyl. In some embodiments, RBis piperazinyl. In some embodiments, RBis morpholinyl. In some embodiments, RBis azepanyl.

[0379] In some embodiments, each RBis independently selected from of

[0380] In some embodiments, each RBis independently. In some embodiments,each RBis independently. In some embodiments, each RBis independently. In some embodiments, each RBis independently. In someembodiments, each RBis independently

[0381] 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 from. In some embodiments, each RBis independently.. In some 121IPTS / 200159134.1Docket No. TGO-030WOembodiments, each RBis independently . In some embodiments, each RBisindependently Cl [n SOme embodiments, each RBis independently I T Z / \ / CIIn some embodiments, each RBis each RBis independently X Cl jnsomeembodiments, each RBis independently. In some embodiments, each RBisindependently

[0382] In some embodiments, RBis 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, 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, each R4is independently selected from -Me, -F, -Cl, -OMe and -CF3. In some embodiments, each RBis independently selected from the group consisting of furanyl (e.g., furan-3-yl) and pyridinyl (e.g, pyridin-2-yl), each unsubstituted or substituted with one instance of R4, wherein R4is methyl. In some embodiments, RBis furanyl (e.g., furan-3-yl) substituted with one instance of R4, wherein R4is methyl. In some embodiments, RBis pyridinyl (e.g., pyridin-2-yl), unsubstituted or substituted with one instance of methyl. In some embodiments, each RBis independently selected from the group consisting of

[0383] In some embodiments RBis -(C1-C2 alkyl)(6-10 membered cycloalkyl) (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0384] In some embodiments, RBis -(C1-C2 alkyl)(6-10 membered heterocyclyl)(e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl,122IPTS / 200159134.1Docket No. TGO-030WOtetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0385] In some embodiments, RBis -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, RBis benzyl.

[0386] In some embodiments, RBis -(C1-C2 alkyl)(5-10 membered heteroaryl) (e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0387] 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(CH3)oxetan-yl, -OCF3). In some embodiments, each RBis independently selected from the group consisting of methoxy, phenoxy, -OCH(CH3)oxetan-yl and -OCF3. In some embodiments, RBis hydroxy. In some embodiments, RBis methoxy. In some embodiments, RBis ethoxy. In some embodiments, RBis propoxy. In some embodiments, RBis isopropoxy. In some embodiments, RBis -Ci-Ce haloalkoxy. In some embodiments, RBis trifluoromethoxy (-OCF3), In some embodiments, RBis di fluoromethoxy (-OCHF2). In some embodiments, RBis -OCH(CH3)oxetan-yl. In some embodiments, RBis phenoxy.

[0388] 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(CH3)iPr, -N(CH3)cyclopropyl, -N(CH3)cyclobutyl). In some embodiments, each RBis independently selected from the group consisting of-N(CH3)2, -N(CH2CH3)2, -NHPhenyl and -NH imidazol-2-yl. In some embodiments, RBis -N(CH3)2. In some embodiments, RBis -N(CH2CH3)2. In some embodiments, RBis NHPhenyl. In some embodiments, RBis NH imidazol-2-yl.

[0389] 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)tBu, -C(=O)'Pr, -C(=O)CH2CH2CH3or -C(=O)OCH3. In some embodiments, RBis acetyl (-C(=O)CH3). In some embodiments, RBis -C(=O)phenyl. In123IPTS / 200159134.1Docket No. TGO-030WOsome embodiments, RBis -C(=O)ORB2. In some embodiments, RBis -COOH. In some embodiments, RBis COOCH3.

[0390] 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)iPr, -NHC(=O)Bu, -NHC(=O)tBu, -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)iPr, -N(CH3)C(=O)Bu, -N(CH3)C(=O)tBu, -N(CH3)C(=O)Cyclopropyl, -N(CH3)C(=O)Cyclobutyl).

[0391] 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)OtBu, -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)OtBu, -N(CH3)C(=O)OCyclopropyl, -N(CH3)C(=O)OCyclobutyl).

[0392] 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)NHTr, -C(=O)NHBu, -C(=O)NHzBu, -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)Tr, -C(=O)N(CH3)Bu, -C(=O)N(CH3)zBu, -C(=O)N(CH3)Cyclopropyl, -C(=O)N(CH3)Cyclobutyl).

[0393] 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.

[0394] In some embodiments, RBis -OC(=O)N(RB2)2wherein 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)NHzBu, -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, -124IPTS / 200159134.1Docket No. TGO-030WOOC(=O)N(CH3)CH2CH2CH3, -OC(=O)N(CH3)'Pr, -OC(=O)N(CH3)Bu, -OC(=O)N(CH3)zBu, -OC(=O)N(CH3)Cyclopropyl, -OC(=O)N(CH3)Cyclobutyl).

[0395] 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(=O)cyclohexyl).

[0396] 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).

[0397] 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, -STr). In some embodiments, RBis -Scycloalkyl (e.g., -Scyclopropyl, -Scyclobutyl, -Scyclopentyl, -Scyclohexyl). In some embodiments, RBis -Saryl (e.g., -Sphenyl).

[0398] 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)tBu, -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).

[0399] 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)2Tr). 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)2aryl (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., -125IPTS / 200159134.1Docket No. TGO-030WO-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).

[0400] 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)2NHTr, -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)Tr, -S(=O)2N(CH3)cyclopropyl, -S(=O)2N(CH3)cyclobutyl).

[0401] In some embodiments, when m is 2 or 3 one instance of RBis halo (e.g., -F, -Cl) and the other is as defined in any of the embodiments described herein.

[0402] As generally defined herein, each R4is independently selected from -D, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-C6haloalkyl, -NH(CI-C6alkyl), -N(CI-C6alkyl)2.

[0403] In some embodiments, each R4is independently selected from =0, halo, -OH, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -OCi-Ce alkyl, OCi-Ce haloalkyl and -Ci-Ce hydroxyalkyl.

[0404] In some embodiments, each R4is independently selected from the group consisting of-F, -Cl, =0, -OH,-OMe, -CN, -Me, -tBu, -CF3, -OCF3, -CH2CH₂OH and -CHF2.

[0405] In some embodiments, each R4is independently selected from the group consisting of-F, -Cl, -Me and -CF3.

[0406] In some embodiments, each R4is independently selected from the group consisting of -Me, -tBu, -OCF3, -CF3and -CN.

[0407] In some embodiments, each R4is independently selected from the group consisting of -Me, and -CF3.

[0408] In some embodiments, each R4is independently selected from the group consisting of =O,-F, -Me, -OH, -CH2CH₂OH, -OMe and -CHF2.

[0409] In some embodiments, each R4is independently -D.

[0410] In some embodiments, each R4is independently =0.

[0411] 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.126IPTS / 200159134.1Docket No. TGO-030WO

[0412] In some embodiments, each R4is independently -OH.

[0413] 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(tri fluoromethoxy).

[0414] In some embodiments, each R4is independently -CN.

[0415] In some embodiments, each R4is independently -C1-C6 alkyl (e.g., -Me, -Et, -wPr, -zPr, -tBu). In some embodiments, each R4is independently selected from -Me- and -tBu. In some embodiments, each R4is independently -Me. In some embodiments, each R4is independently -tBu.

[0416] In some embodiments, each R4is independently -Ci-Ce haloalkyl (e.g., -CF3, -CHF2, -CH2F, -CH2CF3). In some embodiments, each R4is independently -CF3.

[0417] In some embodiments, each R4is independently -Ci-Ce hydroxyalkyl (e.g., -CH2CH₂OH).

[0418] In some embodiments, the moiety represented asis selected from the127IPTS / 200159134.1Docket No. TGO-030WO128IPTS / 200159134.1Docket No. TGO-030WO129IPTS / 200159134.1Docket No. TGO-030WO130IPTS / 200159134.1Docket No. TGO-030WO131IPTS / 200159134.1Docket No. TGO-030WOIPTS / 200159134.1Docket No. TGO-030WO133IPTS / 200159134.1Docket No. TGO-030WO134IPTS / 200159134.1Docket No. TGO-030WO135IPTS / 200159134.1Docket No. TGO-030WO136IPTS / 200159134.1Docket No. TGO-030WO137IPTS / 200159134.1Docket No. TGO-030WO138IPTS / 200159134.1Docket No. TGO-030WO139IPTS / 200159134.1Docket No. TGO-030WO

[0422] In some embodiments, the moiety represented asis selected from the140IPTS / 200159134.1Docket No. TGO-030WO

[0423] In an embodiment, the moiety represented asselected from the group consisting ofIPTS / 200159134.1Docket No. TGO-030WO142IPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety represented asIn some embodiments, the moiety representedsome embodiments, the moiety representedsome 143IPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety represented asembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedsomeembodiments, the moiety representedIPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety representedsomeembodiments, the moiety representedsomeembodiments, the moiety representedsomeembodiments, the moiety representedsomeembodiments, the moiety representedsomeembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety represented145IPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety represented146IPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety represented asembodiments, the moiety represented as147IPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety represented asembodiments, the moiety representedsome embodiments, the moiety represented asIn some embodiments, the moiety representedsome embodiments, the moiety represented as. In someembodiments, the moiety representedsome embodiments, the moiety represented asIn someembodiments, the moiety representedsome148IPTS / 200159134.1Docket No. TGO-030WOembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety represented asIn someembodiments, the moiety represented asembodiments, the moiety representedembodiments, the moiety representedembodiments, the moiety represented asembodiments, the moiety represented asembodiments, the moiety represented as. In someembodiments, the moiety represented as149IPTS / 200159134.1Docket No. TGO-030WO

[0425] As generally defined herein, R5is selected from the group consisting of-H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl. In some embodiments, R5and one instance of RAare taken together with the atoms to which they are attached to a 4-7 membered carbocyclic ring

[0426] In some embodiments, R5is selected from the group consisting of-H, -F, -Cl, -OH, -Me, -Et, and -OCH3.

[0427] In some embodiments, R5is selected from the group consisting of-H, -F, and -OH.

[0428] In some embodiments, R5is -H.

[0429] In some embodiments, R5is -F.

[0430] In some embodiments, R5is -OH.

[0431] As generally defined herein, each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl).

[0432] In some embodiments, each RA1is independently selected from the group consisting of-C1-C6 alkyl, -Ci-Ce haloalkyl, C3-C9cycloalkyl, and 4-10 membered heterocyclyl.

[0433] In some embodiments, each RA1is independently selected from the group consisting of-C1-C6 alkyl, (e.g., -Me, -Et, -Pr, -Pr, - ec-Bu, -T3u) and -Ci-Ce haloalkyl (e.g., -CF3, -CHF2, -CH2CF3).

[0434] In some embodiments, each RA1is independently selected from the group consisting of -Me, -Et, -Pr, -'Pr, -.scc-Bu, -tBu, -CF3, -CHF2and -CH2CF3.

[0435] In some embodiments, each RA1is independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - Pr,-”Bu, -"Bu, - ec-Bu, -Ao-Bu). In some embodiments, each RA1is independently -Me. In some embodiments, each RA1is independently -Et. In some embodiments, each RA1is independently -Pr or -zPr.

[0436] 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).

[0437] In some embodiments, each RA1is independently C3-C9cycloalkyl e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, each RA1is independently cyclopropyl. In some embodiments each RA1is independently cyclobutyl. In150IPTS / 200159134.1Docket No. TGO-030WOsome embodiments, each RA1is independently cyclopentyl. In some embodiments, each RA1is independently cyclohexyl.

[0438] In some embodiments, each RA1is independently 4-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0439] 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.g., thiophen-2-yl, thi ophen-3 -yl). In some embodiments, RA1is 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 (e.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).

[0440] 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.

[0441] In some embodiments, each RA1is independently -(C1-C2 alkyl)(C3-C9cycloalkyl) (e.g, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0442] In some embodiments, each RA1is independently -(C1-C2 alkyl)(4-10 membered heterocyclyl) (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0443] In some embodiments, each RA1is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RA1is independently benzyl.

[0444] In some embodiments, each RA1is independently -(C1-C2 alkyl)(5-10 membered heteroaryl )(e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).151IPTS / 200159134.1Docket No. TGO-030WO

[0445] As generally defined herein, each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl).

[0446] In some embodiments, each RA2is independently selected from the group consisting of H, D, -C1-C6 alkyl, -Ci-Ce haloalkyl, C3-C9cycloalkyl, and 4-10 membered heterocyclyl.

[0447] In some embodiments, each RA2is independently selected from the group consisting of H, D, -C1-C6 alkyl, (e.g., -Me, -Et, -Pr, -Pr, - ec-Bu, -T3u) and -Ci-Ce haloalkyl (e.g, -CF3, -CHF2, -CH2CF3).

[0448] In some embodiments, each RA2is independently selected from the group consisting of H, D, -Me, -Et, -Pr, -Tr, - ec-Bu, -tBu, -CF3, -CHF2and -CH2CF3.

[0449] In some embodiments, each RA2is independently H. In some embodiments, each RA2is independently D.

[0450] In some embodiments, each RA2is independently -C1-C6 alkyl (e.g, -Me, -Et, -Pr, -Pr,-”Bu, -"Bu, -sec-Bu, - / .w-Bu). In some embodiments, each RA2is independently -Me. In some embodiments, each RA2is independently -Et. In some embodiments, each RA2is independently -Pr or -zPr.

[0451] 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).

[0452] In some embodiments, each RA2is independently C3-C9cycloalkyl (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.

[0453] In some embodiments, each RA2is independently 4-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0454] 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 heteroaryl152IPTS / 200159134.1Docket No. TGO-030WOcontaining 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, thi ophen-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).

[0455] 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.

[0456] In some embodiments, each RA2is independently -(C1-C2 alkyl)(C3-C9cycloalkyl) (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0457] In some embodiments, each RA2is independently -(C1-C2 alkyl)(4-10 membered heterocyclyl) (e.g, oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0458] In some embodiments, each RA2is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RA2is independently benzyl.

[0459] In some embodiments, each RA2is independently -(C1-C2 alkyl)(5-10 membered heteroaryl )(e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0460] As generally defined herein, each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl).153IPTS / 200159134.1Docket No. TGO-030WO

[0461] In some embodiments, each RB1is independently selected from the group consisting of-C1-C6 alkyl, -Ci-Ce haloalkyl, C3-C9cycloalkyl, 4-10 membered heterocyclyl and 6-10 membered aryl.

[0462] In some embodiments, each RB1is independently selected from the group consisting of-C1-C6 alkyl, (e.g., -Me, -Et, -Pr, -Pr, - ec-Bu, -T3u), -Ci-Ce haloalkyl (e.g., -CF3, -CHF2, -CH2CF3) and phenyl.

[0463] In some embodiments, each RB1is independently selected from the group consisting of -Me, -Et, -Pr, -Pr, - ec-Bu, -tBu, -CF3, -CHF2, -CH2CF3 and phenyl.

[0464] In some embodiments, each RB1is independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, - Pr,-”Bu, -"Bu, - ec-Bu, -z.w-Bu). In some embodiments, each RB1is independently -Me. In some embodiments, each RB1is independently -Et. In some embodiments, each RB1is independently -Pr or -zPr.

[0465] In some embodiments, each RB1is independently -Ci-Ce haloalkyl. In some embodiments, each RB1is independently trifluoromethyl (-CF3). In some embodiments, each RB1is independently difluoromethyl (-CHF2).

[0466] In some embodiments, each RB1is independently C3-C9cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, 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.

[0467] In some embodiments, each RB1is independently 4-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0468] 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, thi ophen-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,154IPTS / 200159134.1Docket No. TGO-030WOpyrimidinyl, 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).

[0469] 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.

[0470] In some embodiments, each RB1is independently -(C1-C2 alkyl)(C3-C9cycloalkyl) (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0471] In some embodiments, each RB1is independently -(C1-C2 alkyl)(4-10 membered heterocyclyl) (e.g, oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0472] In some embodiments, each RB1is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RB1is independently benzyl.

[0473] In some embodiments, each RB1is independently -(C1-C2 alkyl)(5-10 membered heteroaryl )(e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0474] As generally defined herein, each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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;

[0475] In some embodiments, each RB2is independently selected from the group consisting of H, D, -C1-C6 alkyl, -Ci-Ce haloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S and -(C1-C2 alkyl)(4-10 membered heterocyclyl).

[0476] 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.

[0477] In some embodiments, each RB2is independently-Me.155IPTS / 200159134.1Docket No. TGO-030WO

[0478] In some embodiments, each RB2is independently -C1-C6 alkyl (e.g., -Me, -Et, -Pr, -Pr,-”Bu, -'Bu, - ec-Bu, -z.w-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 -z'Pr.

[0479] In some embodiments, each RB2is independently -Ci-Ce haloalkyl. In some embodiments, each RB2is independently trifluoromethyl (-CF3). In some embodiments, each RB2is independently difluoromethyl (-CHF2).

[0480] 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. In some embodiments, each RB2is independently cyclopentyl. In some embodiments, each RB2is independently cyclohexyl.

[0481] In some embodiments, each RB2is independently 4-10 membered heterocyclyl (e.g., oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl).

[0482] 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, thi ophen-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).

[0483] 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.156IPTS / 200159134.1Docket No. TGO-030WO

[0484] In some embodiments, each RB2is independently -(C1-C2 alkyl)(C3-C9cycloalkyl) (e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl).

[0485] In some embodiments, each RB2is independently -(C1-C2 alkyl)(4-10 membered heterocyclyl) (e.g., oxetanylmethyl, aziridinylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, azepanylmethyl).

[0486] In some embodiments, each RB2is independently -(C1-C2 alkyl)(6-10 membered aryl). In some embodiments, each RB2is independently benzyl.

[0487] In some embodiments, each RB2is independently -(C1-C2 alkyl)(5-10 membered heteroaryl )(e.g., pyridinylmethyl, thiazolylmethyl, triazolylmethyl, pyrazolylmethyl).

[0488] 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.

[0489] 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.

[0490] In some embodiments, provided is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:wherein X1, X2, X3, X4, X5, X6, Y, R3, R4, R5, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0491] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:157IPTS / 200159134.1Docket No. TGO-030WOwherein X1, X2, X3, X4, X5, X6, R3, R4, R5, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0492] In some embodiments, provided is a compound of Formula (F) or a pharmaceutically acceptable salt thereof, wherein:wherein X1, X2, X3, X4, X5, X6, R3, R4, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0493] In some embodiments, provided is a compound of Formula (I”) or a pharmaceutically acceptable salt thereof, wherein:wherein X1, X2, X3, X4, X5, X6, R3, R4, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0494] In some embodiments, the compound of Formula (I) is a compound of Formula (II), or a pharmaceutically acceptable salt thereof,wherein X1, X2, X3, X4, X5, X6, R3, R4, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.158IPTS / 200159134.1Docket No. TGO-030WO

[0495] In some embodiments, the compound of Formula (I) is a compound of Formula (IF), or a pharmaceutically acceptable salt thereof,wherein X1, X2, X3, X4, X5, X6, R3, R4, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0496] In some embodiments, the compound of Formula (I) is a compound of Formula (II”), or a pharmaceutically acceptable salt thereof,wherein X1, X2, X3, X4, X5, X6, R3, R4, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0497] In some embodiments, the compound of Formula (I) is a compound of Formula (II-A), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0498] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.159IPTS / 200159134.1Docket No. TGO-030WO

[0499] In some embodiments, the compound of Formula (I) is a compound of Formula (II-C), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0500] In some embodiments, the compound of Formula (I) is a compound of Formula (II-D), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0501] In some embodiments, the compound of Formula (I) is a compound of Formula (II-E), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0502] In some embodiments, the compound of Formula (I) is a compound of Formula (II-F), or a pharmaceutically acceptable salt thereof,160IPTS / 200159134.1Docket No. TGO-030WOwherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0503] In some embodiments, the compound of Formula (I) is a compound of Formula (II-G), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0504] In some embodiments, the compound of Formula (I) is a compound of Formula (II- H), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0505] In some embodiments, the compound of Formula (A) is a compound of Formula (II-I), or a pharmaceutically acceptable salt thereof,161IPTS / 200159134.1Docket No. TGO-030WOwherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0506] In some embodiments, the compound of Formula (X) is a compound of Formula (III), or a pharmaceutically acceptable salt thereof,wherein X7, RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0507] In some embodiments, the compound of Formula (X) is a compound of Formula (III-A), or a pharmaceutically acceptable salt thereof,wherein RA, Ring B, RB, n, and m are as defined in any of the embodiments described herein.

[0508] In some embodiments, the compound of Formula (I) is a compound of Formula (II-A-1), or a pharmaceutically acceptable salt thereof,162IPTS / 200159134.1Docket No. TGO-030WOwherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0509] In some embodiments, the compound of Formula (I) is a compound of Formula (II- A-2), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0510] In some embodiments, the compound of Formula (I) is a compound of Formula (II- A-3), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0511] In some embodiments, the compound of Formula (I) is a compound of Formula (II- A-4), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0512] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B-1), or a pharmaceutically acceptable salt thereof,163IPTS / 200159134.1Docket No. TGO-030WOwherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0513] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B-2), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0514] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B-3), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0515] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B-4), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0516] In some embodiments, the compound of Formula (I) is a compound of Formula (II-C-1), or a pharmaceutically acceptable salt thereof,164IPTS / 200159134.1Docket No. TGO-030WOwherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0517] In some embodiments, the compound of Formula (I) is a compound of Formula (II-C-2), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0518] In some embodiments, the compound of Formula (I) is a compound of Formula (II-D-1), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0519] In some embodiments, the compound of Formula (I) is a compound of Formula (II-E-1), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0520] In some embodiments, the compound of Formula (I) is a compound of Formula (II-F-1), or a pharmaceutically acceptable salt thereof,165IPTS / 200159134.1Docket No. TGO-030WOwherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0521] In some embodiments, the compound of Formula (I) is a compound of Formula (II-G-1), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0522] In some embodiments, the compound of Formula (I) is a compound of Formula (II-H-1), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0523] In some embodiments, the compound of Formula (A) is a compound of Formula (II- 1-1), or a pharmaceutically acceptable salt thereof,wherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0524] In some embodiments, the compound of Formula (X) is a compound of Formula (III-A-1), or a pharmaceutically acceptable salt thereof,166IPTS / 200159134.1Docket No. TGO-030WOwherein Ring B, RB, and m are as defined in any of the embodiments described herein.

[0525] In some embodiments, provided is a compound selected from the compounds of Table 1, or pharmaceutically acceptable salts thereof.

[0526] Compounds described herein (e.g., a compound of Formula (X) to (III-A-1) or a compound of Table 1, or pharmaceutically acceptable salts thereof) are useful as degraders of HBS1L.

[0527] Table 1 indicates DCso 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 DCso of < 100 nM, “b” indicates a DCso equal to or greater than 100 nM but less than 500 nM, “c” indicates an DCso equal to or greater than 500 nM but less than 5pM and “d” indicates an DCso equal to or greater than 5pM in the HBSIL-HiBiT and GSPTl-HiBiT cells, respectively. In column 6, “A” indicates a DCso ratio greater than or equal to 100 fold between the DCso in the GSPTl-HiBiT cells and the HBSIL-HiBiT cells; “B” indicates a DCso ratio greater than or equal to 30 fold but lower than 100 fold between the between the DCso in the GSPTl-HiBiT cells and the HBSIL-HiBiT cells; “C” indicates a DCso 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 a DC50 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.

[0528] 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 5pM 167IPTS / 200159134.1Docket No. TGO-030WOand “d*” indicates an EC50 equal to or greater than 5pM for the ternary complex formation with HBS1L and GSPT1, respectively.168IPTS / 200159134.1Docket No. TGO-030WOT able 1-Exemplary compounds with selected biological activity data169IPTS / 200159134.1Docket No. TGO-030WO170IPTS / 200159134.1Docket No. TGO-030WO171IPTS / 200159134.1Docket No. TGO-030WO172IPTS / 200159134.1Docket No. TGO-030WO173IPTS / 200159134.1Docket No. TGO-030WO174IPTS / 200159134.1Docket No. TGO-030WO175IPTS / 200159134.1Docket No. TGO-030WO176IPTS / 200159134.1Docket No. TGO-030WO177IPTS / 200159134.1Docket No. TGO-030WO178IPTS / 200159134.1Docket No. TGO-030WO179IPTS / 200159134.1Docket No. TGO-030WO180IPTS / 200159134.1Docket No. TGO-030WO181IPTS / 200159134.1Docket No. TGO-030WO182IPTS / 200159134.1Docket No. TGO-030WOIPTS / 200159134.1Docket No. TGO-030WO184IPTS / 200159134.1Docket No. TGO-030WO185IPTS / 200159134.1Docket No. TGO-030WO186IPTS / 200159134.1Docket No. TGO-030WO187IPTS / 200159134.1Docket No. TGO-030WO188IPTS / 200159134.1Docket No. TGO-030WOIPTS / 200159134.1Docket No. TGO-030WO190IPTS / 200159134.1Docket No. TGO-030WO191IPTS / 200159134.1Docket No. TGO-030WO192IPTS / 200159134.1Docket No. TGO-030WO193IPTS / 200159134.1Docket No. TGO-030WO194IPTS / 200159134.1Docket No. TGO-030WO195IPTS / 200159134.1Docket No. TGO-030WOIPTS / 200159134.1Docket No. TGO-030WO197IPTS / 200159134.1Docket No. TGO-030WO198IPTS / 200159134.1Docket No. TGO-030WO(2)Data obtained using the updated C-terminal knock in cell line described in Example 5Alternative Embodiments

[0529] 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 least90%, 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

[0530] 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 (X)), or a pharmaceutically acceptable salt thereof.

[0531] 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.199IPTS / 200159134.1Docket No. TGO-030WO

[0532] 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-a-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, water, 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-, -, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2 and 3 hydroxypropyl-0-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0533] 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.

[0534] In some embodiments, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0535] Also provided is a compound described herein (e.g., a compound of Formula (X), 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.200IPTS / 200159134.1Docket No. TGO-030WO

[0536] 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..

[0537] Also provided is a compound described herein (e.g., a compound of Formula (X), or pharmaceutically acceptable salts thereof) (or pharmaceutical composition thereof) for use in the treatment of an HBSIL-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.

[0538] 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,201IPTS / 200159134.1Docket No. TGO-030WOglioma (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. Also provided is a compound described herein (e.g., a compound of Formula (X), 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 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.

[0539] 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 renal202IPTS / 200159134.1Docket No. TGO-030WOcarcinoma), 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..

[0540] 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 compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0541] 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, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0542] 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.

[0543] 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, or203IPTS / 200159134.1Docket No. TGO-030WOcompounds 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 corn 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.

[0544] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound 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, Twe...

Claims

Docket No. TGO-030WOClaims1. A compound of Formula (X) or a pharmaceutically acceptable salt thereof, wherein:Ring A is selected from the group consistingindicates the attachment point tX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;X7is CH or N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl or a 4-7 membered heterocyclyl containing 1 heteroatom selected from N, O and S, provided that R3and R3are not both H;543IPTS / 200159134.1Docket No. TGO-030WOeach RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -C3-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl; or R5and one instance of RAcan be taken together with the atoms to which they are attached to form a 4-7 membered carbocyclic ring;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);544IPTS / 200159134.1Docket No. TGO-030WOeach RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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 Ring A is3. A compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein:545IPTS / 200159134.1Docket No. TGO-030WOX1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Y is N or CR5;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORB2, -N(RB2)2, -C(=O)RB1, - 546IPTS / 200159134.1Docket No. TGO-030WOC(=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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(CI-C6 alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl; or R5and one instance of RAcan be taken together with the atoms to which they are attached to form a 4-7 membered carbocyclic ring;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, — (Ci-C2alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(Ci-C2alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N,547IPTS / 200159134.1Docket No. TGO-030WOO and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

4. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, X5and X6are each independently CH or N, provided that no more than two of X1, X2, X3, X4, X5and X6are simultaneously N;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -C3-C9cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -548IPTS / 200159134.1Docket No. TGO-030WOeach RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);549IPTS / 200159134.1Docket No. TGO-030WOeach RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3and R3are each independently -C1-C3 alkyl, wherein each hydrogen of the alkyl can be replaced by deuterium.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3and R3are each independently selected from H, -Me, -CD3 and -Et.

7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R3and R3are both -Me.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein, the compound is of Formula (II):

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof,wherein the moiety representedselected from the group consisting of:IPTS / 200159134.1Docket No. TGO-030WO10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof,11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II- A):551IPTS / 200159134.1Docket No. TGO-030WO12. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Ring A13. A compound of Formula (B) or a pharmaceutically acceptable salt thereof, wherein:Y is N or CR5;Ring B is selected from the group consisting of 6-14 membered aryl, C3-C9cycloalkyl, C3-C9 cycloalkenyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, and 5-14 membered heteroaryl containing 1-4 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, wherein each hydrogen of the alkyl and haloalkyl can be replaced by deuterium, or are taken together with the carbon to which they are attached to form a C3-C9cycloalkyl 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-C9cycloalkyl, 4-552IPTS / 200159134.1Docket No. TGO-030WO10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl), -ORA2, -N(RA2)2, -C(=O)RA1, -each RBis independently selected from the group consisting of-D, halo, -CN, =0, -SF5, -C1-C6 alkyl, -C1-C6 alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -Ci-Ce haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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, =0, halo, -OH, -NH2, -CN, -C1-C6 alkyl, -Ci-Ce haloalkyl, -Ci-Ce hydroxyalkyl, -OCi-Ce alkyl, -OCi-Ce haloalkyl, -NH(Ci-Ce alkyl), -N(CI-C6alkyl)2;R5is selected from the group consisting of H, halo, -OH, -C1-C6 alkyl, and -OCi-Ce alkyl;each RA1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RA2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O553IPTS / 200159134.1Docket No. TGO-030WOand S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB1is independently selected from -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 membered heteroaryl);each RB2is independently selected from -H, -D, -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9cycloalkyl, 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 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, -(C1-C2 alkyl)(C3-C9cycloalkyl), -(C1-C2 alkyl)(4-10 membered heterocyclyl), -(C1-C2 alkyl)(6-10 membered aryl), -(C1-C2 alkyl)(5-10 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.

14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, wherein R3and R3'are both -Me.

15. The compound of any one of claims 1 and 12-14, or a pharmaceutically acceptable saltthereof, wherein the moiety representedwherein554IPTS / 200159134.1Docket No. TGO-030WO16. The compound of any one of claims 1 and 12-14, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III- A):

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of-D, halo, -CN, -SF5, -C1-C6 alkyl, -Ci-Ce alkenyl, -Ci-Ce heteroalkyl, -Ci-Ce haloalkyl, -C3-C9cycloalkyl, 4-10 membered heterocyclyl, -ORA2and -N(RA2)2.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of halo and -C1-C6 alkyl.

19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from the group consisting of-F and -Me.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein n is 0.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein n is 1.

22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein n is 2.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof,wherein the moiety representedselected from the group consisting of:555IPTS / 200159134.1Docket No. TGO-030WO24. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-A-1):

25. The compound of any one of claims 1 and 12-16, or a pharmaceutically acceptable saltthereof, wherein the moiety representedwherein556IPTS / 200159134.1Docket No. TGO-030WOindicates the attachment point tindicates the attachment point26. The compound of any one of claims 1 and 12-16, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III-A-1):

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 6-14 membered aryl, C3-C9cycloalkyl and 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from 6-14 membered aryl and 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

29. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 9-10 membered bicyclic aryl, 13-14 membered tricyclic aryl, 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S and 11-14 membered tricyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

30. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.557IPTS / 200159134.1Docket No. TGO-030WO31. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-14 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

32. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

33. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is 8-10 membered bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S.

34. The compound of any one of claims 1-26, 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, chromanyl, isochromanyl, 2H-chromenyl, 9H fluorenyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclofl.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, bicyclofl.

1. 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, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo[ ]thiazolyl, benzof t / ]oxazolyl, imidazo[2, 1 -b] [ 1,3,4]thiadiazolyl, [ 1,2,4]triazolo[4,3 -a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl and phenanthridinyl.

35. The compound of any one of claims 1-26, 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, 2H-chromenyl, 9,10- 558IPTS / 200159134.1Docket No. TGO-030WOdihydrophenanthrenyl, 6H-benzo[c]chromenyl, 5,6-dihydrophenanthridin-yl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, thiophenyl, pyridinyl, indolyl, benzofuranyl, benzo[b]thiophenyl, benzo[d]thiazolyl, benzo[d]oxazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, 2H-indazolyl and phenanthridinyl.

36. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of phenyl, 2H-chromenyl, bicyclo[1.1.1]pentanyl, thiophenyl, indolyl, benzofuranyl, benzo[d]thiazolyl, benzo[d]oxazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, 2H-indazolyl, and benzo[b]thiophenyl.

37. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,38. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting of559IPTS / 200159134.1Docket No. TGO-030WO39. The compound of any one of claims 1-26, 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, chromanyl, isochromanyl, 2H-chromenyl, 9H fluorenyl, thiophenyl, benzo[b]thiophenyl, benzo [ ]thiazolyl, benzo[d]oxazolyl, benzofuranyl, indolyl, 9,10-dihydrophenanthrenyl, 6H-benzo[c]chromenyl and 5,6-dihydrophenanthridin-yl.

40. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, benzofd] isothiazolyl, indolyl, benzofuranyl, 1H-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[ ]imidazolyl, benzo [ ]thiazolyl, benzo [ ] oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, lH-pyrazolo[4,3-Z>]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, lH-thieno[3,2-c]pyrazolyl, thiazolo[5,4-b]pyridinyl, imidazo[2,l-b][l,3,4]thiadiazolyl and phenanthridinyl.

41. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of thiophenyl, pyridinyl, benzo[b]thiophenyl, benzo [ ]thiazolyl, benzofd] oxazolyl, 2H-indazolyl, phenanthridinyl, indolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, and benzofuranyl.

42. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting of:560IPTS / 200159134.1Docket No. TGO-030WO43. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting of:

44. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of thiophenyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridinyl and pyrimidinyl.

45. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting of46. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of benzo[d]isothiazolyl, indolyl, benzofuranyl, IH-indazolyl, 2H-indazolyl, benzo[b]thiophenyl, quinolinyl, 1,5-naphthyridinyl, isoquinolinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, 1H-pyrazolo[4,3-Z>]pyridinyl, lH-pyrazolo[3,4-b]pyridinyl, lH-thieno[2,3-c]pyrazolyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, and thiazolo[5,4-b]pyridinyl.561IPTS / 200159134.1Docket No. TGO-030WO47. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of benzo [b]thiophenyl, indolyl, benzofuranyl, 2H-indazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, benzo[d]oxazolyl, and b enzo \d] thi azoly 1.

48. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of benzo [b]thiophenyl, benzo[d]thiazolyl, indolyl, 2H-indazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, benzo[d]oxazolyl, and benzofuranyl.

49. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting50. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein Ring B is selected from the group consisting562IPTS / 200159134.1Docket No. TGO-030WO51. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein the moiety represented52. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein the moiety represented as53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-D, halo, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, 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, and wherein each R4is independently 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.

54. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-D, halo,-C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 haloalkenyl, C3-C9 cycloalkyl, 4-10 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S or oxidized forms thereof, 6-10 membered aryl and -ORB2, wherein each aryl, cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl is substituted with 0, 1, 2 or 3 instances of R4, and wherein each R4is independently selected from -F, -Cl, -Me and -CF3and each RB2is -Me.

55. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-F, -Cl, -Me, -Et, -tBu, cyclopropyl, -CHF2, -CF3,-CH(CF3)CH3, --CH2CF3, -C(=CH2)CF3, phenyl, 8- 563IPTS / 200159134.1Docket No. TGO-030WOoxabicyclo[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]oct-2-en-3-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-4-yl, wherein each cyclopropyl, phenyl, 8-oxabicyclo[3.2.1]octan-3-yl, 8-oxabicyclo[3.2.1]oct-2-en-3-yl, tetrahydropyran-3-yl, 3,4-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-4-yl is substituted at available positions with 0, 1 or 2 instances of R4.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from -F, -Cl, -Me and -CF3.

57. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of:564IPTS / 200159134.1Docket No. TGO-030WO58. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of:-F, -Cl, -Me, -Et,-tBu, -CHF2, -CF3, -CF2CH3,-CH(CF3)CH3, -CH2CF3, -C(=CH2)CF3,59. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis halo (e.g., fluoro, chloro, bromo, iodo).

60. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from -F and -Cl.

61. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis -C1-C6 alkyl.565IPTS / 200159134.1Docket No. TGO-030WO62. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently 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.

63. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis -C1-C6 haloalkyl or -C1-C6 haloalkenyl.

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

65. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of-CHF2, -CF3, -CF2CH3, -CH2CF3, -CH(CF3)CH3, and -C(=CH2)CF3.

66. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis C3-C9 cycloalkyl wherein the cycloalkyl is substituted with 0, 1, 2 or 3 instances of R4.

67. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis C3-C7monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), each substituted with 0, 1, 2 or 3 instances of R4.

68. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl and spiro[2.2]pentanyl, each substituted with 0, or 1 instance 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, tBu, -OCF3, -CF3and -CN.566IPTS / 200159134.1Docket No. TGO-030WO70. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof,wherein each RBis independently selected from the group consisting of71. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis C3-C7 monocyclic cycloalkyl substituted with 0, or 1 instance of R4.

72. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof,wherein each RBis independently selected from the group consisting of73. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis 4-10 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S or oxidized forms thereof, wherein the heterocyclyl is substituted with 0, 1, 2 or 3 instances of R4.

74. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein each RBis independently 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[3.2.1]octanyl, 8-oxabicyclo[3.2.1]oct-2-enyl, tetrahydropyranyl, 3,4-dihydro-2H-pyranyl, 2, 3 -dihydro- 1,4-dioxinyl and 3,6-dihydro-2H-pyranyl.

75. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof,wherein each RBis independently selected from the group consisting567IPTS / 200159134.1Docket No. TGO-030WOsubstituted with 0, 1, 2 or 3 instances of R4.

76. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof,77. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof, wherein RBis phenyl substituted with 0, 1 or 2 instances of R4.

78. The compound of claim 77, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from -F, -Cl and -Me.

79. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt thereof,80. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein the moiety represented asselected from the group consisting of568IPTS / 200159134.1Docket No. TGO-030WO569IPTS / 200159134.1Docket No. TGO-030WOIPTS / 200159134.1Docket No. TGO-030WO571IPTS / 200159134.1Docket No. TGO-030WO572IPTS / 200159134.1Docket No. TGO-030WO81. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof,wherein the moiety represented asselected from the group consisting of573IPTS / 200159134.1Docket No. TGO-030WO574IPTS / 200159134.1Docket No. TGO-030WO82. The compound of any one of claims 1-16, 21-22 and 27-81, or a pharmaceutically acceptable salt thereof, wherein each RA1is independently selected from the group consisting of-C1-C6 alkyl, (e.g., -Me, -Et, -Pr, -Pr, - ec-Bu, -T3u) and -Ci-Ce haloalkyl (e.g., -CF3, -CHF2, -CH2CF3).

83. The compound of any one of claims 1-17, 21-22 and 27-81, or a pharmaceutically acceptable salt thereof, wherein each RA2is independently selected from the group consisting of H, D, -C1-C6 alkyl, (e.g., -Me, -Et, -Pr, -Pr, - ec-Bu, -T3u) and -Ci-Ce haloalkyl (e.g, -CF3, -CHF2, -CH2CF3).

84. The compound of any one of claims 1-52 and 82-83, or a pharmaceutically acceptable salt thereof, wherein each RB1is independently selected from the group consisting of-C1-C6 alkyl, (e.g, -Me, -Et, -Pr, - Pr, - ec-Bu, -'Bu), -Ci-Ce haloalkyl (e.g., -CF3, -CHF2, -CH2CF3) and phenyl.

85. The compound of any one of claims 1-53 and 82-83, or a pharmaceutically acceptable salt thereof, wherein each RB2is independently selected from the group consisting of H, D, -C1-C6 alkyl, -Ci-Ce haloalkyl, 6-10 membered aryl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S and -(C1-C2 alkyl)(4-10 membered heterocyclyl).575IPTS / 200159134.1Docket No. TGO-030WO86. The compound of any one of claims 1-85 or a pharmaceutically acceptable salt thereof,wherein the moiety represented87. The compound of any one of claims 1-85 or a pharmaceutically acceptable salt thereof,wherein the moiety represented88. The compound of any one of claims 1-87 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds of Table 1.

89. A pharmaceutical composition comprising a compound of any one of claims 1-88 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

90. The pharmaceutical composition of claim 89, further comprising a second therapeutic agent.

91. An HBSIL-inactivating compound (e.g., an HBS1L degrader) for use in a method of treating an HBSIL-sensitive cancer in a subject in need thereof by administering to the subject an effective amount (e.g., a therapeutically effective amount) of the HBSIL-inactivating compound (e.g., an HBS1L degrader).

92. A compound of any one of claims 1-88, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 89, for use in treating an HBSIL-sensitive cancer in a subject in need thereof.

93. A pharmaceutical composition of claim 90 for use in treating an HBSIL-sensitive cancer in a subject in need thereof94. A compound or pharmaceutical composition for use according to any one of claims 91-93, wherein the cancer is a FOCAD-defi cient cancer.

95. A compound or pharmaceutical composition for use according to claim 94, wherein the FOCAD-deficient cancer is a FOCAD-deleted cancer.576IPTS / 200159134.1Docket No. TGO-030WO96. A compound or pharmaceutical composition for use according to any one of claims 91-95, wherein the cancer is deficient in one or more of TTC37, AVEN, WDR61 and SKIV2L.

97. A compound or pharmaceutical composition for use according to any one of claims 91-93, wherein the cancer is PELO-dependent.

98. A compound or pharmaceutical composition for use according to any one of claims 91-97, wherein the compound, or pharmaceutically acceptable salt thereof, or composition is for use in combination with a second therapeutic agent.

99. A compound or pharmaceutical composition for use according to claim 98, wherein the second therapeutic agent is a PRMT5 inhibitor (e.g., an MTA-cooperative PRMT5 inhibitor).

100. A compound or pharmaceutical composition for use according to claim 98, wherein the second therapeutic agent is a MAT2A inhibitor.

101. A compound or pharmaceutical composition for use according to any one of claims 91- 100, wherein the cancer has previously been treated with a PRMT5 inhibitor.

102. A compound or pharmaceutical composition for use according to any one of claims 91- 101, wherein 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), 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 hepatocellular carcinoma, 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.577IPTS / 200159134.1Docket No. TGO-030WO103. A compound of any one of claims 1-88, or a pharmaceutically acceptable salt thereof, or composition of claim 89 or 90, for use in treating a cancer in a subject in need thereof, wherein:a) the level of FOC D 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) the subject has been identified as having FOCAD deficiency according to the comparison in the preceding paragraph.578IPTS / 200159134.1

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