Somatostatin receptor antagonist compounds and methods of using the same

Abstract

The present invention is directed to somatostatin receptor antagonist compounds having the structure of Formula I: RN I R11 NH *1 R9 O N R10 N *3 R3 *2 R8 L O o N NRR11 RO *7 O*8 N R6 R4 R15 ,N *5 N*6 N R13 n° R5 Formula I, , compositions comprising the same, and methods of using such compounds and compositions. The compounds may be useful in the prevention or treatment of hypoglycemia. 20 24 21 96 10 11 S ep 2 02 4 S O M A T O S T A T I N R E C E P T O R A N T A G O N I S T C O M P O U N D S A N D M E T H O D S O F U S I N G T H E S A M E A B S T R A C T 2 0 2 4 2 1 9 6 1 0 1 1 S e p 2 0 2 4 R N N H R O N N * 2 R ³ L O R O O * 7 N R O * 4 R 4 O N * 5 N R 1 2 O 1 3 R

Description

2024219610   11 Sep 2024 CROSS REFERENCE TO RELATED APPLICATION This application is a divisional of Australian Patent Application No. 2023201653, the entire 5 contents of which are incorporated herein by reference. TECHNICAL FIELD This invention relates to compounds that are somatostatin receptor antagonists. More particularly, this invention relates to cyclic peptides and more particularly to cyclic octapeptides that are somatostatin receptor antagonists. 0 BACKGROUND Somatostatin receptors are ubiquitously expressed in most tissues of the body. Five different subtypes of somatostatin receptors have been discovered. The localization of particular receptor subtypes on different tissues allows for specific receptor antagonists to exert specific inhibitory effects. 15            In a series of structure activity relationship (SAR) studies of the 14 amino acid version of somatostatin (SST-14) and its analogs (Freidinger, R.M., et al., International journal of peptide and protein research 23(2):142-50, 1984; Pattaroni, C., et al., International journal of peptide and protein research 36(5):401-17, 1990; Veber, D.F., et al., Life sciences 34(14):1371-8, 1984), the four amino acid sequence Phe7-Trp8-Lys9-Thr10 (residues 7-10 of SST-14) was reported to be important 20 for binding and activity of somatostatin. While Trp8-Lys9 appears essential, slight modifications in positions 7 and 10 were reportedly possible (Patel, Y.C., Frontiers in neuroendocrinology 20(3):157-98, 1999). Furthermore, cyclization (via the Cys-Cys pair at positions 3 and 14) apparently stabilizes the conformation of these residues, mimicking a P-turn, in a manner favorable for binding to SST receptors (Veber, D.F., et al., Life sciences 34(14):1371-8, 1984; Veber, D.F., et al., Nature 25   280(5722):512-4, 1979). Following these findings, several agonist analogs of somatostatin have been produced over the past several decades and several agonists have been used clinically to treat glandular tumors. Octreotide (Novartis) and lanreotide (Ipsen) are indicated for the treatment of acromegaly (somatotrophic adenoma) and thyrotrophic adenoma and in the management of certain neuroendocrine tumors in the pancreas (e.g., carcinoid tumors). A newer agonist, 30 pasireotide (Novartis), is also used clinically for the treatment of Cushing’s Disease (corticotropic adenoma) (Boscaro, M., et al., The Journal of clinical endocrinology and metabolism 94(1):115-22, 2009), (see www.signifor.com). Bass et al. (at American Cyanamid) (Bass, R.T., et al., Molecular pharmacology 50(4):709-15, 1996) reported that substitution of D-cysteine at the position 2024219610   11 Sep 2024 equivalent to residue 3 of SST-14 gave analogs with antagonist activity. Since then, antagonists that bind to the various SST receptor subtypes with different affinities have been developed. One approach to reducing hypoglycemia is to inhibit somatostatin receptors related to counterregulatory hormone release which are found in the pancreas, adrenal gland, and 5 hypothalamus of the brain. Somatostatin receptor type 2 (SSTR2) are found in these tissues. Within the pancreas, SSTR2 are found nearly exclusively on glucagon-secreting a-cells in rodents (Rossowski, W. and Coy, D., Biochemical and Biophysical Research Communications 205:341-346, 1994; Strowski, M., et al., Endocrinology 141:111-117, 2000). In humans as well, somatostatin exerts its inhibitory effect on glucagon secretion via SSTR2 found on a-cells (Kumar, U., et al., 0 Diabetes 48:77-85, 1999; Reubi, J., et al., J. Clin. Endocrinol. Metab. 83:3746-3749, 1998), while the receptor is also expressed in the p cells (Reubi, J., et al., J. Clin. Endocrinol. Metab. 83:3746-3749, 1998), where it is involved in regulating insulin secretion. In the adrenal gland, SSTR2 have been widely identified in the adrenal medulla of animals and humans (Kimura, N., et al., Endocrine Journal 48:95-102, 2001; Maurer, R. and Reubi, J., Molecular and Cellular Endocrinology 45:81-90, 15    1986). It has been shown that somatostatin inhibits acetylcholine-stimulated release of epinephrine from the adrenal medulla (Role, L., et al., Neuroscience 6:1813-1821, 1981; Mizobe, F., et al., Brain Research 178:555-566, 1979), and this is the mechanism whereby epinephrine is released during hypoglycemia (Havel P. and Taborsky, G. J., Stress-induced activation of the neuroendocrine system and its effects on carbohydrate metabolism. In Ellenberg and Rifkin's Diabetes Mellitus. Porte Jr D, 20 Sherwin R, Baron A, Eds. New York, McGraw-Hill, 2003, p. 127-149). SSTR2 are also found in the hypothalamus of the brain (Fehlmann D., et al., Journal of Physiology (Paris) 94:265-281, 2000; Lanneau C., et al., European Journal of Neuroscience 10:204-212, 1998) where somatostatin also has an inhibitory effect on hormones involved in hypoglycemic counterregulation. The approach of using SSTR2 antagonism to prevent hypoglycemia has been demonstrated 25 in the STZ rat model, in which the glucagon response to hypoglycemia, which is absent in diabetic rats can be restored by administration of a SSTR2 antagonist (Yue J.T., et al., Diabetes 61(1):197-207, 2012). In this experiment, not only was the glucagon response restored, but the corticosterone response which was also deficient in diabetic rats was also improved in hypoglycemia after treatment with a SSTR2 antagonist. Furthermore, restoration of the 30 counterregulatory responses corresponds to prevention or reduction in the severity of hypoglycemia in similar rats given an insulin dose to induce hypoglycemia (Yue J.T., et al., Diabetes 62(7):2215-2222, 2013). Somatostatin levels in the pancreas in diabetic animals are elevated (Rastogi, K., et al., Endocrinology 126:1096-1104, 1990; Rastogi, K., et al., Canadian Journal of Physiology and 2024219610   11 Sep 2024 Pharmacology 71:512-517, 1993) as well as in diabetic humans (Orci, L., et al., Proceedings of the National Academy of Sciences U.S.A 73:1338-1342, 1976). In streptozotocin (STZ)-diabetic rats, there is: (i) hyperplasia and hypertrophy of somatostatin-containing 6-cells in the pancreas (Orci, L., et al., Proceedings of the National Academy of Sciences U.S.A 73:1338-1342, 1976); (ii) increased 5 expression of pancreatic prosomatostatin mRNA (Brubaker, P., et al., Endocrinology 124:3003-3009, 1989; Shi, Z., et al., Endocrinology 137:3193-3199, 1996); (iii) increased pancreatic somatostatin (Inouye, K., et al., American Journal of Physiology Endocrinology and Metabolism 282:E1369-E1379, 2002); and (iv) distribution of somatostatin-secreting 6-cells in the central portions of islets cells (Rossowski, W. and Coy, D., Biochemical and Biophysical Research Communications 205:341-346, 0   1994). It has been reported that excessive somatostatin may inhibit glucagon release during hypoglycemia (Rastogi, K., et al., Endocrinology 126:1096-1104, 1990). Furthermore, it is well documented that somatostatin inhibits stimulated secretion of pancreatic glucagon. In STZ-diabetic rats, the expression of the gene for pro-glucagon and pro-somatostatin are both markedly increased (Inouye, K., et al., American Journal of Physiology Endocrinology and Metabolism 15   282:E1369-E1379, 2002). This increased concentration of somatostatin is observed in diabetic rats, both during euglycemia (i.e. normal blood glucose concentrations) and hypoglycemia (Shi, Z., et al., Endocrinology 137:3193-3199, 1996). Concentration of somatostatin in plasma is also increased during euglycemia and hypoglycemia in diabetic rats (Shi, Z., et al., Endocrinology 137:3193-3199, 1996). However, despite increased gene expression of proglucagon, plasma concentrations of 20 glucagon are not increased during hypoglycemia in diabetic rats, presumably in part due to the marked elevation of somatostatin levels. In isolated islets and in perifused isolated islets, the somatostatin receptor type 2 (SSTR2)-selective antagonist, DC-41-33, also known as PRL-2903, dose-dependently increases glucagon secretion to an arginine stimulus, and subsequently adding somatostatin dose-dependently 25 reverses the actions of the SSTR2 antagonist (Cejvan, K., et al., Diabetes 51 Suppl 3:S381-S384, 2002; Cejvan, K., et al., Diabetes 52:1176-1181, 2003). In isolated, perfused pancreas of non-diabetic rats, this antagonist enhances glucagon secretion without affecting insulin secretion (Cejvan, K., et al., Diabetes 52:1176-1181, 2003). Similar findings have been demonstrated in rat and human pancreatic tissue slices, prefused in 30 hypoglycemic condition with and without SSTR2 antagonist (Karimian N., et al., Diabetes 62(8):2968-2977, 2013). It is also able to reverse the inhibitory effect of glucose-dependent insulinotropic polypeptides, GIP and GIP-(1-30)NH?, and glucagon-like polypeptide, GLP-1(7-36)NH?, on pentagastrin-stimulated gastric acid secretion in non-diabetic rats (Rossowski, W., et al., British Journal of Pharmacology 125:1081-1087, 1998). Somatostatin receptor antagonists are described 2024219610   11 Sep 2024 in U.S. Pat. No. 4,508,711 (April 1985, Coy et al.) and in U.S. Pat. No. 5,846,934 (December 1998, Bass et al.) (Hocart, S.J., et al., Journal of medicinal chemistry 42(11):1863-71, 1999; Rajeswaran, W.G., et al., Journal of medicinal chemistry 44(8):1305-11, 2001). The primary pharmacological treatments for hypoglycemia on the market today are based 5 on various IV glucose or dextrose formulations and, as such, are considered reactionary treatments rather than true management strategies. There are a number of glucagon products on the market (e.g., GlucaGen®, Novo Nordisk), however this too is a rescue approach and is typically administered IV or SC in emergencies because the patient is unconscious. Importantly, glucagon must also be carefully dosed to avoid overstimulating glucose production (unlike a normalized endogenous 0 glucagon response). These therapies are not directed to reducing the incidence of hypoglycemia, and as rescue therapies for severe hypoglycemia, they would not be expected to reduce the apprehension patients feel about the likelihood of experiencing a hypoglycemic event. Preventive therapies are required to reduce or eliminate this complication, and to enable insulin-dependent diabetic patients to more aggressively manage their blood glucose levels, resulting in overall 15 improved long-term health outcomes. There is thus a real and strong demand for the development of a long-term therapeutic approach for the prevention of hypoglycemia. SUMMARY This invention is based, in part, on novel cyclic peptides that exhibit somatostatin receptor (SSTR) antagonist activity. Cyclic peptides of the present invention are often selective for a 20 particular SSTR, such as SSTR 2. This invention is also based, in part, on novel amino acids that can be used in cyclic peptides of the present invention. In illustrative embodiments of the present invention, there is provided a compound having the structure of Formula I: Formula I 25 or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl optionally substituted with one or more substituents; RN is selected from the group consisting of: 2024219610   11 Sep 2024 (i)        H; (ii)       C1-6 alkyl; (iii)     -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, 5           and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (iv)    -C(O)C1-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl optionally substituted with one or more substituents; 0            (v)     -C(O)C1-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents, and wherein R20 is H or C1-6 alkyl; 15            (vi)    -C(O)C1-6 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 20            (vii)    -C(O)C1-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 25            (viii)   -C(O)C1-6 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents; and (ix)     -S(O)2R26, wherein R26 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 30           and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R1 is selected from the group consisting of C1-6alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the Ce-10 aryl of -Ci-6alkylene(C6-io aryl), the 5- to 10-membered heteroaryl and the 5- to 10membered heteroaryl of -Ci-ealkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-e alkylene of -Ci-6alkylene(Ce-io aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents; 5    R3 is selected from the group consisting of: 2024219610   11 Sep 2024 (i)      C6-10 aryl which is optionally substituted with one or more substituents; (ii)     5- to 10-membered heteroaryl which is optionally substituted with one or more substituents; (iii)     -Ci-6alkylene(Ce-io aryl), wherein the Ce-10 aryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; (iv)    -Ci-ealkylene(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents, and wherein the C1-e alkylene is optionally substituted with one or more substituents; 15 (v) -C1-6 alkylene-NR27C(O)R28, wherein: R27 is H or C1-e alkyl; R28 is selected from the group consisting of C1-e alkyl, Ce-10 aryl, 5- to 10-membered heteroaryl, and -NR29R30, wherein the C1-e alkyl is optionally substituted with one or more substituents, and wherein the Ce-10 aryl and 5- to 10-membered heteroaryl are 20 25 30 optionally substituted with one or more substituents; and wherein each of R29 and R30 is independently selected from the group consisting of H, C1-e alkyl, Ce-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-e alkyl is optionally substituted with one or more substituents, and wherein the Ce-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vi)    —(Ce-10 arylene)-C(O)NR31R32 or -C1-e alkylene-(Ce-10 arylene)-C(O)NR31R32, wherein each of R31 and R32 is independently selected from the group consisting of H, C1-e alkyl, Ce-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-e alkyl is optionally substituted with one or more substituents, and wherein the Ce-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vii)    —(Ce-10 arylene)-NR33R34 or -C1-e alkylene-(Ce-10 arylene)-NR33R34, wherein: each of R33 and R34 is independently selected from the group consisting of H, C1-e alkyl, Ce-10 aryl, 5- to 10-membered heteroaryl, -C(O)R35, -C(O)NR3eR37, and -SO2R38, wherein the C1-e alkyl is optionally substituted with one or more substituents, and 2024219610   11 Sep 2024 15 20 25 30 wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R35 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5-to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents; each of R36 and R37 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and R38 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-SO2NR39R40 or -C1-6 alkylene-(C6—io arylene)-SO2NR39R40, wherein each of R39 and R40 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-(Ci—6 alkylene)-NR41R42 or -C1-6 alkylene-(C6—io arylene)-(Ci-6 alkylene)-NR41R42, wherein: each of R41 and R42 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R43, and -C(O)NR44R45, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R43 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R44 and R45 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is 2024219610   11 Sep 2024 optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)    —(C6-10 arylene)-OR46 or -C1-6 alkylene-(C6—io arylene)-OR46, wherein R46 is selected 5           from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and (xi)    -C1-6 alkylene-(C6-10 arylene)-N(R47)-C(O)-CHR48-NR49R50, wherein R47 is H or CH3, 0            R48 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R49 and R50 is independently H, CH3 or acetyl; R4is selected from the group consisting of: (i)     -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently 15           selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R53 is H or C1-6 alkyl; (ii)    -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is selected from the group consisting of C1- 20           6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents, and wherein R55 is H or C1-6 alkyl; (iii)     -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR56R57, wherein 25            each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (iv)     -(C6-10 arylene)-N(R59)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, 30            wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, and wherein R59 is H or C1-6 alkyl; 2024219610   11 Sep 2024 15 20 25 30 (v)     -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6—io arylene)- N(R62)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R62 is H or C1-6 alkyl; (vi)     -(C6-10 arylene)-N(R64)SO2R63 or -C1-6 alkylene-(C6-10 arylene)-N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R64 is H or C1-6 alkyl; (vii)    -(C6-10 arylene)-SO2NR65R66 or -C1-6 alkylene-(C6-10 arylene)-SO2NR65R66, wherein each of R65 and R66 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-NR72R73 or -C1-6 alkylene-(C6-10 arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or 2024219610   11 Sep 2024 more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)     —(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6—io arylene)-OR74, wherein R74 is selected 5           from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (xi)    -C1-6 alkylene-(C6—io arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 is H or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl; and (xii)    -C1-6 alkylene-(C6-10 arylene)-CN; R5 is selected from the group consisting of: 15           (i)     -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, or R79 and R80, together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered 20           heterocycloalkyl are optionally substituted with one or more substituents, R81 is selected from the group consisting of H, -NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and each of R82, R83, and R84 is independently selected from the group consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and 25            (ii)     -N+R85R86R87, wherein each of R85, R86, and R87 is independently C1-6 alkyl; n1 is 1, 2, 3, 4, 5, or 6; R6 is C1-6 alkyl optionally substituted with one or more substituents; R8is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6 alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10 30 membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents; R9 is H or C1-6 alkyl; R10 is H or C1-6 alkyl; R11 is H or C1-6 alkyl; R12 is H or C1-6 alkyl; R13 is H or C1-6 alkyl; R14 is H or C1-6 alkyl; R15 is H or C1-6 alkyl; and L is selected from the group consisting of: i) *          5 2024219610   11 Sep 2024 0                                  X I ; ii) «        s iii)           H ; iv)             ; v)             ; vi)        H , wherein X is S or O; and vii)     N=N ; chiral centre *1 is in the S configuration or the R configuration; chiral centre *2 is in the S configuration or the R configuration; chiral centre *3 is in the S configuration or the R configuration; chiral centre *4 is in the S configuration or the R configuration; chiral centre *5 is in the S configuration or the R configuration; chiral centre *6 is in the S configuration or the R configuration; chiral centre *7 is in the S configuration or the R configuration; and chiral centre *8 is in the S configuration or the R configuration, provided that: ..         . _r. _M.        _____ . bcH2 / \ / Vci ^-ch2< / Vno2 i)       when RC is NH2, RN is H or -C(O)CH2N3, R1 is                 or       ?         , R3 is 10 or R5 is NH2, n1 is 4, R6 is -CH(OH)(CH3), R8 is or , each of R9, R10, R11, R12, R13, R14 and R15 is .    I—S-S—£ .     . bcH2^ VnHC(O)NH2 , H, and L is «          ,, then R4 is not                      ; and ...        .               _M .       . ^-CH2<            . i-CH2< VOH _c.        ,.    _c. ii)       when RC is NH2, RN is H, R1 is                 , R3 is                  , R5 is NH2, n1 is 4, R6 is -CH(CH3)2, R8 is -CH(OH)(CH3), each of R9, R10, R11, R12, R13, R14 and R15 is H, and L is —s-s—t then . bcH-X ) OH 15     R4 is not                 . In illustrative embodiments of the present invention, a compound as defined anywhere herein or a pharmaceutically acceptable salt thereof may be for use in the prevention or treatment of hypoglycemia. In illustrative embodiments of the present invention, the hypoglycemia may be insulin-induced hypoglycemia. In illustrative embodiments of the present invention, a compound as 20 defined anywhere herein or a pharmaceutically acceptable salt thereof may be for use in the treatment of diabetes. In illustrative embodiments of the present invention, there is provided a pharmaceutical composition comprising a compound as defined anywhere herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In illustrative embodiments of the present 25 invention, the pharmaceutical composition may be for use in the prevention or treatment of hypoglycemia. In illustrative embodiments of the present invention, the hypoglycemia may be 2024219610   11 Sep 2024 insulin-induced hypoglycemia. In illustrative embodiments of the present invention, the pharmaceutical composition may be for use in the treatment of diabetes. In illustrative embodiments of the present invention, there is provided a method of inhibiting an activity of an SSTR2 receptor in a subject, the method comprising administering a 5 compound as defined anywhere herein or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In illustrative embodiments of the present invention, there is provided a method of preventing or treating hypoglycemia in a subject, the method comprising administering a compound as defined anywhere herein or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In illustrative embodiments of the present invention, the hypoglycemia is insulin- 0 induced hypoglycemia. In illustrative embodiments of the present invention, there is provided a method of treating diabetes in a subject, the method comprising administering a compound as defined anywhere herein or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In illustrative embodiments of the present invention, there is provided a use of a compound 15 as defined anywhere herein or a pharmaceutically acceptable salt thereof for the prevention or treatment of hypoglycemia. In illustrative embodiments of the present invention, the hypoglycemia is insulin-induced hypoglycemia. In illustrative embodiments of the present invention, there is provided a use of a compound as defined anywhere herein or a pharmaceutically acceptable salt thereof in the treatment of 20 diabetes. In illustrative embodiments of the present invention, there is provided a use of a compound as defined anywhere herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of hypoglycemia. In illustrative embodiments of the present invention, the hypoglycemia is insulin-induced hypoglycemia. In illustrative embodiments of the present invention, there is provided a use of a compound as 25 defined anywhere herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diabetes. In illustrative embodiments of the present invention, there is provided an amino acid selected from the group consisting of: 2024219610   11 Sep 2024 2024219610   11 Sep 2024 o                   ,       0                   ,       0                      , and Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention. 10 15 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic of the study design indicating when animals were made diabetic with STZ injection (week 0) followed by insulin pellet implantation (week 1) to control diabetes, then the subsequent hypoglycemic challenges (weeks 2 and 3). Figures 2A and 2B show a detailed procedure for the hypoglycemic challenges (Figure 2A -Hypoglycemia Challenge #1; Figure 2B - Hypoglycemia Challenge #2) and the timing of measurements and sample collections. Figure 3 is a graph showing blood glucose (BG) values measured over time in STZ diabetic Sprague Dawley rats treated with either vehicle control, Compound 4, or Compound 24 in Hypoglycemic Challenge #1. The inset graph provides measures of the extent of hypoglycemia of the animals from the BG vs time curves as represented by the area under the curve (AUC) for the blood glucose values over time. 2024219610   11 Sep 2024 Figure 4 is a graph showing the time to onset of hypoglycemia of the STZ diabetic Sprague Dawley rats treated with either vehicle control, Compound 4, or Compound 24 in Hypoglycemia Challenge #1. Figure 5 is a graph showing the data from Figure 3, presented as a survival curve, indicating 5 the proportion of rats from each group that were in hypoglycemia (defined as the BG threshold of 3.9 mM) as a function of time. Figure 6 is a graph showing the data from Figure 3, presented as a survival curve, indicating the proportion of rats from each group that were in severe hypoglycemia (defined as the BG threshold of 1.9 mM) as a function of time. 0          Figures 7A and 7B are graphs showing the response of glucagon to hypoglycemia in STZ diabetic Sprague Dawley rats treated with either vehicle control, Compound 4, or Compound 24 in Hypoglycemia Challenge # 1. Figure 8 is a graph showing portal blood glucagon concentrations at hypoglycemia in STZ diabetic Sprague Dawley rats treated with either vehicle control, Compound 4, or Compound 24 15 during Hypoglycemia Challenge #2. DETAILED DESCRIPTION As used herein, “optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not. 20           If an item is described as being “independently selected” from a group, each item is selected independent of the other(s). Each item therefore may be the same as or different from the other item(s). As used herein, the term “substituted,” refers to a group wherein a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon or nitrogen of the group. For example, a 25 substituted alkyl is an alkyl group wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. Non-limiting examples of substituents include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 30 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. A group may be substituted with one or more than one substituent provided that the normal valency of the group is not exceeded, and that the substitution results in a stable compound. For 2024219610   11 Sep 2024 example, if a methyl group (i.e., CH3) is substituted, then 1, 2 or 3 hydrogen atoms on the carbon atom may be replaced with substituents. Where a substituent is attached via a double bond, such as an oxo (=O) substituent, the substituent occupies two available valences, so the total number of other substituents that may be included is reduced by two. If a group is described as being substituted with 5 up to a particular number of substituents, that group may be substituted by up to that particular number of substituents provided that the normal valency of the group is not exceeded, and that the substitution results in a stable compound. Thus, for example, if a group is described as a heteroaryl substituted with up to 3 substituents, then any heteroaryl with less than 3 substitutable positions would be substituted by up to only as many substituents as the heteroaryl has substitutable positions. 0 For example, tetrazolyl (which has only one substitutable position) would be substituted with up to one substituent. As a further example, if an amino nitrogen is described as being substituted with up to 2 substituents, then the nitrogen will be substituted with up to 2 substituents if the amino nitrogen is a primary nitrogen, whereas the amino nitrogen will be substituted with up to only 1 substituent if the amino nitrogen is a secondary nitrogen. If there is more than one substitution on a group, each 15 substituent may be the same or different, unless otherwise stated. As used herein, unless specified, the point of attachment of a substituent can be from any suitable position of the substituent. For example, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl). When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then 20 such substituent may be bonded to any of the ring-forming atoms in that ring that are substitutable, unless otherwise specified or otherwise implicit from the context. As used herein, the terms “optionally substituted” and “substituted or unsubstituted” may be used interchangeably to indicate that the particular group being described may have no nonhydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen 25 substituents (i.e., substituted). If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other(s). Each substituent therefore may be the same as or different from the other substituent(s). As used herein, the term “halo” or “halogen,” by itself or as part of another group or 30 substituent, refers to fluorine, chlorine, bromine, or iodine. Fluorine may also be depicted as F, -F or fluoro. Chlorine may also be depicted as Cl, -Cl or chloro. Bromine may also be depicted as Br, -Br or bromo. Iodine may also be depicted as I, -I or iodo. As used herein, the term “alkyl,” by itself or as part of another group or substituent, refers to a saturated, monovalent aliphatic hydrocarbon radical (i.e., a radical obtained from a hydrocarbon 2024219610   11 Sep 2024 by removal of a hydrogen) having a specified number of carbon atoms. Alkyl includes hydrocarbon radicals having straight or branched chains. The term “Cx-y alkyl” refers to an alkyl group comprising a number from x to y (with all individual integers within the range included, including integers x and y) of carbon atoms in its carbon skeleton. For example, a “C1-6 alkyl” refers to an alkyl group 5 comprising 1, 2, 3, 4, 5, or 6 carbon atom(s) in its carbon skeleton. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, n-hexyl, and 2,3-dimethylbutyl. Alkyl groups may be optionally substituted. Alkyl groups described herein as optionally 0 substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for alkyl groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 15 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Alkyl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). As used herein, the term “alkylene,” by itself or as part of another group or substituent, refers 20 to a saturated, divalent aliphatic hydrocarbon group which can link two other groups together. Alkylene includes hydrocarbon groups having straight or branched chains. The open valences of an alkylene need not be at opposite ends of the chain. The term “Cx-y alkylene” refers to an alkylene group comprising a number from x to y (with all individual integers within the range included, including integers x and y) of carbon atoms in its carbon skeleton. For example, a “C1-6 alkylene” refers 25 to an alkylene group comprising 1, 2, 3, 4, 5, or 6 carbon atom(s) in its carbon skeleton. Non-limiting examples of alkylene include methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), -CH(Me)-, and -C(Me)2-. Alkylene may also be depicted as -(CH2)n- wherein n is 1, 2, 3, 4, 5, or 6, or -(CR'R")n'- wherein R' and R" are H or C1-6 alkyl and n' is 1, 2, 3, 4, 5, or 6. 30           Alkylene groups may be optionally substituted. Alkylene groups described herein as optionally substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for alkylene groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered 2024219610   11 Sep 2024 heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, — NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Alkylene groups 5 may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituent(s). As used herein, the term “alkoxy,” by itself or as part of another group or substituent, refers to an alkyl group that is single bonded to an oxygen atom. The point of attachment of an alkoxy group to the base molecule is through the oxygen atom. An alkoxy group may be depicted as -O-alkyl. The alkoxy group may contain a straight or branched chain. The term “Cx-y alkoxy” refers to an alkoxy 0 group comprising from x to y (with all individual integers within the range included, including integers x and y) of carbon atoms. For example, the term “C1-6 alkoxy” refers to an alkoxy group comprising 1, 2, 3, 4, 5, or 6 carbon atom(s). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and hexyloxy. As used herein, the term “aryl,” by itself or as part of another group or substituent, refers to 15 a monocyclic ring or a fused bicyclic or polycyclic ring system, wherein the monocyclic ring contains a conjugated pi-electron system or at least one ring of the fused ring system contains: (i) a conjugated pi-electron system; and (ii) a ring-forming carbon atom that is the point of attachment to the base molecule. A ring-forming carbon atom of a monocyclic ring may not be replaced by a ring-forming heteroatom. A ring-forming carbon atom of a fused ring system may be replaced by a ring-forming 20 heteroatom selected from N, O and S; however, if a fused ring system contains any ring-forming heteroatoms, the ring-forming heteroatoms are not contained in the ring that contains the ringforming carbon atom that is the point of attachment to the base molecule. The monocyclic ring or fused ring system may contain from 6 to 14 ring-forming atoms, where ring-forming atom includes both ring-forming carbon atoms and heteroatoms. The term “Cx-y aryl” refers to a monocyclic ring or 25 fused ring system comprising a number from x to y (with all individual integers within the range included, including integers x and y) of ring-forming atoms. For example, a “C6-10 aryl” refers to a monocyclic ring or fused ring system comprising 6, 7, 8, 9 or 10 ring-forming atoms. As a further example, where an aryl group contains any ring-forming heteroatoms, “C6-10 aryl” refers to a fused ring system comprising 6, 7, 8, 9 or 10 ring-forming atoms, where ring-forming atom includes both 30 ring-forming carbon atoms and heteroatoms. Fused bicyclic or polycyclic ring systems include a fused ring system comprising an aromatic ring fused to: (i) one or more aromatic rings; ii) one or more nonaromatic cycloalkyl rings; (iii) one or more non-aromatic heterocycloalkyl rings; (iv) one or more heteroaromatic rings; or (v) any combination or subcombination of (i), (ii), (iii), and (iv). The point of attachment to the base molecule on an aryl group is a ring-forming carbon atom. For greater clarity, 2024219610   11 Sep 2024 where an aryl group is a fused ring system, the point of attachment to the base molecule on the fused ring system is a ring-forming carbon atom of an aromatic ring of the fused ring system, wherein the aromatic ring does not contain any ring-forming heteroatoms. Non-limiting examples of aryl groups include phenyl, naphthyl, anthracyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. 5           Aryl groups may be optionally substituted. Aryl groups described herein as optionally substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for aryl groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 0 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Aryl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). 15           As used herein, the term “arylene,” by itself or as part of another group or substituent, refers to a divalent form of an aryl group as defined herein. Arylene groups may be optionally substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for arylene groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 20 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Arylene groups may be substituted by 1, 2, 3, 4, 5, 25    6, 7, 8, 9, or 10 substituent(s). As used herein, the term “heteroaryl,” by itself or as part of another group or substituent, refers to a monocyclic ring or a fused bicyclic or polycyclic ring system, wherein the monocyclic ring contains a conjugated pi-electron system and at least one ring-forming heteroatom selected from N, O and S, or at least one ring of the fused ring system contains: (i) a conjugated pi-electron system; (ii) 30 at least one ring-forming heteroatom selected from N, O and S; and (iii) a ring-forming atom that is the point of attachment to the base molecule. The monocyclic ring or fused ring system may contain from 1, 2, 3, 4, 5, or 6 ring-forming heteroatom(s) selected from N, O and S. The monocyclic ring or fused ring system may contain from 5 to 14 ring-forming atoms, where ring-forming atom includes both ring-forming carbon atoms and heteroatoms. The term “x- to y-membered heteroaryl” refers to 2024219610   11 Sep 2024 a monocyclic ring or a fused ring system comprising a number from x to y (with all individual integers within the range included, including integers x and y) of ring-forming atoms. For example, a “5- to 10membered heteroaryl” refers to a monocyclic ring or a fused ring system comprising 5, 6, 7, 8, 9 or 10 ring-forming atoms. Fused bicyclic or polycyclic ring systems include a fused ring system 5 comprising a heteroaromatic ring fused to: (i) one or more heteroaromatic rings; (ii) one or more aromatic rings; (iii) one or more non-aromatic cycloalkyl rings; (iv) one or more non-aromatic heterocycloalkyl rings; or (v) any combination or subcombination of (i), (ii), (iii), (iv) and (v). The point of attachment to the base molecule on a heteroaryl group is a ring-forming atom. For greater clarity, where a heteroaryl group is a fused ring system, the point of attachment to the base molecule on the 0 fused ring system is a ring-forming atom of a heteroaromatic ring of the fused ring system. Nonlimiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, 15 benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl,  pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,  pyrrolo[3,2-c]pyridinyl,  pyrrolo[3,2-b]pyridinyl,  imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,  pyrazolo[4,3-d]pyidinyl,  pyrazolo[4,3-c]pyidinyl,  pyrazolo[3,4-c]pyidinyl, pyrazolo[3,4-b]pyidinyl, isoindolyl, indazolyl, purinyl, indolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1-2,b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, 20 isoquinolinyl, cinnolinyl, azaquinazoline, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl,     pyrido[4,3-d]pyrimidinyl,     pyrido[3,4-d]pyrimidinyl,     pyrido[2,3- d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, and pyrimido[4,5-d]pyrimidinyl. 25           Heteroaryl groups may be optionally substituted. Heteroaryl groups described herein as optionally substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for heteroaryl groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered 30 heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Heteroaryl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). 2024219610   11 Sep 2024 As used herein, the term “cycloalkyl,” by itself or as part of another group or substituent, refers to a non-aromatic, saturated, monocyclic hydrocarbon ring or a spiro, bridged or fused bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring of the ring system: (i) is a nonaromatic hydrocarbon ring wherein all unfused ring-forming carbon atoms are saturated; and (ii) 5 contains a ring-forming carbon atom that is the point of attachment to the base molecule. A ringforming carbon atom of a ring system may be replaced by a ring-forming heteroatom selected from N, O and S; however, if a ring system contains any ring-forming heteroatoms, the ring-forming heteroatoms are not contained in the ring that contains the ring-forming carbon atom that is the point of attachment to the base molecule. The monocyclic ring or spiro, bridged or fused polycyclic 0 ring system contains from 5 to 14 ring-forming atoms, where ring-forming atom includes both ringforming carbon atoms and heteroatoms. The term “Cx-y cycloalkyl” refers to a monocyclic ring or spiro, bridged or fused polycyclic ring system comprising a number from x to y (with all individual integers within the range included, including integers x and y) of ring-forming atoms. For example, a “C5-10 cycloalkyl” refers to a monocyclic ring or spiro, bridged or fused polycyclic ring system 15 comprising 5, 6, 7, 8, 9, or 10 ring-forming atoms. As a further example, where a cycloalkyl group contains any ring-forming heteroatoms, “C5-10 cycloalkyl” refers to a monocyclic ring or spiro, bridged or fused polycyclic ring system comprising 5, 6, 7, 8, 9, or 10 ring-forming atoms, where ring-forming atom includes both ring-forming carbon atoms and heteroatoms. Fused bicyclic or polycyclic ring systems include a fused ring system comprising a non-aromatic cycloalkyl ring fused to: (i) one or 20 more non-aromatic cycloalkyl rings; (ii) one or more aromatic rings; (iii) one or more non-aromatic heterocycloalkyl rings; (iv) one or more heteroaromatic rings; or (v) any combination or subcombination of (i), (ii), (iii), and (iv). The point of attachment to the base molecule on a cycloalkyl group is a ring-forming carbon atom. For greater clarity, where a cycloalkyl group is a ring system, the point of attachment to the base molecule on the ring system is a ring-forming carbon atom of a non- 25 aromatic cycloalkyl ring of the fused ring system, wherein the non-aromatic cycloalkyl ring does not contain any ring-forming heteroatoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecanyl, octahydropentalenyl, octahydro-1 H-indenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[5.2.0]nonanyl, adamantanyl, and decahydronaphthalenyl. 30           Cycloalkyl groups may be optionally substituted. Cycloalkyl groups described herein as optionally substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for cycloalkyl groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered 2024219610   11 Sep 2024 heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, — NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Cycloalkyl groups 5 may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). As used herein, the term “heterocycloalkyl,” by itself or as part of another group or substituent, refers to a non-aromatic saturated monocyclic hydrocarbon ring or a spiro, bridged or fused bicyclic or polycyclic hydrocarbon ring system, wherein the monocyclic ring contains at least one ring-forming heteroatom selected from N, O and S, or at least one ring of the spiro, bridged or 0 fused ring system: (i) is a non-aromatic hydrocarbon ring wherein all unfused ring-forming atoms are saturated; (ii) contains at least one ring-forming heteroatom selected from N, O and S; and (iii) contains a ring-forming atom that is the point of attachment to the base molecule. The monocyclic ring or spiro, bridged or fused polycyclic ring system may contain from 1, 2, 3, 4, 5, or 6 ring-forming heteroatom(s) selected from N, O and S. The monocyclic ring or spiro, bridged or fused polycyclic ring 15 system may contain from 5 to 14 ring-forming atoms, where ring-forming atom includes both ringforming carbon atoms and heteroatoms. The term “x- to y-membered heterocycloalkyl” refers to a monocyclic ring or spiro, bridged or fused polycyclic ring system comprising a number from x to y (with all individual integers within the range included, including integers x and y) of ring-forming atoms. For example, a “5- to 10-membered heterocycloalkyl” refers to a monocyclic ring or spiro, 20 bridged or fused polycyclic ring system comprising 5 to 10 ring-forming atoms. Fused bicyclic or polycyclic ring systems include a fused ring system comprising a non-aromatic heterocycloalkyl ring fused to: (i) one or more non-aromatic cycloalkyl rings; (ii) one or more aromatic rings; (iii) one or more non-aromatic heterocycloalkyl rings; (iv) one or more heteroaromatic rings; or (v) any combination or subcombination of (i), (ii), (iii), and (iv). The point of attachment to the base molecule 25 on a heterocycloalkyl group is a ring-forming atom. For greater clarity, where a heterocycloalkyl group is a ring system, the point of attachment to the base molecule on the ring system is a ring-forming atom of a non-aromatic heterocycloalkyl ring of the fused ring system. Non-limiting examples of heterocycloalkyl groups include oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyI, tetrahydrothiopyranyI, 30 piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, and 1,4-diazepanyl. Heterocycloalkyl groups may be optionally substituted. Heterocycloalkyl groups described herein as optionally substituted may be substituted by one or more substituents, which are selected 2024219610   11 Sep 2024 independently unless otherwise indicated. Non-limiting examples of substituents for heterocycloalkyl groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, 5    -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, - NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. Heterocycloalkyl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). As used herein, the term “-alkylene(aryl)” refers to an aryl group, as defined herein, which is 0 attached to the base compound through an alkylene linker. The term “-C1-6 alkylene(C6-10 aryl)” refers to a C6-10 aryl group, as defined herein, which is attached to the base compound through a C1-6 alkylene linker. The aryl of the -alkylene(aryl) group may be optionally substituted. The aryl groups described herein as optionally substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for the 15 aryl groups or alkylene groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, - 20    SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. The aryl groups and alkylene groups may each be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). As used herein, the term “-alkylene(heteroaryl)” refers to a heteroaryl group, as defined herein, which is attached to the base compound through an alkylene linker. The term “-C1-6 25 alkylene(5- to 10-membered heteroaryl)” refers to a 5- to 10-membered heteroaryl group, as defined herein, which is attached to the base compound through a C1-6 alkylene linker. The heteroaryl of the -alkylene(heteroaryl) may be optionally substituted. The heteroaryl groups described herein as optionally substituted may be substituted by one or more substituents, which are selected independently unless otherwise indicated. Non-limiting examples of substituents for the heteroaryl 30 groups or alkylene groups include halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, oxo (=O), -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, - 2024219610   11 Sep 2024 SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. The heteroaryl groups and alkylene groups may each be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s). As used herein, the symbol “         ” indicates the point at which the displayed moiety is attached to the remainder of the molecule. This is sometimes referred to as a point of attachment. A point of attachment may also be denoted by a dash symbol “-”, for example, -Br. This invention is based, at least in part, on cyclic peptides that are somatostatin receptor (SSTR) antagonists. Cyclic peptides of the present invention are often selective for a particular SSTR, such as SSTR 2. Illustrative embodiments of the present invention include a compound having a structure of Formula II: 15 Formula II or a salt thereof, wherein: RC is OH or NH2; RN is H, CH3 or acetyl; R1 is selected from the group consisting of C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10 20 membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents; R3 is selected from the group consisting of: (i)      C6-10 aryl which is optionally substituted with one or more substituents; 25           (ii)     5- to 10-membered heteroaryl which is optionally substituted with one or more substituents; 2024219610   11 Sep 2024 15 20 25 30 (iii)     -Ci-6alkylene(C6-io aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; (iv)    -C1-6alkylene(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; (v)     -NR27C(O)R28 or -C1-6 alkylene-NR27C(O)R28, wherein: R27 is H or C1-6 alkyl; R28 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and -NR29R30, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and wherein each of R29 and R30 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vi)    -(C6-10 arylene)-C(O)NR31R32 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR31R32, wherein each of R31 and R32 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vii)    -(C6-10 arylene)-NR33R34 or -C1-6 alkylene-(C6-w arylene)-NR33R34, wherein: each of R33 and R34 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R35, -C(O)NR36R37, and -SO2R38, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R35 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5-to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents; 2024219610   11 Sep 2024 15 20 25 30 each of R36 and R37 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and R38 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-SO2NR39R40 or -C1-6 alkylene-(C6—io arylene)-SO2NR39R40, wherein each of R39 and R40 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-(Ci—6 alkylene)-NR41R42 or -C1-6 alkylene-(C6—io arylene)-(Ci-6 alkylene)-NR41R42, wherein: each of R41 and R42 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R43, and -C(O)NR44R45, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R43 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R44 and R45 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)     -(C6-10 arylene)-OR46 or -C1-6 alkylene-(C6-10 arylene)-OR46, wherein R46 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein 2024219610   11 Sep 2024 the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and (xi)    -C1-6 alkylene-(C6—io arylene)-N(R47)-C(O)-CHR48-NR49R50, wherein R47 is H or CH3, R48 is H or C1-6 alkyl optionally substituted with one or more substituents each 5          independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R49 and R50 is independently H, CH3 or acetyl; R4is selected from the group consisting of: (i)     -N(R53)C(O)NR51R52 or -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 100           membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R53 is H or C1-6 alkyl; (ii) -N(R55)C(O)R54 or -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 15            alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R55 is H or C1-6 alkyl; (iii)     -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR56R57, wherein each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 20           aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (iv)     -(C6-10 arylene)-N(R59)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered 25           heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, and wherein R59 is H or C1-6 alkyl; (v)     -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)- 30           N(R62)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R62 is H or C1-6 alkyl; 2024219610   11 Sep 2024 15 20 25 30 (vi)     -(C6-10 arylene)-N(R64)SO2R63 or -Ci-6 alkylene-(C6—io arylene)-N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R64 is H or C1-6 alkyl; (vii)    -(C6-10 arylene)-SO2NR65R66 or -Ci-6 alkylene-(C6—io arylene)-SO2NR65R66, wherein each of R65 and R66 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)    -(C6-10 arylene)-NR72R73 or -C1-6 alkylene-(C6-10 arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)     -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more 2024219610   11 Sep 2024 substituents; and (xi)    -C1-6 alkylene-(C6—io arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 is H or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each 5          independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl; R5 is selected from the group consisting of: (i)     -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, or R79 and R80, together with the N 0          atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10 membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, R81 is selected from the group consisting of H, -NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 15 aryl, and 5- to 10-membered heteroaryl; and each of R82, R83, and R84 is independently selected from the group consisting of H, C1- 16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (ii)     -N+R85R86R87, wherein each of R85, R86, and R87 is independently C1-6 alkyl; n1 is 1, 2, 3, 4, 5, or 6; R12 is H or CH3; R6 is C1-6 alkyl optionally substituted with one or more 20 substituents; R8is selected from the group consisting of C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10- membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 25 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents; and L is selected from the group consisting of: i) ; ii) S N ; iii)               H ; iv) ; v) ; vi) H , wherein X is S or O; and vii)     N-N ; chiral centre *1 is in the S configuration or the R configuration; chiral centre *3 is in the S configuration or the R configuration; chiral centre *4 is in the S configuration or the R configuration; chiral centre *5 is in 30 the S configuration; chiral centre *6 is in the S configuration or the R configuration; and chiral centre *8 is in the S configuration or the R configuration, provided that: 2024219610   11 Sep 2024 when L is5           , R4 is -CH2-(phenylene)-N(H)C(O)NH2; R3 is -CH2-(phenyl) or -CH2- (phenylene)-N(H)C(O)R35, wherein the phenyl of -CH2-(phenyl) is substituted with hydroxy and wherein R35 is 2,6-dioxohexahydropyrimidine; R5 is NH2; n1 is 4; R12 is H; R6 is -CH(OH)(CH3); and R8 is -CH2-(phenyl) or -CH2-(napthyl), wherein the phenyl is substituted with hydroxy, 5           then R1 is not -CH2-(phenyl), wherein the phenyl is substituted with -Cl or -NO2. In accordance with another embodiment, there is provided a compound having a structure of Formula II or a salt thereof, wherein each of RN, RC, R1, R3, R4, R5, R6, R8, R12, n1, L, chiral centre *1, chiral centre *3, chiral centre *4, chiral centre *5, chiral centre *6, and chiral centre *8 is as defined anywhere herein provided that the compound is not: (i) H-Cpa-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys- 0   Thr-Cys]-2Nal-NH2; (ii) H-Cpa-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2; (iii) H-pNO2-Phe- cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH2; (iv) H-Cpa-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2; (v) H-pNO2-Phe-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2; (vi) H-pNO2-Phe-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2; (vii) H-Cpa-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH2; and (viii) H-pNO2-Phe-cyclo[DCys- 15    4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH2, wherein DCys and Cys of each of (i), (ii), (iii), (iv), (v), (vi), (vii) and (viii) are linked by^ S S L Embodiments of RC and RN In some embodiments, RC is OH or NHR16, wherein R16 is H or C1-6 alkyl optionally substituted with one or more substituents. In other embodiments, RC is OH or NHR16, wherein R16 is H or C1-6 20 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and C6-10 aryl. In some embodiments, RC is OH or NHR16, wherein R16 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, RC is OH or NHR16, wherein R16 is H or C1-6 alkyl. In some embodiments, RC is OH or 25 NHR16, wherein R16 is H or C1-5 alkyl. In some embodiments, RC is OH or NHR16, wherein R16 is H or C1-4 alkyl. In some embodiments, RC is OH or NHR16, wherein R16 is H or C1-3 alkyl. In some embodiments, RC is OH or NHR16, wherein R16 is H or C1-2 alkyl. In some embodiments, RC is OH or NHR16, wherein R16 is H or CH3. In some embodiments, RC is OH or NH2. In other embodiments, RC is OH. In other embodiments, RC is NH2. 30          In some embodiments, RN is selected from the group consisting of: (i)        H; (ii)       C1-6 alkyl; 2024219610   11 Sep 2024 (iii)     -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 5            (iv)    -C(O)C1-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl optionally substituted with one or more substituents; (v)     -C(O)C1-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10 0          membered heteroaryl are optionally substituted with one or more substituents, and wherein R20 is H or C1-6 alkyl; (vi)    -C(O)C1-6 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein 15           the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vii)    -C(O)C1-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, 20           and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -C(O)C1-6 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10 25           membered heteroaryl are optionally substituted with one or more substituents; and (ix)     -S(O)2R26, wherein R26 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. 30           In other embodiments, RN is selected from the group consisting of: (i)        H; (ii)       C1-6 alkyl; (iii)     -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv)     -C(O)Ci-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl; (v)     -C(O)C1-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi)    -C(O)C1-6 alkylene-NR21R22, wherein each of R21 and R22 is independently selected 5            from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii)    -C(O)C1-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 2024219610   11 Sep 2024 heteroaryl; (viii)   -C(O)C1-6 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (ix)     -S(O)2R26, wherein R26 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, RN is selected from the group consisting of: (i)        H; 15               (ii)      C1-6 alkyl; (iii)     -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6alkyl; (v)     -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting 20            of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 25           heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In other embodiments, RN is selected from the group consisting of H, C1-6 alkyl, -C(O)R17, -C(O)C1-6 alkylene-C(O)OR18, -C(O)C1-6 alkylene-N(R20)C(O)R19, -C(O)C1-6 alkylene-NR21R22, -C(O)C1-6 30    alkylene-C(O)NR23R24, and -C(O)C1-6 alkylene-S(O)2R25, wherein R17 is C1-6 alkyl or 5- to 6-membered heteroaryl, R18 is C1-6 alkyl, R19 is C1-6 alkyl or C6 aryl, each of R20, R21, R22, R23 and R24 is H, and R25 is C6 aryl. In some embodiments, RN is selected from the group consisting of H, C1-3 alkyl, -C(O)R17, -C(O)C1-3 alkylene-C(O)OR18, -C(O)C1-3 alkylene-N(R20)C(O)R19, -C(O)C1-3 alkylene-NR21R22, -C(O)C1-3 alkylene-C(O)NR23R24, and -C(O)C1-3 alkylene-S(O)2R25, wherein R17 is C1-6 alkyl or 5- to 6-membered 2024219610   11 Sep 2024 heteroaryl, R18 is C1-3 alkyl, R19 is C1-3 alkyl or C6 aryl, each of R20, R21, R22, R23 and R24 is H, and R25 is C6 aryl. In some embodiments, RN is H, CH3 or acetyl. In some embodiments, RN is H or CH3. In other embodiments, RN is H or acetyl. In other embodiments, RN is CH3 or acetyl. In some embodiments, RN is H. In other embodiments, RN is CH3. In still other embodiments, RN is acetyl. 5           Those of ordinary skill in the art will appreciate that the cyclic octa-peptides of the instant invention may be functionalized either at the C- or N-terminus by methods known in the art. For example, two methods of functionalization include PEGylation and lipidation (Beilstien J. Org. Chem. 2014, 10, 1197-1212). Functionalized peptides of this nature are also contemplated within the scope of the instant invention. For example, in some embodiments, RC is -N(H)[CH2CH2O]n16-0    R210, wherein R210 may be H or C1-6 alkyl. A person of skill in the art is readily able to ascertain a suitable range of values for n16 in the above-referenced formulae for PEG. For example, and without limitation, n16 may be an integer from 1 to 40. In some embodiments, RN is -C(O)-[CH2]n17-O-[CH2CH2O]n18-R211, wherein R211 may be H or C1-6 alkyl and n17 may be an integer from 1 to 6. In another embodiment, n17 may be 1 or 2. In some embodiments, RN is -C(O)-[CH2CH2O]n19—R211, 15 wherein R211 may be H or C1-6 alkyl. In another embodiment, RN is -[CH2]n20-O-[CH2CH2O]n21—R212, wherein R212 may be H or C1-6 alkyl and n20 may be an integer from 1 to 6. In other embodiments, n20 may be 3. In some embodiments, RN is -[CH2CH2O]n22—R212, wherein R212 may be H or C1-6 alkyl. A person of skill in the art is readily able to ascertain a suitable range of values for n18, n19, n21, and n22 in the above-referenced formulae for PEG. For example, and without limitation, each of n18, n19, n21, 20 and n22 may independently be an integer from 1 to 40. Embodiments of R1 In some embodiments, R1is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6alkylene(C6-10 aryl) and -C1-6alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6alkylene(C6-10 aryl), the 5- to 25   10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6alkylene(5- to 10 membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6alkylene of -C1-6alkylene(C6-10 aryl) and -C1-6alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents. In some embodiments, R1 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 30   10-membered heteroaryl, -C1-6alkylene(C6-10 aryl) and -C1-6alkylene(5- to 10-membered heteroaryl), wherein the C1-6alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6alkylene(5- to 10membered heteroaryl) are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 2024219610   11 Sep 2024 haloalkoxy, -NH2, -NH(Ci—6 alkyl), -N(Ci—6 alkyl)2, -C1-6 alkyl, haloCi-6 alkyl, aminoCi-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 5    alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1- 6 alkyl and R209 is C1-6 alkyl, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 0   5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, - COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. 15            In some embodiments, R1 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6 alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10membered heteroaryl) are optionally substituted with one or more substituents each 20 independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and C6-10 aryl. In some embodiments, R1 is selected from the group consisting of C6-10 aryl, 5- to 10 25 membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with 30 one or more substituents. In some embodiments, R1 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) 2024219610   11 Sep 2024 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), —N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 5    aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, - NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group 0 consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is 15 H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R1 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) 20 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and C6-10 aryl. 25            In some embodiments, R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C1-3 alkylene is optionally substituted with one or more substituents each independently selected from the group consisting of C6-10 aryl. In some embodiments, R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted 30 with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In other embodiments, R1 is -C1-3 alkylene(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R1 is -C1-2 alkylene(6-membered heteroaryl), wherein the 6- 2024219610   11 Sep 2024 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R1 is -C1-2alkylene(C6-waryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting 5 of halogen, hydroxyl, -NO2, and C1-6alkoxy. In some embodiments, R1is-C1-2alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy and -NO2. In some embodiments, R1 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and hydroxy. In some 0 embodiments, R1 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with halogen. In some embodiments, R1 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with Cl. In some embodiments, R1 is -C1-2 alkylene(C6 aryl), wherein the C6 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. 15          In some embodiments, R1 is -CH2-phenyl or -CH2-naphthyl, wherein phenyl or naphthyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In other embodiments, R1is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and -NO2. In some 20 embodiments, R1is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and hydroxyl. In some embodiments, R1is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with halogen. In some embodiments, R1is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with Cl. 25          In some embodiments, R1 is -CH2-phenyl, wherein phenyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, and -NO2. In some embodiments, R1 is -CH2-phenyl, wherein 30 phenyl is unsubstituted. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, and -NO2. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is 2024219610   11 Sep 2024 substituted with 1 or 2 substituents each independently selected from the group consisting of halogen and hydroxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of -F, -Cl, -Br, and -I. In some 5 embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -F. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -Cl. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -Br. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -I. In some embodiments, R1 0 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -F. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -Cl. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -Br. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -I. 15          In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is hydroxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is hydroxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -NO2. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -NO2. In some embodiments, 20    R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is independently C1-6 alkoxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is independently C1-3 alkoxy. In some embodiments, R1 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is methoxy. ^\.R88 / X J In some embodiments, R1 is'-           , wherein R88 is H, halogen, hydroxyl or C1-3 25 alkoxy. In some embodiments, R88 is H, halogen or hydroxyl. In some embodiments, R88 is H, Cl or hydroxyl. In some embodiments, R88 is Cl or hydroxyl. In some embodiments, R88 is Cl. In some embodiments, R1 is -C1-2 alkylene(C10 aryl), wherein the C10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl and -NO2, and C1-6 alkoxy. In some embodiments, R1 is -CH2-naphthyl. 30           In some embodiments, R1 is selected from the group consisting of -CH2-pyridinyl, -CH2- indolyl, -CH2-thiophenyl, -CH2-thiazolyl, -CH2-furanyl, -CH2-benzothiophenyl, and -CH2-imidazolyl. In some embodiments, R1 is -CH2-pyridinyl. In some embodiments, R1 is -CH2-indolyl. In some embodiments, R1 is -CH2-thiophenyl. In some embodiments, R1 is -CH2-thiazolyl. In some embodiments, R1 is -CH2-furanyl. In some embodiments, R1 is -CH2—benzothiophenyl. In some embodiments, R1 is -CH2—imidazolyl. Embodiments of R3 In some embodiments, R3 is selected from the group consisting of: (i)      C6-10 aryl which is optionally substituted with one or more substituents; (ii)     5- to 10-membered heteroaryl which is optionally substituted with one or more substituents; (iii)     -Ci—6alkylene(C6—io aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; (iv)    -C1-6alkylene(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; (v)     -C1-6 alkylene-N(R27)C(O)R28, wherein: R27 is H or C1-6 alkyl; R28 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and -NR29R30, wherein the C1-6alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R29 and R30 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vi)    -(C6-10 arylene)-C(O)NR31R32 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR31R32, wherein each of R31 and R32 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vii)    -(C6-10 arylene)-NR33R34 or -C1-6 alkylene-(C6-10 arylene)-NR33R34, wherein: each of R33 and R34 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R35, -C(O)NR36R37, and -SO2R38, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and 2024219610   11 Sep 2024 15 20 25 30 wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R35 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5-to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents; each of R36 and R37 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and R38 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-SO2NR39R40 or -C1-6 alkylene-(C6—io arylene)-SO2NR39R40, wherein each of R39 and R40 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-(Ci—6 alkylene)-NR41R42 or -C1-6 alkylene-(C6—io arylene)-(Ci-6 alkylene)-NR41R42, wherein: each of R41 and R42 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R43, and -C(O)NR44R45, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R43 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R44 and R45 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is 2024219610   11 Sep 2024 optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)    —(C6-10 arylene)-OR46 or -C1-6 alkylene-(C6—io arylene)-OR46, wherein R46 is selected 5           from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and (xi)    -C1-6 alkylene-(C6-10 arylene)-N(R47)-C(O)-CHR48-NR49R50, wherein R47 is H or CH3, 0            R48 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R49 and R50 is independently H, CH3 or acetyl. In other embodiments, R3 is selected from the group consisting of: (i)      C6-10 aryl which is optionally substituted with one or more substituents; 15           (ii)     5- to 10-membered heteroaryl which is optionally substituted with one or more substituents; (iii)     -C1-6 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; 20          (iv)    -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents, and wherein the C1-6 alkylene is optionally substituted with one or more substituents; (v)     -C1-6 alkylene-N(H)C(O)R28, wherein: R28 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered 25                    heteroaryl, and -NR29R30, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R29 and R30 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is 30                  optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vi)    -(C6-10 arylene)-C(O)NR31R32 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR31R32, wherein each of R31 and R32 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 2024219610   11 Sep 2024 15 20 25 30 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (vii)    -(C6-10 arylene)-NR33R34 or -C1-6 alkylene-(C6—io arylene)-NR33R34, wherein: each of R33 and R34 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R35, -C(O)NR36R37, and -SO2R38, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R35 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5-to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents; each of R36 and R37 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and R38 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-SO2NR39R40 or -C1-6 alkylene-(Cs-10 arylene)-SO2NR39R40, wherein each of R39 and R40 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-(C1-6 alkylene)-NR41R42 or -C1-6 alkylene-(C6-w arylene)-(C1-6 alkylene)-NR41R42, wherein: each of R41 and R42 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R43, and -C(O)NR44R45, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein 2024219610   11 Sep 2024 the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R43 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or 5                  more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R44 and R45 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 0                 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)    -(C6-10 arylene)-OR46 or -C1-6 alkylene-(C6—io arylene)-OR46, wherein R46 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein 15           the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and (xi)    -C1-6 alkylene-(C6-10 arylene)-N(R47)-C(O)-CHR48-N(H)R50, wherein R47 is H or CH3, R48 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and 20           -N(H)C(O)NH2, and R50 is H, CH3 or acetyl. In some embodiments, R3 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) 25 are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents. In some embodiments, R3 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), 30 wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10- 2024219610   11 Sep 2024 membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the 5    C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 0 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R3 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), 15 wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with 20 one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and C6-10 aryl. In some embodiments, R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C1-3 alkylene is optionally substituted 25 with one or more substituents each independently selected from the group consisting of C6-10 aryl. In some embodiments, R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R3 is selected from the group consisting of -C1-2 alkylene(C6-10 aryl) 30 and -C1-2 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the 5- to 10membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C1-2 alkylene of -C1-2 alkylene(C6-10 aryl) and -C1-2 alkylene(5- to 10-membered heteroaryl) is optionally 2024219610   11 Sep 2024 substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, C1-6alkoxy, and C6-10 aryl. In other embodiments, R3 is -C1-2 alkylene(C6-io aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting 5 of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C1-2 alkylene is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, C1-6 alkoxy, and C6-10 aryl. In some embodiments, R3 is -C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting 0 of halogen, hydroxyl, -NO2, and C1-6 alkoxy. In some embodiments, R3 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy and -NO2. In some embodiments, R3 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and hydroxy. In some 15 embodiments, R3 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with hydroxy. In some embodiments, R3 is -CH2-phenyl or -CH2-naphthyl, wherein phenyl or naphthyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In other embodiments, R3 is -CH2-phenyl or -20   CH2-naphthyl, wherein the phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and -NO2. In some embodiments, R3 is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and hydroxyl. In some embodiments, R3 is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is 25 optionally substituted with hydroxyl. In some embodiments, R3 is -CH2-phenyl, wherein phenyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R3 is -CH2-phenyl, wherein phenyl may be optionally substituted with 1 or 2 substituents each independently selected from the group 30 consisting of halogen, hydroxy, and -NO2. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is unsubstituted. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of 2024219610   11 Sep 2024 halogen, hydroxy, and -NO2. In some embodiments, R3 is -CH2—phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen and hydroxy. In some embodiments, R3 is -CH2—phenyl, wherein phenyl is substituted with 1 or 2 5 substituents each independently selected from the group consisting of -F, -Cl, -Br, and -I. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -F. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -Cl. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -Br. In some embodiments, R3 is -CH2-phenyl, 0 wherein phenyl is substituted with 1 or 2 substituents each of which is -I. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -F. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -Cl. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -Br. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent 15 which is -I. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is hydroxy. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is hydroxy. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -NO2. In some embodiments, R3 is - 20   CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -NO2. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is independently C1-6 alkoxy. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is independently C1-3 alkoxy. In some embodiments, R3 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is methoxy. R89 / X. X 25           In some embodiments, R3 is1’^           , wherein R89 is H, halogen, hydroxyl or C1-3 alkoxy. In some embodiments, R89 is H, halogen or hydroxyl. In some embodiments, R89 is H, Cl or hydroxyl. In some embodiments, R89 is Cl or hydroxyl. In some embodiments, R89 is hydroxyl. In some embodiments, R3 is -C1-2 alkylene(C10 aryl), wherein the C10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting 30 of halogen, hydroxyl and -NO2, and C1-6 alkoxy. In some embodiments, R3 is -CH2-naphthyl. In some embodiments, R3 is -C1-2 alkylene(6-membered heteroaryl), wherein the 6membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R3 is selected from the group consisting of -CH2-pyridinyl, -CH2- 2024219610   11 Sep 2024 indolyl, -CH2—thiophenyl, -CH2—thiazolyl, -CH2—furanyl, -CH2—benzothiophenyl, and -CH2-imidazolyl. In some embodiments, R3 is -CH2—pyridinyl. In some embodiments, R3 is -CH2—indolyl. In some embodiments, R3 is -CH2—thiophenyl. In some embodiments, R3 is -CH2—thiazolyl. In some 5 embodiments, R3 is -CH2—furanyl. In some embodiments, R3 is -CH2—benzothiophenyl. In some embodiments, R3 is -CH2—imidazolyl. In some embodiments, R3 is selected from the group consisting of -C1-2 alkylene(C6 aryl) and -C1-2alkylene(6-membered heteroaryl), wherein the C6 aryl and the 6-membered heteroaryl are optionally substituted with hydroxyl. In other embodiments, R3 is-CH2-phenyl or -CH2-pyridinyl, 0 wherein the phenyl is optionally substituted with hydroxyl. Embodiments of R4 In some embodiments, R4is selected from the group consisting of: (i)     -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 15            heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R53 is H or C1-6 alkyl; (ii)    -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is selected from the group consisting of C1- 6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally 20           substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10 membered heteroaryl are optionally substituted with one or more substituents, and wherein R55 is H or C1-6 alkyl; (iii)     -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR56R57, wherein each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 25           aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (iv)     -(C6-10 arylene)-N(R59)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered 30           heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, and wherein R59 is H or C1-6 alkyl; 2024219610   11 Sep 2024 15 20 25 30 (v)     -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6—io arylene)- N(R62)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R62 is H or C1-6 alkyl; (vi)     -(C6-10 arylene)-N(R64)SO2R63 or -C1-6 alkylene-(C6-10 arylene)-N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R64 is H or C1-6 alkyl; (vii)    -(C6-10 arylene)-SO2NR65R66 or -C1-6 alkylene-(C6-10 arylene)-SO2NR65R66, wherein each of R65 and R66 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (viii)   -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-NR72R73 or -C1-6 alkylene-(C6-10 arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 2024219610   11 Sep 2024 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)     —(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6—io arylene)-OR74, wherein R74 is selected 5           from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (xi)    -C1-6 alkylene-(C6—io arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 is H or CH3, 0            R76 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl; and (xii)    -C1-6 alkylene-(C6-10 arylene)-CN. In some embodiments, R4is selected from the group consisting of: 15            (i)     -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R53 is H or C1-6 alkyl; 20            (ii)    -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is selected from the group consisting of C1- 6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents, and wherein R55 is H or C1-6 alkyl; 25            (iii)    -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR56R57, wherein each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 30            (iv)     -(C6-10 arylene)-N(R59)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered 2024219610   11 Sep 2024 heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, and wherein R59 is H or C1-6 alkyl; (v)     -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6—io arylene)- N(R62)C(O)NR60R61, wherein R60 is selected from the group consisting of H, C1-6 alkyl, C6-10 5           aryl, and 5- to 10-membered heteroaryl, and R61 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R60 or R61 is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl of R60 or R61 are optionally substituted with one or more substituents, and wherein R62 is H or C1-6 alkyl; 0            (vi)     -(C6-10 arylene)-N(R64)SO2R63 or -C1-6 alkylene-(C6-10 arylene)-N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R64 is H or C1-6 alkyl; 15            (vii)    -(C6-10 arylene)-SO2NR65R66 or -C1-6 alkylene-(C6-10 arylene)-SO2NR65R66, wherein each of R65 and R66 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 20            (viii)   -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein 25                  the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are 30                  optionally substituted with one or more substituents; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 2024219610   11 Sep 2024 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-NR72R73 or -C1-6 alkylene-(C6—io arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5           5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)     -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6—io arylene)-OR74, wherein R74 is selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein 0           the C2-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (xi)     -C1-6 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 is H or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each 15           independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl; and (xii)    -C1-6 alkylene-(C6-10 arylene)-CN. In other embodiments, R4is selected from the group consisting of: (i)     -C1-6 alkylene-N(H)C(O)NR51R52, wherein each of R51 and R52 is independently 20           selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ii)    -C1-6 alkylene-N(H)C(O)R54, wherein R54 is selected from the group consisting of C1-6 25            alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents; (iii)     -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR56R57, wherein each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 30           aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (iv)    -(C6-10 arylene)-N(H)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(H)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered 2024219610   11 Sep 2024 heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents; 5            (v)     -(C6-10 arylene)-N(H)C(O)NR60R61 or -Ci-6 alkylene-(C6—io arylene)-N(H)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents; 0            (vi)    -(C6-10 arylene)-N(H)SO2R63 or -Ci-6 alkylene-(C6—io arylene)-N(H)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 15            (vii)    -(C6-10 arylene)-SO2NR65R66 or -C1-6 alkylene-(C6-10 arylene)-SO2NR65R66, wherein each of R65 and R66 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; 20            (viii)   -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein 25                  the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are 30                  optionally substituted with one or more substituents; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 2024219610   11 Sep 2024 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (ix)     -(C6-10 arylene)-NR72R73 or -C1-6 alkylene-(C6—io arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5           5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (x)     -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6—io arylene)-OR74, wherein R74 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, 0           wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; (xi)    -C1-6 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, wherein R75 is H or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each 15           independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and R78 is H, CH3 or acetyl; and (xii)    -C1-6 alkylene-(C6-10 arylene)-CN. In some embodiments, R4is -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 20 heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R53 is H or alkyl. In other embodiments, R4is -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 25 heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 30 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, - 2024219610   11 Sep 2024 C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is 5 H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein R53 is H or C1-6 alkyl. In some embodiments, R4is -C1-6 alkylene-N(H)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and 0 wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In other embodiments, R4is -C1-6 alkylene-N(H)C(O)NR51R52, wherein each of R51 and R52 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each 15 independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 20 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10 25 membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4 is -C3-4 alkylene-N(H)C(O)NR51R52 and each of R51 and R52 is H. / L ..N   NR90R91 n2^T 30           In some embodiments, R4 is:        0        , wherein each of R90 and R91 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and 2024219610   11 Sep 2024 15 wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n2 is 1, 2, 3 or 4. In some embodiments, each of R90 and R91 is H. In some embodiments, n2 is 3 or 4. In some embodiments, n2 is 3. In other embodiments, n2 is 4. 0 N N r92r93 In some embodiments, R4 is          H           , wherein each of R92 and R93 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 6- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 6- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, each of R92 and R93 is H. O N A N R94R95 In some embodiments, R4 is            H           , wherein each of R94 and R95 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 6- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 6- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In other embodiments, each of R94 and R95 is H. In some embodiments, R4 is -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is selected from the 20 group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents, and wherein R55 is H or C1-6 alkyl. In other embodiments, R4 is -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is selected from the 25 group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 30 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, - NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is 2024219610   11 Sep 2024 H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, 5    C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein R55 is H or C1-6 alkyl. 0           In some embodiments, R4 is -C1-6 alkylene-NHC(O)R54, wherein R54 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents. In other embodiments, R4 is -C1-6 alkylene-NHC(O)R54, wherein R54 is selected from the 15 group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 20 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 25 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein 30    R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4is -C3-4 alkylene-NHC(O)R54 and R54 is 5- to 10-membered heteroaryl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. 2024219610   11 Sep 2024 15 In other embodiments, R4 is -C3-4 alkylene-NHC(O)R54 and R54 is pyridinyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. MNx / R96 ''n3 Y In some embodiments, R4 is:        0    , wherein R96 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n3 is 1, 2, 3, or 4. In some embodiments, R96 is pyridinyl. In some embodiments, n3 is 3 or 4. In some embodiments, n3 is 3. In other embodiments, n3 is 4. 0 V^^n^r97 In some embodiments, R4 is         H      , wherein R97 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, R97 is C6 aryl or 5- to 6-membered heteroaryl. O N A r98 In some embodiments, R4 is           H      , wherein R98 is selected from the group 20 consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, R98 is C6 25 aryl or 5- to 6-membered heteroaryl. In some embodiments, R4 is -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6-10 arylene)-C(O)NR56R57, wherein each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered 30 heteroaryl are optionally substituted with one or more substituents. 2024219610   11 Sep 2024 In other embodiments, R4 is -(C6-10 arylene)-C(O)NR56R57 or -C1-6 alkylene-(C6—io arylene)-C(O)NR56R57, wherein each of R56 and R57 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting 5 of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 0 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, - 15 COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-C(O)NR56R57 and each of R56 and R57 is H. 20 In some embodiments, R4 is: wherein each of R99 and R100 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or 25 more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n4 is 0, 1, 2, 3, or 4. In other embodiments, each of R99 and R100 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each of R99 and R100 is independently selected from the group consisting of H and C1-6 alkyl. In some embodiments, each of R99 and R100 is H. In some 30 embodiments, n4 is 1 or 2. In some embodiments, n4 is 1. In other embodiments, n4 is 2. In some embodiments, R4 is: 2024219610   11 Sep 2024 wherein each of R101 and R102 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy, and 5 wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In other embodiments, each of R101 and R102 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each of R101 and R102 is independently selected from the group consisting of H and C1- 0   6 alkyl. In some embodiments, each of R101 and R102 is H. In some embodiments, R4 is -(C6-10 arylene)-N(R59)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered 15 heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, and wherein R59 is H or C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(R59)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-N(R59)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally 20 substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 25 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, 30    haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 2024219610   11 Sep 2024 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein R59 is H or C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)-5    N(H)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10 membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents. 0            In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)R58 or -C1-6 alkylene-(C6-10 arylene)- N(H)C(O)R58, wherein R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, 15    haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 20 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 25 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4is -C1 alkylene-(C6 arylene)-N(H)C(O)R58 and R58 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered 30 heterocycloalkyl. In some embodiments, R4is -C1 alkylene-(C6 arylene)-N(H)C(O)R58 and R58 is selected from the group consisting of C6-10 aryl and 5- to 10-membered heterocycloalkyl. In some embodiments, R4is -C1 alkylene-(C6 arylene)-N(H)C(O)R58 and R58 is selected from the group consisting of C6 aryl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl.In some 2024219610   11 Sep 2024 embodiments, R4 is -Ci alkylene-(C6 arylene)-N(H)C(O)R58 and R58 is pyrrolidinyl. In other embodiments, R4 is -Ci alkylene-(C6 arylene)-N(H)C(O)R58 and R58 is phenyl. In some embodiments, R4 is , wherein Ri03 is selected from the group consisting of Ci-6 alkyl, C6-i0 aryl, 5- to i0-membered heteroaryl, and 5- to i0-membered 5 heterocycloalkyl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and Ci-6 alkoxy, and wherein the C6-i0 aryl, 5- to i0-membered heteroaryl, and 5- to i0-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and Ci-6 alkoxy, and wherein n5 is 0, i, 2, 3, or 4. i0 In some embodiments, R4 is , wherein Xi is CH, CRi04, or N, X2 is CH, CRi05, or N, X3 is CH, CRi06, or N, X4 is CH, CRi07, or N, and X5 is CH, CRi08, or N, and each of Ri04, Ri05, Ri06, Ri07, and Ri08 is independently selected from the group consisting of halogen, hydroxy, -NO2, and Ci-6 alkoxy. In some embodiments, R4 is , wherein Ri09 is selected from the i5 group consisting of H, halogen, hydroxy, -NO2, and Ci-6 alkoxy. In other embodiments, Ri09 is H. In some embodiments, R4 is -(C6-i0 arylene)-N(R62)C(O)NR60R6i or -Ci-6 alkylene-(C6-i0 arylene)-N(R62)C(O)NR60R6i, wherein each of R60 and R6i is independently selected from the group consisting of H, Ci-6 alkyl, C6-i0 aryl, and 5- to i0-membered heteroaryl, wherein the Ci-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-i0 aryl and 5- to i0- 20 membered heteroaryl are optionally substituted with one or more substituents, and wherein R62is H or Ci-6 alkyl. In some embodiments, R4 is -(C6-i0 arylene)-N(R62)C(O)NR60R6i or -Ci-6 alkylene-(C6-i0 arylene)-N(R62)C(O)NR60R6i, wherein R60 is selected from the group consisting of H, Ci-6 alkyl, C6-i0 aryl, and 5- to i0-membered heteroaryl, and R6i is selected from the group consisting of Ci-6 alkyl, 25    C6-i0 aryl, and 5- to i0-membered heteroaryl, wherein the Ci-6 alkyl of R60 or R6i is optionally substituted with one or more substituents, and wherein the C6-i0 aryl and 5- to i0-membered heteroaryl of R60 or R6i are optionally substituted with one or more substituents, and wherein R62 is H or Ci-6 alkyl. 2024219610   11 Sep 2024 In some embodiments, R4 is -(Ce-io arylene)-N(R62)C(O)NR60R61 or -Ci-6 alkylene-(C6—io arylene)-N(R62)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10 5 membered heteroaryl are optionally substituted with one or more substituents, and wherein R62is H or C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(R62)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is 0 optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, - 15    NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, 20   C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein R62 is H or C1-6 alkyl. 25            In some embodiments, R4 is -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(R62)C(O)NR60R61, wherein R60 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and R61 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R60 or R61 is optionally substituted with one or more substituents each independently selected from the group consisting 30 of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 2024219610   11 Sep 2024 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl of R60 or R61 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, 5   C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein R62 is H or C1-6 alkyl. 0            In some embodiments, R4 is -(C6-10 arylene)-N(R62)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(R62)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -15 C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the 20 C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -25 CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein R62 is H or C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(H)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group 30 consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents. In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(H)C(O)NR60R61, wherein R60 is selected from the group consisting of H, C1-6 alkyl, C6-10 2024219610   11 Sep 2024 aryl, and 5- to 10-membered heteroaryl, and R61 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R60 or R61 is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl of R60 or R61 are optionally substituted with one or more substituents. 5            In some embodiments, R4 is -(Ce-io arylene)-N(H)C(O)NR60R61 or -Ci-6 alkylene-(C6—io arylene)-N(H)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10membered heteroaryl are optionally substituted with one or more substituents. 0            In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(H)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -15    C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10 membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the 20 C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -25    CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(H)C(O)NR60R61, wherein R60 is selected from the group consisting of H, C1-6 alkyl, C6-10 30 aryl, and 5- to 10-membered heteroaryl, and R61 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R60 or R61 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered 2024219610   11 Sep 2024 heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl 5 and 5- to 10-membered heteroaryl of R60 or R61 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, - 0    CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(H)C(O)NR60R61 or -C1-6 alkylene-(C6-10 arylene)-N(H)C(O)NR60R61, wherein each of R60 and R61 is independently selected from the group 15 consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 20 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 25 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein 30 R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-N(H)C(O)NR60R61, wherein R60 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and R61 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 is -C1-2 alkylene-(C6 arylene)-N(H)C(O)NR60R61 and R60 is H and R61 is 2024219610   11 Sep 2024 phenyl. In some embodiments, R4 is wherein each of R110 and R111 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 5 heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n6 is 0, 1, 2, 3, or 4. 10 In some embodiments, R4 is , wherein R110 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and R111 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10- 15 membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n6 is 0, 1, 2, 3, or 4. In some embodiments, R110 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and R111 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. 20 In some embodiments, R4 is wherein each of R110 and R111 is independently selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or 25 more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n6 is 0, 1, 2, 3, or 4. 2024219610   11 Sep 2024 In some embodiments, R4 is H H wherein R112 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n7 is 0, 1, 2, 3, or 4. In some embodiments, R4 is wherein R112 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n7 is 0, 1, 2, 3, or 4. In some embodiments, R112 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10- membered heteroaryl. In some embodiments, R4 is             H H         , wherein X6 is CH, CR113 or N, X7 is CH, CR114 or N, X8 is CH, CR115 or N, X9 is CH, CR116 or N, and X10 is CH, CR117 or N, and each R113, R114, R115, R116, and R117 is independently selected from the group consisting of halogen, hydroxy, - NO2, and C1-6 alkoxy. In some embodiments, R4 is , wherein R118 is selected from the group consisting of H, halogen, hydroxy, -NO2, and C1-6 alkoxy. In other embodiments, R118 is H. In some embodiments, R4 is -(C6-10 arylene)-N(R64)SO2R63 or -C1-6 alkylene-(C6-10 arylene)- N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10- membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R64 is H or C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(R64)SO2R63 or -C1-6 alkylene-(C6-10 arylene)-N(R64)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 1066 2024219610   11 Sep 2024 membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -5    COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group 0 consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is 15 H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl , and wherein R64 is H or C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-N(H)SO2R63 or -C1-6 alkylene-(C6-10 arylene)-N(H)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more 20 substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In some embodiments, R4 is -(C6-10 arylene)-N(H)SO2R63 or -C1-6 alkylene-(C6-10 arylene)-N(H)SO2R63, wherein R63 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents 25 each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 30 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10- 2024219610   11 Sep 2024 15 membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-N(H)SO2R63 and R63 is C6 aryl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In other embodiments, R4is -C1-2 alkylene-(C6 arylene)-N(H)SO2R63 and R63 is phenyl. In some embodiments, R4 is -C1 alkylene-(C6 arylene)-N(H)SO2R63 and R63 is phenyl. / Nx ,R119 zXJ 0 0 \ / 8 In some embodiments, R4 is:                       , wherein R119 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10- membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein n8 is 0, 1, 2, 3, or 4. In other embodiments, R119 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 is: ,,     x11' x13 H i ii / ¼ .x14 S x15 / / \\ 0 0 , wherein X11 is CH, CR120 or N, X12 is CH, CR121 or N, X13 is CH, CR122 or N, X14 is CH, CR123 or N, and X15 is CH, CR124 or N, and each of R120, 20    R121, R122, R123 and R124 is independently selected from the group consisting of halogen, hydroxy, - NO2, and C1-6 alkoxy. ifV S r125 y Ji J 0 0 In some embodiments, R4 is:                          , wherein R125 is selected from the group consisting of H, halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R125 is H. In some embodiments, R4 is -(C6-10 arylene)-SO2NR65R66 or -C1-6 alkylene-(C6-10 arylene)- 25   SO2NR65R66, wherein each of R65 and R66 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In some embodiments, R4 is -(Ce-io arylene)-SO2NR65R66 or -Ci-6 alkylene-(C6—io arylene)-SO2NR65R66, wherein each of R65 and R66 is independently selected from the group consisting of H, C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-1o aryl, 5- to 1o-membered heteroaryl, 5- to 1o-membered heterocycloalkyl, C5-1o cycloalkyl, azido, -CN, -COR2oo wherein R2oo is C1-6 alkyl or C6-1o aryl, -CO2R2o1 wherein R2o1 is H or C1-6 alkyl, -CONR2o2R2o3 wherein R2o2 and R2o3 is H or C1-6 alkyl, -NR2o4COR2o5 wherein R2o4 is H or C1-6 alkyl and R2o5 is C1-6 alkyl, -SO2NR2o6R2o7 wherein R2o6 and R2o7 is H or C1-6 alkyl, and -NR2o8SO2R2o9 wherein R2o8 is H or C1-6 alkyl and R2o9 is C1-6 alkyl, and wherein the C6-1o aryl and 5- to 1o-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-1o aryl, 5- to 1o-membered heteroaryl, 5- to 1o-membered heterocycloalkyl, C5-1o cycloalkyl, azido, -CN, -COR2oo wherein R2oo is C1-6 alkyl or C6-1o aryl, -CO2R2o1 wherein R2o1 is H or C1-6 alkyl, -CONR2o2R2o3 wherein R2o2 and R2o3 is H or C1-6 alkyl, -NR2o4COR2o5 wherein R2o4 is H or C1-6 alkyl and R2o5 is C1-6 alkyl, -SO2NR2o6R2o7 wherein R2o6 and R2o7 is H or C1-6 alkyl, and -NR2o8SO2R2o9 wherein R2o8 is H or C1-6 alkyl and R2o9 is C1-6 alkyl. In some embodiments, R4 is wherein each of R126 and R127 is independently selected from the group consisting of H, C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-1o aryl and 5- to 1o-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n9 is o, 1, 2, 3, or 4. In some embodiments, each of R126 and R127 is independently selected from the group consisting of H, C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl. In some embodiments, R4 is , wherein X16 is CH, CR128 or N, X17 is CH, CR129 or N, X18 is CH, CR13o or N, X19 is CH, CR131 or N, and X2o is CH, CR132 or N, and each of R128, 2024219610   11 Sep 2024 R129, R130, R131 and R132 is independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. r^R133 N / JI J H In some embodiments, R4 is                           , wherein r133 is selected from the group consisting of H, halogen, -OH, -NO2, and C1-6 alkoxy. In other embodiments, R133 is H. 5            In some embodiments, R4 is -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5-to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered 0 heteroaryl are optionally substituted with one or more substituents; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and 15 each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In some embodiments, R4 is -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(C6-10 20    arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5-to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, 25    haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl 30 and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 2024219610   11 Sep 2024 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is Ci-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-5    6 alkyl and R209 is C1-6 alkyl; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered 0 heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or 15 more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and 20    R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 25 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein 30    R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5-to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or 2024219610   11 Sep 2024 C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-(C1-6 alkylene)-NR67R68 or -C1-6 alkylene-(Cs-10 5    arylene)-(C1-6 alkylene)-NR67R68, wherein: each of R67 and R68 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5-to 10-membered heteroaryl, -C(O)R69, and -C(O)NR70R71, wherein the C1-6alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy, and wherein the C6-10 aryl and 5- to 10-membered 0 heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; R69 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 15 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; and each of R70 and R71 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 20 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, R4is -C1 alkylene-(C6 arylene)-(C1 alkylene)-NR67R68 and each of R67 and R68 is H. In other embodiments, R4is -C1 alkylene-(C6 arylene)-(C1 alkylene)-NR67R68, R67 is H, 25 R68 is -C(O)R69, and R69 is C1 alkyl. In some embodiments, R4is -C1 alkylene-(C6 arylene)-(C1 alkylene)-NR67R68, R67 is H, R68 is -C(O)NR70R71, and each of R70 and R71 is H. 134^135 In some embodiments, R4 is: , wherein: each of R134 and R135 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5-to 10-membered heteroaryl, -C(O)R136, and -C(O)NR137R138, wherein the C1-6 alkyl is optionally 30 substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected 2024219610   11 Sep 2024 from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy, and wherein n10 is 0, 1, 2, 3, or 4, and wherein n11 is 0, 1, 2, 3, or 4; R136 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently 5 selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; and each of R137 and R138 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more 0 substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, R4 is                     , wherein: 15 each of R139 and R140 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5-to 10-membered heteroaryl, -C(O)R141, and -C(O)NR142R143, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected 20 from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; R141 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents 25 each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; and each of R142 and R143 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with 30 one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy. In some embodiments, each of R139 and R140 is independently selected from the group consisting of H, -C(O)R141, and -C(O)NR142R143, wherein R141 is C1-6 alkyl and each of R142 and R143 is H. 2024219610   11 Sep 2024 In some embodiments, R4 is -(Ce-io arylene)-NR72R73 or -Ci-6 alkylene-(C6—io arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-1o aryl and 5- to 1o-membered heteroaryl are 5 optionally substituted with one or more substituents. In some embodiments, R4 is -(C6-1o arylene)-NR72R73 or -C1-6 alkylene-(C6-1o arylene)-NR72R73, wherein each of R72 and R73 is independently selected from the group consisting of H, C1-6 alkyl, C6-1o aryl, and 5- to 1o-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -o OH, -NO2, C1-6 alkoxy, C1-6haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-1o aryl, 5- to 1o-membered heteroaryl, 5- to 1o-membered heterocycloalkyl, C5-1o cycloalkyl, azido, -CN, -COR2oo wherein R2oo is C1-6 alkyl or C6-1o aryl, -CO2R2o1 wherein R2o1 is H or C1-6 alkyl, -CONR2o2R2o3 wherein R2o2 and R2o3 is H or C1-6 alkyl, -NR2o4COR2o5 wherein R2o4 is H or C1-6 alkyl and R2o5 is C1-6 alkyl, -SO2NR2o6R2o7 wherein R2o6 and R2o7 is H or C1-6 alkyl, and -NR2o8SO2R2o9 15 wherein R2o8 is H or C1-6 alkyl and R2o9 is C1-6 alkyl, and wherein the C6-1o aryl and 5- to 1o-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-1o aryl, 5- to 1o-membered heteroaryl, 5-to 1o-membered heterocycloalkyl, C5-1o cycloalkyl, azido, -CN, -COR2oo wherein R2oo is C1-6 alkyl or 2o C6-1o aryl, -CO2R2o1 wherein R2o1 is H or C1-6 alkyl, -CONR2o2R2o3 wherein R2o2 and R2o3 is H or C1-6 alkyl, -NR2o4COR2o5 wherein R2o4 is H or C1-6 alkyl and R2o5 is C1-6 alkyl, -SO2NR2o6R2o7 wherein R2o6 and R2o7 is H or C1-6 alkyl, and -NR2o8SO2R2o9 wherein R2o8 is H or C1-6 alkyl and R2o9 is C1-6 alkyl. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-NR72R73 and each of R72 and R73 is independently selected from the group consisting of H and C1-6 alkyl, wherein the C1-6 alkyl is 25 optionally substituted with one or more substituents each independently selected from the group consisting of 5- to 1o-membered heterocycloalkyl, halogen, hydroxy, -NO2, and C1-6 alkoxy. In other embodiments, R4 is -C1-2 alkylene-(C6 arylene)-NR72R73 and R72 is H and R73 is C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of 5- to 1o-membered heterocycloalkyl, halogen, hydroxy, -NO2, and C1-6 alkoxy. In some 3o embodiments, R4 is -C1-2 alkylene-(C6 arylene)-NR72R73 and R72 is H and R73 is C2 alkyl substituted with morpholinyl. In some embodiments, R4 is -C1-2 alkylene-(C6 arylene)-NR72R73 and R72 is H and R73 is C1-6 alkyl. In other embodiments, R4 is -C1-2 alkylene-(C6 arylene)-NR72R73 and R72 is H and R73 is C5 alkyl. In some embodiments, R4 is: 2024219610   11 Sep 2024 wherein each of R144 and R145 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, Ci-6alkoxy, and 5- to 105 membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n12 is 0, 1, 2, 3, or 4. In some embodiments, n12 is 1 or 2. In other embodiments, n12 is 1. In other embodiments, R144 is H and R145 is C1-6 alkyl optionally substituted with one or more substituents 0 each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl. In some embodiments, R144 is H and R145 is C2 alkyl substituted with morpholinyl. In other embodiments, R144 is H and R145 is C1-6 alkyl. In other embodiments, R144 is H and R145 is C5 alkyl. In some embodiments, R4 is -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, 15 wherein R74 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In other embodiments, R4 is -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 1020 membered heteroaryl, wherein the C2-6 alkyl is optionally substituted with one or more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In some embodiments, R4 is -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the group consisting of C3-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C3-6 alkyl is optionally substituted with one or 25 more substituents, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents. In some embodiments, R4 is -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each 30 independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, - 2024219610   11 Sep 2024 COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are 5 optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -0    NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R4 is -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each 15 independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, and 5- to 10membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl. In other embodiments, R4 is -(C6-10 arylene)-OR74 or -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is 20 selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C2-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting 25 of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-OR74 and R74 is C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of 5- to 10-membered heterocycloalkyl, halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-OR74 and R74 is C2-6 alkyl optionally substituted with 30 one or more substituents each independently selected from the group consisting of 5- to 10membered heterocycloalkyl, halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R4is -C1-2 alkylene-(C6 arylene)-OR74 and R74 is C2-6 alkyl. In other embodiments, R4is -C1-2 alkyene-(C6 arylene)-OR74 and R74 is C2 alkyl substituted with morpholinyl. 2024219610   11 Sep 2024 15 I 4q o146 In some embodiments, R4 is:                    , wherein R146 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n13 is 0, 1, 2, 3, or 4. In some embodiments, n13 is 1 or 2. In other embodiments, n13 is 1. In some embodiments, R146 is selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl. In other embodiments, R146 is selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. 147 y £1 In some embodiments, R4 is                    , wherein R147 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein 20 the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl. In other embodiments, R147 is selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C2-6 alkyl is optionally substituted with one or more substituents each independently selected from the group 25 consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl. In some embodiments, R147 is selected from the group consisting of C2-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In other embodiments, 30    R147 is C2-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered 2024219610   11 Sep 2024 heterocycloalkyl. In some embodiments, R147 is C2 alkyl substituted with morpholinyl. In other embodiments, R147 is C2 alkyl. In some embodiments, R4 is -C1-6 alkylene-(C6—io arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 is H or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents 5 each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl. In some embodiments, R4 is -C1-6 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, wherein R75 is H or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -0    N(H)C(O)NH2, and R78 is H, CH3 or acetyl. In some embodiments, R4 is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is H, and R78 is H or acetyl. In other embodiments, R4is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is H, and R78 is H. In some embodiments, R4 is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is H, and R78 is acetyl. 15            In some embodiments, R4 is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and R78 is H. In some embodiments, R4is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is C1-6 alkyl substituted with hydroxyl, and R78 is H. In some embodiments, R4is -C1-2 alkylene- 20    (C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is C1-6 alkyl substituted with -COOH, and R78 is H. In some embodiments, R4is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is C1-6 alkyl substituted with-NH2, and R78 is H. In some embodiments, R4is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, R76 is C1-6 alkyl substituted with -C(O)NH2, and R78 is H. In some embodiments, R4is -C1-2 alkylene-(C6-10 arylene)-N(R75)-C(O)-CHR76-N(H)R78, R75 is H, 25    R76 is C1-6 alkyl substituted with -N(H)C(O)NH2, and R78 is H. In some embodiments, R4 is: O NHR150 , wherein R148 is H or CH3, R149 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and R150 is H, CH3 or acetyl, and wherein n14 is 0, 1, 2, 3, or 4. In other embodiments, n14 is 1 or 2. In some embodiments, 30 n14 is 1. In some embodiments, R148 is H, R149 is H, and R150 is H or acetyl. In other embodiments, R148 is H, R149 is H, and R150 is H. In some embodiments, R148 is H, R149 is H, and R150 is acetyl. In some embodiments, R148 is H, R149 is C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and - 2024219610   11 Sep 2024 N(H)C(O)NH2, and R150 is H. In some embodiments, R148 is H, R149 is C1-6 alkyl substituted with hydroxyl, and R150 is H. In some embodiments, R148 is H, R149 is C1-6 alkyl substituted with -COOH, and R150 is H. In some embodiments, R148 is H, R149 is C1-6 alkyl substituted with -NH2, and R150 is H. In 5 some embodiments, R148 is H, R149 is C1-6 alkyl substituted with -C(O)NH2, and R150 is H. In some embodiments, R148 is H, R149 is C1-6 alkyl substituted with -N(H)C(O)NH2, and R150 is H. In some embodiments, R4 is -C1-6 alkylene-(C6-10 arylene)-CN. In other embodiments, R4 is - C1-2 alkylene-(C6 arylene)-CN. In other embodiments, R4 is -C1 alkylene-(C6 arylene)-CN. In some embodiments, R4 is , wherein n15 is 0, 1, 2, 3, or 4. In other embodiments, n15 is 1 or 2. In some embodiments, R4 is In some embodiments, R4 is selected from the group consisting of: 2024219610   11 Sep 2024 . In some embodiments, R4 is selected from the nh2 and group consisting of: , , , 10 2024219610   11 Sep 2024 H ,N. _NH2 H ?    A YY n nh2 , ^nYD aAY o haYj and 0 \' / ^^'N'^'NH2 / t consisting of:            H        , H                       H r T Y NH2    £Y / \YxY °    ^^YxY , H H                    H / YT Y YY . YY 5                                           , is selected from the group consisting of: 3               H Yy^n / U^nh2    YYn' / AJ H / AJ , H H                    H / YT Y YY , YY x     ° YY YYxY , i          H / YY"2 z AY is                         or H AY          H H A A   XAyNYY YYf y^nh2   £ Y Y Y J YY 0                ^-^OCHa ,                                                                                  , :N . In some embodiments, R4 is selected from the group 0                   0 xAh2   YYn^nH2 H       / JY J H ,                                                               , H Al AYaY <         1 II Z / A Y-YYY 0 0 ,                                                              , . / ££      <x\xCN O       ? JY J , and ?             . in some embodiments, R4 0 0         A A       YYr nh2 n nh2 y L II ,, H Yy^s^V <         | IT Z / A Y\YYY 0 0 ,                                                              , O              / JJ , and               . in some embodiments, R4 H ) IJ . in some embodiments, R4 is 0 A              / \ / ^- / N NH2                           N 10             H       . In some embodiments, R4 is            H 0 r5 H H J                         /    1 is                        . in some embodiments, R4 is YY^nHj                £ R4 is     '"YY        . in some embodiments, R4 is ^'''- / '''Y. 0 YNh2 . in some embodiments, R4 0 £jKNH2 . in some embodiments, o Y^n^ JJ H ""'            . in some 2024219610   11 Sep 2024 embodiments, R4 is In some embodiments, R4 is embodiments, R4 is 10 . In some embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is H H . In some . In some embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is . In some ^CO2H embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is . In some . In some embodiments, R4 is embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is H H N_ O F . In some embodiments, R4 is 2024219610   11 Sep 2024 Cl. In some embodiments, R4 is some embodiments, R4 is embodiments, R4 is o ocH3 . . In some embodiments, R4 is . In some embodiments, R4 is . In some embodiments, R4 is . In some . In some embodiments, R4 is In some embodiments, R4 is Embodiments of R5 and n1 . In some embodiments, R4 is 10 In some embodiments, R5 is selected from the group consisting of: (i)     -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, or R79 and R80, together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents, 15                     R81 is selected from the group consisting of H, -NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and each of R82, R83, and R84 is independently selected from the group consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (ii)     -N+R85R86R87, wherein each of R85, R86, and R87 is independently C1-6 alkyl. 20          In some embodiments, R5 is selected from the group consisting of: (i)     -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, or R79 and R80, together with the N 2024219610   11 Sep 2024 atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 5           alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 0          alkyl, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, 15            azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, R81 is selected from the group consisting of H, -NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 20                  aryl, and 5- to 10-membered heteroaryl; and each of R82, R83, and R84 is independently selected from the group consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (ii)     -N+R85R86R87, wherein each of R85, R86, and R87 is independently C1-6 alkyl. In other embodiments, R5 is -NR79R80, wherein: 25           each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, - C(O)R81, and -C(=NR82)NR83R84, or R79 and R80, together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally 30           substituted with one or more substituents, R81 is selected from the group consisting of H, - NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and each of R82, R83, and R84 is independently selected from the group consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In other embodiments, R5 is -NR79R80, wherein: 2024219610   11 Sep 2024 each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, or R79 and R80, together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each 5           independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or 0            C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and - NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the 5- to 10membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 15            alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10 membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and 20            R209 is C1-6 alkyl, R81 is selected from the group consisting of H, -NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and each of R82, R83, and R84 is independently selected from the group consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is independently selected 25 from the group consisting of H and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1- 30    6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is H. In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is independently C1-6 alkyl. In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is 2024219610   11 Sep 2024 independently C1-3 alkyl. In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is CH3. In other embodiments, R5 is -NR79R80, wherein R79 is H and R80 is C1-6 alkyl. In other embodiments, R5 is -NR79R80, wherein R79 is H and R80 is C1-3 alkyl. In other embodiments, R5 is -NR79R80, wherein R79 is H and R80 is CH3. 5           In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H and -C(O)R81, wherein R81 is selected from the group consisting of H, -NH2, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In other embodiments, R5 is -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H and -C(=NR82)NR83R84, wherein each of R82, R83, and R84 is independently selected from the group 0 consisting of H, C1-16 alkyl, C1-6 haloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H. In other embodiments, R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H and C1-6alkyl. In some embodiments, R5 is -NH2, -NHCH3 or 15   -N(CH3)2. In other embodiments, R5 is -NH2. In some embodiments, R5 is -NHCH3. In other embodiments, R5 is -N(CH3)2. In other embodiments, R5 is -NR79R80, wherein R79 and R80, together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10membered heterocycloalkyl, wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently 20 selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein 25    R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R5 is -N+R85R86R87, wherein each of R85, R86, and R87 is independently C1-6 alkyl. In other embodiments, each of R85, R86, and R87 is independently C1-3 alkyl. In other embodiments, each of R85, R86, and R87 is CH3. In some embodiments, n1 is 1, 2, 3, 4, 5, or 6. In some embodiments, n1 is 2, 3, 4, 5, or 6. In some embodiments, n1 is 2, 3, 4, or 5. In some embodiments, n1 is 3, 4, or 5. 30 In some embodiments, n1 is 3 or 4. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 4. In some embodiments, n1 is 5. In some embodiments, n1 is 6. Embodiments of R6 2024219610   11 Sep 2024 In some embodiments, R6 is alkyl optionally substituted with one or more substituents. In other embodiments, R6 is C1-6 alkyl optionally substituted with one or more substituents. In some embodiments, R6 is C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy. In 5 some embodiments, R6 is C1-6 alkyl optionally substituted with hydroxy. In other embodiments, R6 is C1-5 alkyl optionally substituted with hydroxy. In some embodiments, R6 is C1-4 alkyl optionally substituted with hydroxy. In some embodiments, R6 is C1-3 alkyl optionally substituted with hydroxy. In some embodiments, R6 is C1-2 alkyl optionally substituted with hydroxy. In some embodiments, R6 is selected from the group consisting of -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, - 0   CH2CH2CH3, -CH(CH3)CH2OH, -CH(CH3)2, -C(CH3)3, -CH(CH3)OH, and -CH2CH3. In other embodiments, R6 is selected from the group consisting of -CH(CH3)OH, -CH(CH3)2, -C(CH3)3, -CH2OH and -CH2CH3. In some embodiments, R6 is selected from the group consisting of -CH(CH3)OH, -CH(CH3)2, -C(CH3)3, and -CH2CH3. In some embodiments, R6 is -CH(CH3)OH. In some embodiments, R6 is -CH(CH3)2. In some embodiments, R6 is -C(CH3)3. In some embodiments, R6 is -15 CH2CH3. In some embodiments, R6 is -CH2OH. Embodiments of R8 In some embodiments, R8is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6 alkylene(C6-10 aryl), the 5- to 20   10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10 membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents. In some embodiments, R8 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 25    10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6 alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10membered heteroaryl) are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6 30    haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1- 2024219610   11 Sep 2024 6 alkyl and R209 is C1-6 alkyl, and wherein the C1-6alkylene of -Ci—6alkylene(C6—io aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5   5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, - COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. 0            In some embodiments, R8 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C1-6 alkyl, the C6-10 aryl, the C6-10 aryl of -C1-6 alkylene(C6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10membered heteroaryl) are optionally substituted with one or more substituents each 15 independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and C6-10 aryl. In some embodiments, R8 is selected from the group consisting of C6-10 aryl, 5- to 1020 membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with 25 one or more substituents. In some embodiments, R8 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) 30 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, - 2024219610   11 Sep 2024 NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl, and wherein the C1-6alkylene of -C1-6alkylene(C6-10 aryl) and -C1-6alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group 5 consisting of halogen, -OH, -NO2, C1-6alkoxy, C1-6haloalkoxy, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 alkyl)2, -C1-6 alkyl, haloC1-6 alkyl, aminoC1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, 5- to 10membered heterocycloalkyl, C5-10 cycloalkyl, azido, -CN, -COR200 wherein R200 is C1-6 alkyl or C6-10 aryl, -CO2R201 wherein R201 is H or C1-6 alkyl, -CONR202R203 wherein R202 and R203 is H or C1-6 alkyl, -NR204COR205 wherein R204 is H or C1-6 alkyl and R205 is C1-6 alkyl, -SO2NR206R207 wherein R206 and R207 is 0 H or C1-6 alkyl, and -NR208SO2R209 wherein R208 is H or C1-6 alkyl and R209 is C1-6 alkyl. In some embodiments, R8 is selected from the group consisting of C6-10 aryl, 5- to 10membered heteroaryl, -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl), wherein the C6-10 aryl and the C6-10 aryl of -C1-6 alkylene(C6-10 aryl) and the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of -C1-6 alkylene(5- to 10-membered heteroaryl) 15 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C1-6 alkylene of -C1-6 alkylene(C6-10 aryl) and -C1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and C6-10 aryl. 20            In some embodiments, R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C1-3 alkylene is optionally substituted with one or more substituents each independently selected from the group consisting of C6-10 aryl. In some embodiments, R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted 25 with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R8 is -C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NO2, and C1-6 alkoxy. In some embodiments, R8 is-C1-2 alkylene(C6-10 aryl), 30 wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy and -NO2. In some embodiments, R8 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and hydroxy. In some embodiments, R8 is-C1-2 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with 2024219610   11 Sep 2024 hydroxy. In other embodiments, R8 is -Ci-2alkylene(C6aryl), wherein the C6 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NO2, and C1-6 alkoxy. In some embodiments, R8 is -CH2—phenyl or -CH2—naphthyl, wherein phenyl or naphthyl 5 may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy. In other embodiments, R8is -CH2—phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and -NO2. In some embodiments, R8is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted 0 with one or more substituents each independently selected from the group consisting of halogen and hydroxyl. In some embodiments, R8 is -CH2-phenyl or -CH2-naphthyl, wherein the phenyl is optionally substituted with hydroxyl. In some embodiments, R8 is -CH2-phenyl, wherein phenyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, 15 hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R8 is -CH2-phenyl, wherein phenyl may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, and -NO2. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is unsubstituted. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, 20 hydroxy, -NO2, and C1-6 alkoxy. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, and -NO2. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of halogen and hydroxy. 25           In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each independently selected from the group consisting of -F, -Cl, -Br, and -I. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -F. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -Cl. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is 30 substituted with 1 or 2 substituents each of which is -Br. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -I. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -F. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -Cl. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is - 2024219610   11 Sep 2024 Br. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -I. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is hydroxy. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is 5 substituted with 1 substituent which is hydroxy. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is -NO2. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is -NO2. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 or 2 substituents each of which is independently C1-6 alkoxy. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted 0 with 1 or 2 substituents each of which is independently C1-3 alkoxy. In some embodiments, R8 is -CH2-phenyl, wherein phenyl is substituted with 1 substituent which is methoxy. In some embodiments, R8 is?R^            , wherein R151 is H, halogen, hydroxyl or C1-3 alkoxy. In some embodiments, R151 is H, halogen or hydroxyl. In some embodiments, R151 is H, Cl or hydroxyl. In some embodiments, R151 is Cl or hydroxyl. In some embodiments, R151 is hydroxyl. 15            In some embodiments, R8 is -C1-2 alkylene(C10 aryl), wherein the C10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl and -NO2, and C1-6 alkoxy. In some embodiments, R8 is -CH2-naphthyl. In some embodiments, R8 is selected from the group consisting of -CH2-pyridinyl, -CH2-indolyl, -CH2-thiophenyl, -CH2-thiazolyl, -CH2-furanyl, -CH2-benzothiophenyl, and -CH2- 20 imidazolyl. In some embodiments, R8 is -CH2-pyridinyl. In some embodiments, R8 is -CH2-indolyl. In some embodiments, R8 is -CH2-thiophenyl. In some embodiments, R8 is -CH2-thiazolyl. In some embodiments, R8 is -CH2-furanyl. In some embodiments, R8 is -CH2-benzothiophenyl. In some embodiments, R8 is -CH2-imidazolyl. Embodiments of R9, R10, R11, R12, R13, R14 and R15 25            In some embodiments, R9 is H or C1-6 alkyl. In other embodiments, R9 is H or C1-5 alkyl. In some embodiments, R9 is H or C1-4 alkyl. In some embodiments, R9 is H or C1-3 alkyl. In other embodiments, R9 is H or C1-2 alkyl. In some embodiments, R9 is H or CH3. In some embodiments, R9 is H. In other embodiments, R9 is CH3. In some embodiments, R10 is H or C1-6 alkyl. In other embodiments, R10 is H or C1-5 alkyl. In some embodiments, R10 is H or C1-4 alkyl. In some 30 embodiments, R10 is H or C1-3 alkyl. In other embodiments, R10 is H or C1-2 alkyl. In some embodiments, R10 is H or CH3. In some embodiments, R10 is H. In other embodiments, R10 is CH3. In some embodiments, R11 is H or C1-6 alkyl. In other embodiments, R11 is H or C1-5 alkyl. In some embodiments, R11 is H or C1-4 alkyl. In some embodiments, R11 is H or C1-3 alkyl. In other 2024219610   11 Sep 2024 embodiments, R11 is H or C1-2 alkyl. In some embodiments, R11 is H or CH3. In some embodiments, R11 is H. In other embodiments, R11 is CH3. In some embodiments, R12 is H or C1-6 alkyl. In other embodiments, R12 is H or C1-5 alkyl. In some embodiments, R12 is H or C1-4 alkyl. In some embodiments, R12 is H or C1-3 alkyl. In other embodiments, R12 is H or C1-2 alkyl. In some 5 embodiments, R12 is H or CH3. In some embodiments, R12 is H. In other embodiments, R12 is CH3. In some embodiments, R13 is H or C1-6 alkyl. In other embodiments, R13 is H or C1-5 alkyl. In some embodiments, R13 is H or C1-4 alkyl. In some embodiments, R13 is H or C1-3 alkyl. In other embodiments, R13 is H or C1-2 alkyl. In some embodiments, R13 is H or CH3. In some embodiments, R13 is H. In other embodiments, R13 is CH3. In some embodiments, R14 is H or C1-6 alkyl. In other 0 embodiments, R14 is H or C1-5 alkyl. In some embodiments, R14 is H or C1-4 alkyl. In some embodiments, R14 is H or C1-3 alkyl. In other embodiments, R14 is H or C1-2 alkyl. In some embodiments, R14 is H or CH3. In some embodiments, R14 is H. In other embodiments, R14 is CH3. In some embodiments, R15 is H or C1-6 alkyl. In other embodiments, R15 is H or C1-5 alkyl. In some embodiments, R15 is H or C1-4 alkyl. In some embodiments, R15 is H or C1-3 alkyl. In other 15 embodiments, R15 is H or C1-2 alkyl. In some embodiments, R15 is H or CH3. In some embodiments, R15 is H. In other embodiments, R15 is CH3. In other embodiments, each of R9, R10, R11, R12, R13, R14 and R15 is independently H or CH3. In some embodiments, each of R9, R10, R11, R12, R13, R14 and R15 is H. Embodiments of L £ —s~s—I —s— 20            In some embodiments, L is selected from the group consisting of: i) 5          , ii) 5       5 o                                     x ; iii)          H ; iv)               ; v)              ; vi)        H , wherein X is S or O; and vii) n=n . For each l moiety, either point of attachment may bond to either of the two carbon atoms on the remainder of the compound of Formula I or II to which L is bonded (as set out in Formula I or II above) provided that they are not bonded to the same carbon atom. In other words, 25 the L moieties set out herein are able to bond to the remainder of the compound of Formula I or II £ —s—s— in either direction. In some embodiments, L is5          . L may be made using techniques known I —s—s— I to a person of skill in the art. For example, when L is5         \ suitable methods are described in Lin Chen, L., et al., “Disulfide Bond Formation in Peptides”, Current Protocols in Protein Science £ —s— £ (2001) 18.6.1-18.6.19, John Wiley & Sons, Inc. In some embodiments, L is5        . When L is I —s— 30    5       ,, suitable methods are described in, Rew, Y., et al. “Synthesis and Biological Activities of 2024219610   11 Sep 2024 Cyclic Lanthionine Enkephalin Analogues: 5-Opioid Receptor Selective Ligands”, J. Med. Chem., 2002, 45 (17), pp 3746-3754; Bregant S., et al., “Orthogonally Protected Lanthionines: Synthesis and Use for the Solid-Phase Synthesis of an Analogue of Nisin Ring C'", J. Org. Chem., 2005, 70 (7), pp 2430-2438; and Dugave, C., et al., “Synthesis of natural and non natural orthogonally protected 5 lanthionines from N-tritylserine and allo-threonine derivatives”, Tetrahedron: Asymmetry, Volume o 8, Number 9, 8 May 1997, pp. 1453-1465(13). In some embodiments, L is       H . When L is H , suitable methods are described in Besret, S., et al., “Thiocarbamate-linked peptides by chemoselective peptide ligation”, Journal of Peptide Science Volume 14, Issue 12, pages 1244- 1250, December 2008. In some embodiments, L is          . In some embodiments, L is 10              . When L is           or^^^^  , suitable methods are described in Stymiest, J. L., et al., “Synthesis of Biologically Active Dicarba Analogues of the Peptide Hormone Oxytocin Using Ring-Closing Metathesis", Org. Lett., 2003, 5 (1), pp 47-49. In some embodiments, L is      H , x wherein X is S or O. In some embodiments, L is      H , wherein X is S. In some embodiments, L is      H , wherein X is O. In some embodiments, L is N-N     . When L is N-N    , 15 suitable methods are described in Holland-Nell, K., et al., “Maintaining Biological Activity by Using Triazoles as Disufide Bond Mimetics", Angewandte Chemie Int Ed 2011, 50, 5204-5206. Embodiments of Chiral Centres *1, *2, *3, *4, *5, *6, *7, and *8 In some embodiments, chiral centre *1 is in the S configuration or the R configuration. In some embodiments, chiral centre *1 is in the S configuration. In some embodiments, chiral centre 20   *1 is in the R configuration. In some embodiments, chiral centre *2 is in the S configuration or the R configuration. In some embodiments, chiral centre *2 is in the S configuration. In some embodiments, chiral centre *2 is in the R configuration. In some embodiments, chiral centre *3 is in the S configuration or the R configuration. In some embodiments, chiral centre *3 is in the S configuration. In some embodiments, chiral centre *3 is in the R configuration. In some 25 embodiments, chiral centre *4 is in the S configuration or the R configuration. In some embodiments, chiral centre *4 is in the S configuration. In some embodiments, chiral centre *4 is in the R configuration. In some embodiments, chiral centre *5 is in the S configuration or the R 2024219610   11 Sep 2024 configuration. In some embodiments, chiral centre *5 is in the S configuration. In some embodiments, chiral centre *5 is in the R configuration. In some embodiments, chiral centre *6 is in the S configuration or the R configuration. In some embodiments, chiral centre *6 is in the S configuration. In some embodiments, chiral centre *6 is in the R configuration. In some 5 embodiments, chiral centre *7 is in the S configuration or the R configuration. In some embodiments, chiral centre *7 is in the S configuration. In some embodiments, chiral centre *7 is in the R configuration. In some embodiments, chiral centre *8 is in the S configuration or the R configuration. In some embodiments, chiral centre *8 is in the S configuration. In some embodiments, chiral centre *8 is in the R configuration. In some embodiments, chiral centre *1 is in 0 the S configuration or the R configuration, chiral centre *2 is in the S configuration or the R configuration, chiral centre *3 is in the S configuration or the R configuration, chiral centre *4 is in the S configuration or the R configuration, chiral centre *5 is in the S configuration or the R configuration, chiral centre *6 is in the S configuration or the R configuration, chiral centre *7 is in the S configuration or the R configuration, and chiral centre *8 is in the S configuration or the R 15 configuration. In some embodiments, chiral centre *1 is in the S configuration or the R configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration or the R configuration, chiral centre *4 is in the S configuration or the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration or the R configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the S configuration or the R 20 configuration. In some embodiments, chiral centre *1 is in the S configuration or the R configuration, chiral centre *2 is in the S configuration or the R configuration, chiral centre *3 is in the S configuration or the R configuration, chiral centre *4 is in the S configuration or the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration or the R configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the S 25 configuration or the R configuration. In some embodiments, chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration or the R configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration or the R configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. In some embodiments, chiral 30 centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. In some embodiments, chiral centre *1 is in the S configuration, chiral centre *2 is in the R configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the 2024219610   11 Sep 2024 R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. In some embodiments, chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is 5 in the S configuration, chiral centre *6 is in the R configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. In some embodiments, chiral centre *1 is in the S configuration, chiral centre *2 is in the R configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the R configuration, chiral centre *7 is in the R configuration, and chiral centre 0    *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene- 15 C(O)OR18, wherein R18 is H or C1-6alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the 20 group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is 25 optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R4 is selected from the group consisting of: A.n nr90r91 n2 n (i)        0        , wherein each of R90 and R91 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl 30           is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents 2024219610   11 Sep 2024 10 15 each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n2 is 3 or 4; (ii)         0    , wherein R96 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, - OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n3 is 3 or 4; (iii) wherein each of R99 and R100 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n4 is 1 or 2; (iv) , wherein R103 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein 20 the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein n5 is 1 or 2; (v) , wherein R110 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, R111 is selected from the group 25 consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R110 or R111 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the 2024219610   11 Sep 2024 C6-10 aryl and 5- to 10-membered heteroaryl of R110 or R111 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and Ci-6alkoxy, and wherein n6 is 1 or 2; (vi) „R119 0 0 , wherein R119 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein n8 is 1 or 2; (vii) wherein each of R126 and R127 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the 15 C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n9 is 1 or 2; (viii) wherein: each of R134 and R135 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R136, and 20 -C(O)NR137R138, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n10 is 1 or 2, and wherein n11 25 is 1 or 2; R136 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 2024219610   11 Sep 2024 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy; and each of R137 and R138 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; 15 20 R144 y k vN' /  p145 \ / 12 (ix)     n            , wherein each of R144 and R145 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n12 is 1 or 2; kX.XX /  D146 \ / n 13      K (x)                      , wherein R146 is selected from the group consisting of C2-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C2-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n13 is 1 or 2; 25 (xi) O NHR150 , wherein R148 is H or CH3, R149 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and R150 is H, CH3 or acetyl, and wherein n14 is 1 or 2; and 2024219610   11 Sep 2024 ; X^cn \ / 15 (xii)      n         , wherein n15 is 1 or 2; R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, Ci-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is Ci-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the 5    C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy; each of R9, R10, R11, R12, R13, R14, and | —s—s— R15 is independently H or CH3; L is 5          5; and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, 0 chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene- 15 C(O)OR18, wherein R18 is H or C1-6 alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the 20 group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is 25 optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R4 is selected from the group consisting of: NR90R91 n2 n (i)        0        , wherein each of R90 and R91 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl 30           is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents 2024219610   11 Sep 2024 each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n2 is 3 or 4; (iii) 100 wherein each of R99 and R100 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n4 is 1 or 2; (iv) , wherein R103 is selected from the group consisting of C1-6 alkyl, 15 C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy, and wherein n5 is 1 or 2; (v) , wherein R110 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, R111 is selected from the group 20 25 consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R110 or R111 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl of R110 or R111 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n6 is 1 or 2; 2024219610   11 Sep 2024 ,. ,... (vi)                        , wherein R119 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy, and wherein the C6-10 aryl and 5- to 10-membered 5           heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy, and wherein n8 is 1 or 2; (viii) wherein: each of R134 and R135 is independently selected from 10           the group consisting of H, C1-6 alkyl, C6-10 aryl, 5- to 10-membered heteroaryl, -C(O)R136, and -C(O)NR137R138, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group 15           consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n10 is 1 or 2, and wherein n11 is 1 or 2; R136 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 20           alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; and each of R137 and R138 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with 25          one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy; 2024219610   11 Sep 2024 R144 / JvNr-(ix)                  , wherein each of R144 and R145 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6alkoxy, and 5- to 10membered heterocycloalkyl, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, C1-6 alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n12 is 1 or 2; and (xii)                , wherein n15 is 1 or 2; R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and £ —S—s— £ R15 is independently H or CH3; L is 5          *; and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6 alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting 2024219610   11 Sep 2024 of halogen, hydroxy, -NO2, and C1-6alkoxy; R3 is -Ci—3alkylene(C6—io aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R4 is selected from the group consisting of: aXX NR"R100 (iii)     n                , wherein each of R99 and R100 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n4 is 1 or 2; and H R110 f / ¥V1 ° \ / n6 (v)                          , wherein R110 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, R111 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl of R110 or R111 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl of R110 or R111 are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n6 is 1 or 2; 20    R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and 25    R15 is independently H or CH3; L is S S ^; and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure 30 of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected 15 from the group consisting of: (i) H; (ii) C1-6alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R4 is selected from the group consisting of: (iii) o '            nr"r100 n               , wherein each of R99 and R100 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein n4 is 1 or 2; and H R110 r^^Y^R111 O (v)      n                    , wherein R110 is selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and R111 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein n6 is 1 or 2; R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and R15 is £ —s~s— independently H or CH3; L is 5          , and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected 2024219610   11 Sep 2024 from the group consisting of: (i) H; (ii) C1-6alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R4 is selected from the group consisting of: (iii) o '            nr"r100 n               , wherein each of R99 and R100 is independently selected from the group H ,R110 0 consisting of H and C1-6 alkyl, and wherein n4 is 1 or 2; and (v)                          , wherein R110 is H, and R111 is C6 aryl, and wherein n6 is 1 or 2; R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally 20 substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally 15 substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and R15 is independently £ —s—s—i H or CH3; L is 5          5; and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, 25 chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6 alkyl; (iii) -C(O)R17, wherein R17 is selected from the group 30 consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene- 2024219610   11 Sep 2024 C(O)OR18, wherein R18 is H or C1-6alkyl; (v) -C(O)Ci—3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) 5   -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting 0 of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group nr"r100 consisting of halogen, hydroxy, -NO2, and C1-6alkoxy; R4 is: (iii)     n                , wherein each of R99 and R100 is independently selected from the group consisting of H and C1-6 alkyl, and wherein n4 is 1 or 2; R5 is -NR79R80 and each of R79 and R80 is independently selected from the group 15 consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and R15 is independently H or CH3; L is S S ^; and chiral centre 20    *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure 25 of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6 alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein 30    R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)Ci—3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-w aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy; R3 is -C1-3alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy; R4 is: (iii) 100 wherein each of R99 and R100 is H, and wherein n4 is 1 or 2; R5 is -NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1- 6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-w aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, - NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and R15 is independently H or CH3; L is £ —s—s—£ 5          5; and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6 alkyl; (iii) -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6 alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group 2024219610   11 Sep 2024 o consisting of halogen, hydroxy, -NO2, and C1-6alkoxy; R4 is                  or H H . f ¥ n 1 j 0     >■ ; R5 is —NR79R80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 alkyl optionally substituted with hydroxyl; R8 is -C1-3 5 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; each of R9, R10, R11, R12, R13, R14, and R15is independently H or CH3; L is S S ^; and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, 10 chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NHR16, wherein R16 is H or C1-6 alkyl; RN is selected from the group consisting of: (i) H; (ii) C1-6alkyl; (iii) -C(O)R17, wherein R17 is selected 15 from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; (iv) -C(O)C1-3 alkylene-C(O)OR18, wherein R18 is H or C1-6alkyl; (v) -C(O)C1-3 alkylene-N(R20)C(O)R19, wherein R19 is selected from the group consisting of C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R20 is H or C1-6alkyl; (vi) -C(O)C1-3 alkylene-NR21R22, wherein each of R21 and R22 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered 20 heteroaryl; (vii) -C(O)C1-3 alkylene-C(O)NR23R24, wherein each of R23 and R24 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and (viii) -C(O)C1-3 alkylene-S(O)2R25, wherein R25 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; R1 is -C1-3 alkylene(C6-w aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the group 25 consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R3 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is optionally substituted with one or more substituents each independently selected from the 0 group consisting of halogen, hydroxy, -NO2, and C1-6 alkoxy; R4 isf / ¥ / ¥¥       ; R5 is -nr79r80 and each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H; n1 is 3 or 4; R6 is C1-6 30 alkyl optionally substituted with hydroxyl; R8 is -C1-3 alkylene(C6-10 aryl), wherein the C6-10 aryl is 2024219610   11 Sep 2024 optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, -NO2, and C1-6alkoxy; each of R9, R10, R11, R12, R13, R14, and R15 is £ —s~s— independently H or CH3; L is 5          , and chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration. Illustrative embodiments of the present invention include a compound having the structure of Formula I or a salt thereof, wherein: RC is OH or NH2; RN is selected from the group consisting of H, C1-3 alkyl, -C(O)R17, -C(O)C1-3 alkylene-C(O)OR18, -C(O)C1-3 alkylene-N(R20)C(O)R19, -C(O)C1-3 alkylene-NR21R22, -C(O)C1-3 alkylene-C(O)NR23R24, and -C(O)C1-3 alkylene-S(O)2R25, wherein R17 is C1-6 alkyl or 5- to 6-membered heteroaryl, R18 is C1-3 alkyl, R19 is C1-3 alkyl or C6 aryl, each of R20, R21, 15 R22, R23 and R24 is H, and R25 is C6 aryl; R1 is                , wherein R88 is H, halogen, hydroxyl or C1-3 ^\.R89 / X. JJ alkoxy; R3 is9^           , wherein R89 is H, halogen, hydroxyl or C1-3 alkoxy; R4 is selected from the group consisting of: nr90r91 n2 n (i)        0        , wherein each of R90 and R91 is independently selected from the group consisting of H, C1-6 alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents 20          each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and wherein n2 is 3 or 4; A<>N^R96 Ai3 H (ii)         0    , wherein R96 is selected from the group consisting of C1-6alkyl, C6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, - 25           OH, -NO2, and C1-6 alkoxy, and wherein the C6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -NO2, and C1-6 alkoxy, and w...

Claims

1. A method of treating Type II diabetes in a subject, the method comprisingadministering to the subject an effective amount of a compound having the structure of Formula I:rnFormula Ior a salt thereof, wherein:RC is OH or NHR16, wherein R16 is H or C1-6 alkyl;RN is selected from the group consisting of:(i)          H;(ii)       -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl,and 5- to 6-membered heteroaryl;(iii)         C1-6 alkyl;(iv)      -C(O)Ci-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl;(v)      -C(O)Ci-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the groupconsisting of C1-6 alkyl, and C6-10 aryl, and wherein R20 is H or C1-6 alkyl;(vi)      -C(O)Ci-6 alkylene-NR21R22, wherein each of R21 and R22 is independentlyselected from the group consisting of H, and C1-6 alkyl;(vii)     -C(O)Ci-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 isindependently selected from the group consisting of H, and C1-6 alkyl;(viii)     -C(O)Ci-6 alkylene-S(O)2R25, wherein R25 is C6 aryl; and(ix)       -S(O)2R26, wherein R26 is selected from the group consisting of C1-6 alkyl,and C6 aryl;R1 is -C1-6alkylene(C6 aryl)-R88, wherein R88 is H, halogen, hydroxyl or C1-3 alkoxy;R3 is -C1-6alkylene(C6 aryl)- R89, wherein R89 is H, halogen, hydroxyl or C1-3 alkoxy;R4 is selected from the group consisting of:2024219610   30 Jun 2026(i)       -C1-6 alkylene-(C6 arylene)-C(O)NR56R57,wherein each of R56 and R57 is independently selected from the group consisting ofH, and C1-6 alkyl;(ii)       -C1-6 alkylene-(C6 arylene)-N(R62)C(O)NR60R61,wherein R60 is H or C1-6 alkyl, wherein R61 is C6 aryl which is optionally substituted with C1-6 alkoxy, and wherein R62 is H or C1-6 alkyl;(iii)      -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51, R52 and R53 isindependently selected from the group consisting of H, and C1-6 alkyl;(v)      -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is 5- to 6-membered heteroaryl,and wherein R55 is H or C1-6 alkyl;(vi)      —C1-6 alkylene-(C6 arylene)-N(R59)C(O)R58, wherein R58 is selected fromthe group consisting of C6 aryl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl, and wherein R59 is H or C1-6 alkyl;(v)      -C1-6 alkylene-(C6 arylene)-N(R64)SO2R63, wherein R63 is C6 aryl, andwherein R64 is H or C1-6 alkyl;(vi)      -C1-6 alkylene-(C6-10 arylene)-(C1-6 alkylene)-NR67R68, wherein:each of R67 and R68 is independently selected from the group consisting of H, -C(O)R69, and -C(O)NR70R71;R69 is C1-6 alkyl; andeach of R70 and R71 is independently H, or C1-6 alkyl;(vii)     -C1-6 alkylene-(C6 arylene)-NR72R73, wherein each of R72 and R73 isindependently selected from the group consisting of H, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 5- to 10-membered heterocycloalkyl;(viii)     —C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from thegroup consisting of H, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 5- to 10-membered heterocycloalkyl;(ix)      -C1-6 alkylene-(C6 arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 isH or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl; and(x)      -C1-6 alkylene-(C6 arylene)-CN;R5 is selected from the group consisting of:(i) -NR79R80, wherein each of R79 and R80 is independently selected from the group consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein2024219610   30 Jun 2026R81 is C1-6 alkyl, and wherein each of R82, R83, and R84 is independently selected from the group consisting of H, and C1-6 alkyl;n1 is 2, 3, 4, or 5;R6 is C1-6 alkyl optionally substituted with hydroxyl;R8 is -C1-6 alkylene(C6 aryl) - R151, wherein R151 is H, halogen, hydroxyl or C1-3 alkoxy;R9 is H or C1-6 alkyl;R10 is H or C1-6 alkyl;R11 is H or C1-6 alkyl;R12 is H or C1-6 alkyl;R13 is H or C1-6 alkyl;R14 is H or C1-6 alkyl;R15 is H or C1-6 alkyl; andL is selected from the group consisting of:i) Hs-s-Liii)iv)Xv)        H , wherein X is S or O; andN=Nvi)chiral centre *1 is in the S configuration or the R configuration;chiral centre *2 is in the S configuration or the R configuration;chiral centre *3 is in the S configuration or the R configuration;chiral centre *4 is in the S configuration or the R configuration;chiral centre *5 is in the S configuration or the R configuration;chiral centre *6 is in the S configuration or the R configuration;chiral centre *7 is in the S configuration or the R configuration; andchiral centre *8 is in the S configuration or the R configuration.

2. The method of claim 1, wherein R4 is:(i)       -C1-2 alkylene-(C6 arylene)-C(O)NR56R57, wherein each of R56 and R57 isH;2024219610   30 Jun 2026(ii)       -C1-2 alkylene-(C6 arylene)-N(R62)C(O)NR60R61, wherein each of R60 andR62 is H, and wherein R61 is C6 aryl which is optionally substituted with -OCH3; or (iii)       -C1-2 alkylene-(C6 arylene)-(C1-2 alkylene)-NR67R68, wherein R67 is H, andR68 is -C(O)NR70R71, wherein each of R70 and R71 is H.

3. The method of claim 2, wherein R4 isCH2-NHC(O)NH24.      The method of any one of claims 1 to 4, wherein R4 is -NR79R80 and each of R79and R80 is independently selected from the group consisting of H, C1-6alkyl, -C(O) R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl and each of R82, R83, and R84 is H.

5. The method of claim 4, wherein R5 is -NH2, -NHCH3 or -N(CH3)2.

6. The method of any one of claims 1 to 5, wherein n1 is 3 or 4.

7. The method of any one of claims 1 to 6, wherein RC is OH or NH2.

8. The method of any one of claims 1 to 7, wherein RN is H.r889.      The method of any one of claims 1 to 8, wherein R1 is / \ / ^^    , wherein R88 isH, halogen, hydroxyl or C1-3 alkoxy.^\^R8910.     The method of any one of claims 1 to 9, wherein R3 is, wherein R89 isH, halogen, hydroxyl or C1-3 alkoxy.

11. The method of any one of claims 1 to 10, wherein R6 is selected from the groupconsisting of -CH(CH3)OH, -CH(CH3)2, -C(CH3)3, -CH2OH and -CH2CH3.2024219610   30 Jun 202612.The method of any one of claims 1 to 11, wherein R8 iswherein R151is H, halogen, hydroxyl or C1-3 alkoxy.

13. The method of any one of claims 1 to 12, wherein each of R9, R10, R11, R13, R14,and R15 is H.

14. The method of any one of claims 1 to 13, wherein R12 is H or CH3.I —s—s—I15.     The method of any one of claims 1 to 14, wherein L is 5        5.

16. The method of any one of claims 1 to 15, wherein chiral centre *1 is in the Sconfiguration, chiral centre *2 is in the S configuration, chiral centre *3 is in the Sconfiguration, chiral centre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre *7 is in the Rconfiguration, and chiral centre *8 is in the R configuration.2024219610   30 Jun 20262 Cl (X Y       OH I xNH2 Jy X  (J 0 VH H J H0Y7   A Y / Y    y o A ~^A 0 S         NH        0 h2n. X JL J Z°H oY,,       A 2 A n a—- o A      N NH II H I - 11          I                                 H 0     HN.     A .NH n N Y A H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-HoCit-Lys-Thr-Cys]-D-Tyr-NH2 3 Cl (X A     OH L ,xnh2 Jy X C J 0 H Y ha A A    y o A A 0 S     0^ NH       0 H2N.        J zOH               -^\ / Y 2 Y N Y—- 0            N Y 'N o H hn^A XXh      h Xy1 >1 N A o H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Lys(Ne-nicotinoyl)-Lys-Thr-Cys]-D-Tyr-NH2 4 Cl fj Y        0H X -'NH2 yX X O 0 YH H T Hon A-v ? Y / Y       0 A     A A 0 S      O^ NH Y II NH2 H!MynAA"o Y 0 H HN. A / XaH N y A H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH22024219610   30 Jun 20265 Cl Y       OH L ,xNH2 / k X  (J 0     H T H°n Av kA      o A )   0 S            NH Y II NH2 H’N A A 'A A 0 H HN. A A ,NH Y n y A H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-aminomethyl)-Lys-Thr-Cys]-D-Tyr-NH2 6 Cl 0 A     OH L anh2 A. X t J 0 AH H T V AV  £ AJA      0 A      A Y 0 S      0^ NH Y IT N H.N / .Y„YOHo oY ’-A h 0 H HN„ A A ^NH kl N Y 0 H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-acetamidomethyl)-Lys-Thr-Cys]-D-Tyr- NH2 7 ci (j Y        0H L ^nh2 X (J 0 AH H T "Y1             i Y O S     0^ NH Ykr N NH2 hany,yoho “Y-A h O H HN.     A .NH Y n A 0 H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-ureidomethyl)-Lys-Thr-Cys]-D-Tyr-NH22024219610   30 Jun 20268 Cl (j X     OH l.NH2 / L X  (J 0 T h T hx           « X           0 X       , N... o s      o^nh y n n NH2 X""^ 0 0 H HN^X Y ^NH n n Y o H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Gly)-Lys-Thr-Cys]-D-Tyr-NH2 9 Cl (X Y     OH L ,xNH2 / k X   (J 0 Y H y Y\ / ny XX      Xy X    h I? XY^ o s-s 0 qYnh Y?YN'Y'N H2NyX\"X0H0 0^-,     o H 0 H HN. X Y^NH n n y o H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-4-(Gly-Ac)Aph-Lys-Thr-Cys]-D-Tyr-NH2 10 Cl (X Y        0H L ,'NH2 / k X  (J 0 T H y H°x X H o h^yjyhx^X s h 0 H HN. X Y ^NH n n y A H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Pro)-Lys-Thr-Cys]-D-Tyr-NH22024219610   30 Jun 202611 Cl fj Y        OH L ,nh2 / L X J J 0    H T HOn             « 0 S'S 0 O^NH YAX^^ H2N0^.,. 0 H HN. A A NH n n Y o H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Aph(2-(4-morpholinyl)ethyl)-Lys-Thr-Cys]-D- Tyr-NH2 12 Cl (j Y        OH X.NH2 A. X   (j 0 XH h T Hon             « XX\ Q s-s 0 cXNH "AAA A O H HN. A A ,NH H N Y A H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-n-pentylamino)-Lys-Thr-Cys]-D-Tyr-NH2 13 I o < / X °A / = / IZ * h° Z—(               / =\ O=^ I '—w     o ,—L \—o / ■"X IZ   O    \_z  z \_1   _ / I   I / =O / —Y o O ZI T / b o 02024219610   30 Jun 2026H-Cpa-cyclo[D-Cys-Tyr-D-Tyr(2-(4-morpholinyl)ethyl)-Lys-Thr-Cys]-D-Tyr-NH214H-Cpa-cyclo[D-Cys-Tyr-D-Aph(benzenesulfonyl)-Lys-Thr-Cys]-D-Tyr-NH215H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-phenylureido)-Lys-Thr-Cys]-D-Tyr-NH2162024219610   30 Jun 2026H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Ser)-Lys-Thr-Cys]-D-Tyr-NH217H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Lys)-Lys-Thr-Cys]-D-Tyr-NH2182024219610   30 Jun 202619H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Asp)-Lys-Thr-Cys]-D-Tyr-NH2H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Asn)-Lys-Thr-Cys]-D-Tyr-NH220H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Glu)-Lys-Thr-Cys]-D-Tyr-NH22024219610   30 Jun 202621 Cl (j A     OH L ^NH2 / k °X H U A2 “A             H = YA\     .S O A » o s     0 NH YA Y NH2 H2Nyl^.YAY O^ „z     o 0 H HN^A Ya X N A 0 H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Gln)-Lys-Thr-Cys]-D-Tyr-NH2 22 Cl 0 A     OH L s\NH2    Y. ]                      fl 1                                           H A    \A         .N„^NH2 0 nh h t          r y HO.         A.AA        / 0 A H          I Y I         H ? AA^     xS o A     ^n.^. o S    0^ NH YY Y nh2 h2n^.^        0^,.      0 o H HN^A -Y^NH n N t H I nh2 H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Cit)-Lys-Thr-Cys]-D-Tyr-NH2 23 Cl (j "A      OH L ^nh2 X  (J 0 Y H T H°n ay „ v- A 0 S    0^ NH YA A NH2 H2NylNJ^.YY°H0 °^'X^ 0 O H HN. A Y^NH >T N A A H I nh22024219610   30 Jun 2026H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Val)-Lys-Thr-Cys]-D-Tyr-NH2 24 Cl (j Y    OH L ,xNH2 / k J o °yh h t "Vi / Y ? 0 S            NH      if nh2 h^n / n^-^OHo V"" II H                        -           || I 0     HN.,^^ n N T ... X HN^ H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr- NH2 25 Cl (j OH L xnh2     / L X o O^^NH H0XY      y’x^^ Il 1                               H                              H H >  0  S        NH Y X Y tT Y h2n^J\ JL J / 0H o^X, JLJ o  YY o     HN. Y\ X ^NH ri    N Y^ II        H 1 0 \ HN^ H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-phenylureido)-Lys(N£-Me)-Thr-Cys]-D- Tyr-NH2262024219610   30 Jun 2026H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Ac)-Thr-Cys]-D-Tyr-NH227H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-benzamidophenyl)-Lys-Thr-Cys]-D-Tyr-NH2282024219610   30 Jun 2026H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-(4-methoxyphenyl)ureido)-Lys-Thr-Cys]-D-Tyr-NH229H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Arg-Thr-Cys]-D-Tyr-NH230H-Cpa-cyclo[D-Cys-Tyr-D-Lys(Ne-nicotinoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH2312024219610   30 Jun 2026H-Cpa-cyclo[D-Cys-Tyr-D-Cit-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH232H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-diMe)-Thr-Cys]-D-Tyr-NH22024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 2026492024219610   30 Jun 2026H-P-Ala-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH250HN,.Ph(CO)NHCH2(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH22024219610   30 Jun 202651                                  ciHNPhSO2CH2(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH252                              ciHN^t-BuCH2(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH2532024219610   30 Jun 20262-Pyridyl(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH254H2N(CO)(CH2)2(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH2552024219610   30 Jun 2026Ac-Gly-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH256CH3(CH2)4(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH2572024219610   30 Jun 2026(Furan-2-carboxy)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH258CH3O2C(CH2)2(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(Ne-Me)-Thr-Cys]-D-Tyr-NH2343344345346712024219610   30 Jun 202672H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-(Na-Me)Lys-Thr-Cys]-D-Tyr-NH2732024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 20262024219610   30 Jun 202618.    A pharmaceutical composition comprising a compound having the structure ofFormula I and a pharmaceutically acceptable carrier:Formula Ior a salt thereof, wherein:RC is OH or NHR16, wherein R16 is H or C1-6 alkyl;RN is selected from the group consisting of:(i)         H;(ii)       -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl,and 5- to 6-membered heteroaryl;(iii)       C1-6 alkyl;(iv)     -C(O)Ci-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl;(v)      -C(O)Ci-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the groupconsisting of C1-6 alkyl, and C6-10 aryl, and wherein R20 is H or C1-6 alkyl;2024219610   30 Jun 2026(vi)      -C(O)Ci-6 alkylene-NR21R22, wherein each of R21 and R22 is independentlyselected from the group consisting of H, and C1-6 alkyl;(vii)     -C(O)Ci-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 isindependently selected from the group consisting of H, and C1-6 alkyl;(viii)     -C(O)Ci-6 alkylene-S(O)2R25, wherein R25 is C6 aryl; and(ix)       -S(O)2R26, wherein R26 is selected from the group consisting of C1-6 alkyl,and C6 aryl;R1 is -C1-6alkylene(C6 aryl)-R88, wherein R88 is H, halogen, hydroxyl or C1-3 alkoxy;R3 is -C1-6alkylene(C6 aryl)- R89, wherein R89 is H, halogen, hydroxyl or C1-3 alkoxy;R4 is selected from the group consisting of:(i)       -C1-6 alkylene-(C6 arylene)-C(O)NR56R57,wherein each of R56 and R57 is independently selected from the group consisting of H, and C1-6 alkyl;(ii)      -C1-6 alkylene-(C6 arylene)-N(R62)C(O)NR60R61,wherein R60 is H or C1-6 alkyl, wherein R61 is C6 aryl which is optionally substituted with C1-6 alkoxy, and wherein R62 is H or C1-6 alkyl;(iii)      -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51, R52, and R53 isindependently selected from the group consisting of H, and C1-6 alkyl;(v)      -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is 5- to 6-membered heteroaryl,and wherein R55 is H or C1-6 alkyl;(vi)      -C1-6 alkylene-(C6 arylene)-N(R59)C(O)R58, wherein R58 is selected fromthe group consisting of C6 aryl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl, and wherein R59 is H or C1-6 alkyl;(vii)     -C1-6 alkylene-(C6 arylene)-N(R64)SO2R63, wherein R63 C6 aryl, andwherein R64 is H or C1-6 alkyl;(ix)      -C1-6 alkylene-(C6 arylene)-(C1-6 alkylene)-NR67R68, wherein:each of R67 and R68 is independently selected from the group consisting of H, -C(O)R69, and -C(O)NR70R71;R69 is C1-6 alkyl; andeach of R70 and R71 is independently H, or C1-6 alkyl;(x)        -C1-6 alkylene-(C6 arylene)-NR72R73, wherein each of R72 and R73 isindependently selected from the group consisting of H, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 5- to 10-membered heterocycloalkyl;(xi)      -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the groupconsisting of H, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 5-to 10-membered heterocycloalkyl ;2024219610   30 Jun 2026(xii)     -C1-6 alkylene-(C6 arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 isH or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 oracetyl; and(xiii)     -C1-6 alkylene-(C6 arylene)-CN;R5 is selected from the group consisting of:(i)       -NR79R80, wherein each of R79 and R80 is independently selected from thegroup consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is C1-6 alkyl, and wherein each of R82, R83, and R84 is independently selected from thegroup consisting of H, and C1-6 alkyl; n1 is 2, 3, 4, or 5;R6 is C1-6 alkyl optionally substituted with hydroxyl;R8is -C1-6 alkylene(C6 aryl) - R151, wherein R151 is H, halogen, hydroxyl or C1-3 alkoxy;R9 is H or C1-6 alkyl;R10 is H or C1-6 alkyl;R11 is H or C1-6 alkyl;R12 is H or C1-6 alkyl;R13 is H or C1-6 alkyl;R14 is H or C1-6 alkyl;R15 is H or C1-6 alkyl; andL is selected from the group consisting of:i) Hs-s-Liii)iv)Xvi)        H , wherein X is S or O; andvii)chiral centre *1 is in the S configuration or the R configuration;chiral centre *2 is in the S configuration or the R configuration;chiral centre *3 is in the S configuration or the R configuration;chiral centre *4 is in the S configuration or the R configuration;2024219610   30 Jun 2026chiral centre *5 is in the S configuration or the R configuration;chiral centre *6 is in the S configuration or the R configuration;chiral centre *7 is in the S configuration or the R configuration; andchiral centre *8 is in the S configuration or the R configuration.

19. Use of a compound having the structure of Formula I in the manufacture of amedicament for treating Type II diabetes in a subject:Formula Ior a salt thereof, wherein:RC is OH or NHR16, wherein R16 is H or C1-6 alkyl;RN is selected from the group consisting of:(i)         H;(ii)       -C(O)R17, wherein R17 is selected from the group consisting of C1-6 alkyl,and 5- to 6-membered heteroaryl;(iii)       C1-6 alkyl;(iv)     -C(O)Ci-6 alkylene-C(O)OR18, wherein R18 is H or C1-6 alkyl;(v)      -C(O)Ci-6 alkylene-N(R20)C(O)R19, wherein R19 is selected from the groupconsisting of C1-6 alkyl, and C6-10 aryl, and wherein R20 is H or C1-6 alkyl;(vi)      -C(O)Ci-6 alkylene-NR21R22, wherein each of R21 and R22 is independentlyselected from the group consisting of H, and C1-6 alkyl;(vii)     -C(O)Ci-6 alkylene-C(O)NR23R24, wherein each of R23 and R24 isindependently selected from the group consisting of H, and C1-6 alkyl;(viii)     -C(O)Ci-6 alkylene-S(O)2R25, wherein R25 is C6 aryl; and(ix)       -S(O)2R26, wherein R26 is selected from the group consisting of C1-6 alkyl,and C6 aryl;R1 is -C1-6alkylene(C6 aryl)-R88, wherein R88 is H, halogen, hydroxyl or C1-3 alkoxy;R3 is -C1-6alkylene(C6 aryl)- R89, wherein R89 is H, halogen, hydroxyl or C1-3 alkoxy;2024219610   30 Jun 2026R4 is selected from the group consisting of:(i)       -C1-6 alkylene-(C6 arylene)-C(O)NR56R57,wherein each of R56 and R57 is independently selected from the group consisting ofH, and C1-6 alkyl;(ii)       -C1-6 alkylene-(C6 arylene)-N(R62)C(O)NR60R61,wherein R60 is H or C1-6 alkyl, wherein R61 is C6 aryl which is optionally substituted with C1-6 alkoxy, and wherein R62 is H or C1-6 alkyl;(iii)      -C1-6 alkylene-N(R53)C(O)NR51R52, wherein each of R51, R52, and R53 isindependently selected from the group consisting of H, and C1-6 alkyl;(v)      -C1-6 alkylene-N(R55)C(O)R54, wherein R54 is 5- to 6-membered heteroaryl,and wherein R55 is H or C1-6 alkyl;(vi)      -C1-6 alkylene-(C6 arylene)-N(R59)C(O)R58, wherein R58 is selected fromthe group consisting of C6 aryl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl, and wherein R59 is H or C1-6 alkyl;(vii)     -C1-6 alkylene-(C6 arylene)-N(R64)SO2R63, wherein R63 C6 aryl, andwherein R64 is H or C1-6 alkyl;(ix)      -C1-6 alkylene-(C6 arylene)-(C1-6 alkylene)-NR67R68, wherein:each of R67 and R68 is independently selected from the group consisting of H, -C(O)R69, and -C(O)NR70R71;R69 is C1-6 alkyl; andeach of R70 and R71 is independently H, or C1-6 alkyl;(x)        -C1-6 alkylene-(C6 arylene)-NR72R73, wherein each of R72 and R73 isindependently selected from the group consisting of H, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 5- to 10-membered heterocycloalkyl;(xi)      -C1-6 alkylene-(C6-10 arylene)-OR74, wherein R74 is selected from the groupconsisting of H, and C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 5-to 10-membered heterocycloalkyl ;(xii)     -C1-6 alkylene-(C6 arylene)-N(R75)-C(O)-CHR76-NR77R78, wherein R75 isH or CH3, R76 is H or C1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, -COOH, -NH2, -C(O)NH2, and -N(H)C(O)NH2, and each of R77 and R78 is independently H, CH3 or acetyl; and(xiii)     -C1-6 alkylene-(C6 arylene)-CN;R5 is selected from the group consisting of:(i)       -NR79R80, wherein each of R79 and R80 is independently selected from thegroup consisting of H, C1-6 alkyl, -C(O)R81, and -C(=NR82)NR83R84, wherein R81 is 3562024219610   30 Jun 2026C1-6 alkyl, and wherein each of R82, R83, and R84 is independently selected from the group consisting of H, and C1-6 alkyl;n1 is 2, 3, 4, or 5;R6 is C1-6 alkyl optionally substituted with hydroxyl;R8 is -C1-6 alkylene(C6 aryl) - R151, wherein R151 is H, halogen, hydroxyl or C1-3 alkoxy;R9 is H or C1-6 alkyl;R10 is H or C1-6 alkyl;R11 is H or C1-6 alkyl;R12 is H or C1-6 alkyl;R13 is H or C1-6 alkyl;R14 is H or C1-6 alkyl;R15 is H or C1-6 alkyl; andL is selected from the group consisting of:i) Hs-s-Liii)iv)Xvi)        H , wherein X is S or O; andvii) n=n ;chiral centre *1 is in the S configuration or the R configuration;chiral centre *2 is in the S configuration or the R configuration;chiral centre *3 is in the S configuration or the R configuration;chiral centre *4 is in the S configuration or the R configuration;chiral centre *5 is in the S configuration or the R configuration;chiral centre *6 is in the S configuration or the R configuration;chiral centre *7 is in the S configuration or the R configuration; andchiral centre *8 is in the S configuration or the R configuration.

20. The pharmaceutical composition of claim 18, or the use of claim 19, wherein thecompound of Formula I is as defined in any one of claims 2 to 17.

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