Combination of a menin inhibitor with a pyrazolopiperidine GLP-1 receptor agonist for treating diabetes and obesity

Abstract

Disclosed herein are combinations comprising an GLP-1R agonist and an inhibitor of menin. Also described are combinations of specific GLP-1R agonists and irreversible inhibitors or reversible inhibitors of menin. Also described are methods of using the combinations for the treatment of diabetes, obesity and overweight condition.

Description

122787.00374BMEA-053PCTMENIN INHIBITOR COMBINATION THERAPY FOR DIABETES AND COMPOSITIONSTHEREFORCROSS-REFERENCE

[0001] This application claims the benefit of US provisional application nos. 63 / 712,737, filed October 28, 2024, and 63 / 691,184, filed September 5, 2024, the contents of which are hereby incorporated in their entireties.FIELD

[0002] Described herein are combination therapies comprising a GLP-1R agonist and a menin inhibitor, compositions for the therapies, and methods of using such combinations to treat diabetes or obesity.BACKGROUND

[0003] Diabetes is a chronic condition and a major public health concern due to its high prevalence and health risks (Sakran N. et al, BMC Endocrine Disorders, 2022, 22, 9). The condition is primarily manifested by the high levels of glucose in blood, that occurs when the body cannot produce enough insulin, effectively use available insulin or both. Pancreatic [3 cells are primarily responsible for the production of insulin. In diabetic patients, high levels of glucose can cause serious damage to many organs over time. There are two common forms of diabetes: Type 1 and Type 2. Type 1 diabetes (T1D) is the result of body’s immune system destroying [3 cells. Type 2 diabetes (T2D), on the other hand, develops when the body does not produce enough insulin and / or develops a resistance to the actions of insulin. Patients with T2D have been shown to have significantly higher risks of coronary related diseases in addition to many other life-threatening diseases. Obesity is also a highly prevalent chronic condition and is associated with the development of many diseases including stroke, heart disease, hypertension, and some cancers (Del Prato S. Obesity Rev. 2022, 23). Importantly, obesity has been found to correlate directly with T2D and insulin resistance.

[0004] Incretin hormones modulate glucose metabolism by stimulating the release of insulin by pancreatic [3 cells. One of the incretin hormones, glucagon -like-peptide-1 (GEP-1) exerts its effects to induce glucose-stimulated insulin secretion and lower glucose through its receptor (Seino Y. et al. J. Diabet. Inv., 2010, 1 (1 / 2), 8-23). GEP-1 is athirty-one amino acid hormone which is secreted from intestinal L-cells. GLP-1 binds to GLP-1 receptor (GLP-1R), a GPCR, which is particularly expressed in pancreatic [3 cells and other metabolically relevant tissues. GLP-1 undergoes rapid proteolytic digestion by dipeptidyl peptidase-4 (DPP -4) and has a relatively short half-life of few minutes. Binding of GLP-1 to its receptor activates a cascade of signaling pathways including activation of adenylate cyclase and an increase of cyclic adenosine monophosphate (cAMP) in [3 cells, which then lead to stimulation of insulin. Additionally, GLP-1 has anti-apoptotic function in pancreatic [3 cells, and it can enhance [3 cell proliferation and delay gastric emptying. GLP-1 can also stimulate the proliferation of [3 cells, which happens through activation of RAF / MEK / ERK and PI3K pathways. Both anti-apoptotic and proliferative effects of GLP-1 can have clinical implication for the treatment of patients with diabetes and obesity.Page 1 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0005] Diabetes and obesity together represent one of the most preventable causes of premature complications including death. Various pharmacological approaches have been developed to treat diabetes. One of such approaches has been the application of GLP-1R agonists, which increase the secretion of insulin through binding to GLP-1R on pancreatic (3 cells. GLP-1R agonist

[0006] Menin inhibitors could provide potential additional therapeutics for the treatment of diabetes. Menin is thought to act as a control on beta cell turnover / beta cell growth (Hughs et al. Endocrinology, March 2011, 152(3):847-855), and it has previously been shown that knocking out the gene responsible for the production of menin (MEN1) results in profound glycemic control in diabetic animal models (Yang et al., 2010, 107 (47) 20358-20363. Also, menin is a repressor for the GLP-1 receptor expression. Consequent to menin inhibition an increased GLP-1 receptor expression has been observed and additivity with GLP-1 RA follows.SUMMARY

[0007] In one aspect, described herein are combination therapies comprising an GLP-1 R agonist and an inhibitor of menin. In some embodiments, the GLP-1R agonists are peptides. In some embodiments, the GLP-1R agonists are non-peptides.

[0008] In another aspect, described herein are methods for using such combinations of GLP-1 R agonists and menin inhibitors in the treatment of diabetes. In certain embodiments, the GLP-1R agonist and menin inhibitor are administered in separate compositions. Lor example, in certain embodiments, the GLP-1R agonist is administered in a first composition according to a first schedule, and the menin inhibitor is administered in a second composition according to a second schedule. In other embodiments, the GLP-1 R agonist and the menin inhibitor are administered in the same composition. In certain particular embodiments, the menin inhibitor is administered in a first composition according to a first schedule, and the GLP-1 R agonist is administered in a second composition according to a second schedule.Accordingly, further described are pharmaceutical compositions that comprise an GLP-1R agonist, an inhibitor of menin, and one or more pharmaceutically acceptable carriers, excipients, or diluents. In certain embodiments, the combinations and pharmaceutical compositions described herein are used for the treatment of diabetes. In certain embodiments, the combinations and pharmaceutical compositions described herein are used for the treatment of obesity and overweight condition.

[0009] The GLP-1 R agonist can be any GLP-1 R agonist known to the person of skill, including combinations thereof. In certain embodiments, the GLP-1 R agonist is a GIP / GLP-1 dual receptor agonist. In certain embodiments, the GLP-1R agonist is a GIL / GLP-1 / glucagon receptor triple agonist. In certain embodiments, the GLP-1 R agonist is an amylin receptor and GLP-1 receptor co-agonist, or a combination comprising an an amylin receptor agonist and a GLP-1 receptor agonist. In some embodiments, the GLP- 1R agonist is albiglutide (Tanzeum®), dulaglutide (Trulicity®), exenatide (Byetta®), exenatide extended- release (Bydureon®), liraglutide (Victoza®), liraglutide (Saxenda®), lixisenatide (Adlyxin®), semaglutide injection, (Ozempic®), semaglutide (Rybelsus®), tirzepatide (Mounjaro®), tirzepatide (Zepbound®), retatrutide (LY3437943®), AMG 133, CagriSema, Cagrilintide, danuglipron, orforglipron, lotiglipron, ID110521156, GS-4571, TERN-601, aleniglipron,, ECC5005 (AZD5004), ASC30, MWN109,Page 2 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTHS-I0535, CT-996, KAI-9531, KAI-7535, KAI 9531, KAI-4729, or TTP273, or a combination thereof. In certain embodiments, provided herein are combinations comprising a menin inhibitor and an amylin receptor agonist. In certain embodiments, the amylin receptor agonist is cagrilintide.

[0010] In some embodiments, the GLP-1R agonist is liraglutide, dulaglutide, exenatide, semaglutide, or tirzepatide. In certain embodiments, the GLP-1R agonist is orforglipron.

[0011] In some embodiments, the GLP-1R agonist is a compound according to Formula (GL'-I) having the structure:or a stereoisomer or a pharmaceutically acceptable salt thereof, whereinCy1is substituted or unsubstituted 5,6-fused or 6,6-fused heteroaryl;Cy2is substituted or unsubstituted heteroaryl; or -Cy2-R’ is -C(O)-NR6a-(CH2)m-R1; and wherein R6ais H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3;Cy3is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is substituted or unsubstituted aryl or heteroaryl;R2is CN, or substituted or unsubstituted heteroaryl; each R3aand R3bis independently H, or substituted or unsubstituted alkyl; or R3aand R3bform an oxo; or R3aand R3bare joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; each R4is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, or arylsulfmyl; and n is 1, 2, 3, 4, or 5; each R5a, R5band R5cis independently H, or substituted or unsubstituted alkyl;Page 3 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT or R5aand R5bor R5aand R5care joined together to form a heterocycloalkyl; and wherein the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1 -3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1 -3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo.

[0012] In more particular embodiments, the compound is according to formula (lie):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0013] In more particular embodiments, the compound is according to formula (L-VIIIa), (L-VIIIb), (L- VIIIc), or (L-VIIId):Page 4 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTor a stereoisomer or a pharmaceutically acceptable salt thereof.

[0014] In more particular embodiments, the compound is according to formula (M-VIIa), (M-VIIb), (M- VIIc), or (M-VIId):Page 5 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTa pharmaceutically acceptable salt thereof.

[0015] In particular embodiments, the GLP-1R agonist is Table 1 Compound 36, 112, 211, 213, 214, 220, 225, 226, 302, 311, 313, 323, 406, 410, 427, 429, 433, 436, 437, 503, 518, 525, 606, 607, 610, 611,612, 614, 615, 618, 619, 703, 705, 707, 710, 711, 713, 714, 715, or 716. In more particular embodiments, the GLP-1R agonist is Table 1 Compound 36, or 214. In a most particular embodiments, the GLP-1R agonist is Table 1 Compound 214. In further particular embodiments, the GLP-1R agonist is a sodium salt of Compound 214. For avoidance of any doubt due to duplicate numbering, GLP-1R agonists are listed in Table 1 and menin inhibitors are listed in Table 2, Table 3, and Table 3.

[0016] In some embodiments, the menin inhibitor is a compound according to Formula (I) having the structure:or a pharmaceutically acceptable salt thereof, wherein:A is C or N;Cy is substituted or unsubstitutedPage 6 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTQ is N, -N(H)-, -O-, or -S-;Z is -CR5a= or -N=;X is -NR3a-, -C(R3b)2-, or -O-;Y is a single bond, -NR3a-, -C(R3b)2-, or -O-;W is -C(0)-, -S(0)-, or -S(O)2-; one of R1and R2is Cy2-N(H)C(O)-C(R6a)=C(R6b)(R6c) or CH2-Cy2-N(H)C(O)-C(R6a)=C(R6b)(R6c); and the other is H, Ci-6 alkyl, Ci-6 haloalkyl, halo, or CN;Cy2is an optionally substituted group selected from phenyl, pyridyl, or a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R3aand R3bis independently H or Ci-e alkyl; each R4aand R4bis independently H, halo, CN, OR, -N(R)2, -C(O)N(R)2,-NRC(O)R, -SO2R, -C(O)R, -CO2R, or an optionally substituted group selected from Ci-e alkyl, C3-7 cycloalkyl, a 4-7 membered heterocycloalkyl ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently H, or an optionally substituted group selected from Ci-e aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:Page 7 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;R5ais H, Ci-6 alkyl, Ci-ehaloalkyl, halo, or CN; each R6aand R6bis independently H or Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis H or substituted or unsubstituted Ci-6 alkyl; m is 1, 2, or 3; and n is 1, 2, 3, or 4.[0017j In some embodiments, the menin inhibitors are compounds according to Formula:Page 8 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTCompound 13 or a salt thereof.

[0018] In particular embodiments, the menin inhibitor is Compound 10 (BMF-219 or icovamenib).

[0019] In another aspect of the invention, provided herein are combinations of Compound 10 (BMF-219 or icovamenib), or any other menin inhibitor described herein, and Cobicistat

[0020] Any combination of the groups described above for the various variables is contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those set forth herein.

[0021] In certain embodiments, provided herein is a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier, diluent, and / or excipient; and ii) a GLP-1R agonist and / or a menin inhibitor provided herein.

[0022] In some embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of (i) a GLP-1R agonist; (ii) an inhibitor of menin, and (iii) a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of (i) a GLP-1R agonist; (ii) an inhibitor of menin, and (iii) a pharmaceutically acceptable carrier, excipient, or diluent.

[0023] In certain embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, and / or excipient and a GLP-1R agonist for administration in combination with a pharmaceutical composition comprising a menin inhibitor and a pharmaceutically acceptable carrier, diluent, and / or excipient and a menin inhibitor.

[0024] In some embodiments, the pharmaceutical compositions described herein are formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration. In some embodiments, provided herein are methods for preventing, treating or ameliorating in a mammal a disease or condition that is related to the aberrant activity of GLP-1R, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a combination comprising (i) a GLP-1R agonist or aPage 9 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT pharmaceutically acceptable salt thereof and (ii) an inhibitor of menin or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for preventing, treating or ameliorating in a mammal a disease or condition that is related to the aberrant activity of GLP-1R, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a combination comprising (i) a GLP-1R agonist of Formula (GL'-I) or a pharmaceutically acceptable salt thereof and (ii) an inhibitor of menin or a pharmaceutically acceptable salt thereof. In certain embodiments, the GLP-1R agonist and the menin inhibitor are administered separately, each in its own composition and according to its own schedule. In other embodiments, the GLP-1R agonist inhibitor and the menin inhibitor are administered in the same composition on the same schedule. In other embodiments, provided herein are methods for preventing, treating or ameliorating in a mammal a disease or condition that is related to GLP-1R which comprises administering to the mammal an effective disease-treating or condition-treating amount of a combination described herein.

[0025] In any of the aforementioned embodiments are some embodiments in which administration of the GLP-1R agonist in combination with the menin inhibitor is enteral, parenteral, or both, and wherein (a) an effective amount of the GLP-1R agonist and / or menin inhibitor is systemically administered to the mammal; (b) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered orally to the mammal; (c) an effective amount of the GLP-1R agonist and / or menin inhibitor is intravenously administered to the mammal; (d) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered by inhalation; (e) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered by nasal administration; (f) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered by injection to the mammal; (g) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered topically (dermal) to the mammal; (h) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered by ophthalmic administration; or (i) an effective amount of the GLP-1R agonist and / or menin inhibitor is administered rectally to the mammal.

[0026] In any of the aforementioned embodiments are some embodiments in which administration of the GLP-1R agonist in combination with the menin inhibitor comprises single administrations of an effective amount of the GLP-1R agonist and / or menin inhibitor including some embodiments in which (i) the GLP-1R agonist and / or menin inhibitor is administered once; (ii) the GLP-1R agonist and / or menin inhibitor is administered to the mammal multiple times over the span of one day; (iii) continually; or (iv) continuously.

[0027] In any of the aforementioned embodiments are some embodiments in which administration of the GLP-1R agonist in combination with the menin inhibitor comprises multiple administrations of an effective amount of the GLP-1R agonist and / or menin inhibitor, including some embodiments in which (i) the GLP-1R agonist and / or menin inhibitor is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the GLP-1R agonist and / or menin inhibitor is administered to the mammal every 8 hours. In some embodiments, the method comprises a drug holiday, wherein the administration of the GLP-1R agonist and / or menin inhibitor is temporarily suspended or the dose of the GLP-1R agonist and / or menin inhibitor being administered is temporarily reduced; at the end of the drugPage 10 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT holiday, dosing of the compound is resumed. The length of the drug holiday can vary from 2 days to 1 year.

[0028] In certain embodiments, provided herein are articles of manufacture including packaging material, a compound(s) or composition(s) thereof provided herein within the packaging material, and a label that indicates that the compound(s) or composition(s) is administered to treat a disease or condition.

[0029] Other objects, features, and advantages of the methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 shows Compound 36 increases the responsiveness of Type 2 diabetic donor islets to glucose stimulation. Islets from a Type 2 diabetic donor were cultured ex vivo for 8 days (1A) or 12 days (IB) were assayed for GSIS in the presence of compound 36 (cpd 36), orforglipron or DMSO. Basal insulin secretion, stimulated insulin secretion and secretion index were measured.

[0031] Figure 2 depicts Compound 36 (cpd 36) increases glucose-stimulated insulin secretion in islets from a non-diabetic donor. Donor islets cultured ex vivo were assayed for GSIS in the presence of compound 36 (cpd 36), orforglipron or DMSO. Basal insulin secretion, stimulated insulin secretion and secretion index were measured.

[0032] Figure 3 shows BMF-219 enhances glucose stimulated insulin secretion potentiated by peptide GIP / GLP-1 dual receptor agonist tirzepatide. Cadaver-derived islets were from a 38-yr non-diabetic white male (HbAlc 5.2%). Islets were cultured under glucotox conditions (8 mM glucose) in the presence or absence of BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence (white bar) or presence (grey bars) of 30 nM tirzepatide (TZP). Stimulated insulin secretion was expressed as normalized to total islet DNA (3 A) and normalized to basal insulin secretion at 2.8 mM glucose (3B). As observed, tirzepatide potentiated insulin secretion from the islets. In comparison, insulin secretion potentiated by tirzepatide was significantly increased when islets were cultured in the presence of BMF -219. These data support the exploration of combination treatment with menin inhibitor BMF -219 and GLP-1 receptor agonists for the treatment of diabetes. (Experiment 1, Figure 3A and Figure 3B).

[0033] Figure 4 shows BMF-219 enhances glucose stimulated insulin secretion potentiated by peptide GIP / GLP-1 dual receptor agonist tirzepatide. Cadaver-derived islets were from a 38-yr non-diabetic Asian male (HbAlc 5.7%). Islets were cultured under glucotox conditions (11 mM glucose) in the presence or absence of BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in thePage 11 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT absence (light grey bars) or presence (dark grey bars) of 30 nM tirzepatide (TZP). Stimulated insulin secretion was expressed as normalized to total islet DNA (4A) and normalized to basal insulin secretion at 2.8 mM glucose (4B). As observed, tirzepatide potentiated insulin secretion from the islets. In comparison, insulin secretion potentiated by tirzepatide was significantly increased when islets were cultured in the presence of BMF-219. These data support the exploration of combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists for the treatment of diabetes. (Experiment 2, Figure 4A and Figure 4B).

[0034] Figure 5 shows BMF-219 enhances glucose stimulated insulin secretion potentiated by GLP-1 receptor agonists. Cadaver-derived islets were from a 47-yr non-diabetic White male (HbAlc 5.2%). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (light grey bars) or presence (dark grey bars) of BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence or presence of 100 nM semaglutide or 400 nM orforglipron. Stimulated insulin secretion was expressed as normalized to total islet DNA (5 A) and normalized to basal insulin secretion at 2.8 mM glucose (5B). Insulin secretion potentiated by semaglutide and orforglipron was increased when islets were cultured in the presence of BMF -219. These data support the exploration of combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists for the treatment of diabetes. (Figure 5 A and Figure 5B).

[0035] Figure 6 shows BMF-219 enhances glucose stimulated insulin secretion potentiated by small molecule GLP-1 receptor agonist. Cadaver-derived islets were from a 44-yr Type 2 diabetic Hispanic male (HbAlc 6.5%, donor was managing his diabetes with diet). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (light grey bars) or presence (dark grey bars) of 0.3 pM BMF- 219 for 4 days. Size matched islets were selected and subjected to GSIS assay with BMF-219, orforglipron or Compound 36. Stimulated insulin secretion was expressed as normalized to total islet DNA (6A) and normalized to basal insulin secretion at 2.8 mM glucose (6B). Under the tested conditions, insulin secretion potentiated by Compound 36 was notably increased when islets were cultured in the presence of BMF-219. These data support the exploration of combination treatment with menin inhibitor BMF-219 and small molecule GLP-1 receptor agonists for the treatment of diabetes. (Figure 6A and Figure 6B).

[0036] Figure 7 shows BMF-219 enhances glucose stimulated insulin secretion potentiated by GLP-1 receptor agonists. Cadaver-derived islets were from a 54-yr non-diabetic White female (BMI 28.6, HbAlc 5.7%). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (-) or presence of 100 nM or 300 nM BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence or presence of compound 214 (cpd 214). Stimulated insulin secretion was expressed as normalized to total islet DNA (7A) and normalized to basal insulin secretion at 2.8 mM glucose (7B).

[0037] Figure 8 shows BMF-219 enhances glucose stimulated insulin secretion potentiated by GLP-1 receptor agonists. Cadaver-derived islets were from a 43 -yr non-diabetic White male (BMI 27. 1, HbAlc 5.5%). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (-) or presence of 100 nM or 300 nM BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay inPage 12 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT the absence or presence of compound 36 (cpd 36). Stimulated insulin secretion was expressed as normalized to total islet DNA (8A) and normalized to basal insulin secretion at 2.8 mM glucose (8B).

[0038] Figure 9 shows BMF-219 enhances the expression of the GLP-1 receptor and insulin at both transcript and protein levels. Cadaver-derived human islets were cultured under glucotox conditions (8 mM glucose) in the absence (-) or presence of 100 nM or 300 nM BMF-219 for 7 days. At the end of treatment, size-matched islets were selected and analyzed for transcript levels of GLP-1 receptor (9A) and insulin (9B). Data shows results from islets from 8 independent donors. In a separate set of assays, islets were analyzed for GLP-1 receptor protein (9C) and intra cellular insulin levels (9D).

[0039] Figure 10 shows that combination of BMF-219 and low dose semaglutide promotes efficient glycemic control compared to low dose semaglutide alone. Schematic shows study plan (10A). Briefly, ZDF rats were randomized into two groups where Group 1 received vehicle (PO, QD) daily during weeks 1 to 4 and low dose semaglutide, 5 nmol / kg (SQ, QD) during weeks 3 and 4. Group 2 received 200 mg / kg BMF-219 (PO, QD) daily during weeks 1 to 4 and low dose semaglutide, 5nmol / kg (SQ, QD) during weeks 3 and 4. Following last dose on Day 28, animals were followed through Days 29-39 (drug wash-out period). Glycemic parameters, food and water intake, body weight and body composition were monitored throughout the study. Readouts for fasting blood glucose (FBG) (10B) and HbAlc (10C), measured at baseline (Day -3) and on Days 15, 21 and 28 are shown. Glucose AUC measured during oral glucose tolerance test (OGTT) on Days 15 and 28 are shown (10D).

[0040] Figure 11 shows that combination of BMF-219 and low dose semaglutide enhances beta cell function and improves insulin sensitivity, compared to low dose semaglutide alone. Measurements of fasting C-peptide to blood glucose ratio (11A), HOMA-B (1 IB) and HOMA-IR (11C) are shown.

[0041] Figure 12 shows that combination of BMF-219 and low dose semaglutide promotes appetite suppression and enhanced body weight reduction compared to low dose semaglutide alone. Food intake (12A) and change in body weight from baseline (12B) were monitored through the duration of study.

[0042] Figure 13 shows that combination of BMF-219 and low dose semaglutide promotes healthy weight loss with complete preservation of lean mass. Minispec whole body composition analyzer was used to measure lean tissue, fat and fluid. Body weight (13A), fat mass (13B), and lean mass (13C) measured at baseline (Day -3) and on Day 25. Fat mass and lean mass expressed as fraction of body weight were compared at baseline and Day 25 (13D) for both treatment groups.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Certain Terminology

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can bePage 13 of 238110550952511 \AME RICAS122787.00374BMEA-053PCT found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0044] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4THED.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPEC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer’s specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0045] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the appended claims.

[0046] All publications and patents mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the methods, compositions and compounds described herein. The publications discussed herein are provided solely for their disclosure prior to the fding date of the present application. Nothing herein is to be construed as an admission that the inventors described herein are not entitled to antedate such disclosure by virtue of prior invention or for any other reason.

[0047] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In somePage 14 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In certain embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl (n-pr), 1 -methylethyl (iso-propyl or i-Pr), n-butyl (n-Bu), n-pentyl, 1,1 -dimethylethyl (t-butyl, or t-Bu), 3 -methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as defined and described below and herein.

[0048] The alkyl group could also be a “lower alkyl” having 1 to 6 carbon atoms.

[0049] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx

[0050] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In some embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as defined and described below and herein.

[0051] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms . In certain embodiments, an alkynyl comprises two to eight carbon atoms. In some embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as defined and described below and herein.

[0052] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as defined and described below and herein.

[0053] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted as defined and described below and herein.Page 15 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0054] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, for example butyne. The alkynylene chain is attached to the rest of the molecule through a triple bond or a single bond and to the radical group through a triple bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted as defined and described below and herein.

[0055] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) 7t- electron system in accordance with the Hiickel theory. Aryl groups include, but are not limited to, groups such as phenyl (Ph), fluorenyl, and naphthyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as defined and described below and herein.

[0056] “Aralkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, benzyl, diphenylmethyl and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0057] “Aralkenyl” refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0058] “Aralkynyl” refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0059] “Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In some embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is optionally saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as “cycloalkyl.” Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclylPage 16 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted as defined and described below and herein.

[0060] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

[0061] The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures, respectively, in which at least one hydrogen is replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In some embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0062] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0063] As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl” or “heteroalicyclic” refers to a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom. A “non- aromatic heterocycle” or “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. Heterocycloalkyl rings can be formed by three to 14 ring atoms, such as three, four, five, six, seven, eight, nine, or more than nine atoms. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H- pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3- oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1, 3, 5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3 -dioxolane, 1,3- dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3 -oxathiolane. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:Page 17 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTand the like. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0064] “Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) it -electron system in accordance with the Htickel theory. Heteroaryl includes fused or bridged ring systems. In some embodiments, heteroaryl rings have five, six, seven, eight, nine, or more than nine ring atoms. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl,6.7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta[d]pyridazinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,5.8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to includePage 18 of 238110550952511 \AME RICAS122787.00374BMEA-053PCT heteroaryl radicals as defined above which are optionally substituted as defined and described below and herein.

[0065] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0066] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical . A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0067] “Epoxide” refers to a three-membered cyclic ether. The epoxide is optionally substituted as defined and described below and herein.

[0068] “Heteroarylalkyl” refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0069] “Sulfanyl” refers to the -S- radical.

[0070] “Sulfinyl” refers to the -S(=O)- radical.

[0071] “Sulfonyl” refers to the -S(=O)2- radical.

[0072] “Amino” refers to the -NH2 radical. A “substituted amino” refers to an “alkylamino” or “dialkylamino” group as defined herein.

[0073] “Cyano” refers to the -CN radical.

[0074] “Nitro” refers to the -NO2 radical.

[0075] “Oxa” refers to the -O- radical.

[0076] “Oxo” refers to the =0 radical.

[0077] “Imino” refers to the =NH radical.

[0078] “Thioxo” refers to the =S radical.

[0079] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0080] An “aryloxy” group refers to an (aryl)O- group, where aryl is as defined herein.

[0081] “Carbocyclylalkyl” means an alkyl radical, as defined herein, substituted with a carbocyclyl group. “Cycloalkylalkyl” means an alkyl radical, as defined herein, substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0082] As used herein, the terms “heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals in which one or more skeletal chain atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-O-CH3, -CH2-Page 19 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTCH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2- N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2,-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, - Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0083] The term “heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.

[0084] The term “bond,” “direct bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[0085] An “isocyanato” group refers to a -NCO group.

[0086] An “isothiocyanate” group refers to a -NCS group.

[0087] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0088] A “thioalkoxy” or “alkylthio” group refers to a -S-alkyl group.

[0089] A “alkylthioalkyl” group refers to an alkyl group substituted with a -S-alkyl group.

[0090] As used herein, the term “acyloxy” refers to a group of formula RC(=O)O-.

[0091] “Carboxy” means a -C(O)OH radical.

[0092] As used herein, the term “acetyl” refers to a group of formula -C(=O)CH3.

[0093] “Acyl” refers to the group -C(O)R.

[0094] As used herein, the term “trihalomethanesulfonyl” refers to a group of formula X3CS(=O)2- where X is a halogen.

[0095] “Cyanoalkyl” means an alkyl radical, as defined herein, substituted with at least one cyano group.

[0096] As used herein, the term “N-sulfonamido” or “sulfonylamino” refers to a group of formula RS(=O)2NH-.

[0097] As used herein, the term “O-carbamyl” refers to a group of formula -OC(=O)NR2.

[0098] As used herein, the term “N-carbamyl” refers to a group of formula ROC(=O)NH-.

[0099] As used herein, the term “O-thiocarbamyl” refers to a group of formula -OC(=S)NR2.

[0010] As used herein, “N-thiocarbamyl” refers to a group of formula ROC(=S)NH-.

[0101] As used herein, the term “C-amido” refers to a group of formula -C(=O)NR2.

[0102] “Aminocarbonyl” refers to a -CONH2 radical.

[0103] As used herein, the term “N-amido” refers to a group of formula RC(=O)NH-.

[0104] “Hydroxyalkyl” refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of a hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3 -hydroxypropyl, I-(hydroxymethyl)-2 -methylpropyl, 2-hydroxybutyl, 3-Page 20 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, l-(hydroxymethyl)-2-hydroxyethyl, 2,3- dihydroxybutyl, 3, 4 -dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.

[0105] “Alkoxyalkyl” refers to an alkyl radical, as defined herein, substituted with an alkoxy group, as defined herein.

[0106] An “alkenyloxy” group refers to a (alkenyl)O- group, where alkenyl is as defined herein.

[0017] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHygroup, where x and y are either (i) x=l and y=l or (ii) x=2 and y=0. When x=2, the alkyl groups, taken together with the N atom to which they are attached, can optionally form a cyclic ring system. In certain embodiments, the “alkylamino” group is a “dialkylamino” group wherein x=2 and y=0. In certain embodiments, the “dialkylamino” group is one wherein the alkyl groups are taken together with the N atom to which they are attached to form a cyclic ring system.

[0108] “Alkylaminoalkyl” refers to an alkyl radical, as defined herein, substituted with an alkylamine, as defined herein.

[0019] An “amide” is a chemical moiety with the formula -C(O)NHR or -NHC(O)R, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). An amide moiety may form a linkage between an amino acid or a peptide molecule and a compound described herein, thereby forming a prodrug. Any amine, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

[0110] The term “ester” refers to a chemical moiety with formula -COOR, where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.

[0111] As used herein, the term “ring” refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non- aromatic heterocycles). Rings can be optionally substituted. Rings can be monocyclic or polycyclic. [00112| As used herein, the term “ring system” refers to one, or more than one ring.

[0113] The term “membered ring” can embrace any cyclic structure. The term “membered” is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5 -membered rings.

[0114] The term “fused” refers to structures in which two or more rings share one or more bonds.Page 21 of 2381105509525\1 \AME RICAS

[0115] As described herein, compounds provided herein may be “optionally substituted”. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of a designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents provided herein are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0116] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CtUju ^R°; -(CtUju4OR°: -0(CH2)o4R°, -O-lCTbju ^C(O)OR°; - (CtUR ^CH(OR°)2; -(CH2)()4SR0: -(CEhju4Ph. which may be substituted with R°; -(CH2)u4O(CH2)u 1 Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CPhjo AXCIUjo 1- pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CThju 4N(R°)2: -(CH2)o ^N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)„ 4N(R°)C(O)NR°2: -N(RO)C(S)NR°2; -(CH2)O^N(R°)C(0)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(Ro)C(0)NRo2; -N(R°)N(R°)C(O)OR°; -(CH2)o^C(0)R°; -C(S)R°; - (CH2)O^C(0)OR°; -(CH2)O^C(0)SR°; -(CH2)o^C(0)OSiR°3; -(CH2)o^OC(0)R°; -OC(O)(CH2)0 4SR-. -SC(S)SR°; -(CH2)O^SC(0)R°; -(CH2)O^C(0)NR02; -C(S)NRO2; -C(S)SR°; -(CH2)O4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)O^SSR°; - (CH2)O^S(0)2R0; -(CH2)O^S(0)2OR0; -(CH2)„4OS(O)2R°: -S(0)2NRO2; -(CH2)O4S(O)R°; -N(RO)S(0)2NRO2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; - (Ci^ straight or branched alkylene)O-N(R°)2; or -(Ci^ straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2PI1, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.[00117| Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CPhjo 2R*, -(CPhjo2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* - (Ci^ straight or branched alkylene)C(O)OR*, or - SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6-memberedPage 22 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0118] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C ,()aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 00119| Suitable substituents on the aliphatic group of R* include halogen, -R’, -(haloR*). -OH, -OR’, - O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0120] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ' . -NRf2, -C(O)Rt, -C(O)ORt, -C(O)C(O)R:. -C(O)CH2C(O)Rt, -S(O)2Rf, -S(O)2NRt2, -C(S)NRf2, - C(NH)NRf2, or -N(R1')S(O)2R1'; wherein each R' is independently hydrogen, C i-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R1', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0121] Suitable substituents on the aliphatic group of R ' are independently halogen, -R*, -(haloR*), - OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0012] The term “nucleophile” or “nucleophilic” refers to an electron rich compound, or moiety thereof.

[0123] The term “electrophile”, or “electrophilic” refers to an electron poor or electron deficient molecule, or moiety thereof. Examples of electrophiles include, but in no way are limited to, Michael acceptor moieties.

[0124] The term “acceptable” or “pharmaceutically acceptable”, with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.Page 23 of 238110550952511 \AME RICAS122787.00374BMEA-053PCT

[0125] As used herein, “amelioration” of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0126] “Bioavailability” refers to the percentage of the weight of compounds disclosed herein dosed that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(o-co)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). “Oral bioavailability” refers to the extent to which compounds disclosed herein, such as, compounds of any of Formula (P-1), (P2-1), (L-I), or (I) are absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0127] “Blood plasma concentration” refers to the concentration of compounds disclosed herein in the plasma component of blood of a subject. It is understood that the plasma concentration of compounds of any of Formula (P-1), (P2-1), (L-I), or (I) may vary significantly between subjects, due to variability with respect to metabolism and / or possible interactions with other therapeutic agents. In accordance with some embodiments disclosed herein, the blood plasma concentration of the compounds of any of Formula (P-1), (P2-1), (L-I), or (I) may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(o-co)) may vary from subject to subject. Due to this variability, the amount necessary to constitute “a therapeutically effective amount” of a compound or combination may vary from subject to subject.

[0128] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0129] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. An “effective amount” of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that “an effect amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound of any of Formula (GL'-I), age, weight, general condition of the subject, the condition beingPage 24 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.

[0130] The terms “enhance” or “enhancing” means to increase or prolong either in potency or duration a desired effect. By way of example, “enhancing” the effect of therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in the treatment of a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician.

[0131] The term “identical,” as used herein, refers to two or more sequences or subsequences which are the same. In addition, the term “substantially identical,” as used herein, refers to two or more sequences which have a percentage of sequential units which are the same when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using comparison algorithms or by manual alignment and visual inspection. By way of example only, two or more sequences may be “substantially identical” if the sequential units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. Such percentages to describe the “percent identity” of two or more sequences. The identity of a sequence can exist over a region that is at least about 75-100 sequential units in length, over a region that is about 50 sequential units in length, or, where not specified, across the entire sequence. This definition also refers to the complement of a test sequence. By way of example only, two or more polypeptide sequences are identical when the amino acid residues are the same, while two or more polypeptide sequences are “substantially identical” if the amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. The identity can exist over a region that is at least about 75-100 amino acids in length, over a region that is about 50 amino acids in length, or, where not specified, across the entire sequence of a polypeptide sequence. In addition, by way of example only, two or more polynucleotide sequences are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are “substantially identical” if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical, or about 95% identical over a specified region. The identity can exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, where not specified, across the entire sequence of a polynucleotide sequence.

[0132] The term “isolated,” as used herein, refers to separating and removing a component of interest from components not of interest. Isolated substances can be in either a dry or semi-dry state, or in solution, including but not limited to an aqueous solution. The isolated component can be in aPage 25 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT homogeneous state or the isolated component can be a part of a pharmaceutical composition that comprises additional pharmaceutically acceptable carriers and / or excipients. By way of example only, nucleic acids or proteins are “isolated” when such nucleic acids or proteins are free of at least some of the cellular components with which it is associated in the natural state, or that the nucleic acid or protein has been concentrated to a level greater than the concentration of its in vivo or in vitro production. Also, by way of example, a gene is isolated when separated from open reading frames which flank the gene and encode a protein other than the gene of interest.

[0133] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes, such as, oxidation reactions) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyl transferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Both methods are well known in the art. In some embodiments, metabolites of a compound are formed by oxidative processes and correspond to the corresponding hydroxy-containing compound. In some embodiments, a compound is metabolized to pharmacologically active metabolites.

[0134] The term “modulate,” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0135] As used herein, the term “modulator” refers to a compound that alters an activity of a molecule. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator.

[0136] The term “prophylactically effective amount,” as used herein, refers that amount of a composition applied to a patient that will relieve to some extent one or more of the symptoms of a disease, disease or condition being treated. In such prophylactic applications, such amounts may depend on thePage 26 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT patient’s state of health, weight, and the like. It is considered well within the skill of the art for one to determine such prophylactically effective amounts by routine experimentation, including, but not limited to, a dose escalation clinical trial.

[0137] As used herein, the term “selective binding compound” refers to a compound that selectively binds to any portion of one or more target proteins.

[0138] As used herein, the term “selectively binds” refers to the ability of a selective binding compound to bind to a target protein, such as, for example, GLP-1R, with greater affinity than it binds to a non -target protein. In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 or more times greater than the affinity for a non -target.

[0139] As used herein, the term “selective modulator” refers to a compound that selectively modulates a target activity relative to a non-target activity. In certain embodiments, specific modulator refers to modulating a target activity at least 10, 50, 100, 250, 500, 1000 times more than a non-target activity.

[0140] The term “substantially purified,” as used herein, refers to a component of interest that may be substantially or essentially free of other components which normally accompany or interact with the component of interest prior to purification. By way of example only, a component of interest may be “substantially purified” when the preparation of the component of interest contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating components. Thus, a “substantially purified” component of interest may have a purity level of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or greater.

[0141] The term “subject” or “patient” as used herein, refers to an animal which is the object of treatment, observation, or experiment. By way of example only, a subject may be, but is not limited to, a mammal including, but not limited to, a human.

[0012] As used herein, the term “target activity” refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation, or inflammation- related processes, and amelioration of one or more symptoms associated with a disease or condition.

[0143] As used herein, the term “target protein” refers to a molecule or a portion of a protein capable of being bound by a selective binding compound. In certain embodiments, a target protein is menin.

[0144] The terms “treat,” “treating” or “treatment”, as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms “treat,” “treating” or “treatment”, include, but are not limited to, prophylactic and / or therapeutic treatments.Page 27 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT

[0145] As used herein, the IC50 refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of menin, in an assay that measures such response.

[0146] As used herein, EC50 refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.Combinations

[0147] Methods described herein include administering to a subject in need a composition containing a therapeutically effective amount of one or more GLP-1R agonist compounds in combination with one or more menin inhibitors described herein.

[0148] In some embodiments, methods described herein can be used to treat diabetes, e.g., Type 1 diabetes or Type 2 diabetes.

[0149]

[0150] A number of animal models of are useful for establishing a range of therapeutically effective doses of GLP-1R agonist compounds for treating any of the foregoing diseases.

[0151] Animal models for treatment of thromboembolic disorders are also known.

[0152] The therapeutic efficacy of the provided compounds for one of the foregoing diseases can be optimized during a course of treatment. For example, a subject being treated can undergo a diagnostic evaluation to correlate the relief of disease symptoms or pathologies to inhibition of in vivo GLP-1R activity achieved by administering a given dose of a GLP-1R agonist.

[0153] In certain embodiments, the amount of the GLP-1R agonist compound is therapeutically effective. In certain embodiments, the amount of the menin inhibitor is therapeutically effective. In certain embodiments, the amount of the GLP-1R agonist compound is therapeutically effective, and the amount of the menin inhibitor is therapeutically effective. In certain embodiments, the amount of the GLP-1R agonist compound is sub-therapeutic. In certain embodiments, the amount of the menin inhibitor is sub- therapeutic. In certain embodiments, the amount of the GLP-1R agonist compound is sub-therapeutic, and the amount of the menin inhibitor is sub-therapeutic. In certain sub-therapeutic embodiments, the combination is therapeutic while one or more components are at sub -therapeutic doses.

[0154] In certain embodiments, the GLP-1R agonist compound and the menin inhibitor are administered consecutively in either order. As used herein, the terms “consecutively,” “serially,” and “sequentially” refer to administration of a GLP-1R agonist compound after a menin inhibitor, or administration of the menin inhibitor after the GLP-1R agonist compound. For instance, consecutive administration may involve administration of the GLP-1R agonist compound in the absence of the menin inhibitor during an induction phase (primary therapy), which is followed by a post-induction treatment phase comprising administration of the menin inhibitor. The methods may further comprise a maintenance phase comprising administration of the GLP-1R agonist compound or the menin inhibitor, or both. Alternatively, consecutive administration may involve administration of the menin inhibitor in the absence of the GLP-Page 28 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT1R agonist compound during an induction phase (primary therapy), which is followed by a post-induction treatment phase comprising administration of the GLP-1R agonist compound. The methods may further comprise a maintenance phase comprising administration of the GLP-1R agonist compound or the menin inhibitor, or both.

[0155] In certain embodiments, the GLP-1R agonist compound and the menin inhibitor are administered concurrently. As used herein, the terms “concurrently,” “simultaneously,” and “in parallel” refer to administration of a GLP-1R agonist compound and a menin inhibitor during the same doctor visit or during the same phase of treatment. For instance, both the GLP-1R agonist compound and the menin inhibitor may be administered during one or more of an induction phase, a treatment phase, and a maintenance phase. However, concurrent administration does not require that the GLP-1R agonist compound and the menin inhibitor be present together in a single formulation or pharmaceutical composition, or that the GLP-1R agonist compound and the menin inhibitor be administered at precisely the same time.

[0156] In certain embodiments, provided herein is a method of treating diabetes responsive to GLP-1R activity, the method comprising administering an effective amount of a combination provided herein to an individual to treat the diabetes responsive to GLP-1R activity. In certain embodiments, provided herein is a method of treating diabetes responsive to menin inhibition, the method comprising administering an effective amount of a combination provided herein to an individual to treat the diabetes responsive to menin inhibition.

[0157] In certain embodiments, provided herein is a method of treating diabetes that is nonresponsive to GLP-1R activity alone, the method comprising administering an effective amount of a combination provided herein to such an individual to treat the diabetes nonresponsive to GLP-1R activity. In certain embodiments, provided herein is a method of treating diabetes that is nonresponsive to menin inhibition alone, the method comprising administering an effective amount of a combination provided herein to such an individual to treat the diabetes nonresponsive to menin inhibition.

[0158] The GLP-1R agonist compound or composition thereof is suitably administered to the individual at one time or over a series of treatments. In certain embodiments, the treatment includes multiple administrations of the GLP-1R agonist compound or composition, wherein the interval between administrations may vary. For example, the interval between the first administration and the second administration is about one month, and the intervals between the subsequent administrations are about three months. In certain embodiments, a GLP-1R agonist compound is administered at a flat dose. In certain embodiments, a GLP-1R agonist compound described herein is administered to an individual at a fixed dose based on the individual’s weight (e.g., mg / kg).

[0159] The menin inhibitor or composition thereof is suitably administered to the individual at one time or over a series of treatments. In certain embodiments, the treatment includes multiple administrations of the menin inhibitor or composition, wherein the interval between administrations may vary. For example, the interval between the first administration and the second administration is about one month, and the intervals between the subsequent administrations are about three months. In certain embodiments, a meninPage 29 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT inhibitor is administered at a flat dose. In certain embodiments, a menin inhibitor is administered to an individual at a fixed dose based on the individual’s weight (e.g., mg / kg).

[0160] In one aspect, described herein are pharmaceutical compositions comprising an GLP-1R agonist and an inhibitor of menin. In some embodiments, the GLP-1R agonists are irreversible inhibitors. In some embodiments, the GLP-1R agonists are reversible inhibitors. In some embodiments, the GLP-1R agonists are covalent inhibitors. In some embodiments, the inhibitors of menin are irreversible inhibitors. In some embodiments, the inhibitors of menin are reversible inhibitors. In some embodiments, the inhibitors of menin are covalent inhibitors.

[0161] In another aspect, described herein are methods for using such compositions of GLP-1R agonist and menin inhibitor in the treatment of diseases (including diseases wherein GLP-1R and / or menin provides therapeutic benefit to a patient having the disease). Further described are pharmaceutical compositions that comprise an GLP-1R agonist, an inhibitor of menin and one or more pharmaceutically acceptable carriers, excipients, or diluents. In certain embodiments, the combinations and pharmaceutical compositions described herein are used for the treatment of metabolic diseases including diabetes.GLP-1R Agonists

[0162] In the following description of GLP-1R agonist compounds suitable for use in the methods described herein, definitions of referred-to standard chemistry terms may be found in reference works (if not otherwise defined herein), including Carey and Sundberg “Advanced Organic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the ordinary skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0163] GEP-1R agonist compounds can be used for the manufacture of a medicament for treating any of the foregoing conditions (e.g., hematological malignancies).

[0164] In some embodiments, the GEP-1R agonist compound used for the methods described herein inhibits GEP-1R activity with an in vitro IC50 of less than about 10 pM (e.g., less than about 1 pM, less than about 0.5 pM, less than about 0.4 pM, less than about 0.3 pM, less than about 0.1 pM, less than about 0.08 pM, less than about 0.06 pM, less than about 0.05 pM, less than about 0.04 pM, less than about 0.03 pM, less than about 0.02 pM, less than about 0.01 pM, less than about 0.008 pM, less than about 0.006 pM, less than about 0.005 pM, less than about 0.004 pM, less than about 0.003 pM, less than about 0.002 pM, less than about 0.001 pM, less than about 0.00099 pM, less than about 0.00098 pM, less than about 0.00097 pM, less than about 0.00096 pM, less than about 0.00095 pM, less than about 0.00094 pM, less than about 0.00093 pM, less than about 0.00092 pM, or less than about 0.00090 pM).Page 30 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0165] Further described are pharmaceutical compositions that include an GLP-1R agonist.Menin Inhibitors

[0166] The menin inhibitors used in the combination of the present invention are described in US11,084,825, WO 2023 / 235618, or US2024-0124467 (incorporated by reference in its entirety).Combination Therapy

[0167] In one aspect, described herein are methods of treating diabetes using a combination comprising an GLP-1R and a menin inhibitor. In another aspect, described herein are methods of treating obesity using a combination comprising an GLP-1R and a menin inhibitor.

[0168] In certain embodiments, the GLP-1R agonist is , the GLP-1R agonist is Albiglutide (Tanzeum), Dulaglutide (Trulicity), Exenatide (Byetta), Exenatide extended-release (Bydureon), Liraglutide (Victoza), Liraglutide (Saxenda), Lixisenatide (Adlyxin), Semaglutide injection, (Ozempic), Semaglutide (Rybelsus), Tirzepatide (Mounjaro), Tirzepatide (Zepbound), Retatrutide (LY3437943), AMG 133, CagriSema, Cagrilintide, Danuglipron, orforglipron, lotiglipron, ID110521156, GS-4571, or TTP273. [00169| In some embodiments, the GLP-1R agonist is Liraglutide, dulaglutide, exenatide, semaglutide, and tirzepatide. In some embodiments, the GLP-1R agonist is orforglipron.

[0170] In a particular aspect, described herein are methods of treating diabetes using a combination comprising a compound according to formula (GL'-I):or a stereoisomer or a pharmaceutically acceptable salt thereof, whereinCy1is substituted or unsubstituted 5,6-fused or 6,6-fused heteroaryl;Cy2is substituted or unsubstituted heteroaryl; or -Cy2-R’ is -C(O)-NR6a-(CH2)m-R1; and wherein R6ais H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3;Cy3is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;Page 31 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT R1is substituted or unsubstituted aryl or heteroaryl;R2is CN, or substituted or unsubstituted heteroaryl; each R3aand R3bis independently H, or substituted or unsubstituted alkyl; or R3aand R3bform an oxo; or R3aand R3bare joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; each R4is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, or arylsulfmyl; and n is 1, 2, 3, 4, or 5; each R5a, R5band R5cis independently H, or substituted or unsubstituted alkyl; or R5aand R5bor R5aand R5care joined together to form a heterocycloalkyl; and wherein the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1 -3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1 -3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo; and a menin inhibitor.

[0171] In certain embodiments, the GLP-1R agonist is according to formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf)::Page 32 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTor a stereoisomer or a pharmaceutically acceptable salt thereof.

[0172] In certain embodiments, the GLP-1R agonist is according to formula (Via), (VIb), or(Vic):Via vib VicPage 33 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0173] In certain embodiments, the GLP-1R agonist is according to formula (M-VIa), (M-VIb), (M- VIc), or (M-VId):or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0174] In certain embodiments, the GLP-1R agonist is according to formula (M-VIIa), (M-VIIb), (M- VIIc), or (M-VIId):Page 34 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTa pharmaceutically acceptable salt thereof.

[0175] In certain embodiments, the GLP-1R agonist is according to formula (M-VIIIa), (M-VIIIb), (M- VIIIc), or (M-VIIId):Page 35 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTa pharmaceutically acceptable salt thereof.

[0176] In certain embodiments, the GLP-1R agonist is Albiglutide (Tanzeum), Dulaglutide (Trulicity), Exenatide (Byetta), Exenatide extended-release (Bydureon), Liraglutide (Victoza), Liraglutide (Saxenda), Lixisenatide (Adlyxin), Semaglutide injection (Ozempic), Semaglutide (Rybelsus), Tirzepatide (Mounjaro), Tirzepatide (Zepbound), Retatrutide (LY3437943), AMG 133, CagriSema, Cagrilintide, Danuglipron, orforglipron, lotiglipron, ID110521156, GS-4571, PF-06954222, aleniglipron,, ECC5005 (AZD5004), ASC30, MWN109, HS-10535, CT-996, KAI-9531, KAI-7535, KAI 9531, KAI-4729 or TTP273.

[0177] In certain embodiments, the GLP-1R agonist is liraglutide, dulaglutide, exenatide, semaglutide, and tirzepatide.

[0178] In certain embodiments, the GLP-1R agonist is any one of compounds listed in Table 1.

[0179] In certain embodiments, the GLP-1R agonist is Compound 36, 112, 211, 213, 214, 220, 225, 226, 302, 311, 313, 323, 406, 410, 427, 429, 433, 436, 437, 503, 518, 525, 606, 607, 610, 611, 612, 614,Page 36 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT615, 618, 619, 703, 705, 707, 710, 711, 713, 714, 715, or 716. In particular embodiments, the GLP-1R agonist is Compound 36, or 214. In a more particular embodiment, the GLP-1R agonist is Compound 214.

[0180] In certain embodiments, the GLP-1R agonist isPage 37 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0181] In certain embodiments, the GLP-1R agonist is PF-06954222.Menin Inhibitors

[0182] In one embodiment, the menin inhibitor is a compound according to formula (I):or a pharmaceutically acceptable salt thereof, wherein:A is C or N;Cy is substituted or unsubstitutedQ is N, -N(H)-, -O-, or -S-;Page 38 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTZ is -CR5a= or -N=;X is -NR3a-, -C(R3b)2-, or -O-;Y is a single bond, -NR3a-, -C(R3b)2-, or -O-;W is -C(O)-, -S(O)-, or -S(O)2-; one of R1and R2is Cy2-N(H)C(O)-C(R6a)=C(R6b)(R6c), or CH2-Cy2-N(H)C(O)-C(R6a)=C(R6b)(R6c); and the other is H, Ci-6 alkyl, Ci-6 haloalkyl, halo, or CN;Cy2is an optionally substituted group selected from phenyl, pyridyl, or a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R3a, and R3bis independently H or Ci-e alkyl; each R4aand R4bis independently H, halo, CN, OR, -N(R)2, -C(O)N(R)2, -NRC(O)R, -SO2R, -C(O)R, -CO2R, or an optionally substituted group selected from Ci-e alkyl, C3-7 cycloalkyl, a 4-7 membered heterocycloalkyl ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently H, or an optionally substituted group selected from Ci-e aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;R5ais H, C1-6 alkyl, C1-6 haloalkyl, halo, or CN; each R6aand R6bis independently H or Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis H or substituted or unsubstituted C1-6 alkyl; m is 1, 2, or 3; andPage 39 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT n is 1, 2, 3, or 4.

[0183] In certain embodiments, the menin inhibitor is a compound according to formula (XXI):or a pharmaceutically acceptable salt thereof, wherein each R8and R9is independently H, Ci-6 alkyl, Ci-ehaloalkyl, halo, or CN; and Cy, Cy2, R4a, R4b, R6a, R6b, R6c, m and n are as defined in Formula (I).Compound 3 , or a salt thereof.

[0185] In certain embodiments, the menin inhibitor isCompound 6 , or a salt thereof.

[0186] In certain embodiments, the menin inhibitor isCompound 10 , or a salt thereof.Page 40 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0187] In certain embodiments, the menin inhibitor is according to Formula (L-I) having the structure:Cy1— Cy2-X-W-Y-Cy3— L — Cy4— R1(L-l) or a pharmaceutically acceptable salt thereof, wherein:Cy1is substituted or unsubstitutedand the substitution on Cy1is C1-C4 alkyl, CN, or halo;Cy2is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on Cy2is selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo;X is -NR3a-, -C(R3b)2-, or -O-;W is -C(R3b)2-, -C(O)-, -S(O)-, or -S(O)2-;Y is absent, -NR3a-, -C(R3b)2-, or -O-; or X-W-Y is -N(H)-, or -S(O)2-N(H)-C(R3b)2-;Cy3is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and the substitution on Cy3is selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo;L is a single bond, substituted or unsubstituted -N(H)-, -C(F)2-O-, or substituted or unsubstituted C1-4 alkylene; the substitution on alkylene is C1-C4 alkyl, CN, or halo; and the substitution on -N(H)- is C1-C4 alkyl; i) R1is -B-C(R6a)=C(R6b)-C(O)-R6c, -B-C(R6a)=C(R6b)-S(O)-R6c, -B-C(R6a)=C(R6b)-S(O)2-R6c, -B- C(R6a)=C(R6b)-P(O)-R6aR6b; or -B-C(R6a)=C(R6b)-P(O)-OR6aOR6b; B is substituted or unsubstituted Ci.4alkylene; R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy4is absent, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and thePage 41 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT substitution on Cy4, and heterocycloalkyl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo; and the substitution on amino is C1-C4 alkyl or C1-C4 haloalkyl; each R6aand R6bis independently H, CN, halo, or substituted or unsubstituted Ci- e alkyl; and the substitution on alkyl is independently selected from 1, 2, or 3 groups independently selected from halo, alkoxy, alkylamino, dialkylamino, or heterocycloalkyl; ii) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; and Cy4is absent; iii) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; Cy4is absent, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R6ais alkyl, substituted with halo, alkoxy, alkylamino, dialkylamino, or heterocycloalkyl; iv) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; Cy4is substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene;Cy4is absent, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; each R3a, R3b, and R3cis independently H or substituted or unsubstituted C1-4 alkyl; each R6aand R6bis independently H, CN, halo, or substituted or unsubstituted Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R6eand R6fis independently H, CN, halo, or Ci-e alkyl; and the substitution on heterocycloalkyl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, Ci- C4 alkoxy, and halo; and the substitution on amino and alkoxy is C1-C4 alkyl; andR7is a 4-10 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and thePage 42 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT substitution on heterocycloalkyl, phenyl, bicyclic aryl, and heteroaryl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy; or the compound is any one of compounds listed in Table 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2J or 2K.

[0188] In certain embodiments, the menin inhibitor is according to Formula (L-I) having the structure:Cy1— Cy2-X-W-Y-Cy3— L — Cy4— R1(L-l) or a pharmaceutically acceptable salt thereof, wherein:Cy1is substituted or unsubstitutedCy2is substituted or unsubstitutedX is -NR3a-, -C(R3b)2-, or -O-;W is -C(R3b)2-, -C(O)-, -S(O)-, or -S(O)2-;Y is absent, -NR3a-, -C(R3b)2-, or -O-; or X-W-Y is -N(H)-, or -S(O)2-N(H)-C(R3b)2Page 43 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCTCy3is substituted or unsubstituted phenylene, pyridylene, pyrimidinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene;L is a single bond, substituted or unsubstituted -N(H)-, -C(F)2-O-, or substituted or unsubstituted Ci-4 alkylene;Cy4is absent, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene;R1is -C(O)-B-C(R6a)=C(R6b)-C(O)-R6c, -S(O)-B-C(R6a)=C(R6b)-C(O)-R6c, -S(O)2-B-C(R6a)=C(R6b) - C(O)-R6c, -B-C(R6a)=C(R6b)-C(O)-R6c, -B-C(R6a)=C(R6b)-S(O)-R6c, -B-C(R6a)=C(R6b)-S(O)2-R6c, -B- C(R6a)=C(R6b)-P(O)-R6aR6b; or -B-C(R6a)=C(R6b)-P(O)-OR6aOR6b; B is substituted or unsubstituted Ci.4alkylene, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R3a, R3b, and R3cis independently H or substituted or unsubstituted Ci-4 alkyl; each R6aand R6bis independently H, CN, halo, or Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R7is H, an optionally substituted group selected from alkyl, a 4-10 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0189] In certain embodiments, the menin inhibitor is according to Formula (L-I) having the structure:Cy1— Cy2-X-W-Y-Cy3— L — Cy4— R1(L-l) or a pharmaceutically acceptable salt thereof, whereinCy1is substituted or unsubstitutedPage 44 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTand the substitution on Cy1is C1-C4 alkyl, CN, or halo;Cy2is substituted or unsubstitutedand the substitution on Cy2is selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo;X is -NR3a-, -C(R3b)2-, or -O-;W is -C(R3b)2-, -C(O)-, -S(O)-, or -S(O)2-;Y is absent, -NR3a-, -C(R3b)2-, or -O-; or X-W-Y is -N(H)-, or -S(O)2-N(H)-C(R3b)2-;Cy3is substituted or unsubstituted phenylene, pyridylene, pyrimidinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and the substitution on Cy3is selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo;L is a single bond, substituted or unsubstituted -N(H)-, -C(F)2-O-, or substituted or unsubstituted C1-4 alkylene; the substitution on alkylene is C1-C4 alkyl, CN, or halo; and the substitution on -N(H)- is C1-C4 alkyl; i) R1is -B-C(R6a)=C(R6b)-C(O)-R6c, -B-C(R6a)=C(R6b)-S(O)-R6c, -B-C(R6a)=C(R6b)-S(O)2-R6c, -B- C(R6a)=C(R6b)-P(O)-R6aR6b; or -B-C(R6a)=C(R6b)-P(O)-OR6aOR6b; B is substituted or unsubstituted Ci.4alkylene; R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy4is absent, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and the substitution on Cy4, and heterocycloalkyl is independently selected from 1, 2, or 3Page 45 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo; and the substitution on amino is C1-C4 alkyl or C1-C4 haloalkyl; ii) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; and Cy4is absent; iii) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; Cy4is substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and R6ais alkyl, substituted with halo, alkoxy, alkylamino, dialkylamino, or heterocycloalkyl; iv) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; Cy4is substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and the compound is any one of compounds listed in Table 2B, and 2E;Cy4is absent, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; each R3a, R3b, and R3cis independently H or substituted or unsubstituted C1-4 alkyl; each R6aand R6bis independently H, CN, halo, or Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R6eand R6fis independently H, CN, halo, or Ci-e alkyl; and the substitution on heterocycloalkyl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, Ci- C4 alkoxy, and halo; and the substitution on amino and alkoxy is C1-C4 alkyl; andR7is a 4-10 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and thePage 46 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT substitution on heterocycloalkyl, phenyl, bicyclic aryl, and heteroaryl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy.

[0190] In certain embodiments, the menin inhibitor is according to Formula (L-I) having the structure:Cy1— Cy2-X-W-Y-Cy3— L — Cy4— R1(L-l) or a pharmaceutically acceptable salt thereof, whereinCy1is substituted or unsubstitutedand the substitution on Cy1is C1-C4 alkyl, CN, or halo;Cy2is substituted or unsubstitutedand the substitution on Cy2is selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo;X is -NR3a-, -C(R3b)2-, or -O-;W is -C(R3b)2-, -C(O)-, -S(O)-, or -S(O)2-;Y is absent, -NR3a-, -C(R3b)2-, or -O-; or X-W-Y is -N(H)-, or -S(O)2-N(H)-C(R3b)2-;Cy3is substituted or unsubstituted phenylene, pyridylene, pyrimidinylene, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, orPage 47 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT substituted or unsubstituted piperazinylene; and the substitution on Cy3is selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo;L is a single bond, substituted or unsubstituted -N(H)-, -C(F)2-O-, or substituted or unsubstituted C1-4 alkylene; the substitution on alkylene is C1-C4 alkyl, CN, or halo; and the substitution on -N(H)- is C1-C4 alkyl; i) R1is -B-C(R6a)=C(R6b)-C(O)-R6c, -B-C(R6a)=C(R6b)-S(O)-R6c, -B-C(R6a)=C(R6b)-S(O)2-R6c, -B- C(R6a)=C(R6b)-P(O)-R6aR6b; or -B-C(R6a)=C(R6b)-P(O)-OR6aOR6b; B is substituted or unsubstituted Ci.4alkylene; R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Cy4is absent, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and the substitution on Cy4, and heterocycloalkyl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy, and halo; and the substitution on amino is C1-C4 alkyl or C1-C4 haloalkyl; ii) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; and Cy4is absent; iii) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; Cy4is substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and R6ais alkyl, substituted with halo, alkoxy, alkylamino, dialkylamino, or heterocycloalkyl; iv) R1is -C(O)-C(R6a)=C(R6b)R6c, -S(O)-C(R6a)=C(R6b)R6c, -S(O)2-C(R6a)=C(R6b) R6c, -NR3c-C(O)- C(R6a)=C(R6b) R6c, -NR3c-S(O)-C(R6a)=C(R6b)R6c, or -NR3c-S(O)2-C(R6a)=C(R6b)R6c; Cy4is substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene; and the compound is any one of compounds listed in Table 2B, and 2E; or v) R1isCy4is absent, substituted or unsubstituted azetidinylene, substituted or unsubstituted pyrrolidinylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted piperazinylene;Page 48 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT each R3a, R3b, and R3cis independently H or substituted or unsubstituted Ci-4 alkyl; each R6aand R6bis independently H, CN, halo, or Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted heterocycloalkyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R6eand R6fis independently H, CN, halo, or Ci-e alkyl; and the substitution on heterocycloalkyl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, Ci- C4 alkoxy, and halo; and the substitution on amino and alkoxy is C1-C4 alkyl; andR7is a 4-10 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and the substitution on heterocycloalkyl, phenyl, bicyclic aryl, and heteroaryl is independently selected from 1, 2, or 3 groups independently selected from C1-C4 alkyl, hydroxy, CN, C1-C4 alkoxy.

[0191] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I); and wherein R3ais H or substituted or unsubstituted C1-4 alkyl; and each of R3b, and R3cis independently H, OH, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted C1-4 alkoxy.[00192 J In certain embodiments, the menin inhibitor is a compound according to Formula (L-I); and wherein Cy4is substituted or unsubstituted heterocycloalkylene, and the heterocycloalkylene includes bicyclic, fused and bridged heterocycloalkyls. In one embodiment, Cy4is a bridged heterocycloalkylene.

[0193] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I); and wherein Cy4isand wherein at least one pair of Rlaand Rlc, Rlaand Rld, Rlband Rlc, or Rlband Rldis joined together to form heterocycloalkyl, and the rest of Rla, Rlb, Rlc, and Rldare each H.

[0194] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I) having the structure:or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof, wherein Cy1, Cy2, Cy3, Cy4, L, and R1are as described herein.Page 49 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT

[0195] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I) having the structure:or a pharmaceutically acceptable salt thereof, wherein Cy1, Cy2, Cy3, Cy4, L, and R1are as described herein.

[0196] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I) having the structure:(LXIII) or a pharmaceutically acceptable salt thereof, wherein Cy1, Cy2, Cy3, Cy4, L, and R1are as described herein.

[0017] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I) having the structure:or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof, wherein Cy1, Cy2, Cy3, Cy4, L, and R1are as described herein.

[0018] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I) having the structure:OCy1- Cy2— NH — — Cy3- L - Cy4— R1(LXV)Page 50 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof, wherein Cy1, Cy2, Cy3, Cy4, L, and R1are as described herein.

[0199] In certain embodiments, the menin inhibitor is a compound according to Formula (L-I) having the structure:R3bCy1- Cy2- 1 - Cy3- L - Cy4— R1R3a(LXVI) or a stereoisomer thereof; or a pharmaceutically acceptable salt thereof, wherein Cy1, Cy2, Cy3, Cy4, L, R1, and R3aare as described herein; and R3bis OH, or substituted or unsubstituted Ci-4 alkoxy.

[0200] In one embodiment, R3bis OH, or substituted or unsubstituted C1.4 alkoxy; and R3ais H, or substituted or unsubstituted C1.4 alkyl. In one embodiment, R3bis OH, or substituted or unsubstituted C1.4 alkoxy; and R3ais H, or C1.4 alkyl, or halo C1.4 alkyl. In one embodiment, R3bis OH, or OMe; and R3ais H, or Me, or CF3.

[0201] In certain embodiments, R6ais F.

[0202] In certain embodiments the menin inhibitor compound is any one of compounds listed in Table 2A-2K. In certain embodiments the menin inhibitor compound is any one of compounds listed in Table 3.

[0203] In certain embodiments, the combination comprises a compound or GLP-1R agonist selected from any one of the compounds listed in Table 1 or described herein and the menin inhibitor Compound 10. In certain embodiments, Compound 10 is BMF-219 or icovamenib. The compound can be referred to as Compound 10, BMF-219, or icovamenib.

[0204] In certain embodiments, the combination comprises a GLP-1R agonist as described herein and the menin inhibitor KO-539 or Ziftomenib. In certain embodiments, the combination comprises the GLP- 1R agonist as described herein and the menin inhibitor SNDX-5613 or Revumenib. In certain embodiments, the combination comprises the GLP-1R agonist as described herein and the menin inhibitor JNJ-75276617, DS-1594, or DSP-5336,KO-539 SNDX-5613Page 51 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0205] In certain embodiments, the menin inhibitor is a reversible menin inhibitor. In certain embodiments, the menin inhibitor is an irreversible menin inhibitor.

[0206] In certain embodiments, the menin inhibitor is Ziftomenib, Revumenib, BN-104, DSP-5336, Bleximenib, DS-1594, HMPL-506, HG-153, D0060-319. In certain embodiments, the menin inhibitor is Ziftomenib, Revumenib, BN-104, DSP-5336, Bleximenib, or DS-1594. In certain embodiments, the menin inhibitor is HMPL-506, HG-153, or D0060-319.

[0207] In certain embodiments, the GLP-1R agonist is Orfoglipron, Danuglipron, GSBR-1290, CT-996, Tem-601, ZT-006, VK-2735, RGT-075, K-757, HDM-1002, XW-004, XW-014, KAI-7535, PF- 06954522, ID-10052, ASC30, SAL0112, THDBH-110 / 111, Amycretin (amylin / GLPl), ECC-5005 (AZD- 5004), GZR-18, TTP-273, GS-4571, BLX-7006, RT-114, HPG-5119, BEBT-808, Dulaglutide (Tnilicity), Exenatide (Byetta), Exenatide extended-release (Bydureon), Liraglutide (Victoza), Lixisenatide (Adlyxin), Semaglutide injection (Ozempic), Semaglutide tablets (Rybelsus), Tirzepatide (Mounjaro), or Zepbound.

[0208] In certain embodiments, the GLP-1R agonist is orfoglipron, danuglipron, GSBR-1290, CT-996, Tem-601, ZT-006, VK-2735, RGT-075, K-757, HDM-1002, XW-004, XW-014, KAI-7535, PF- 06954522, ID-10052, ASC30, SAL0112, THDBH-110 / 111, Amycretin (amylin / GLPl), ECC-5005 (AZD- 5004), GZR-18, or TTP -273. In certain embodiments, the GLP-1R agonist is GS-4571, BLX-7006, RT- 114, HPG-5119, or BEBT-808. In certain embodiments, the GLP-1R agonist is dulaglutide (Trulicity), Exenatide (Byetta), Exenatide extended-release (Bydureon), liraglutide (Victoza), lixisenatide (Adlyxin), semaglutide injection (Ozempic), semaglutide tablets (Rybelsus), tirzepatide (Mounjaro), or zepbound.

[0209] In certain embodiments, the GLP-1R agonist is ASC-30, CT-996, DA-1726, HDM-1002, ID- 110521156, PF-06954522, RGT-028, SAL-0112, TERN-601, THDBH-110 / 111, tirzepatide, XW-004, XW-014, amycretin, danuglipron, ECC-5005, exenatide-4, GSBR-1290, GZR-18, HRS 7535, K-757, K- 833, MRANK-001, NN-9541, RGT-075, semaglutide, sublingual liraglutide, TTP-273, VK-2735, orforglipron, Uni-GLP, BEBT-808, BLX-7006, DD-02, DD-03, DD-14, exenatide, HPG-5119, HTL-097, liraglutide, LXM-2, PT-3, RT-114, YG-X1, or ZT-006.

[0210] In some embodiments, provided herein is a pharmaceutical composition comprising a GLP-1R agonist or a pharmaceutically acceptable salt thereof and a menin inbitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0211] In some embodiments, provided herein is a pharmaceutical composition comprising a compound selected from Formula (GL'-I) or pharmaceutically acceptable salt thereof, an menin inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0021] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (GL'-I), an menin inhibitor, and a pharmaceutically acceptable excipient.

[0213] The pharmaceutical composition comprising the GLP-1R agonist and the pharmaceutical composition comprising the menin inhibitor can be administered in separate or simultaneous compositions.Page 52 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0214] In certain embodiments, provided herein are combinations of Compound 10 (BMF-219 or icovamenib), or any other menin inhibitor described herein, and Cobicistat. In certain embodiments, provided herein is a pharmaceutical composition comprising a combination of Compound 10 (BMF-219 or icovamenib), or any other menin inhibitor described herein, and Cobicistat. In particular, embodiments, provided herein is a pharmaceutical composition comprising Compound 10 (BMF-219 or icovamenib) and Cobicistat.

[0215] In some embodiments, provided herein is a pharmaceutical composition comprising a GLP-1R agonist or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for administration in combination with a menin inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0216] In some embodiments, the pharmaceutical compositions provided herein are formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.

[0217] In some embodiments, provided herein are methods for treating a proliferative disease or condition comprising administering to a patient in need the pharmaceutical composition(s) provided herein.

[0218] In some embodiments, provided herein are methods for treating a proliferative disease or condition comprising administering to a patient in need a pharmaceutical composition comprising a GLP- 1R agonist provided herein in combination with administering a menin inhibitor provided herein.

[0219] In some embodiments, provided herein are methods for treating an autoimmune disease comprising administering to a patient in need the pharmaceutical composition(s) provided herein.

[0220] In some embodiments, provided herein are methods for treating an autoimmune disease comprising administering to a patient in need a pharmaceutical composition comprising a GLP-1R agonist provided herein in combination with administering a menin inhibitor provided herein.

[0221] In some embodiments, provided herein are methods for treating a heteroimmune disease or condition comprising administering to a patient in need the pharmaceutical composition(s) provided herein.

[0222] In some embodiments, provided herein are methods for treating a heteroimmune disease or condition comprising administering to a patient in need a pharmaceutical composition comprising a GLP- 1R agonist provided herein in combination with administering a menin inhibitor provided herein.

[0223] In some embodiments, provided herein are methods for treating metabolic diseases comprising administering to a patient in need the pharmaceutical composition(s) provided herein.[00224| In some embodiments, provided herein are methods for treating obesity comprising administering to a patient in need the pharmaceutical composition(s) provided herein.

[0225] In some embodiments, provided herein are methods for treating overweight condition comprising administering to a patient in need the pharmaceutical composition(s) provided herein.

[0226] In some embodiments, provided herein are methods for treating diabetes comprising administering to a patient in need the pharmaceutical composition(s) provided herein.Page 53 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0227] In some embodiments, provided herein are methods for treating a diabetes comprising administering to a patient in need a pharmaceutical composition comprising a GLP-1R agonist provided herein in combination with administering a menin inhibitor provided herein.

[0228] In some embodiments, the diabetes is Type 1 diabetes. In some embodiments, the diabetes is Type 2 diabetes.

[0229] In some embodiments, provided herein are methods for treating a heteroimmune disease or condition comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of an GLP-1R agonist of Formula (GL'-I), or any other GLP-1R agonist described herein or a pharmaceutically acceptable salt thereof in combination with administering a therapeutically effective amount of a menin inhibitor or a pharmaceutically acceptable salt thereof provided herein.

[0230] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a combination of compound according to any one of the formulas described herein.

[0231] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an GLP-1R agonist according to any one of the formulas described herein for administration in combination with a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a menin inhibitor according to any of the other formulas described herein.

[0232] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula (I) for administration in combination with and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of (GL’-l), or any GLP-1R agonist described herein.

[0233] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula (I) for administration in combination with and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of (GL’-I).

[0234] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula (I) for administration in combination with and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a GLP-1R agonist like Liraglutide, dulaglutide, exenatide, semaglutide, or tirzepatide .[00235| In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of BMF-219 for administration in combination with and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a GLP-1R agonist like orforglipron, liraglutide, dulaglutide, exenatide, semaglutide, or tirzepatide.Page 54 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0236] In some embodiments, provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of BMF-219 for administration in combination with and a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of tirzepatide.

[0237] In some embodiments, a pharmaceutical composition described herein is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.

[0238] In one embodiment, GLP-1R agonist is orforglipron and menin inhibitor is icovamenib, or ziftomenib.

[0239] In one embodiment, GLP-1R agonist is Compound 214 (Table 1), and menin inhibitor is icovamenib, or ziftomenib.

[0240] In one embodiment, GLP-1R agonist is Compound 214 (Table 1), and menin inhibitor is icovamenib, or ziftomenib.

[0241] In one embodiment, GLP-1R agonist is semaglutide, and menin inhibitor is icovamenib, or ziftomenib.

[0242] In one embodiment, GLP-1R agonist is tirzpatide, and menin inhibitor is icovamenib, or ziftomenib.

[0243] In some embodiments, the carrier is a parenteral carrier.

[0244] In some embodiments, the carrier is an oral carrier.

[0245] In some embodiments, the carrier is a topical carrier.

[0246] Any combination of the groups described above for the various variables is contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those set forth herein.

[0247] Further representative embodiments of compounds of Formula (GL'-I), include compounds listed in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

[0248] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.Preparation of Compounds

[0249] The GLP-1R agonists described herein, including those of Formula (GL'-I), may be synthesized using standard synthetic reactions known to those of skill in the art or using methods known in the art. In particular, the GLP-1R agonists of Formula (GL'-I) are or can be prepared following the procedures described in US provisional 63 / 768,592 filed March 7, 2025, the contents of which are incorporated by reference in their entireties. The reactions can be employed in a linear sequence to provide the compounds, or they may be used to synthesize fragments which are subsequently joined by the methods known in the art. Exemplary methods are provided in the Examples herein. Specifically the GLP-1RPage 55 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT agonists are or can be prepared following the representative synthetic method depicted in Scheme 32 and using appropriate reagents and starting materials. Menin inhibitors may be prepared according to US patent No. 11,084,825 B2, US patent No. 11,174,263 B2, US-2024-0124467, or WO 2023 / 235618 the contents of which are incorporated by reference in their entireties.

[0250] Also described herein are GUP-1R agonist compounds, and processes for their preparation. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and combination of such compounds with menin inhibitors including BMF-219. Pharmaceutical compositions that include at least one such compound or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically active metabolite or pharmaceutically acceptable prodrug of such compound, are provided.

[0251] The starting material used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma Chemical Co. (St. Uouis, Mo.). The compounds described herein, and other related compounds having different substituents can be synthesized using techniques and materials known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4thEd., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4thEd., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rdEd., (Wiley 1999); Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). (all of which are incorporated by reference in their entirety). Additional methods for the synthesis of compounds described herein may be found in International Patent Publication No. WO 01 / 01982901, Arnold et al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for the preparation of compound as disclosed herein may be derived from known reactions in the field, and the reactions may be modified by the use of appropriate reagents and conditions, as would be recognized by the skilled person, for the introduction of the various moieties found in the formulae as provided herein.

[0252] The products of the reactions may be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0253] Compounds described herein may be prepared as a single isomer or a mixture of isomers.

[0254] In some embodiments, representative compounds of Formula (GL'-I) are prepared according to synthetic schemes depicted herein.Further Forms of CompoundsPage 56 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0255] In some embodiments, the GLP-1R agonists disclosed herein have a structure of Formula (GL'- I). It is understood that when reference is made to compounds described herein, it is meant to include compounds of any of Formula (GL'-I) as well as to all of the specific compounds that fall within the scope of these generic formulae, unless otherwise indicated.

[0256] Compounds described herein may possess one or more stereocenters and each center may exist in the R or S configuration. Compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns.

[0257] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known, for example, by chromatography and / or fractional crystallization. In some embodiments, enantiomers can be separated by chiral chromatographic columns. In some embodiments, enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers, and mixtures thereof are considered as part of the compositions described herein.

[0258] Methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of compounds presented herein are also considered to be disclosed herein.

[0259] Compounds described herein in unoxidized form can be prepared from N-oxides of compounds described herein by treating with a reducing agent, such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80°C.

[0260] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acidPage 57 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound, (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388- 392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

[0261] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0262] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to sitespecific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405- 413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein in their entirety.

[0263] Sites on the aromatic ring portion of the compounds described herein can be susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway.[00264| Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as2H,3H,13C,14C,15N,180,170,35S,18F,36C1, respectively. Certain isotopically-labeled compounds describedPage 58 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.

[0265] In additional or some embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0266] Compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluene sulfonic acid, 2- naphthalene sulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’- methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0267] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.

[0268] It should be understood that a reference to a salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.

[0269] Compounds described herein may be in various forms, including but not limited to, amorphous forms, milled forms and nano -particulate forms. In addition, compounds described herein include crystalline forms, also known as polymorphs.[00270| The screening and characterization of the pharmaceutically acceptable salts, polymorphs, and / or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy.

[0271] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.Page 59 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPharmaceutical Composition / Formulation

[0272] Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.

[0273] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.

[0274] The pharmaceutical compositions described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.

[0275] The pharmaceutical compositions will include at least one compound described herein, such as, for example, a compound of any of Formula (GL'-I) as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. Dosage Forms

[0276] The compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. As used herein, the term “subject” is used to mean an animal, preferably a mammal, including a human or non -human. The terms patient and subject may be used interchangeably.Examples of Methods of Dosing and Treatment Regimens

[0277] The compounds described herein can be used in the preparation of medicaments for the treatment of diseases or conditions that would benefit, at least in part, from GLP-1R activity. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one GLP-1R agonist described herein in combination with the administration of a menin inhibitor described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.Page 60 of 238110550952511 \AME RICAS122787.00374 BMEA-053PCT

[0278] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments.Methods of Treatment.

[0279] In particular embodiments, provided herein are methods of treating, ameliorating, or preventing a disease or condition in a patient in need thereof comprising administering an amount of an GLP-1R agonist compound described herein in combination with the administration of an amount of a menin inhibitor described herein to treat, ameliorate, or prevent the disease or condition. In particular embodiments, provided herein are methods of treating, ameliorating, or preventing a disease or condition in a patient in need thereof comprising administering an amount of a pharmaceutical composition comprising a GLP-1R agonist described herein in combination with the administration of an amount of a menin inhibitor described herein to treat, ameliorate, or prevent the disease or condition. In certain embodiments, provided herein are any of the compounds described herein for use in therapy. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for use in therapy. In certain embodiments, provided herein are any of the compounds described herein for use in treating, ameliorating, or preventing a disease or condition in a patient in need thereof. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for use in treating, ameliorating, or preventing a disease or condition in a patient in need thereof. In certain embodiments, provided herein are any of the compounds described herein for use the manufacture of a medicament for therapy. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for therapy. In certain embodiments, provided herein are any of the compounds described herein for use the manufacture of a medicament for treating, ameliorating, or preventing a disease or condition in a patient in need thereof. In certain embodiments, provided herein are any of the pharmaceutical compositions described herein for the manufacture of a medicament for treating, ameliorating, or preventing a disease or condition in a patient in need thereof. Useful conditions and disorders are described herein.

[0280] In certain embodiments, the disease or condition is diabetes.

[0281] In some embodiments, compounds provided herein are administered to a human.

[0282] In some embodiments, compounds provided herein are orally administered.

[0283] In some embodiments, the disease or condition is a Type 1 diabetes or a Type 2 diabetes.Combination Treatments[00284| The GLP-1R agonist and menin inhibitor compositions described herein can also be used in combination with other well known therapeutic reagents that are selected for their therapeutic value for the condition to be treated. In general, the compositions described herein and, in embodiments where combinational therapy is employed, other agents do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. The determination of the mode of administration and the advisabilityPage 61 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0285] In certain instances, it may be appropriate to administer at least one GLP-1R agonist compound described herein and at least one menin inhibitor described herein in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the GLP-1R agonist compounds described herein is nausea, then it may be appropriate to administer an anti -nausea agent in combination with the initial therapeutic agents. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0286] In addition to GLP-1R agonists described herein, an menin inhibitor such as BMF-219 can be used in with one or more of second therapeutic agents in any combination. In certain embodiments, the second agent is an alpha-glucosidase agonists. In certain embodiments, the second agent is miglitol or acarbose. In certain embodiments, the second agent is an amylin analog. In certain embodiments, the second agent is pramlintide. In certain embodiments, the second agent is dipeptidyl peptidase 4 inhibitor. In certain embodiments, the second agent is selected from sitagliptin, linagliptin, saxagliptin, and alogliptin. In certain embodiments, the second agent is an incretin mimetic. In certain embodiments, the second agent is selected from liraglutide, semaglutide, dulaglutide, tirzepatide, exenatide, albiglutide, and lixisenatide. In certain embodiments, the second agent is insulin. In certain embodiments, the second agent is selected from insulin, insulin degludec, insulin glargine, insulin detemir, insulin lispro, insulin isophane, insulin aspart, insulin glulisine, and insulin zinc. In certain embodiments, the second agent is a meglitinide. In certain embodiments, the second agent is selected from repaglinide and nateglinide. In certain embodiments, the second agent is teplizumab. In certain embodiments, the second agent is a nonsulfonylurea. In certain embodiments, the second agent is metformin. In certain embodiments, the second agent is an SGLT-2 inhibitor. In certain embodiments, the second agent is empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, or bexagliflozin. In certain embodiments, the second agent is a sulfonylurea. In certain embodiments, the second agent is glimepiride, glipizide, tolazamide, tolbutamide, glyburide, or chlorpropamide. In certain embodiments, the second agent is a thiazolidinedione. In certain embodiments, the second agent is pioglitazone or rosiglitazone.

[0287] The particular choice of compounds used will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol. ThePage 62 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT compounds may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the patient, and the actual choice of compounds used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.

[0288] It is known to those of skill in the art that therapeutically -effective dosages can vary when the drugs are used in treatment combinations. Methods for experimentally determining therapeutically - effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.Exemplary Therapeutic Agents for Use in Combination with a GLP-1R agonist Compound[00289|

[0290] In certain embodiments, the combination is administered once a day, two times per day, three times per day, four times per day, or five times per day.

[0021] In certain embodiments, the menin inhibitor is administered at a dosage of about 40 mg / day to about 1000 mg / day.

[0292] In certain embodiments, the menin inhibitor is administered orally.

[0293] In certain embodiments, the GLP-1R agonist and the menin inhibitor are administered in separate compositions. In certain embodiments, the GLP-1R agonist and the menin inhibitor are administered simultaneously, sequentially or intermittently.

[0294] In certain embodiments, the compound of formula (GL'-I) and the menin inhibitor are administered in separate compositions. In certain embodiments, the compound of formula (GL'-I) and the menin inhibitor are administered simultaneously, sequentially or intermittently.EXAMPLES

[0295] The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present disclosure to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.Page 63 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0296] The examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. aq = aqueous min minuteBoc = tert-butyloxycarbonyl ml milliliter t-BuOH = tertiary butanol mM millimolarDCE = 1,2-dichloroethane mmol millimoleDCM = dichloromethane m.p. melting pointDIAD = diisopropyl MS mass spectrometry azodicarboxylate m / z mass-to-charge ratioDIEA or DIPEA = N,N- N normal diisopropylethylamine NIS N-iodosuccinimideDMAP = dimethylaminopyridine nM nanomolarDMF = dimethylformamide nm nanometerDMSO = dimethylsulfoxide Pd(dppf)C12 [1,1'-ESI = electron spray Bis(diphenylphosphino ionization )ferrocene] dichloropallEA = ethyl acetate adium(II) g = gram PE petroleum etherHC1 = hydrogen chloride PyBOP benzotriazol- 1 -yl-HPLC = high performance oxytripyrrolidinophosp liquid chromatography honium hr = hour hexafluorophosphate’H NMR = proton nuclear quant, quantitative magnetic resonance RP reverse phaseIPA = isopropyl alcohol rt or r.t. room temperatureKO Ac = potassium acetate Sat. saturatedLC-MS = liquid chromatography TEA triethylamine mass spectroscopy TFA trifluoroacetic acidM = molar p,L microliterMeCN = acetonitrile ,M MicromolarMe OH = methanol mg = milligramGeneral Synthetic Scheme IExample 32 (Compound 32)3-((lS,2S)-I-(5-((S)-2,2-dimethyhetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-I-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-IH-imidazol-I-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-Page 64 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT epiminocyclohepta[c]pyrazole-9-carbonyl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)- oneScheme 32Step 1: tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate

[0297] A mixture of tert-butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (20 g, 88.78 mmol, 1 eq) in 1,1-dimethoxy-N, N-dimethyl-methanamine (200 mb) was stirred at 100°C for 16 hours under N2 atmosphere. LCMS showed reaction was completed. The residue was concentrated to give crude product. The residue was purified by column chromatography (SiC>2, Petroleum ether / ethyl acetate=100 / l to 1 / 1) to give tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (12 g, 39.12 mmol, 44.07% yield). LC-MS (ES+, m / z): 281.3 [(M+H)+]; Rt=0.375 min.Step 2: tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta [c]pyrazole-9-carboxylate.Page 65 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0298] To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxo-8-azabicyclo [3.2.1] octane-8- carboxylate (12 g, 42.80 mmol, 1 eq) in EtOH (120 mL) was added N2H4.H2O (3.68 g, 58.81 mmol, 3.57 m , 80% purity, 1.37 eq). The mixture was stirred for 12 hours at 80°C under N2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H2O (300 mL), extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 2 / 1) to give tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (8.1 g, 29.96 mmol, 69.99% yield). LC-MS (ES+, m / z): 250.2 [(M+H)+]; Rt=0.390 min.Step 3: tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylateBoc Boc

[0299] A mixture of tert-butyl 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (9 g, 36.10 mmol, 1 eq), K2CO3 (14.97 g, 108.30 mmol, 3 eq) and I2(18.32 g, 72.20 mmol, 14.54 mL, 2 eq) in DMF (90 mL) was stirred at 80°C for 17 hours under N2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H2O (500 mL), extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC ( neutral condition column: Welch Xtimate C18 250* 100mm#10um;mobile phase: [FLOQOmM NFLHCC^-ACN] gradient: 30%-60% B over 20.0 min) to give tert-butyl 3-iodo- 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (8 g, 19.72 mmol, 54.63% yield). LC-MS (ES+, m / z): 376.2 [(M+H)+]; Rt=0.468 min.Step 4: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylate

[0300] To a solution of tert-butyl 3-iodo-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9- carboxylate (5 g, 13.33 mmol, 1 eq), (4-fhroro-3,5-dimethylphenyl)boronic acid (4.48 g, 26.65 mmol, 2 eq) in DMF (50 mL) was added Py (2.11 g, 26.65 mmol, 2.15 mL, 2 eq), Cu(OAc)2 (242.04 mg, 1.33 mmol, 0.1 eq) and 4A MS (200 mg, 26.65 mmol, 2 eq). The mixture was stirred for 12 hours at 100°C under 02 (15 Psi). LCMS indicated the reaction was completed. The reaction mixture was quenched byPage 66 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT saturated addition saturated EDTA solution (200 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 4 / 1) to provide tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylate (1.5 g, 2.75 mmol, 20.64% yield). LC-MS (ES+, m / z): 498.3 [(M+H)+]; Rt=2.324 min and (tert-butyl l-(4-fluoro-3,5-dimethylphenyl)-3-iodo-l,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylate (3.2 g, 5.93 mmol, 44.47% yield). 'H NMR (400 MHz, DMSO-d6) 5 = 7.35 - 7.23 (m, 2H), 4.65 - 4.54 (m, 1H), 4.51 - 4.38 (m, 1H), 3.27 - 3.10 (m, 1H), 2.71 - 2.57 (m, 1H), 2.30 - 2.16 (m, 7H), 2.10 - 1.92 (m, 1H), 1.78 - 1.65 (m, 1H), 1.64 - 1.53 (m, 1H), 1.42 - 1.28 (m, 9H). LC-MS (ES+, m / z): 498.3 [(M+H)+]; Rt=2.429 min.Step 5: tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro- 4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

[0301] A mixture of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-iodo-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylate (1.2 g, 2.41 mmol, 1 eq), diphenylmethanimine (874.56 mg, 4.83 mmol, 809.78 pL, 2 eq), Xantphos Pd G4 (232.20 mg, 241.28 pmol, 0.1 eq) and CS2CO3 (1.57 g, 4.83 mmol, 2 eq) in t-AmylOH (12 mL) was stirred at 90°C for 12 hours under N2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition saturated EDTA solution (100 mL) and ethyl acetate (50 mL), stirred for 0.5 hour, and then extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / ethyl acetate=100 / l to 1 / 1). to give tert-butyl 3- ((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 1.77 mmol, 73.23% yield). LC-MS (ES+, m / z): 551.4[(M+H)+]; Rt=0.729 min.Step 6: tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylatePage 67 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0302] A mixture of tert-butyl 3-((diphenylmethylene)amino)-2-(4-fluoro-3,5-dimethylphenyl)- 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (1 g, 1.82 mmol, 1 eq), NaOAc (446.92 mg, 5.45 mmol, 3 eq) and NH2OH.HCI (252.39 mg, 3.63 mmol, 2 eq) in MeOH (10 mb) was stirred at 25°C for 12 hours under N2 atmosphere. LCMS showed reaction was completed. The reaction mixture was quenched by addition H2O (200 mb), extracted with ethyl acetate (100 mb * 3). The combined organic layers were washed with saturated brine (50 mb), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / l to 1 / 1) to give tert-butyl 3-amino-2-(4- fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (500 mg, 1.23 mmol, 67.82% yield). LC-MS (ES+, m / z): 387.2 [(M+H)+]; Rt=0.477 min.Step 7: tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

[0303] A mixture of tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carboxylate (400 mg, 1.04 mmol, 1 eq), N-(2,2-dimethoxyethyl)-lH- imidazole-1 -carboxamide (412.37 mg, 2.07 mmol, 2 eq) and t-BuOK (1 M, 5.18 mb, 5 eq) in DMA (4 mb) was stirred at 25°C for 1 hour under N2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H2O (100 mb), extracted with DCM (100 mb * 3). The combined organic layers were washed with saturated brine (50 mb), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiC>2, Petroleum ether / ethyl acetate = 1: 1) to give tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4- fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (300 mg, 528.02 pmol, 51.02% yield). LC-MS (ES+, m / z): 518.4 [(M+H)+]; Rt=0.508 min.Step 8: tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carboxylatePage 68 of 238110550952511 \AME RICAS122787.00374BMEA-053PCT

[0304] To a solution of tert-butyl 3-(3-(2,2-dimethoxyethyl) ureido)-2-(4-fluoro-3,5-dimethylphenyl)- 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (300 mg, 579.61 pmol, 1 eq) in THF (5 mL) was added CH3SO3H (83.56 mg, 869.41 pmol, 62.12 pL, 1.5 eq). The mixture was stirred for 3 hours at 60°C. K3PO4 (369.09 mg, 1.74 mmol, 3 eq) was then added followed by BOC2O (126.50 mg, 579.61 pmol, 133.15 pL, 1 eq) at 25°C. The mixture was stirred for 1 hour at 25°C. LCMS showed reaction was completed. The reaction mixture was quenched by addition H2O (100 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / ethyl acetate=100 / l to 1 / 1) to give tertbutyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2 -oxo-2, 3-dihydro- l / / -imidazol- l -yl)-2.4, 5,6,7, 8-hexahydro- 4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 416.75 pmol, 71.90% yield). LC-MS (ES+, m / z): 454.3 [(M+H)+]; Rt=0.497 min.Step 9: tert-butyl 3 -(3 -(4-fluoro- 1 -methyl- lH-indazol-5 -yl)-2 -oxo-2, 3 -dihydro- IH-imidazol- 1 -yl)-2-(4- fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate

[0305] To a solution of tert-butyl 2-(4-fluoro-3,5-dimethylphenyl)-3-(2-oxo-2,3-dihydro-lH-imidazol-l- yl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (200 mg, 441.01 pmol, 1 eq), 5 -bromo-4-fluoro-l -methyl- 1 / / -indazole (202.02 mg, 882.01 pmol, 2 eq) in NMP (4 mb) was added Cui (167.98 mg, 882.01 pmol, 2 eq), K2CO3 (121.90 mg, 882.01 pmol, 2 eq) followed by (1S,2S)-N1,N2- dimethylcyclohexane-l,2-diamine (125.46 mg, 882.01 pmol, 2 eq). The mixture was stirred at 130°C for 5 hours under N2 atmosphere. LCMS indicated the reaction was completed. The reaction mixture was quenched by addition H2O (100 mL), extracted with ethyl acetate (100 mb * 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (Si O2- Petroleum ether / Ethyl acetate=4 / l) to give tert-butyl 3 -(3 -(4-fluoro- 1 -methyl- 1 / / -indazol -5 -yl)-2-oxo-2, 3 -dihydro- 127-im idazol - 1 -yl)-2-(4-Page 69 of 238110550952511 \AME RICAS122787.00374BMEA-053PCT fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate (150 mg, 237.35 pmol, 53.82% yield). LC-MS (ES+, m / z): 602.5 [(M+H)+]; Rt=2.002 min.Step 10: l-(4-fhioro-l-methyl-lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazol-3-yl)-lH-imidazol-2(327)-one

[0306] A mixture of tert-butyl 4-(4-fhioro-3,5-dimethyl-phenyl)-3-[3-(4-fluoro-l-methyl-indazol-5-yl)- 2-oxo-imidazol-l-yl]-4,5,ll-triazatricyclo[6.2.1.02’6]undeca-2,5-diene-l 1-carboxylate (80 mg, 132.97 pmol, 1 eq) in HCl / MeOH (4 M, 2 mL) was stirred at 25°C for 1 hour. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give l-(4-fluoro-l -methyl - lH-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazol-3-yl)-lH-imidazol-2(3H)-one (60 mg, 111.50 pmol, 83.85% yield). LC-MS (ES+, m / z): 502.4 [(M+H)+]; Rt=0.389 min.Step 11: 3-((lS,2S)-l-(5-((S)-2,2-dimethyhetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-l-methyl-lH- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol -5 (4H) -one

[0307] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((lS,2S)-2-methyl-l-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2-carboxylic acid (10 mg, 24.30 pmol, 1 eq) in DMF (1 mL) was added HATU (13.86 mg, 36.46 pmol, 1.5 eq), DIEA (9.42 mg, 72.91 pmol, 12.70 pL, 3 eq), l-(4-fluoro-l-methyl-lH-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazol-3-yl)-lH-imidazol-2(3H)-one (13.08 mg, 24.30 pmol, 1 eq). The mixture was stirred at 25°C for 1 hour. LCMS showed reaction was completed. The reaction mixture was fdtered. The fdtrate was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18Page 70 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:55%-85% B over 8.0 min) to give 3- ((lS,2S)-l-(5-((S)-2,2-dimethyhetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2- oxo-2.3-dihydro-l / / -imidazol-l-yl)-2-(4-fluoro-3.5-dimcthylphcnyl)-2.4.5.6.7.8-hcxahydro-4.7- epiminocyclohepta[c]pyrazole-9-carbonyl)- 1 H-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2.4-oxadiazol-5(4 / / )- one (2.01 mg, 2.25 pmol, 9.24% yield, 100% purity). ’H NMR (400 MHz, DMSO-t / e) 5 = 12.15 - 11.73 (m, 1H), 8.35 - 8.08 (m, 1H), 7.66 - 6.75 (m, 10H), 5.60 - 4.90 (m, 2H), 4.12 - 4.05 (m, 3H), 3.78 - 3.59 (m, 3H), 3.24 - 2.81 (m, 3H), 2.28 - 2.07 (m, 8H), 1.90 - 1.72 (m, 2H), 1.64 - 1.33 (m, 6H), 1.26 - 0.98 (m, 9H). ’HNMR (400 MHz, DMSO-6, T=273+80K) 5 = 11.77 - 11.61 (m, 1H), 8.26 - 8.17 (m, 1H), 7.59 - 7.15 (m, 8H), 6.94 - 6.84 (m, 2H), 5.46 - 5.10 (m, 2H), 4.11 - 4.07 (m, 3H), 3.75 - 3.52 (m, 3H), 3.10 (m, 3H), 2.30 (m, 8H), 1.96 - 1.74 (m, 2H), 1.68 - 1.41 (m, 6H), 1.27 - 1.08 (m, 9H). LC-MS (ES+, m / z): 895.4[(M+H)+]; Rt=3.168 min. HRMS (El): m / z [M+H]+found: 895.3844.Example 35 (Compound 35)3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-l-methyl-lH- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol-5(4H)-oneExample 36 (Compound 36)3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol-5(4H)-onePage 71 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTStep 1 : 3 -(( 1 S,2S)- 1 -(5 -((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3 -(3 -(4-fluoro- 1 -methyl- 1H- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol -5 (4H) -one

[0308] To a solution of 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-l-((lS,2S)-2-methyl-l-(5-oxo- 4, 5-dihydro-l, 2, 4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2 -carboxylic acid (50 mg, 115.45 pmol, 1 eq) in DMF (1 mb) was added 65.84 mg, 173.17 pmol, 1.5 eq), DIEA (44.76 mg, 346.34 pmol, 60.32 pL, 3 eq), and l-(4-fluoro-l-methyl-lH-indazol-5-yl)-3-((4S,7R)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazol-3-yl)-lH-imidazol-2(3H)-one (57.90 mg, 115.45 pmol, 1 eq). The mixture was stirred at 25°C for 1 hour. LCMS showed reaction was completed. The reaction mixture was fdtered. The fdtrate was purified by prep-HPLC (TFA condition column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient:55%-85% B over 8.0 min) toPage 72 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT give 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(3-(3-(4-fluoro-l-methyl-lH-indazol- 5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4-oxadiazol-5(4H)- one (20.0 mg, 22.35 pmol, 22.42% yield). LC-MS (ES+, m / z): 895.3[(M+H)+]; Rt=2.360 min.Step 2: 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-l-methyl- lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol-5(4H)-one and 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4- fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)- 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-lH-indol-l-yl)-2- methylcyclopropyl)- 1 ,2, 4-oxadiazol-5(4H)-one

[0309] The 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-l- methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)- 2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-lH-indol-l-yl)-2- methylcyclopropyl)- 1, 2, 4-oxadiazol-5(4H)-one (20 mg) was further purified by SFC (column: REGIS(S,S)WHELK-O1, 250 mm*25 mm, 10 um); mobile phase: [CO2-EtOH:ACN=l: 1 (0.1% NH3H2O)]; B%: 50%, isocratic elution mode) to give 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H- pyran-4-yl)-2-((4R,7S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)- 2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)- lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (7.48 mg, 8.36 pmol, 43.8% yield, first eluent). ’HNMR (400 MHz, DMS0-< ) 8 = 12.20 - 11.72 (m, 1H), 8.38 - 8.16 (m, 1H), 6.74 (br s, 10H), 5.50 - 4.79 (m, 2H), 4.15 - 4.02 (m, 3H), 3.80 - 3.33 (m, 3H), 3.25 - 2.61 (m, 3H), 2.29 - 2.08 (m, 8H), 1.97 - 1.78 (m, 2H), 1.72 - 1.58 (m, 2H), 1.53 (m, 4H), 1.06 (m, 9H). ’H NMR (400 MHz, DMSO-tC T=273+80K) 5 = 12.00 - 11.43 (m, 1H), 8.25 - 8.17 (m, 1H), 7.61 - 7.50 (m, 1H), 7.42 - 7.25 (m, 3H), 7.24 - 7.11 (m, 3H), 7.06 - 6.66 (m, 3H), 5.54 - 4.95 (m, 2H), 4.06 (s, 3H), 3.71 - 3.52 (m, 2H), 3.40 - 3.19 (m, 1H), 2.98 - 2.74 (m, 2H), 2.44 - 2.33 (m, 1H), 2.31 - 2.07 (m, 8H), 1.93 - 1.77 (m, 2H), 1.71 - 1.34 (m, 6H), 1.28 - 1.02 (m, 9H). LC-MS (ES+, m / z): 895.4[(M+H)+]; Rt=3.166 min. HRMS (El): m / z [M+H]+found: 895.3857.Page 73 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTAnd 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4, 7-epiminocyclohepta[c]pyrazole-9-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol-5(4H)-one (7.11 mg, 7.94 pmol, 41.6% yield, second eluent). 'HNMR (400 MHz, DMSO-t / e) 5 = 12.34 - 11.39 (m, 1H), 8.34 - 8.16 (m, 1H), 7.68 - 6.69 (m, 10H), 5.62 - 4.84 (m, 2H), 4.15 - 4.03 (m, 3H), 3.43 (m, 3H), 3.23 (m, 3H), 2.28 - 2.09 (m, 8H), 1.90 - 1.69 (m, 2H), 1.61 - 1.33 (m, 6H), 1.28 - 0.98 (m, 9H). ’HNMR (400 MHz, DMSO- e, T=273+80K) 5 = 11.87 - 11.08 (m, 1H), 8.28 - 8.09 (m, 1H), 7.10 (m, 7H), 6.97 - 6.67 (m, 3H), 5.74 - 4.65 (m, 2H), 4.10 - 4.07 (m, 3H), 3.83 - 3.10 (m, 3H), 3.04 - 2.75 (m, 3H), 2.27 - 2.13 (m, 8H), 1.99 - 1.71 (m, 2H), 1.65 - 1.42 (m, 6H), 1.31 - 1.09 (m, 9H). LC-MS (ES+, m / z): 895.4[(M+H)+]; Rt=3.154 min. HRMS (El): m / z [M+H]+found: 895.3857.Example 41 Compound 120 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S,8R)-3-(3-(4-fluoro-l-methyl-lH- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9- hexahydro-4, 8-epiminooxocino[5,4-c]pyrazole- 1 -carbonyl)- 1 H-indol- 1 -yl)-2 -methylcyclopropyl)- 1,2,4- oxadiazol-5 (4 / / )-oncAndCompound 1213 -(( IS, 25)- 1 -(5 -((.S)-2.2-dimcthyltctrahydro-2 / / -pyran-4-yl)-2-((4 / ?.8.S)-3 -(3 -(4-fluoro- 1 -methyl- 1H- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9- hexahydro-4, 8-epiminooxocino[5,4-c]pyrazole- 10-carbonyl)- 177-indol- 1 -yl)-2 -methylcyclopropyl)- 1,2,4- oxadiazol-5(4H)-onePage 74 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0310] Step 1 : 3 -(( 1S,2S)- 1 -(5-((S)-2.2-dimcthyltctrahydro-2 / / -pyran-4-yl )-2-((4S.8 / ?)-3-(3-(4-fluoro- 1 - methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)- 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-lH-indol-l-yl)-2- methylcyclopropyl)- 1 ,2,4-oxadiazol-5(427)-one and 3-(( 1S,2S)- 1 -(5-((S)-2,2-dimethyltetrahydro-2H- py ran -4-yl )-2-((4 / ?.8S)-3 -(3 -(4-fluoro- 1 -methyl- 1 H-indazol -5 -yl)-2-oxo-2, 3 -dihydro- 1 H-im idazol - 1 -yl)-2- (4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)- 1 H-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4-oxadiazol-5(427)-one[0031 11 The 3-(( IS, 25)- 1 -(5-((.S')-2.2-dimcthyltctrahydro-2 / / -pyran-4-yl)-2-(3-(3-(4-fluoro- 1 -methyl- 1H- indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9- hexahydro-4,8-epiminooxocino[5,4-c]pyrazole- 10-carbonyl)- IH-indol- 1 -yl)-2 -methylcyclopropyl)- 1 ,2,4- oxadiazol -5 (427) -one (45 mg, 49.40 pmol, 1 eq ) was separated by SFC (column: REGIS(S,S)WHELK- 01(250mm*25mm,10um); mobile phase: [CC>2-IPA:ACN=1: 1 (0.1% NH3H2O)]; B%:44%, isocratic elution mode) to provide 3-(( IS.2S)- l -(5-((S)-2.2-dimcthyltctrahydro-2 / / -pyran-4-yl)-2-((4S.8 / ?)-3-(3-(4- fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)- 2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-lH-indol-l-yl)-2- methylcyclopropyl)- 1, 2, 4-oxadiazol-5(427)-one (15.38 mg, 16.74 pmol, 33.88% yield, 99.14% purity, first eluent). ’H NMR (400 MHz, DMSO-t / e) 5 = 12.23 - 11.69 (m, 1H), 8.37 - 8.18 (m, 1H), 7.69 - 7.47 (m, 2H), 7.42 - 7.29 (m, 2H), 7.28 - 7.09 (m, 4H), 7.07 - 6.95 (m, 1H), 6.85 (br d, J = 16.6 Hz, 1H), 5.64 - 5.53 (m, 1H), 5.17 - 4.74 (m, 1H), 4.22 - 3.83 (m, 5H), 3.55 (br s, 4H), 3.29 - 2.64 (m, 3H), 2.36 - 2.17 (m, 6H), 1.73 - 1.35 (m, 6H), 1.31 - 0.84 (m, 10H). LC-MS (ES+, m / z): 911.4[(M+H)+], Rt=2.911 min. HRMS (El): m / z [M+H]+found: 911.3780; and 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-Page 75 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT yl)-2-((4 / ?.8.S)-3-(3-(4-fluoro-l-mcthyl-l H-indazol-5-yl)-2-oxo-2.3-dihydro-l / / -imidazol-l-yl)-2-(4- fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-lH- indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4E7)-one (12.33 mg, 13.48 pmol, 27.30% yield, 99.62% purity, second eluent). ’H NMR (400 MHz, DMSO-6) 5 = 12.22 - 11.67 (m, 1H), 8.34 - 8.13 (m,1H), 7.68 - 7.60 (m, 1H), 7.56 - 7.44 (m, 1H), 7.42 - 7.17 (m, 4H), 7.16 - 6.98 (m, 2H), 6.94 - 6.82 (m,1H), 6.78 - 6.66 (m, 1H), 5.70 - 5.24 (m, 1H), 5.08 - 4.75 (m, 1H), 4.18 - 4.02 (m, 4H), 4.00 - 3.85 (m,1H), 3.81 - 3.52 (m, 4H), 3.23 - 2.83 (m, 3H), 2.30 - 2.18 (m, 6H), 1.78 - 1.36 (m, 6H), 1.34 (s, 8H), 1.05 -0.94 (m, 2H). LC-MS (ES+, m / z): 911.3[(M+H)+], Rt=2.906 min. HRMS (El): m / z [M+H]+found: 911.3780.Example 50 Compound 2143-((l S,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2 -oxo-2, 3-dihydro-lH-imidazol-l- yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9- carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)- oneCompound 2153-((l S,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2 -oxo-2, 3-dihydro-lH-imidazol-l- yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9- carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)- onePage 76 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTStep 1: 3-((l S,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2 -oxo-2, 3-dihydro-lH- imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole- 9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol- 5(4H)-one and 3-((lS,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro- lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2- methylcyclopropyl)- 1 ,2, 4-oxadiazol-5(4H)-onefirst eluent second eluent

[0312] The compound 3-((lS,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3- dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7- epiminocyclohepta[c]pyrazole-9-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2- methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (30 mg, purity 100%) was further separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um); mobile phase: [CO2-MeOH(0.1%NH3H2O)- H2O=95:5]; B%:65%, isocratic elution mode) to give 3-((lS,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl- lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8- hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l- yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)-one (first eluent, Rt = 2.747 min; 10.33 mg, 11.57 pmol, 34.50% yield). 'HNMR (400 MHz, DMSO-6) 5 = 12.06 - 11.16 (m, 1H), 8.20 (br s, 1H), 7.70 - 6.52 (m, 10H), 5.58 - 5.22 (m, 1H), 5.15 - 4.82 (m, 1H), 4.10 (d, J = 1.2 Hz, 3H), 3.91 - 3.52 (m, 3H), 3.07 - 2.78 (m, 2H), 2.31 - 2.09 (m, 9H), 1.93 - 0.94 (m, 11H), 0.81 - 0.38 (m, 4H). LC-MS (ES+, m / z): 893.3 [(M+H)+]; Rt= 3.168 min. HRMS (El): m / z [M+H]+found: 893.3681.Page 77 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTAnd 3-((l S,2S)-l-(2-((4S,7R)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2 -oxo-2, 3-dihydro-lH-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9- carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(4H)- one (second eluent, Rt = 4.457 min; 10.70 mg, 11.98 pmol, 35.74% yield). 'H NMR (400 MHz, DMSO- d6) 5 = 12.33 - 11.61 (m, 1H), 8.41 - 8.09 (m, 1H), 7.74 - 6.59 (m, 10H), 5.63 - 4.87 (m, 2H), 4.18 - 4.02 (m, 3H), 3.94 - 3.55 (m, 2H), 3.25 - 2.61 (m, 3H), 2.39 - 1.98 (m, 9H), 1.94 - 0.97 (m, 11H), 0.83 - 0.25 (m, 4H). LC-MS (ES+, m / z): 893.3 [(M+H)+]; Rt= 3.054 min. HRMS (El): m / z [M+H]+found: 893.3736.Example 54 Compound 2203 -((IS, 2S)-l-(2-((4R, 8S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2 -oxo-2, 3-dihydro-lH-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2 -methylcyclopropyl)-!, 2, 4-oxadiazol-5(4E7)-oneStep 1: 3-(( IS.2S)-l-(2-((4 / ?.8.S)-3-(3-(4-fluoro-l-mcthyl-l / / -indazol-5-yl)-2 -oxo-2, 3-dihydro-lH- imidazol- 1 -yl)-2-(4-fluoro-3 ,5 -dimethylphenyl)-2,4,5 ,7, 8,9-hexahydro-4, 8-epiminooxocino [5 ,4- c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4- oxadiazol -5 (4H) -onePage 78 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0313] To a solution of l -(4-fluoro- l -mcthyl- l / / -indazol-5-yl)-3-((4 / ?.8.S)-2-(4-fluoro-3.5- dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazol-3-yl)-l,3-dihydro-2H- imidazol-2-one(15 mg, 27.08 pmol, 1 eq, HC1), l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)cyclopropyl)-5-(4-oxaspiro[2.5]octan-7-yl)-lH-indole-2-carboxylic acid (12.05 mg, 27.08 pmol, 1 eq) in DMF (1 mL) was added DIEA (17.50 mg, 135.38 pmol, 23.58 pL, 5 eq) and BOP (14.37 mg, 32.49 pmol, 1.2 eq). The mixture was stirred at 25°C for 2 hours. LCMS indicated that the reaction was completed. The reaction mixture was partitioned between ethyl acetate (30 mL) and H2O (10 mL). The organic phase was separated, washed with saturated brine (30 mL * 3), dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H20(0.1%TFA)-ACN];gradient:50%-80% B over 8.0 min) to give 3 -(( IS, 25)- 1 -(2-((4R,8S)-3 -(3 -(4-fluoro- 1 -methyl- 1 H-indazol -5 -yl)-2-oxo-2, 3 -dihydro- IH-imidazol- l-yl)-2-(4-fhioro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10- carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4-oxadiazol-5(427)-one (5.09 mg, 5.56 pmol, 20.55% yield). ’H NMR (400 MHz, DMSO-6) 5 = 12.23 - 11.68 (m, 1H), 8.34 - 8.11 (m, 1H), 6.68 (s, 10H), 5.77 - 4.70 (m, 2H), 4.15 - 4.05 (m, 3H), 4.01 - 3.63 (m, 5H), 3.22 - 2.81 (m, 4H), 2.31 - 2.16 (m, 6H), 2.00 - 1.86 (m, 1H), 1.81 - 1.70 (m, 2H), 1.68 - 1.51 (m, 2H), 1.38 - 1.21 (m, 4H), 1.15 - 0.95 (m, 1H), 0.81 - 0.26 (m, 4H). LC-MS (ES+, m / z): 909.3 [(M+H)+], Rt = 3.039 min. HRMS (El): m / z [M+H]+found: 909.3632.Example 55Compound 2263-((lS, 2S)-l-(2-((4R, 8.S)-3-(3-(4-fluoro- l -mcthyl- l / / -indazol-5-yl)-2 -oxo-2, 3-dihydro-lH-imidazol-l-yl)-2-(4-fhioro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-((S)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2 -methylcyclopropyl)-!, 2, 4-oxadiazol-5(4 / / )-oncPage 79 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT3 -((IS, 2S)-l-(2-((47?, 8S)-3-(3-(4-fluoro-l-methyl-177-indazol-5-yl)-2 -oxo-2, 3-dihydro-177-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8-epiminooxocino[5,4-c]pyrazole-10-carbonyl)-5-(( / ?)-4-oxaspiro|2.5 |octan-7-yl)- l / 7-indol- l -yl)-2 -methylcyclopropyl)-!, 2, 4-oxadiazol-5(4 / 7)-oncStep 1: 3-(( I.S'.2.S)- l -(2-((4 / ?.85)-3-(3-(4-fluoro-l-methyl-177-indazol-5-yl)-2 -oxo-2, 3 -dihydro- 177- imidazol- 1 -yl)-2-(4-fluoro-3 ,5 -dimethylphenyl)-2,4,5 ,7, 8,9-hexahydro-4, 8-epiminooxocino [5 ,4- c]pyrazole-10-carbonyl)-5-((5)-4-oxaspiro[2.5]octan-7-yl)-177-indol-l-yl)-2-methylcyclopropyl)-l,2,4- oxadiazol -5 (427) -one and 3-(( 1 ,S'.2.S')- 1 -(2-((4 / ?.8,S)-3-(3-(4-flnoro- 1 -methyl- 1 / 7-indazol-5-yl)-2-oxo-2.3 - dihydro-177-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8- epiminooxocino [5 ,4-c]pyrazole- 10-carbonyl)-5 -(( / ?)-4-oxaspi ro| 2.5 |octan -7 -yl)- 177-indol - 1 -yl)-2- methylcyclopropyl)- 1 ,2.4-oxadiazol-5(4 / 7)-oncfirst eluent second eluent

[0314] 3-(( IS.2.S)- l -(2-((4 / ?.8S)-3-(3-(4-fluoro-l-methyl-177-indazol-5-yl)-2 -oxo-2, 3 -dihydro- 177- imidazol- 1 -yl)-2-(4-fluoro-3 ,5 -dimethylphenyl)-2, 4,5 ,7, 8, 9-hexahydro-4, 8-epiminooxocino [5 ,4- c]pyrazole-10-carbonyl)-5-(4-oxaspiro[2.5]octan-7-yl)-177-indol-l-yl)-2-methylcyclopropyl)-l,2,4- oxadiazol -5 (427) -one (35 mg, 38.47 pmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO2-MeOH(0.1%NH3H2O)-H2O=95:5]; B%:65%, isocratic elution mode) to give 3-((lS,2S)-l-(2-((47?,8S)-3-(3-(4-fluoro-l-methyl-177-indazol-5-yl)-2-oxo-2,3- dihydro-177-imidazol-l-yl)-2-(4-fluoro-3,5-dimethylphenyl)-2,4,5,7,8,9-hexahydro-4,8- epiminooxocino [5 ,4-c]pyrazole- 10-carbonyl)-5 -((.S')-4-oxaspi ro| 2.5 |octan -7 -yl)- 177-indol- 1 -yl)-2- methylcyclopropyl)-l,2,4-oxadiazol-5(477)-one (first eluent, Rt = 3.490 min; 9.15 mg, 10.07 pmol, 26. 17% yield); ’H NMR (400 MHz, DMSO-6) 5 = 12.25 - 11.65 (m, 1H), 8.38 - 8.13 (m, 1H), 7.72 -Page 80 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT6.49 (m, 10H), 5.76 - 4.73 (m, 2H), 4.16 - 4.06 (m, 3H), 4.03 - 3.57 (m, 5H), 3.26 - 2.99 (m, 4H), 2.30 - 2.19 (m, 6H), 1.96 - 1.51 (m, 5H), 1.41 - 1.31 (m, 2H), 1.30 - 1.20 (m, 2H), 1.10 (br s, 1H), 0.77 - 0.33 (m, 4H); LC-MS (ES+, m / z): 909.3 [(M+H)+], Rt = 3.037 min; HRMS (El): m / z [M+H]+found: 909.3652; and 3-((lS,2S)-l-(2-((4R,8S)-3-(3-(4-fluoro-l-methyl-lH-indazol-5-yl)-2-oxo-2,3-dihydro-lH- imidazol- 1 -yl)-2-(4-fluoro-3 ,5 -dimethylphenyl)-2,4,5 ,7, 8,9-hexahydro-4, 8-epiminooxocino [5 ,4- c]pyrazole-10-carbonyl)-5-((R)-4-oxaspiro[2.5]octan-7-yl)-lH-indol-l-yl)-2-methylcyclopropyl)-l,2,4- oxadiazol -5 (427) -one (second eluent, Rt = 4.961min; 9.20 mg, 10.12 pmol, 26.31% yield); 'HNMR (400 MHz, DMSO-d6) 5 = 12.23 (s, 1H), 8.36 - 8.15 (m, 1H), 7.77 - 6.47 (m, 10H), 5.72 - 4.74 (m, 2H), 4.14 - 4.06 (m, 3H), 3.99 - 3.44 (m, 5H), 3.27 - 2.98 (m, 4H), 2.29 - 2.17 (m, 6H), 2.00 - 1.88 (m, 1H), 1.86 - 1.70 (m, 2H), 1.67 - 1.52 (m, 2H), 1.38 - 0.98 (m, 5H), 0.74 (br s, 4H); LC-MS (ES+, m / z): 909.3 [(M+H)+], Rt = 3.037 min; HRMS (El): m / z [M+H]+found: 909.3652.Additional Exemplary Compounds

[0315] The representative compounds prepared or can be prepared from readily available starting materials using the general methods and procedures described herein are depicted in Table 1, Table 2A- 2K, and Table 3.Example BiaGLP-1R agonistsGLP-1R cAMP assay

[0316] Assay was carried out with HEK293 expressing human GLP-1R using HTRF assay, developed by Wuxi Apptec. The method is a competitive assay between native cAMP produced by the cells and exogenous cAMP labeled with a proprietary dye d2. The tracer binding is visualized by a mAb anti-cAMP labeled with Cryptate. The signal (i.e. energy transfer) is inversely proportional to the concentration of cAMP in either standard or experimental sample. Compounds were tested in the absence of BETP. Ten microliter of cell suspension in assay buffer (5 mM HEPES, 500 pM IB MX, 0.1% BSA) were added to each well (1,000 cells per well) in a low volume 384-well plate for the assay. Serially diluted compounds were added in 100 nL volume to duplicate wells, by Labcyte Echo. GLP-1 (7-37) was used as positive control. Assay plate was incubated for 30 minutes at room temperature. Stock of cAMP Detection Solution was prepared by mixing 38 parts of cAMP lysis buffer, 1 part of cAMP-D2, 1 part of anti-cAMP cryptate reagent (Cisbio #62AM4PEJ). Ten microliter of the cAMP Detection Solution was added to each well, and the assay plate was incubated for 1 hour at room temperature in the dark. Plates were read on Envision plate reader. The data were analyzed by ScreenUltra in Dotmatics, with % activation expressed using following formula: (Well data-negative control) / (postive control-negative control)* 100. Dose response curves were plotted and EC50 values calculated by non-linear regression using 4-parameter fit. The potency (EC50) values for cAMP accumulation in HEK293 cells are reported in the Table 1 below (***** <!nM, **** iHonM, ***10-100 nM, ** 100-500 nM, * >500 nM):Page 81 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTTable 1: Representative GLP-1R agonists and their EC50 valuesPage 82 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 83 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 84 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 85 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 86 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 87 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 88 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 89 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 90 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 91 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 92 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 93 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 94 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 95 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 96 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 97 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 98 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 99 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 100 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 101 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 102 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 103 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 104 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 105 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 106 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 107 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 108 of 2381105509525\1 SAME RICAS122787.00374BMEA-053PCTPage 109 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 110 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 111 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 112 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 113 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 114 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 115 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 116 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 117 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 118 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 119 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 120 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 121 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 122 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 123 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 124 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 125 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 126 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 127 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 128 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 129 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 130 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 131 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 132 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 133 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 134 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 135 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 136 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 137 of 2381105509525\1 \AME RICASPage 138 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTTable 2: Representative Menin InhibitorsPage 139 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 140 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 141 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 142 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 143 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 144 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 145 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 146 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 147 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 148 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 149 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 150 of 23811055095254 \AME RICAS122787.00374BMEA-053PCTPage 151 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 152 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 153 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 154 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 155 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 156 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 157 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 158 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 159 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 160 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 161 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 162 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 163 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 164 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 165 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 166 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 167 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 168 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 169 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 170 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 171 of 2381105509525\1 \AME RICASPage 172 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTTable 3 : Additional Menin InhibitorsPage 173 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 174 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 175 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 176 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 177 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 178 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 179 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 180 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 181 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 182 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 183 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 184 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 185 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 186 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 187 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 188 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 189 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 190 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 191 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 192 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 193 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 194 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTTable 4: Further Additional Menin InhibitorsPage 195 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 196 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 197 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 198 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 199 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTPage 200 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTExample BibGlucose-stimulated insulin secretion (GSIS) assay

[0317] Purified islets from healthy or T2D donors (Prodo Laboratory, Inc., Aliso Viejo, CA) were cultured in PIM(S) media (Prodo) with 8 mM or 11 mM glucose in a 37°C water-jacketed incubator with 5% CO2. The GSIS assay followed published procedure (Zhu et al. 2015; Ho et al. 2023). Briefly, islets were conditioned in Krebs-Ringer bicarbonate buffer (KRB, 111 mM NaCl, 4.8 mM KC1, 25 mM NaHCOs, 2.3 mM CaCl2, 1.2 mM MgSO4, 0.15 mM Na2HPO4, 1.2 mM KH2PO4, 10 mM HEPES, 0.2% BSA) containing 2.8 mM glucose for 2 hours with 0.05% DMSO, compound 36 or orforglipron. Size- matched islets were used for each test condition. Islets were washed with KRB once and incubated in fresh KRB containing 2.8 mM glucose with 0.05% DMSO or corresponding compound for one hour to measure the basal insulin secretion in 2.8 mM glucose. Glucose concentration was increased to 11 mM and islets stimulated for one hour in the presence of 0.05% DMSO or corresponding compound to measure stimulated insulin secretion. Supernatants were harvested and insulin secreted under basal and glucose stimulated conditions were quantified using an ELISA kit (ALPCO, Salem, NH). Islets were lysed and genomic DNA was extracted using silicon spin column (Qiagen, Venlo, Netherlands). Insulin secretion was normalized to total genomic DNA.

[0318] In ex-vivo cultured islets from a T2D donor, Compound 36 potentiated GSIS (Figure 1). Compound 36 decreased basal insulin secretion (Fig. 1A) and improved stimulated insulin as well as insulin secretion index (Fig. 1A and B) and was overall relatively better than orforglipron. Insulin secretion index is the ratio of stimulated insulin secretion at 11 mM glucose / basal insulin secretion at 2.8 mM glucose. In ex-vivo cultured islets from a healthy donor, compound 36 potentiated islets to secretePage 201 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT more insulin upon glucose stimulation compared to DMSO (Fig. 2). (Ho, K. H., A. Jayathilake, Y. Mahircan, A. Nour, A. B. Osipovich, M. A. Magnuson, G. Gu, and I. Kaverina. 2023. CAMSAP2 localizes to the Golgi in islet beta-cells and facilitates Golgi-ER trafficking, Science. 26: 105938.Zhu X., R. Hu, M. Brissova, R. W. Stein, A. C. Powers, G. Gu, and I. Kaverina. 2015. Microtubules Negatively Regulate Insulin Secretion in Pancreatic beta Cells, Dev Cell, 34: 656-68).Orforglipron:Example BicCombination Study with Menin Inhibitor BMF-219 and tirzepatide, orforglipron, semaglutide or Compound 36BMF-219 enhances glucose stimulated insulin secretion potentiated by peptide GIP / GLP-1 dual receptor agonist tirzepatideExperiment 1.

[0319] For combination studies Experiments 1 and 2, islets were cultured in PIM(S) media with desired glucose concentration in the absence or presence of BMF-219 (30 nM to 300 nM) for 4-7 days, with media changed every 2-3 days. High glucose concentrations (8mM or 1 ImM) were used to induce glucose-stress conditions, and 5.4 mM glucose was used as normal condition. After 7 days in culture, islets were subjected to glucose-stimulated insulin secretion (GSIS) assay following published procedure (Zhu et al. 2015, Ho et al. 2023). Size matched islets were used across the different treatment groups with 4-6 islets per well and 3-4 replicates per treatment group. Briefly, islets were conditioned in Krebs-Ringer bicarbonate buffer (KRB, 111 mM NaCl, 4.8 mM KC1, 25 mM NaHCOs, 2.3 mM CaCl2, 1.2 mM MgSO4, 0.15 mM Na2HPO4, 1.2 mM KH2PO4, 10 mM HEPES, 0.2% BSA) containing 2.8 mM glucose for 2 hours. Islets were then washed with KRB and incubated for one hour in fresh KRB containing 2.8 mM glucose with 0.05% DMSO or select concentration of receptor agonist, to measure the basal insulin secretion. Maintaining the receptor agonist concentration constant, glucose concentration was increased to 11 mM and islets stimulated for one hour to measure stimulated insulin secretion. Secreted insulin in thePage 202 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCT culture supernatants was quantified using an ELISA kit (ALPCO, Salem, NH). At the end of the assay, islets were lysed and total insulin content as well as genomic DNA content were measured. DNA was extracted using silicon spin column (Qiagen, Venlo, Netherlands).

[0320] Cadaver-derived islets were from a 38-yr non-diabetic White male (HbAlc 5.2%). Islets were cultured under glucotox conditions (8 mM) in the presence or absence of BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence (filled circles) or presence (open symbols) of 30 nM tirzepatide. Stimulated insulin secretion was expressed as normalized to total islet DNA (Figure 3A) and normalized to basal insulin secretion at 2.8mM glucose (Figure B).

[0321] As observed, tirzepatide potentiated insulin secretion from the islets. In comparison, insulin secretion potentiated by tirzepatide was significantly increased when islets were cultured in the presence of BMF-219. These data support combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists and / or GIP / GLP-1 dual receptor agonists for the treatment of diabetes.Experiment 2.

[0322] Cadaver-derived islets were from a 38-yr non-diabetic Asian male (HbAlc 5.7%). Islets were cultured under glucotox conditions (8 mM) in the presence or absence of BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence (filled symbols) or presence (open symbols) of 30 nM tirzepatide. Stimulated insulin secretion was expressed as normalized to total islet DNA (Figure 4A) and normalized to basal insulin secretion at 2.8 mM glucose (Figure 4B). As observed, tirzepatide potentiated insulin secretion from the islets. In comparison, insulin secretion potentiated by tirzepatide was significantly increased when islets were cultured in the presence of BMF- 219. These data support combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists and / or GIP / GLP-1 dual receptor agonists for the treatment of diabetes.BMF-219 enhances glucose stimulated insulin secretion potentiated by semaglutide, a GLP-1 receptor agonistCadaver-derived islets were from a 47-yr non-diabetic White male (HbAlc 5.2%). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (light grey bars) or presence (dark grey bars) of BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence or presence of 100 nM semaglutide or 400 nM orforglipron. Stimulated insulin secretion was expressed as normalized to total islet DNA (Figure 5A) and normalized to basal insulin secretion at 2.8 mM glucose (Figure 5B).Insulin secretion potentiated by semaglutide and orforglipron was increased when islets were cultured in the presence of BMF -219. These data support the exploration of combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists for the treatment of diabetes.BMF-219 enhances glucose stimulated insulin secretion potentiated by small molecule GLP-1 receptor agonistPage 203 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT

[0323] Cadaver-derived islets were from a 44-yr T2D Hispanic male (HbAlc 6.5%, donor was managing his diabetes with diet). Islets were cultured under glucotox conditions (8 mM) in the absence (fdled symbols) or presence (open symbols) of 0.3 pM BMF-219 for 4 days. Size matched islets were selected and subjected to GSIS assay with BMF-219, orforglipron or Compound 36. Stimulated insulin secretion was expressed as normalized to total islet DNA (Figure 6A) and normalized to basal insulin secretion at 2.8 mM glucose (Figure 6B).

[0324] Under the tested conditions, insulin secretion potentiated by Compound 36 was notably increased when islets were cultured in the presence of BMF-219. These data support the exploration of combination treatment with menin inhibitor BMF-219 and small molecule GLP-1 receptor agonists for the treatment of diabetes.

[0325] BMF-219 enhances glucose stimulated insulin secretion potentiated by GLP-1 receptor agonists. Cadaver-derived islets were from a 54-yr non-diabetic White female (BMI 28.6, HbAlc 5.7%). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (-) or presence of 100 nM or 300 nM BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence or presence of compound 214 (cpd 214). Stimulated insulin secretion was expressed as normalized to total islet DNA (Figure 7A) and normalized to basal insulin secretion at 2.8 mM glucose (Figure 7B).

[0326] Treatment with BMF-219 enhanced GSIS potentiated by the small molecule GLP-1 receptor agonist, compound 214. These data support the exploration of combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists for the treatment of diabetes.

[0327] BMF-219 enhances glucose stimulated insulin secretion potentiated by GLP-1 receptor agonists. Cadaver-derived islets were from a 43-yr non-diabetic White male (BMI 27.1, HbAlc 5.5%). Islets were cultured under glucotox conditions (8 mM glucose) in the absence (-) or presence of 100 nM or 300 nM BMF-219 for 7 days. Size matched islets were selected and subjected to GSIS assay in the absence or presence of compound 36 (cpd 36). Stimulated insulin secretion was expressed as normalized to total islet DNA (Figure 8A) and normalized to basal insulin secretion at 2.8 mM glucose (Figure 8B).

[0328] Treatment with BMF-219 enhanced GSIS potentiated by the small molecule GLP-1 receptor agonist, compound 36. These data support the exploration of combination treatment with menin inhibitor BMF-219 and GLP-1 receptor agonists for the treatment of diabetes.Example BldClinical study of Combination of BMF-219 and semaglutideNumber of Arms: 4Blinding: blinded (participants, care providers / investigators)Number of Participants: Randomly assigned to trial intervention; 240 participants [target]; 120 active (BMF-219 lOOmg QD, BMF-219 lOOmg QD + semaglutide), 120 placebo (placebo, placebo + semaglutide)Page 204 of 2381105509525\1 \AME RICAS122787.00374 BMEA-053PCTArms and Duration:

[0329] Total duration of trial intervention for each participant: 40 to 52 weeks (approximately 12 weeks of BMF-219 or BMF-219 +semaglutide or matching placebo followed by 28 or 40 weeks of semaglutide).

[0330] The study uses a randomized, double-blind, placebo-controlled design with parallel assignment between 4 treatments. The trial begins with a screening period of up to 28 days.• On Day 1, eligible participants will be randomly assigned to 1 of 4 treatments using a 1: 1: 1: 1 ratio with randomization stratified according to sulfonylurea use, HbAlc range, and BMI. o Arm A: BMF-219 lOOmg QD for approximately 12 weeks (83 days; BMF-219 should not be taken on Day 84). o Arm B: Matching lOOmg placebo for approximately 12 weeks (83 days: Matching placebo should not be taken day 84) o Arm C: BMF-219 lOOmg QD + semaglutide for approximately 12 weeks (83 days; BMF-219 should not be taken on Day 84). o Arm D: Matching lOOmg Placebo QD + semaglutide for approximately 12 weeks (83 days; Matching lOOmg placebo should not be taken on Day 84).• At Week 12, participants will begin or continue semaglutide injection (according to the escalation schedule below) for 28 weeks (ie, until Week 40)• At Week 40, participants in each treatment arm (Arm A: BMF-219, Arm B: Placebo Arm C: BMF-219 +semaglutide, Arm D: placebo +semaglutide) will be randomly assigned to 1 of 2 treatments using a 1: 1 ratio: o Continued semaglutide injection for 12 weeks (ie, until Week 52) o Follow-up for 12 weeks (ie, until Week 52) without semaglutide injection.

[0331] The total duration of the trial is approximately 57 weeks.Example Ble

[0332] Menin Inhibitor BMF-219 enhances the expression of the GLP-1 receptor and insulin at the transcript and protein levels.

[0333] Cadaver-derived human islets from non-daibetic donors were cultured at a density of around 1000 IEQS in 10 mL complete PIM(S) media [500mL PIM(S) media supplemented with 25mL PIM(ABS), 5mL PIM(G), and 6mL PIM(3X)] in 10-cm Petri dishes. Cultures were maintained at 37°C in a humidified incubator with 5% CO2. The media was replaced every two or three days. To study the effect of BMF-219, islets were cultured under glucotoxic conditions (8 mM glucose) in the presence of vehicle or BMF-219 for 7 days, with media refreshed every two days. Following treatment, islets were harvested and the expression levels of GLP-1 and insulin quantified at the transcript and protein levels.

[0334] For RNA extraction, islets were carefully collected under a dissection microscope tube and washed twice with cold PBS. Total RNA was extracted using the RNeasy Mini kit (Qiagen). cDNAPage 205 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT synthesis was performed using SuperScript IV VILO Master Mix (Thermo Fisher) using 0. 1 to 0.5 mg total RNA. Quantitative PCR was performed with TaqMan multiplex PCR master mix (Applied Biosystems) using the QuanStudio ABI 7100 (Applied Biosystems). Probes for human GLP-1R (Hs00157705_ml) and insulin (Hs00355773_ml) were purchased from ThermoFisher and for human RPL30 (Hs.PT.58.25080412) from Integrated DNA Technology (IDT). Following qPCR (3-4 replicates per sample), the 2(-Delta Delta C(T)) method (Livak 2001) was used, where ACt = Ct of GLP-1R - Ct of RPL30 (housekeeping gene) and A ACt = ACt (icovamenib treatment) - ACt (DMSO). The figures show fold change of 2A-AACt ± standard deviation (SD) of the icovamenib treated group vs DMSO group.

[0335] For GLP-1 receptor protein analysis by Western Blot, islets were collected carefully into a 1.5mL tube under a dissection microscope, followed by washing with cold PBS. Islets were lysed using RIPA buffer supplemented with proteinase (Thermo Scientific) for 1 hr with mixing every 10 mins. Samples were centrifuged for 30 mins, supernatants collected, and protein concentration determined by BCA kit (Thermo Fisher Scientific). Samples were analyzed using the JESS Simple automated Western system (ProteinSimple), with 3-5 mg of lysate loaded per well and probed with anti GLP-1R (Novus Biologicals, NBP197308) and vinculin (Invitrogen, NB600-1293) antibodies. The Jess results were analyzed by the installed Compass software for SimpleWestem according to manufacturer’s protocol. GLP-1 R peak area was normalized to vinculin peak area.

[0336] To measure intracellular insulin concentrations in the human islets, size-matched islets were selected under the dissection microscope and lysed in 30uL of lysis buffer (ATL + 0.3 uL 0.5M EDTA + 0.06 pL Pepstatin A (Img / mL)) in a 96 well plate. Samples were incubated at RT for 10 mins with shaking (750 rpm), after which 3uL lysate was transferred into a fresh 96-well plate, mixed with lOuL EtOH / HCI, and subjected to freeze-thaw once for 15mins. Thawed samples were diluted 10-fold and insulin concentrations determined using a human Insulin ELISA kit (catalogue #80-INSHU-E10.1, ALPCO, Salem, NH) and the Victor Nivo plate reader (PerkinElmer, Inc.). Analysis of the data followed the manual of the ALPCO human Insulin ELISA kit. Insulin concentrations in test samples were determined using an insulin standard curve (Findlay 2007) and normalized by total genomic DNA amount in the lysate of the same sample. Genomic DNA in the lysate was extracted using the DNeasy Blood & Tissue Kit (catalogue #69504, Qiagen, Venlo, Netherlands) and quantified by NanoDrop eight (Thermo Scientific, Waltham, MA).

[0337] Published literature describes the role of menin in regulating the expression of both, the GLP-1 receptor and insulin, where menin inhibition leads to their enhanced expression. To probe into the potential mechanisms by which BMF-219 may enhance insulin secretion potentiated by GLP-1 receptor agonists, gene expression and protein expression were evaluated in human islet cultures treated with BMF-219 under hyperglycemic conditions for one week. Combined results from assays performed with islets from eight independent donors demonstrate a BMF-219 dose-dependent enhancement in the transcript levels of the GLP-1 receptor (Figure 9A) as well as insulin (Figure 9B). BMF-219-induced expression of these targets was also observed at the protein level in islets from independent donors (Figures 9C and 9D). The observed effects of icovamenib provide mechanistic explanation for its abilityPage 206 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT to enhance the responsiveness of human islets to GLP-1 -based therapies and enhance potentiation of insulin secretion, as observed in the GSIS assays with the human islets (Figures 3 to 8). The GLP-1 based therapies include peptide and small molecule GLP-1 R agonists, including but not limited to semaglutide and orforglipron. The peptide agonists include and are not limited to the GLP-l / GIP dual receptor agonists such as tirzepatide.References

[0338] Livak, K.J. and T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001. 25(4): p. 402-8.Findlay, J.W. and R.F. Dillard, Appropriate calibration curve fitting in ligand binding assays. AAPS J, 2007. 9(2): p. E260-7.Example Blf

[0339] Combination with Menin Inhibitor BMF-219 and GLP-1 Receptor Agonist, Semaglutide

[0340] Combination of BMF-219 and low dose semaglutide enhances glycemic control and body weight loss while preserving lean mass in a type 2 diabetes animal model.

[0341] Efficacy of combination therapy with icovamenib and low dose semaglutide was evaluated in the ZDF rat model of T2D and compared against semaglutide alone. Male ZDF rats (11 to 12 weeks old) were randomized into two groups (n=10 / group), based on body weight (BW), HbAlc and HOMA-IR. Group 1 was administered vehicle daily for 4 weeks (dosed PO), while Group 2 was administered 200 mg / kg BMF-219 PO daily for 4 weeks (dosed PO). During weeks 3 and 4, both groups were administered low dose semaglutide (5 nmol / kg) subcutaneously daily, followed by a two-week wash-out period (no treatment). Water and food intake per cage and body weight per animal were measured three times a week. Fasting blood glucose, plasma insulin and HbAlc levels were measured every two weeks and HOMA-IR was calculated for each measurement. Oral glucose tolerance test (OGTT) was performed on days 15, 28 and 39 of treatment, and plasma insulin levels measured following oral glucose bolus.

[0342] Animals treated with the combination of BMF-219 and low dose semaglutide showed significant reductions in fed blood glucose levels, compared to the animals treated with low dose semaglutide alone.

[0343] FBG levels and HbAlc were also significantly reduced in the combination treatment group, accompanied by improvements in HOMA-IR and HOMA-P, indicating better insulin sensitivity and beta-cell function (Figures 10 and 11). As seen from the Day 15 data, the mean FBG was 21% lower following two weeks of BMF-219 treatment compared to vehicle treatment (Figure 10B). On Day 21, following 1 week of low dose semaglutide + BMF-219 combination treatment, the mean FBG in Group 2 was significantly reduced and 57% lower than the mean FBG in the low dose semaglutide group (Group 1) (Figure 10B). The reduction in blood glucosePage 207 of 2381105509525\1 \AME RICASin Group 2 persisted through week 4, with Group 2 showing -60% lower mean FBG in than the low dose semaglutide group. In the combination treatment group, mean reduction in HbAlc from baseline was >1% by Day 28 and >2% by Day 39 (Figure 10C). In comparison, mean reduction in HbAlc from baseline was only 1.1% only by Day 39 in the low dose semaglutide group. During oral glucose tolerance tests (OGTT), the combination treatment of BMF-219 and low dose semaglutide significantly reduced blood glucose levels and improved insulin response, compared to low dose semaglutide alone. Mean blood glucose AUC from the Day 28 OGTT was 50% lower in the combination treatment group compared to low dose semaglutide treated group (Figure 10D). C-peptide to glucose ratio (C-peptide index) on Day 28 was twice as high in the combination treatment group compared to low dose semaglutide group (Figure 11 A). On Day 21, following 1 week of low dose semaglutide + BMF-219 combination treatment, the mean HOMA- B for Group 2 was significantly increased compared to that of the low dose semaglutide group (Group 1) (Figure 1 IB). HOMA-IR showed slight (22%) reduction, following 2 weeks treatment with BMF-219 compared to vehicle (Figure 11C). Combination treatment of low dose semaglutide + BMF-219 significantly improved insulin sensitivity (indicated by HOMA-IR reduction), compared to low dose semaglutide alone (Figure 11C). Mean HOMA-IR for Group 2 was 66% and 75% lower than Group 1 on Days 21 and 28, respectively. Overall, the data demonstrates the superior glycemic control of BMF-219 + low dose semaglutide combination, compared to low dose semaglutide alone. BMF-219 helped enhance the efficacy of semaglutide, allowing for a low dose to achieve high therapeutic efficacy. This effect is thought to be potentiated by icovamenib’s ability to increase the GLP-1 receptor expression as well an insulin in the target cells and thereby enhancing insulin secretion.[00344 J The combination treatment of low dose semaglutide + BMF-219 significantly increased appetite suppression (Figure 12A) and increased body weight reduction (Figure 12B) compared to low dose semaglutide alone. Low dose semaglutide, promoted more notable reductions in appetite and body weight, when compared to icovamenib, and reaching a plateau at -3.4% reduction in body weight by Day 27 (Figure 12B). In comparison, the combination treatment with low dose semaglutide + BMF-219 induce a more significant suppression of appetite and reduction in body weight reduction, when compared to icovamenib alone or low dose semaglutide alone. For the combination treated group, a 12.8% reduction in body weight was reached by Day 27 and had not reached a plateau.[00345J Body composition analysis was performed at baseline and Day 25 to assess the effects of the treatments on lean mass and fat mass (Figure 13). Analysis revealed that despite the significant reductio in body weight in the low dose semaglutide + BMF-219 combination treatment group, there was complete preservation of lean mass (Figures A, B and C). The bodyPage 208 of 2381105509525\1 \AME RICASweight reduction was exclusively from fat mass loss. The low dose semaglutide induced only a modest 3.4% reduction in body weight. Overall results reveal combination treatment had superior appetite suppression and promoted muscle-sparing body weight reduction. The body weight reduction was exclusively due to fat mass loss with complete preservation of lean mass. Notably, the results demonstrate the ability of icovamenib to enhanced efficacy of GLP-l-based therapies such as semaglutide, potentially enabling lower doses of GLP-l-based therapies to achieve glycemic and weight loss targets and improve tolerability of these agents.

[0346] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0347] At least some of the chemical names of compounds provided herein as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control. In the chemical structures where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.Page 209 of 2381105509525\1 \AME RICAS

Claims

122787.00374BMEA-053PCTWHAT IS CLAIMED IS:

1. A method of treating diabetes, obesity, or an overweight condition in a patient in need thereof comprising administering to the patient a GLP-1R agonist, or a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with a menin inhibitor, or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the GLP-1R agonist is a compound according to Formula (GL'-I):or a stereoisomer or a pharmaceutically acceptable salt thereof, whereinCy1is substituted or unsubstituted 5,6-fused or 6,6-fused heteroaryl;Cy2is substituted or unsubstituted heteroaryl; or -Cy2-R’ is -C(O)-NR6a-(CH2)m-R1; and wherein R6ais H, or substituted or unsubstituted alkyl; and m is 0, 1, 2, or 3;Cy3is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R1is substituted or unsubstituted aryl or heteroaryl;R2is CN, or substituted or unsubstituted heteroaryl; each R3aand R3bis independently H, or substituted or unsubstituted alkyl; or R3aand R3bform an oxo; or R3aand R3bare joined together to form substituted or unsubstituted cycloalkyl or heterocycloalkyl ring; each R4is independently H, halo, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, or arylsulfmyl; and n is 1, 2, 3, 4, or 5; each R5a, R5band R5cis independently H, or substituted or unsubstituted alkyl;Page 210 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT or R5aand R5bor R5aand R5care joined together to form a heterocycloalkyl; and wherein the substitution on each alkyl is independently selected from halo, CN, hydroxy, and alkoxy; the substitution on each alkoxy is independently selected from halo, CN, and substituted or unsubstituted alkyl; the substitution on each cycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heterocycloalkyl is independently selected from halo, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each aryl is independently 1 -3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy; the substitution on each heteroaryl is independently 1 -3 groups independently selected from halo, haloalkyl, amino, dialkylamino, amido, CN, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and oxo.

3. The method according to claim 1, wherein the GLP-1R agonist is according to formula:or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1, wherein the GLP-1R agonist is orforglipron.

5. The method according to claim 1, wherein the GLP-1R agonist is according to formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf):Page 211 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTor a stereoisomer or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1, wherein the GLP-1R agonist is according to formula (M-VIIa), (M- Vllb), (M-VIIc), or (M-VIId):Page 212 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTor a pharmaceutically acceptable salt thereof.

7. The method according to claim 1, wherein GLP-1R agonist is according to formula (M-VIIIa), (M- Vlllb), (M-VIIIc), or (M-VIIId):Page 213 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTa pharmaceutically acceptable salt thereof.

8. The method according to claim 1, wherein the GLP-1R agonist is any one of the compounds listed in Table 1.

9. The method according to claim 1, wherein the GLP-1R agonist is Albiglutide (Tanzeum), Dulaglutide (Trulicity), Exenatide (Byetta), Exenatide extended-release (Bydureon), Liraglutide (Victoza), Liraglutide (Saxenda), Lixisenatide (Adlyxin), Semaglutide injection (Ozempic), Semaglutide (Rybelsus), Tirzepatide (Mounjaro), Tirzepatide (Zepbound), Retatrutide (LY3437943), AMG 133, CagriSema, Cagrilintide, Danuglipron, orforglipron, lotiglipron, ID110521156, GS-4571, PF-06954222, aleniglipron,, ECC5005 (AZD5004), ASC30, MWN109, HS-10535, CT-996, KAI-9531, KAI-7535, KAI 9531, KAI-4729or TTP273.

10. The method according to claim 1, wherein the GLP-1R agonist is liraglutide, dulaglutide, exenatide, semaglutide, or tirzepatide.

11. The method according to claim 1, wherein the GLP-1R agonist is Compound 36, 112, 211, 213, 214, 220, 225, 226, 302, 311, 313, 323, 406, 410, 427, 429, 433, 436, 437, 503, 518, 525, 606, 607, 610, 611, 612, 614, 615, 618, 619, 703, 705, 707, 710, 711, 713, 714, 715, or 716.Page 214 of 2381105509525\1 \AME RICAS12. The method according to claim 1, wherein the GLP-1R agonist is Compound 36, or 214.

13. The method according to claim 1, wherein the GLP-1R agonist is Compound 21414. The method according to claim 1, wherein the GLP-1R agonist is a sodium salt of Compound 214Page 215 of 2381105509525\1 \AME RICAS15. The method according to claim 1, wherein the GLP-1R agonist isPage 216 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT16. The method according to claim 1, wherein the menin inhibitor is a covalent menin inhibitor.

17. The method according to claim 1, wherein the menin inhibitor is according to formula (I):or a pharmaceutically acceptable salt thereof, wherein:A is C or N;Cy is substituted or unsubstitutedPage 217 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCTQ is N, -N(H)-, -0-, or -S-;Z is -CR5a= or -N=;X is -NR3a-, -C(R3b)2-, or -O-;Y is a single bond, -NR3a-, -C(R3b)2-, or -O-;W is -C(O)-, -S(O)-, or -S(O)2-; one of R1and R2is Cy2-N(H)C(O)-C(R6a)=C(R6b)(R6c) or CH2-Cy2-N(H)C(O)-C(R6a)=C(R6b)(R6c); and the other is H, Ci-6 alkyl, Ci-6 haloalkyl, halo, or CN;Cy2is an optionally substituted group selected from phenyl, pyridyl, or a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R3aand R3bis independently H or Ci-e alkyl; each R4aand R4bis independently H, halo, CN, OR, -N(R)2, -C(O)N(R)2,-NRC(O)R, -SO2R, -C(O)R, -CO2R, or an optionally substituted group selected from Ci-e alkyl, C3-7 cycloalkyl, a 4-7 membered heterocycloalkyl ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently H, or an optionally substituted group selected from Ci-e aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;R5ais H, C1-6 alkyl, C1-6 haloalkyl, halo, or CN; each R6aand R6bis independently H or Ci-e alkyl; or R6aand R6bare joined together to form a bond;R6cis H or substituted or unsubstituted C1-6 alkyl; m is 1, 2, or 3; and n is 1, 2, 3, or 4.

18. The method according to claim 1, wherein the menin inhibitor is according to formula (XXI):or a pharmaceutically acceptable salt thereof,Page 218 of 2381105509525\1 \AME RICAS122787.00374BMEA-053PCT wherein each R8and R9is independently H, Ci-6 alkyl, Ci-ehaloalkyl, halo, or CN.

19. The method according to claim 1, wherein the menin inhibitor isCompound 10 , or a salt thereof.

20. The method according to claim 1, wherein the menin inhibitor is, or a salt thereof.

21. The method according to claim 1, wherein the menin inhibitor is any one of compounds listed in Table 2A-2K or Table 3.

22. The method according to claim 1, wherein the menin inhibitor is BMF-219.

23. The method according to claim 1, wherein the menin inhibitor is ziftotmenib.

24. The method of any one of claims 1-23, wherein the diabetes is Type 1 diabetes.

25. The method of any one of claims 1-23, wherein the diabetes is Type 2 diabetes.

26. The method of any one of claims 1-23, wherein the method is for treating obesity.

27. The method of any one of claims 1-23, wherein the method is for treating an overweight condition.

28. The method of any one of claims 1-27, wherein the combination is administered once a day, two times per day, three times per day, four times per day, or five times per day.

29. The method of any one of claims 1-28, wherein the menin inhibitor is administered at a dosage of about 40 mg / day to about 1000 mg / day.

30. The method of any one of claims 1-29, wherein the menin inhibitor is administered orally.

31. The method of any one of claims 1 -30, wherein the compound of formula (GL'-I) and the menin inhibitor are administered in separate compositions.

32. The method of any one of claims 1-31, wherein the compound of formula (GL'-I) and the menin inhibitor are administered simultaneously, sequentially or intermittently.

33. The method of any one of claims 1-32, further comprising administering an additional antidiabetes agent.Page 219 of 2381105509525\1 \AME RICAS34. A pharmaceutical combination comprising: a) a compound according to formula (GL'-I); and b) a menin inhibitor; and c) one or more pharmaceutically acceptable excipient.

35. The pharmaceutical combination of claim 34, that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.

36. A method for treating a metabolic disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical combination of claim 34.

37. A method for treating a metabolic disease or condition comprising administering to a patient in need thereof the pharmaceutical combination of claim 34.

38. A method for treating a diabetes, obesity, or an overweight condition comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical combination of claim 34.

39. Use of the pharmaceutical composition as defined in claim 34, in the manufacture of a medicament for the treatment of diabetes, obesity, or an overweight condition.Page 220 of 2381105509525\1 \AME RICAS

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