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US-12617783-B2 - Heterocyclic GLP-1R agonists

US12617783B2US 12617783 B2US12617783 B2US 12617783B2US-12617783-B2

Abstract

Disclosed herein are heterocyclic compounds that activate GLP-1R pathways. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the GLP-1R agonists are disclosed, alone or in combination with other therapeutic agents, for the treatment of diabetes, obesity, and other diseases or conditions dependent on GLP-1R pathways.

Inventors

  • Xiaodong Wang
  • Yeyu Cao
  • Solomon B. Ungashe
  • Nan-Horng Lin
  • Mini Balakrishnan
  • Petr Jansa
  • Satish Goud Pappali
  • Thorsten A. Kirschberg
  • Johannes H. Voigt
  • Thomas Butler
  • Ravindra B. Upasani
  • Yongli Su
  • Thu Phan
  • James T. Palmer
  • Neil Howard Squires

Assignees

  • BIOMEA FUSION, INC.

Dates

Publication Date
20260505
Application Date
20250328

Claims (20)

  1. 1 . A compound selected from the group consisting of: TABLE 1′ Com- pound ID Structure 32 C49H48F2N10O5 36 C49H48F2N10O5 114 C48H46F2N10O5 115 C45H42F2N10O6 116 C49H48F2N10O6 117 C47H45F2N9O6 118 C47H46F2N12O3 119 C48H45FN10O5 121 C49H48F2N10O6 122 C46H42F2N10O6 123 C48H46F2N10O5 124 C48H45FN10O5 125 C47H45F2N9O6 126 C49H46F2N10O5 127 C49H47FN10O5 128 C48H48F2N12O3 129 C47H44F2N10O5S 131 C54H57F2N11O6 132 C54H57F2N11O6 134 C49H48F2N10O5 135 C49H47F2N11O5 136 C48H44F2N10O6 137 C48H47F2N9O3 138 C48H49F2N9O4 139 C46H45F2N11O5S 140 C48H48F2N10O5 201 C49H51F2N9O6S 203 C52H59FN9O6P 204 C51H53F2N9O6S 205 C50H54F2N10O6S 206 C46H45F2N11O5S 208 C47H44F2N10O5 209 C48H47F2N11O5 210 C48H47F2N11O5 211 C48H47F2N11O5 212 C48H47F2N11O5 213 C49H46F2N10O5 214 C49H46F2N10O5 215 C49H46F2N10O5 216 C50H55FN9O6P 217 C48H47F2N11O5 218 C48H47F2N11O5 219 C50H45F2N11O4 220 C49H46F2N10O6 221 C47H44F2N10O6 222 C49H48ClFN10O6 223 C48H49FN806 224 C49H47F3N10O6 225 C48H47F2N11O6 226 C49H46F2N10O6 227 C49H46F2N10O6 228 C50H51FN10O6 229 C48H47F2N11O5 230 C49H46ClFN10O6 231 C48H47F2N11O6 232 C48H47F2N11O6 233 C49H48F2N10O6 235 C49H47F3N10O5 236 C48H46F3N11O5 237 Isomer 1 C48H44F2N10O5 238 C48H47F2N11O6 239 C48H47F2N11O6 240 C50H53F2N9O4 241 C50H53F2N9O5 242 C49H45F3N10O6 243 C50H53F2N9O4 244 C49H51F2N9O4 246 C51H53F2N9O4 302 C49H49FN10O5 305 C50H51FN10O5 306 C46H45F2N11O5S 307 C46H45F2N11O5S 308 C49H48ClFN10O5 309 C49H46F4N10O5 310 C49H46F4N10O5 311 C48H47F2N11O5 312 C48H47F2N11O5 313 C48H47F2N11O5 318 Isomer 1a C50H48F2N10O5 319 Isomer 1b C50H48F2N10O5 323 C49H47FN10O5 324 C48H47F2N11O6 406 C48H46F2N10O5 410 C49H46F2N10O5 412 C48H47F2N9O6 413 C48H46F2N10O5 415 C50H48F2N10O5 416 C48H48F2N10O5 417 C49H50F2N10O4 418 C48H46F2N10O5 419 C48H46F2N10O5 420 C48H46F2N10O5 421 C48H48F2N10O5 422 C48H47F2N9O6 423 C48H46F2N10O5 424 C50H48F2N10O5 425 C48H46F2N10O5 426 C50H48F2N10O5 427 C50H50F2N10O5 428 C49H51F2N9O6S 429 C49H48F2N10O6 431 C49H48F2N10O6 432 C48H50F2N10O4 433 C50H50F2N10O5 434 C50H50F2N10O5 435 C50H50F2N10O5 436 C48H44F2N10O5 437 C49H44F2N10O5 501 C51H59FN9O6P 502 C46H44F2N10O5 503 C48H48F2N10O6S 504 C48H48F2N10O6S 505 C47H46F2N10O5 506 C49H55FN9O6P 507 C49H47F3N10O5 508 C47H48F2N10O6S 509 C50H48F2N10O5 510 C49H45F2N11O5 511 C49H47F3N10O5 512 C49H47F3N10O5 515 C49H47F3N10O5 516 C49H46F2N10O5 518 C49H50F2N10O5 519 C49H46F2N10O5 521 C48H46F2N10O5 522 C50H50F2N10O5 523 C50H50F2N10O5 525 C48H48F2N10O6S 526 C46H44F2N10O7S 527 C49H50F2N10O6S 528 C49H46F2N10O5 529 C49H46F2N10O5 532 C50H50F2N10O5 533 C47H46F2N10O6S 534 C47H46F2N10O6S 535 C48H47F2N11O6S 536 C48H48F2N10O7S 537 C51H52F2N10O5 542 C49H46F2N10O5 545 C53H54FN9O6 602 C50H49F2N9O6S 604 C49H48F2N10O6S 605 C50H49F2N906S 606 C49H48F2N10O5 607 C47H46F2N10O5 608 C49H48F2N10O6S 609 C49H48F2N10O6S 610 C51H47F2N9O5 611 C51H53F2N9O6 612 C53H55ClFN9O6 613 C50H50F2N10O5 614 C51H47F2N9O5 615 C50H49F3N10O5 616 C49H49F2N11O4 617 C51H50F2N10O6 618 C49H47F3N10O5 619 C49H47F3N10O6 701 C50H49F3N10O5 702 C49H50F2N10O5 703 C49H50F2N10O5 704 C53H54FN9O6 705 C49H47F3N10O6 706 C49H47F3N10O6 707 C50H49F3N10O5 708 C49H47F3N10O5 709 C49H47F3N10O5 710 C51H50FN9O7 711 C49H47F3N10O5 712 C49H47F3N10O5 713 C49H47F3N10O5 714 C53H54FN9O6 715 C49H46F2N10O6 and 716 C49H47F3N10O5; or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound according to claim 1 , selected from the group consisting of the compounds with ID numbers 36, 121, 128, 208, 209, 213, 214, 220, 225, 226, 302, 311, 313, 323, 406, 410, 417, 427, 428, 429, 433, 436, 437, 611-619, 703, 705-708, 710-715 and 716, or a pharmaceutically acceptable salt thereof.
  3. 3 . The pharmaceutically acceptable salt of the compound of claim 1 .
  4. 4 . The pharmaceutically acceptable salt of claim 3 , selected from L-arginine, hemi-calcium, mono-potassium, mono-sodium, L-lysine, and betaine salt forms.
  5. 5 . The pharmaceutically acceptable salt of claim 3 , wherein the salt is compound 214 monosodium salt or compound 36 monosodium salt.
  6. 6 . The pharmaceutically acceptable salt of claim 5 , wherein the salt is amorphous.
  7. 7 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  8. 8 . A method of treating a GLP-1 related disorder in a subject in need thereof comprising administering a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
  9. 9 . The compound according to claim 1 , wherein the compound is selected from the group consisting of compounds with ID numbers 36, 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, 617, 705-708, 710-715 and 716, or a pharmaceutically acceptable salt thereof.
  10. 10 . The compound according to claim 1 , wherein the compound is selected from the group consisting of compounds with ID numbers 36, 121, 214, 226, 302, 323, 36, 428, 429, 433, 509, 518, 525, 606, 607, 610, 612, 614, and 617, or a pharmaceutically acceptable salt thereof.
  11. 11 . The compound according to claim 1 , with the ID number 36: or a pharmaceutically acceptable salt thereof.
  12. 12 . The compound according to claim 1 , with the ID number 214: or a pharmaceutically acceptable salt thereof.
  13. 13 . The compound according to claim 1 , with the ID number 707: or a pharmaceutically acceptable salt thereof.
  14. 14 . The compound according to claim 1 , with the ID number 710: or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound according to claim 1 , with the ID number 711: or a pharmaceutically acceptable salt thereof.
  16. 16 . The compound according to claim 1 , with the ID number 713: or a pharmaceutically acceptable salt thereof.
  17. 17 . The compound according to claim 1 , with the ID number 714: or a pharmaceutically acceptable salt thereof.
  18. 18 . The compound according to claim 1 , with the ID number 225:
  19. 19 . The compound according to claim 1 , with the ID number 226: or a pharmaceutically acceptable salt thereof.
  20. 20 . The pharmaceutically acceptable salt of claim 3 , wherein the pharmaceutically acceptable salt is compound ID number 214 monosodium salt.

Description

CROSS-REFERENCE This application claims the benefit of U.S. provisional application Nos. 63/768,592, filed Mar. 7, 2025, 63/760,318, filed Feb. 19, 2025, 63/720,442, filed Nov. 14, 2024, 63/706,540, filed Oct. 11, 2024, 63/689,349, filed Aug. 30, 2024, 63/672,080, filed Jul. 16, 2024, 63/635,840, filed Apr. 18, 2024, and 63/571,826, filed Mar. 29, 2024, the contents of which are hereby incorporated in their entireties. FIELD Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments containing such compounds, and methods of using such compounds and compositions to activate GLP-1R. BACKGROUND 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 body cannot produce enough insulin, effectively use available insulin or both. Pancreatic β 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 (TID) conditions are the result of body's immune system destroying β cells. Type 2 diabetes (T2D), on the other hand, develops when the body does not produce enough insulin or develops a resistance to 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. Incretin hormones modulate glucose metabolism by stimulating the release of insulin by pancreatic β cells. One of the incretin hormones, glucagon-like-peptide-1 (GLP-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). GLP-1 is a thirty-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 β 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 β cells, which then lead to stimulation of insulin. Additionally, GLP-1 has anti-apoptotic function in pancreatic β cells, and it can enhance β cell proliferation and delay gastric emptying. GLP-1 can also stimulate the proliferation of β 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. 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 β cells. Currently marketed agonists are peptides and are primarily administered via subcutaneous injection. These peptide GLP-1 agonists often suffer from inconvenient dosing regimen and poor bioavailability. Currently, there is no approved small molecule GLP-1 agonist to treat diabetes or other metabolic diseases. Therefore, GLP-1 small molecule agonist that can be easily administered may be useful to treat wide ranges diseases and conditions including diabetes and obesity. SUMMARY In one aspect, described herein are agonists of GLP-1R. Also described herein are specific heterocyclic agonists of GLP-1R. In another aspect, described herein are methods for synthesizing such agonists, methods for using such agonists in the treatment of diseases (including diseases wherein agonists of GLP-1R provides therapeutic benefit to a patient having the disease). Further described are pharmaceutical compositions that include agonists of GLP-1R. Specifically, described herein are compounds and methods of use thereof to activate GLP-1R. In another aspect, provided herein is a compound according to Formula (L-I) having the structure: or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each of dotted bond is independently a single or a double bond;Z is substituted or unsubstituted C1-C4 alkylene, —C(O)—, —S(O)—, S(O)2, or —C(R3c)(R3d)—;Cy1 is substituted or unsubstituted 5,6-fused heteroaryl or 6,6-fused het