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WO2025111318A1 - Somatostatin subtype receptor 3 (sstr3) agonists and uses thereof - Google Patents

Somatostatin subtype receptor 3 (sstr3) agonists and uses thereof Download PDF

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WO2025111318A1
WO2025111318A1 PCT/US2024/056625 US2024056625W WO2025111318A1 WO 2025111318 A1 WO2025111318 A1 WO 2025111318A1 US 2024056625 W US2024056625 W US 2024056625W WO 2025111318 A1 WO2025111318 A1 WO 2025111318A1
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Sun Hee Kim
Yunfei Zhu
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Crinetics Pharmaceuticals Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • SSTR3 somatostatin receptor subtype 3 agonists
  • Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors (GPCRs) and inhibition of the release of numerous secondary hormones.
  • GPCRs G-protein-coupled somatostatin receptors
  • Six subtype somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity.
  • Somatostatin acts on five GPCRs (SSTR1 to 5).
  • binding to these receptors inhibits adenylyl cyclases (ACs) and mitogen-activated protein kinase, cell proliferation, and secretion of several hormones (growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin, thyroid stimulating hormone, and adrenocorticotrophic hormone) and growth factors (IGF-I and vascular endothelial growth factor). All five SSTRs are expressed in renal tubular epithelial cells and cholangiocytes. SSTR1 and SSTR2 are expressed in the thick ascending limb of Henle, distal tubule, and collecting duct.
  • ACs adenylyl cyclases
  • mitogen-activated protein kinase cell proliferation, and secretion of several hormones (growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin, thyroid stimulating hormone, and
  • SSTR3, SSTR4, and SSTR5 are expressed in proximal tubules.
  • somatostatin has been shown to (1) inhibit cAMP generation in MDCK cells and rat collecting ducts, (2) antagonize vasopressin effects in the toad urinary bladder and dog collecting ducts, (3) inhibit cAMP generation, fluid secretion, and cell proliferation in cholangiocytes, and (4) suppress the growth of bile ducts and periportal connective tissue in rats with extrahepatic biliary obstruction. Because somatostatin has a half- life of approximately 3 minutes, more stable synthetic peptides (octreotide, lanreotide, and pasireotide) have been developed for clinical use.
  • octreotide which binds to SSTR2 and SSTR5, but preferentially to SSTR2
  • pasireotide which binds with high affinity to SSTR2, SSTR3, and SSTR5
  • kidney growth is halted during the first year of treatment and then resumes, possibly at a lower rate than without treatment. Liver volume decreases by 4%-6% during the first year of treatment, and this reduction is sustained during the second year.
  • SSTR3 selective small molecule modulator has been prepared or tested for the treatment of ciliopathies, such as polycystic kidney disease (PKD).
  • ciliopathies such as polycystic kidney disease (PKD).
  • the compounds described herein are non-peptide somatostatin agonists that selectively activate somatostatin receptor subtype 3 (SSTR3) that in turn reduce cAMP levels that can lead to the ciliopathies described herein, such as PKD.
  • X is NR X , wherein R x is H or Ci-6 alkyl
  • L is a bond, Ci-6 alkyl, or (CR L1 R L2 )t, wherein R L1 and R L2 are each independently H or Ci-6 alkyl, and t is 1, 2, 3, 4, 5, or 6;
  • R 1 is Ci-6 alkyl, C3.10 cycloalkyl, C 3.6 cycloalkoxy, Ci. 6 haloalkoxy, 6 to 10-membered aryl, and 4-7-membered heteroaryl, which are each optionally substituted with 1, 2, 3, 4, or 5 wherein each R 1A is independently halogen, CN, Ci. 6 alkyl, Ci. 6 haloalkyl, OR 11 , C(O)OR n , or C(O)N(R n ) 2 , wherein each R 11 is independently H or Ci. 6 alkyl;
  • R 2 is C3-7 cycloalkyl, C5-9 bicycloalkyl, or 7 to 9-membered heterocycloalkyl, which are each substituted with 1, 2, 3, 4, or 5 R 2A ; wherein R 2A is independently H, halogen, Ci. 6 alkyl, or C(O)OR 21 , wherein the Ci. 6 alkyl is optionally substituted with 1, 2, or 3 halogen, OH, CN, or Ci-6 alkoxy; wherein R 21 is H or Ci-6 alkyl; or two R 2A together with the atoms to which they are attached form a C 3.6 carbocycle;
  • R 3 , R 4 , R 5 , and R 6 are each independently H, halogen, CN, Ci. 6 alkyl, C 3.6 cycloalkyl, Ci-6 alkoxy, Ci-6 haloalkyl, or C 3 .6 cyclohaloalkyl; and
  • R 7 is H, halogen, Ci. 6 alkyl, C 3.6 heterocycloalkyl, OR 71 , or NR 72 R 73 ; wherein R 71 is absent, H, or Ci. 6 alkyl, wherein the Ci. 6 alkyl is optionally substituted with 1, 2, or 3 R 7A , provided that when R 71 is absent, R 7 is a carbonyl group;
  • R 72 and R 73 are independently H or Ci. 6 alkyl, wherein the Ci. 6 alkyl is optionally substituted with 1 , 2, or 3 R 7B ; or R 72 and R 73 together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 R 7C ; wherein R 7A , R 7B , and R 7C are each independently halogen, carbonyl, Ci. 6 alkyl, Ci. 6 alkylamine, 5 -membered heterocycle, OR 7B1 , C(O)OR 7A1 , and C(O)NR 7A2 R 7A2 , wherein the 5- membered heterocycle is optionally substituted with Ci.
  • Ci-6 alkyl carbonyl, or OH
  • the Ci-6 alkylamine is optionally substituted with a 6-membered cycloalkyl that is optionally substituted with CO 2 H
  • R 7A1 , R 7A2 , R 7B1 , R 7B2 , and R 7B3 are each independently H, Ci-6 alkyl, or Ci-6 alkylsulfonyl, wherein the Ci-6 alkyl and Ci-6 alkylsulfonyl are each optionally substituted with 1 or 2 R 7B4 ; wherein R 7B4 is independently OC(O)-R 7B5 or 5 -membered heterocycle that is optionally substituted with Ci. 6 alkyl; and wherein R 7B5 is Ci. 6 alkyl, which is optionally substituted with NH 2 .
  • FIG. 1 depicts how abnormal primary cilia function triggers cystogenesis in autosomal dominant polycystic kidney disease (ADPKD).
  • ADPKD autosomal dominant polycystic kidney disease
  • FIG. 2 depicts interplay of calcium ions and cAMP ciliary signaling pathways in renal tissue of (A) healthy individuals and (B) individuals with ADPKD.
  • FIG. 3 depicts the mechanism of action by which SSTR3 activation can inhibit adenylyl cyclase activity and decrease cilio-plasma cAMP levels.
  • FIG. 4 depicts an analysis of the mRNA expression of SSTR2, SSTR3, SSTR5, and vasopressin receptor 2 (AVPR2) in healthy and cystic tissue.
  • AVPR2 vasopressin receptor 2
  • Somatostatin also known as somatotropin release inhibiting factor (SRIF) was initially isolated as a 14-amino acid peptide from ovine hypothalami (Brazeau etal., Science 179, 77-79, 1973).
  • An TV-terminal extended 28-amino acid peptide with similar biological activity to 14-amino acid somatostatin was subsequently isolated (Pradayrol et, al., FEBS Leters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980).
  • SSTR is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SSTR acts through both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and gut and have multiple functions including modulation of secretion of growth hormone (GH), insulin, glucagon, as well as many other hormones that are anti-proliferative.
  • GH growth hormone
  • somatostatin receptor proteins SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5
  • the six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All the receptors are members of the class-A subgroup of the GPCR superfamily.
  • the SSTR3 agonists described herein are used in the treatment of a variety of diseases or conditions such as, but not limited to, ciliopathic diseases, including, but not limited to, polycystic kidney disease (PKD) and polycystic liver disease (PLD) .
  • PPD polycystic kidney disease
  • PLD polycystic liver disease
  • SSTR3 agonists described herein are used in the treatment of a variety of diseases or conditions associated with dysfunction of cilia such as, but not limited to, PKD, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and combinations thereof.
  • SSTR3 agonists described herein are used in the treatment of PKD.
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • SSTR3 agonists described herein are used in the treatment of PKD.
  • ADPKD
  • Ciliopathies are a class of developmental and degenerative single-gene disorders characterized by dysfunction of a hairlike cellular organelle called the cilium.
  • Cilia are microtubule-based structures found on almost all vertebrate cells. They originate from a basal body, a modified centrosome, which is the organelle thatformsthe spindle poles during mitosis. Most of the proteins that are altered in the single-gene disorders that make up ciliopathies function at the cilium-centrosome complex, which represents nature’s universal system for cellular detection and management of external signals. The important role that the cilium- centrosome complex plays in the normal function of most tissues accounts for the involvement of multiple organ systems in ciliopathies. The dysfunction of cilia can cause a variety of ciliopathic diseases and conditions, including, but not limited to, PLD, PKD, ADPKD, ARPKD, and combinations thereof.
  • Polycystic kidney disease also known as polycystic kidney syndrome, is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts, non-functioning tubules filled with fluid pumped into them, within the kidney. Cysts range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.
  • ADPKD and ARPKD.
  • the mutated gene is expressed in all cells in the body; as a result, cysts may also occur in the liver.
  • tissue levels of cAMP are increased in numerous animal models of ciliopathies, including those for PKD.
  • tissue levels of cAMP are determined by the activities of membrane-bound and soluble adenylyl cyclases (ACs) and cAMP phosphodiesterases (PDEs), which are subject to complex regulatory mechanisms.
  • ACs can be under the positive or negative control of G protein-coupled receptors (GPCRs) and extracellular ligands.
  • GPCRs G protein-coupled receptors
  • somatostatin acts on the five somatostatin receptors (SSTR 1 to 5), which in turn inhibits ACs and decreases intracellular cAMP levels.
  • Increased cAMP levels disrupt tubulogenesis, stimulate chloride and fluid secretion within the cyst cavity, and activate proproliferative signaling pathways, including mitogen- activated protein kinase/extracellularly -regulated kinase, mTOR, and P-catenin signaling.
  • Activated mTOR transcriptionally stimulates aerobic glycolysis, increasing ATP synthesis and lowering AMP levels, which together with B-Raf-dependent activation of LKB1, inhibits AMPK, further enhancing mTOR activity and CFTR-driven chloride and fluid secretion.
  • Increased PKA signaling due to increased cAMP levels, also activates a number of transcription factors, including STAT3 and cAMP response element-building protein (CREB).
  • CREB cAMP response element-building protein
  • Activated STAT3 induces the transcription of cytokines, chemokines, and growth factors that, in turn, activates STAT3 on interstitial alternatively activated (M2) macrophages, which results in a feed forward loop between cyst-lining cells and M2 macrophages.
  • M2 macrophages interstitial alternatively activated
  • Aberrant integrin-extracellular membrane interaction and cAMP signaling within focal adhesion complexes may also contribute to the increased adhesion of cyst-derived cells to laminin-322 and collagen.
  • Hyperactive CREB in ADPKD medicates cAMP-dependent gene regulation that can govern a wide range of cellular processes, including metabolism, cell survival and proliferation, differentiation, apoptosis, and immune responses.
  • the central role of cAMP in the pathogenesis of PKD provides a strong rationale for strategies to lower its levels in cystic tissues.
  • ADPKD is the most common genetic cause of kidney disease, affecting about 1 : 1000 individuals (Clin. Med. (Lond) 2009 Jun; 9(3): 278-283).
  • the disease is characterized by slow and gradual bilateral kidney cyst formation, which often results in renal insufficiency usually around the fifth or sixth decade of life.
  • the cysts that are formed in the ADPKD patient kidney originate in renal tubules where mutation in PKD1 or PKD2, genes which encode the poly cystin-1 or poly cystin-2 protein, respectively, impairs cilia functions in epithelial cells (J. Nephrol. 1997 Nov-Dec; 10(6): 295-310; AIMS Mol. Sci. 2014; 1(1): 27-46).
  • GFR glomerular filtration rate
  • SSTR3 is a prototypical ciliary GPCR (Neuroscience 1999 Mar; 89(3): 909-26). SSTR3 trafficking to the cilia requires a series of highly regulated processes that include the translocation of the receptor from the cytoplasm to the axoneme through the transition zone owing to a particular amino acid sequence located in the third transmembrane domain (J. Cell. Biol. 2018 May 7: 217(5): 1847-1868). As a Gi coupled receptor, SSTRR3 activation can inhibit adenylyl cyclase activity (Murthy et al., J. Biol. Chem. 1996: 271(38): 23458-23463) and decrease cilio-plasma cAMP levels, which is central to the establishment of ADPKD. See FIG. 3.
  • ARPKD an important cause of ESRD and mortality in infants and children, is caused by mutations in PKD1 (encoding fibrocystin).
  • PKD1 encoding fibrocystin
  • cyst formation is caused by disruption of mechanisms controlling cellular differentiation, leading to excessive cell proliferation and fluid secretion, and pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages.
  • Dy sregulation of the crosstalk between ciliary calcium and cyclic adenosine monophosphate (cAMP) signaling play central roles in the development of PKD.
  • the compounds described herein are somatostatin agonists that selectively activate somatostatin receptor subtype 3 (SSTR3) that in turn reduce cAMP levels and cAMP dependent signaling.
  • somatostatin receptor modulators described herein are used to treat ciliopathies in a mammal. In some embodiments, somatostatin receptor modulators described herein lead to a decrease in cAMP levels, which is useful for the treatment of ciliopathies described herein.
  • the ciliopathic disease or condition is selected from PKD, ADPKD, ARPKD, PLD, and combinations thereof. In some embodiments, the ciliopathic disease or condition is selected from PKD, ADPKD, and ARPKD. In some embodiments, the ciliopathic disease or condition is PKD. In some embodiments, the ciliopathic disease or condition is ADPKD. In some embodiments, the ciliopathic disease or condition is ARPKD.
  • Also described herein is a method of treating a disease or condition in a mammal that would benefit from the modulation of somatostatin receptor subtype 3 (SSTR3) activity comprising administering to the mammal in need thereof a selective small molecule SSTR3 agonist compound.
  • SSTR3 somatostatin receptor subtype 3
  • the disease or condition is any one of the diseases or conditions described herein, or combinations thereof. In some embodiments, the disease or condition is associated with dysfunction of cilia. In some embodiments, the disease or condition is a ciliopathic disease or condition. In some embodiments, the selective small molecule SSTR3 agonist is a compound described herein.
  • Compounds [0032] Provided are compounds of Formula (I), Formula (II), and Formula (III), including pharmaceutically acceptable salts thereof, which are somatostatin subtype 3 receptor (SSTR3) agonists.
  • SSTR3 somatostatin subtype 3 receptor
  • X is NR X , wherein R x is H or Ci-6 alkyl
  • L is a bond, Ci. 6 alkyl, or (CR L1 R L2 )t, wherein R L1 and R L2 are each independently H or Ci-6 alkyl, and t is 1, 2, 3, 4, 5, or 6;
  • R 1 is Ci-6 alkyl, C3.10 cycloalkyl, C 3.6 cycloalkoxy, Ci. 6 haloalkoxy, 6 to 10-membered aryl, and 4-7-membered heteroaryl, which are each optionally substituted with 1, 2, 3, 4, or 5 R 1A ; wherein each R 1A is independently halogen, CN, Ci-6 alkyl, Ci-6 haloalkyl, OR 11 , C(O)OR n , or C(O)N(R n ) 2 , wherein each R 11 is independently H or Ci. 6 alkyl;
  • R 2 is C3.7 cycloalkyl, C5.9 bicycloalkyl, or 7 to 9-membered heterocycloalkyl, which are each substituted with 1, 2, 3, 4, or 5 R 2A ; wherein R 2A is independently H, halogen, Ci. 6 alkyl, or C(O)OR 21 , wherein the Ci. 6 alkyl is optionally substituted with 1, 2, or 3 halogen, OH, CN, or Ci. 6 alkoxy; wherein R 21 is H or Ci-6 alkyl; or two R 2A together with the atoms to which they are attached form a C3-6 carbocycle;
  • R 3 , R 4 , R 5 , and R 6 are each independently H, halogen, CN, Ci. 6 alkyl, C 3.6 cycloalkyl, Ci-6 alkoxy, Ci. 6 haloalkyl, or C 3.6 cyclohaloalkyl; and
  • R 7 is H, halogen, Ci. 6 alkyl, C 3.6 heterocycloalkyl, OR 71 , or NR 72 R 73 ; wherein R 71 is absent, H, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 R 7A , provided that when R 71 is absent, R 7 is a carbonyl group;
  • R 72 and R 73 are independently H or Ci. 6 alkyl, wherein the Ci. 6 alkyl is optionally substituted with 1, 2, or 3 R 7B ; or R 72 and R 73 together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 R 7C ; wherein R 7A , R 7B , and R 7C are each independently halogen, carbonyl, Ci-6 alkyl, Ci-6 alkylamine, 5 -membered heterocycle, OR 7B1 , C(O)OR 7A1 , and C(O)NR 7A2 R 7A2 , wherein the 5-membered heterocycle is optionally substituted with Ci.
  • Ci-6 alkyl carbonyl, or OH
  • the Ci-6 alkylamine is optionally substituted with a 6-membered cycloalkyl that is optionally substituted with CO 2 H
  • R 7A1 , R 7A2 , R 7B1 , R 7B2 , and R 7B3 are each independently H, Ci-6 alkyl, or Ci-6 alkylsulfonyl, wherein the Ci. 6 alkyl and Ci. 6 alkylsulfonyl are each optionally substituted with 1 or2 R 7B4 ; wherein R 7B4 is independently OC(O)-R 7B5 or 5-membered heterocycle that is optionally substituted with Ci. 6 alkyl; and wherein R 7B5 is Ci. 6 alkyl, which is optionally substituted with NH 2 .
  • R 2A is H, halogen, C(O)OH, C(O)OCi-6 alky( or Ci-6 alkyl optionally substituted with OH, CN, or Ci-6 alkoxy 1; m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; q is 1, 2, 3, or 4; r is 1, 2, 3, or 4; and s is 1, 2, 3, 4, or 5.
  • m is 2 and n is 2. In some emodiments, in Formula (II) m is 1 and n is 3. In some embodiments, in Formula (II) m is 3 and n is 1 . In some embodiments, in Formula (III) q is 1 and r is 2. In some embodiments, in Formula (III) q is 2 and r is 1. [0036] In some embodiments, Z is NH or NMe. In some embodiments, Z is NH. In some embodiments, Z is NMe.
  • X is NH or NMe. In some embodiments, X is NH. In some embodiments, X is NMe.
  • L is a bond, Ci. 6 alkyl, or (CR L1 R L2 )t, wherein each R L1 and R L2 are independently H or Ci-6 alkyl and t is 1 or 2.
  • L is a bond, CH 2 , CH 2 CH 2 , or
  • L is a bond. In some embodiments, L is CH 2 . In some embodiments, L is CH 2 CH 2 . In some embodiments, L is . In some embodiments, L is ⁇ OMe . In some embodiments, L is j n some embodiments, L is
  • R 1 is C3.8 cycloalkyl, phenyl, or 4 to 6-membered heteroaryl, which are each independently substituted with 1, 2, or 3 R 1A .
  • R 1 is C 3.8 cycloalkyl, phenyl, or pyridyl, which are each independently substituted with 1, 2, or 3 R 1A .
  • R 1 is ° . In some embodiments, R 1 is Y In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments,
  • R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 , . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is . some embodiments, some embodiments, R 1 is . , in some embodiments, R 1 is , . In some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 . In some embodiments, R 1 is . , . In some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments,
  • R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is . , . In some embodiments, R 1 is . , . In some embodiments, R 1 is , some embodiments, R 1 is
  • R 1 is . In some embodiments, R 1 is some embodiments, R 1 is In some embodiments, embodiments, R 1 is In some embodiments, embodiments, R 1 is embodiments, R 1 is In some embodiments, R 1 is embodiments, R 1 is In some embodiments, R 1 is . in some embodiments, embodiments, embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, embodiments, embodiments, embodiments, embodiments, some embodiments, some embodiments, some embodiments, embodiments, some embodiments, embodiments, some embodiments, embodiments, some embodiments, embodiments, some embodiments, embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments,
  • R 1 is CO 2 H . In some embodiments, R 1 is CO 2 Et In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, R 1 is , some embodiments, some embodiments, some embodiments, some embodiments,
  • R 2 is 7 to 9-membered heterocycloalkyl, C3-7 cycloalkyl, or C5-9 bicycloalkyl which are each substituted with 1, 2, or 3 R 2A ;
  • R 2A is independently H, halogen, CN, Ci. 6 alkyl, C(O)OR 21 , or C(O)NR 22 R 23 , wherein the Ci-6 alkyl is optionally substituted with 1 or 2 OH, NH 2 , CN, Ci-6 alkyl, or Ci-6 alkoxy; and
  • R 21 , R 22 , and R 23 are each independently H or Ci-6 alkyl; or two R 2A together with the atoms to which they are attached form a C 3.6 carbocycle.
  • R 2 is 7 to 9-membered heterocycloalkyl which is substituted with 1, 2, or 3 R 2A ;
  • R 2A is independently H, halogen, CN, Ci. 6 alkyl, C(O)OR 21 , or C(O)NR 22 R 23 , wherein the Ci-6 alkyl is optionally substituted with 1 or 2 OH, NH 2 , CN, Ci. 6 alkyl, or Ci. 6 alkoxy; and
  • R 21 , R 22 , and R 23 are each independently H or Ci-6 alkyl; or two R 2A together with the atoms to which they are attached form a C 3.6 carbocycle.
  • R 2A is H, halogen, Ci-6 alkyl, or C(O)OR 21 , wherein the Ci-6 alkyl is optionally substituted with OH, CN, or Ci. 6 alkoxy;
  • R 21 is H or Ci-6 alkyl.
  • R 2 is , some embodiments,
  • R 2 is - ⁇ L- . In some embodiments, R 2 is —J— . In some embodiments, some embodiments, some embodiments, R 2 is , some embodiments,
  • R 3 is H or F. In some embodiments, R 3 is H. In some embodiments, R 3 is F.
  • R 4 is H, halogen, Ci-6 alkyl, Ci-6 alkoxy, or C3-6 cycloalkyl. In some embodiments, R 4 is H, F, Cl, methyl, methoxy, or cyclopropyl. In some embodiments, R 4 is H. In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is methoxy. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is methoxy.
  • R 5 is H, halogen, CN, Ci. 6 alkyl, or Ci. 6 haloalkyl. In some embodiments, R 5 is halogen or Ci. 6 haloalkyl. In some embodiments, R 5 is H, F, Cl, CN, CF 3 , CF 2 Me, OMe, or cyclopropyl. In some embodiments, R 5 is Cl, CF 3 , or cyclopropyl. In some embodiments, R 5 is H. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is CN. In some embodiments, R 5 is CF 3 . In some embodiments, R 5 is CF 2 Me. In some embodiments, R 5 is OMe. In some embodiments, R 5 is cyclopropyl. In some
  • R 5 is CF 3 . In some embodiments, R 5 is
  • R 6 is H, halogen, Ci. 6 alkyl, or C 3.6 cycloalkyl. In some embodiments, R 6 is H.
  • R 7 is H, halogen, OR 71 , NR 72 R 73 , or Ci-6 alkyl; wherein R 71 is absent, H, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with R 7A ; wherein R 72 and R 73 are each independently H or Ci. 6 alkyl, wherein the Ci.
  • 6 alkyl is each optionally substituted with R 7B ; or R 72 and R 73 together with the nitrogen atom to which they are attached form a 3 to 6 -membered heterocycloalkyl which is optionally substituted with 1 or 2 R 7C ; wherein R 7A is independently 4 to 6-membered heterocycle, C(O)OR 7A1 , and C(O)NR 7A2 R 7A2 , wherein the 4 to 6-membered heterocycle is optionally substituted with carbonyl, OH, or NH 2 ; wherein R 7A1 and R 7A2 are each independently H, Ci. 6 alkyl, or Ci.
  • R 7B is independently OR 7B1 , C(O)OR 7B2 , C(O)NR 7B3 R 7B3 , and 4 to 6- membered heterocycle, wherein the 4 to 6-membered heterocycle is optionally substituted with methyl, carbonyl, OH, orNH 2 ; wherein R 7B1 , R 7B2 , and R 7B3 are each independently H, Ci. 6 alkyl, or Ci. 6 alkylsulfonyl, wherein the Ci.
  • R 7C is independently carbonyl, halogen, OH, Ci-6 alkoxy, CO 2 H, C(O)OCi-6 alkyl, Ci-6 alkyl, or Ci-6 alkylamine, wherein the Ci-6 alkylamine is optionally substituted with a 6-membered heterocycle that is optionally substituted with CO 2 H.
  • R 7 is H, halogen, OR 71 , NR 72 R 73 , or Ci-6 alkyl;
  • R 71 is absent, H or Ci. 6 alkyl, wherein the Ci. 6 alkyl is optionally substituted with R 7A ;
  • R 72 and R 73 are independently H or Ci. 6 alkyl, wherein the Ci. 6 alkyl is optionally substituted with R 7B ; or
  • R 72 and R 73 together with the nitrogen atom to which they are attached form which are each optionally substituted with 1 or 2 R 7C ;
  • R 7A is independently , C(O)OR 7A1 , or C(O)NR 7A2 R 7A2 ;
  • R 7A1 is independently H or Ci. 6 alkyl
  • R 7A2 is independently H or Ci. 6 alkylsulfonyl
  • R 7B1 is independently H or Ci. 6 alkyl
  • R 7B2 is H or Ci-6 alkyl, wherein the Ci. 6 alkyl is optionally substituted with OC(O)-R 7B4
  • R 7B3 is independently H or Ci. 6 alkylsulfonyl
  • R 7B4 is Ci-6 alkyl, which is optionally substituted with NH 2 ;
  • R 7C is independently carbonyl, halogen, OH, Ci. 6 alkoxy, CO 2 H, C(O)OCi_ 6 alkyl, Ci. 6 alkyl, or Ci-6 alkylamine, wherein the Ci-6 alkylamine is optionally substituted with a 6- membered heterocycle that is optionally substituted with CO 2 H. .
  • R 7 is H.
  • R 7 is O.
  • R 7 is Cl.
  • R 7 is Me.
  • R 7 is NH 2 .
  • R 7 is NHMe.
  • R 7 is NMe 2 .
  • R 7 is .
  • R 7 is .
  • R 7 is H . In some embodiments, R 7 is H . In some embodiments, R 7 is H . In some embodiments, R 7 is H . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 ,
  • R 7 is H. In some embodiments, R 7 is O. In some embodiments,
  • R 7 is OH. In some embodiments, R 7 is OMe. In some embodiments, R 7 is NH 2 . In some embodiments, R 7 is NHMe. In some embodiments, R 7 is . In some embodiments,
  • R 7 is . In some embodiments, R 7 is HO 2 C In some embodiments, R 7 is , some embodiments, R 7 is , some embodiments, R 7 is
  • R 7 is In some embodiments, R 7 is . In some embodiments, some embodiments, i n some embodiments, R 7 is . In some embodiments, R 7 is In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is In some embodiments, R 7 is , some embodiments, R 7 is , some embodiments, R 7 is , some embodiments, R 7 is
  • R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is , . In some embodiments, R 7 is . , . In some embodiments, , embodiments, some embodiments, R 7 is ,
  • R 7 is H, O, . In some embodiments,
  • R 7 is H. In some embodiments, R 7 is O. In some embodiments, R 7 is . In some embodiments, R 7 is In some embodiments, R 7 is a carbonyl group.
  • the compound of Formula (I) is compound 1.
  • the compound of Formula (I) is compound 2.
  • the compound of Formula (I) is compound 3.
  • the compound of Formula (I) is compound 4.
  • the compound of Formula (I) is compound 5.
  • the compound of Formula (I) is compound 6.
  • the compound of Formula (I) is compound 7.
  • the compound of Formula (I) is compound 8.
  • the compound of Formula (I) is compound 9.
  • the compound of Formula (I) is compound 10.
  • the compound of Formula (I) is compound 11.
  • the compound of Formula (I) is compound 12.
  • the compound of Formula (I) is compound 13.
  • the compound of Formula (I) is compound 14.
  • the compound of Formula (I) is compound 15.
  • the compound of Formula (I) is compound 16.
  • the compound of Formula (I) is compound 17.
  • the compound of Formula (I) is compound 18.
  • the compound of Formula (I) is compound 19.
  • the compound of Formula (I) is compound 20.
  • the compound of Formula (I) is compound 21.
  • the compound of Formula (I) is compound 22. [0087] In certain embodiments, the compound of Formula (I) is compound 23.
  • the compound of Formula (I) is compound 24.
  • the compound of Formula (I) is compound 25.
  • the compound of Formula (I) is compound 26.
  • the compound of Formula (I) is compound 27.
  • the compound of Formula (I) is compound 28.
  • the compound of Formula (I) is compound 29.
  • the compound of Formula (I) is compound 30.
  • the compound of Formula (I) is compound 31.
  • the compound of Formula (I) is compound 32.
  • the compound of Formula (I) is compound 33.
  • the compound of Formula (I) is compound 34.
  • the compound of Formula (I) is compound 35.
  • the compound of Formula (I) is compound 36.
  • the compound of Formula (I) is compound 37.
  • the compound of Formula (I) is compound 38.
  • the compound of Formula (I) is compound 39.
  • the compound of Formula (I) is compound 40.
  • the compound of Formula (I) is compound 41.
  • the compound of Formula (I) is compound 42.
  • the compound of Formula (I) is compound 43.
  • the compound of Formula (I) is compound 44.
  • the compound of Formula (I) is compound 45.
  • the compound of Formula (I) is compound 46.
  • the compound of Formula (I) is compound 47.
  • the compound of Formula (I) is compound 48.
  • the compound of Formula (I) is compound 49.
  • the compound of Formula (I) is compound 50.
  • the compound of Formula (I) is compound 51.
  • the compound of Formula (I) is compound 52.
  • the compound of Formula (I) is compound 53.
  • the compound of Formula (I) is compound 54.
  • the compound of Formula (I) is compound 55.
  • the compound of Formula (I) is compound 56. [00121]In certain embodiments, the compound of Formula (I) is compound 57.
  • the compound of Formula (I) is compound 58.
  • the compound of Formula (I) is compound 59.
  • the compound of Formula (I) is compound 60.
  • the compound of Formula (I) is compound 61.
  • the compound of Formula (I) is compound 62.
  • the compound of Formula (I) is compound 63.
  • the compound of Formula (I) is compound 64.
  • the compound of Formula (I) is compound 65.
  • the compound of Formula (I) is compound 66.
  • the compound of Formula (I) is compound 67.
  • the compound of Formula (I) is compound 68.
  • the compound of Formula (I) is compound 69.
  • the compound of Formula (I) is compound 70.
  • the compound of Formula (I) is compound 71.
  • the compound of Formula (I) is compound 72.
  • the compound of Formula (I) is compound 73.
  • the compound of Formula (I) is compound 74.
  • the compound of Formula (I) is compound 75.
  • the compound of Formula (I) is compound 76.
  • the compound of Formula (I) is compound 77.
  • the compound of Formula (I) is compound 78.
  • the compound of Formula (I) is compound 79.
  • the compound of Formula (I) is compound 80.
  • the compound of Formula (I) is compound 81.
  • the compound of Formula (I) is compound 82.
  • the compound of Formula (I) is compound 83.
  • the compound of Formula (I) is compound 84.
  • the compound of Formula (I) is compound 85.
  • the compound of Formula (I) is compound 86.
  • the compound of Formula (I) is compound 87.
  • the compound of Formula (I) is compound 88.
  • the compound of Formula (I) is compound 89.
  • the compound of Formula (I) is compound 90. [00155]In certain embodiments, the compound of Formula (I) is compound 91.
  • the compound of Formula (I) is compound 92.
  • the compound of Formula (I) is compound 93.
  • the compound of Formula (I) is compound 94. [00159]In certain embodiments, the compound of Formula (I) is compound 95. [00160]In certain embodiments, the compound of Formula (I) is compound 96. [00161]In certain embodiments, the compound of Formula (I) is compound 97. [00162]In certain embodiments, the compound of Formula (I) is compound 98. [00163]In certain embodiments, the compound of Formula (I) is compound 99. [00164]In certain embodiments, the compound of Formula (I) is compound 100. [00165]In certain embodiments, the compound of Formula (I) is compound 101. [00166]In certain embodiments, the compound of Formula (I) is compound 102.
  • the compound of Formula (I) is compound 103. [00168]In certain embodiments, the compound of Formula (I) is compound 104. [00169]In certain embodiments, the compound of Formula (I) is compound 105. [00170]In certain embodiments, the compound of Formula (I) is compound 106. [00171]In certain embodiments, the compound of Formula (I) is compound 107. [00172]In certain embodiments, the compound of Formula (I) is compound 108. [00173]In certain embodiments, the compound of Formula (I) is compound 109. [00174]In certain embodiments, the compound of Formula (I) is compound 110. [00175]In certain embodiments, the compound of Formula (I) is compound 111.
  • the compound of Formula (I) is compound 112. [00177]In certain embodiments, the compound of Formula (I) is compound 113. [00178]In certain embodiments, the compound of Formula (I) is compound 114. [00179]In certain embodiments, the compound of Formula (I) is compound 115. [00180]In certain embodiments, the compound of Formula (I) is compound 116. [00181]In certain embodiments, the compound of Formula (I) is compound 117. [00182]In certain embodiments, the compound of Formula (I) is compound 118. [00183]In certain embodiments, the compound of Formula (I) is compound 119. [00184]In certain embodiments, the compound of Formula (I) is compound 120.
  • the compound of Formula (I) is compound 121. [00186]In certain embodiments, the compound of Formula (I) is compound 122. [00187]In certain embodiments, the compound of Formula (I) is compound 123. [00188]In certain embodiments, the compound of Formula (I) is compound 124. [00189]In certain embodiments, the compound of Formula (I) is compound 125.
  • the compound of Formula (I) is compound 126.
  • the compound of Formula (I) is compound 127.
  • the compound of Formula (I) is compound 128.
  • the compound of Formula (I) is compound 129.
  • the compound of Formula (I) is compound 130.
  • the compound of Formula (I) is compound 131.
  • the compound of Formula (I) is compound 132.
  • the compound of Formula (I) is compound 133.
  • the compound of Formula (I) is compound 134.
  • the compound of Formula (I) is compound 135.
  • the compound of Formula (I) is compound 136.
  • the compound of Formula (I) is compound 137.
  • the compound of Formula (I) is compound 138.
  • the compound of Formula (I) is compound 139.
  • the compound of Formula (I) is compound 140.
  • the compound of Formula (I) is compound 141.
  • the compound of Formula (I) is compound 142.
  • the compound of Formula (I) is compound 143.
  • the compound of Formula (I) is compound 144.
  • the compound of Formula (I) is compound 145.
  • the compound of Formula (I) is compound 146.
  • the compound of Formula (I) is compound 147.
  • the compound of Formula (I) is compound 148.
  • the compound of Formula (I) is compound 149.
  • the compound of Formula (I) is compound 150.
  • the compound of Formula (I) is compound 151.
  • the compound of Formula (I) is compound 152.
  • the compound of Formula (I) is compound 153.
  • the compound of Formula (I) is compound 154.
  • the compound of Formula (I) is compound 155.
  • the compound of Formula (I) is compound 156.
  • the compound of Formula (I) is compound 157.
  • the compound of Formula (I) is compound 158. [00223]In certain embodiments, the compound of Formula (I) is compound 159.
  • the compound of Formula (I) is compound 160.
  • the compound of Formula (I) is compound 161.
  • the compound of Formula (I) is compound 162.
  • the compound of Formula (I) is compound 163.
  • the compound of Formula (I) is compound 164.
  • the compound of Formula (I) is compound 165.
  • the compound of Formula (I) is compound 166.
  • the compound of Formula (I) is compound 167.
  • the compound of Formula (I) is compound 168.
  • the compound of Formula (I) is compound 169.
  • the compound of Formula (I) is compound 170.
  • the compound of Formula (I) is compound 171.
  • the compound of Formula (I) is compound 172.
  • the compound of Formula (I) is compound 173.
  • the compound of Formula (I) is compound 174.
  • the compound of Formula (I) is compound 175.
  • the compound of Formula (I) is compound 176.
  • the compound of Formula (I) is compound 177.
  • the compound of Formula (I) is compound 178.
  • the compound of Formula (I) is compound 179.
  • the compound of Formula (I) is compound 180.
  • the compound of Formula (I) is compound 181.
  • the compound of Formula (I) is compound 182.
  • the compound of Formula (I) is compound 183.
  • the compound of Formula (I) is compound 184.
  • the compound of Formula (I) is compound 185.
  • the compound of Formula (I) is compound 186.
  • the compound of Formula (I) is compound 187.
  • the compound of Formula (I) is compound 188.
  • the compound of Formula (I) is compound 189.
  • the compound of Formula (I) is compound 190.
  • the compound of Formula (I) is compound 191.
  • the compound of Formula (I) is compound 192.
  • the compound of Formula (I) is compound 193.
  • the compound of Formula (I) is compound 194.
  • the compound of Formula (I) is compound 195.
  • the compound of Formula (I) is compound 196.
  • the compound of Formula (I) is compound 197.
  • the compound of Formula (I) is compound 198.
  • the compound of Formula (I) is compound 199.
  • the compound of Formula (I) is compound 200.
  • the compound of Formula (I) is compound 201.
  • the compound of Formula (I) is compound 202.
  • the compound of Formula (I) is compound 203.
  • the compound of Formula (I) is compound 204.
  • the compound of Formula (I) is compound 205.
  • the compound of Formula (I) is compound 206.
  • the compound of Formula (I) is compound 207.
  • the compound of Formula (I) is compound 208.
  • the compound of Formula (I) is compound 209.
  • the compound of Formula (I) is compound 210.
  • the compound of Formula (I) is compound 211.
  • the compound of Formula (I) is compound 212.
  • the compound of Formula (I) is compound 213.
  • the compound of Formula (I) is compound 214.
  • the compound of Formula (I) is compound 215.
  • the compound of Formula (I) is compound 216.
  • the compound of Formula (I) is compound 217.
  • the compound of Formula (I) is compound 218.
  • the compound of Formula (I) is compound 219.
  • the compound of Formula (I) is compound 220.
  • the compound of Formula (I) is compound 221.
  • the compound of Formula (I) is compound 222.
  • the compound of Formula (I) is compound 223.
  • the compound of Formula (I) is compound 224.
  • the compound of Formula (I) is compound 225.
  • the compound of Formula (I) is compound 226. [00291] In certain embodiments, the compound is
  • the compound of Formula (I) is compound 228.
  • the compound of Formula (I) is compound 229.
  • the compound of Formula (I) is compound 230.
  • the compound of Formula (I) is compound 231.
  • the compound of Formula (I) is compound 232.
  • the compound of Formula (I) is compound 233.
  • the compound of Formula (I) is compound 234.
  • the compound of Formula (I) is compound 235.
  • the compound of Formula (I) is compound 236.
  • the compound of Formula (I) is compound 237.
  • the compound of Formula (I) is compound 238.
  • the compound of Formula (I) is compound 239.
  • the compound of Formula (I) is compound 240.
  • the compound of Formula (I) is compound 241.
  • the compound of Formula (I) is compound 242.
  • the compound of Formula (I) is compound 243.
  • the compound of Formula (I) is compound 244.
  • the compound of Formula (I) is compound 245.
  • the compound of Formula (I) is compound 246.
  • the compound of Formula (I) is compound 247.
  • the compound of Formula (I) is compound 248.
  • the compound of Formula (I) is compound 249.
  • the compound of Formula (I) is compound 250.
  • the compound of Formula (I) is compound 251.
  • the compound of Formula (I) is compound 252.
  • the compound of Formula (I) is compound 253.
  • the compound of Formula (I) is compound 254.
  • the compound of Formula (I) is compound 255.
  • the compound of Formula (I) is compound 256.
  • the compound of Formula (I) is compound 257.
  • the compound of Formula (I) is compound 258.
  • the compound of Formula (I) is compound 259.
  • the compound of Formula (I) is compound 260. [00325] In certain embodiments, the compound is
  • the compound of Formula (I) is compound 262.
  • the compound of Formula (I) is compound 263.
  • the compound of Formula (I) is compound 264.
  • the compound of Formula (I) is compound 265.
  • the compound of Formula (I) is compound 266.
  • the compound of Formula (I) is compound 267.
  • the compound of Formula (I) is compound 268.
  • the compound of Formula (I) is compound 269.
  • the compound of Formula (I) is compound 270.
  • the compound of Formula (I) is compound 271.
  • the compound of Formula (I) is compound 272.
  • the compound of Formula (I) is compound 273.
  • the compound of Formula (I) is compound 274.
  • the compound of Formula (I) is compound 275.
  • the compound of Formula (I) is compound 276.
  • the compound of Formula (I) is compound 277.
  • the compound of Formula (I) is compound 278.
  • the compound of Formula (I) is compound 279.
  • the compound of Formula (I) is compound 280.
  • the compound of Formula (I) is compound 281.
  • the compound of Formula (I) is compound 282.
  • the compound of Formula (I) is compound 283.
  • the compound of Formula (I) is compound 284.
  • the compound of Formula (I) is compound 285.
  • the compound of Formula (I) is compound 286.
  • the compound of Formula (I) is compound 287.
  • the compound of Formula (I) is compound 288.
  • the compound of Formula (I) is compound 289.
  • the compound of Formula (I) is compound 290.
  • the compound of Formula (I) is compound 291.
  • the compound of Formula (I) is compound 292.
  • the compound of Formula (I) is compound 293.
  • the compound of Formula (I) is compound 294. [00359] In certain embodiments, the compound is
  • the compound of Formula (I) is compound 296.
  • the compound of Formula (I) is compound 297.
  • the compound of Formula (I) is compound 298.
  • the compound of Formula (I) is compound 299.
  • the compound of Formula (I) is compound 300.
  • the compound of Formula (I) is compound 301.
  • the compound of Formula (I) is compound 302.
  • the compound of Formula (I) is compound 303.
  • the compound of Formula (I) is compound 304.
  • the compound of Formula (I) is compound 305.
  • the compound of Formula (I) is compound 306.
  • the compound of Formula (I) is compound 307.
  • the compound of Formula (I) is compound 308.
  • the compound of Formula (I) is compound 309.
  • the compound of Formula (I) is compound 310.
  • the compound of Formula (I) is compound 311.
  • the compound of Formula (I) is compound 312.
  • the compound of Formula (I) is compound 313.
  • the compound of Formula (I) is compound 314.
  • the compound of Formula (I) is compound 315.
  • the compound of Formula (I) is compound 316.
  • the compound of Formula (I) is compound 317.
  • the compound of Formula (I) is compound 318.
  • the compound of Formula (I) is compound 319.
  • the compound of Formula (I) is compound 320.
  • the compound of Formula (I) is compound 321.
  • the compound of Formula (I) is compound 322.
  • the compound of Formula (I) is compound 323.
  • the compound of Formula (I) is compound 324.
  • the compound of Formula (I) is compound 325.
  • the compound of Formula (I) is compound 326.
  • the compound of Formula (I) is compound 327.
  • the compound of Formula (I) is compound 328. [00393] In certain embodiments, the compound is
  • the compound of Formula (I) is compound 330.
  • the compound of Formula (I) is compound 331.
  • the compound of Formula (I) is compound 332.
  • the compound of Formula (I) is compound 333.
  • the compound of Formula (I) is compound 334.
  • the compound of Formula (I) is compound 335.
  • the compound of Formula (I) is compound 336.
  • the compound of Formula (I) is compound 337.
  • the compound of Formula (I) is compound 338.
  • the compound of Formula (I) is compound 339.
  • the compound of Formula (I) is compound 340.
  • the compound of Formula (I) is compound 341.
  • the compound of Formula (I) is compound 342.
  • the compound of Formula (I) is compound 343.
  • the compound of Formula (I) is compound 344.
  • the compound of Formula (I) is compound 345.
  • the compound of Formula (I) is compound 346.
  • the compound of Formula (I) is compound 347.
  • the compound of Formula (I) is compound 348.
  • the compound of Formula (I) is compound 349.
  • the compound of Formula (I) is compound 350.
  • the compound of Formula (I) is compound 351.
  • the compound of Formula (I) is compound 352.
  • the compound of Formula (I) is compound 353.
  • the compound of Formula (I) is compound 354.
  • the compound of Formula (I) is compound 355.
  • the compound of Formula (I) is compound 356.
  • the compound of Formula (I) is compound 357.
  • the compound of Formula (I) is compound 358.
  • the compound of Formula (I) is compound 359.
  • the compound of Formula (I) is compound 360.
  • the compound of Formula (I) is compound 361.
  • the compound of Formula (I) is compound 362.
  • the compound of Formula (I) is compound 363.
  • the compound of Formula (I) is compound 364.
  • the compound of Formula (I) is compound 365.
  • the compound of Formula (I) is compound 366.
  • the compound is a pharmaceutically acceptable salt of a compound described in Table 1.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, ie., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (II), or Formula (III) with an acid.
  • the free base form of the compound of Formula (I), Formula (II), or Formula (III) is basic and is reacted with an organic acid or an inorganic acid.
  • pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (II), or Formula (III) with a base.
  • the compound of Formula (I), Formula (II), or Formula (III) is acidic and is reacted with a base.
  • the compounds of Formula (I), Formula (II), or Formula (III) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compound of Formula (I), Formula (II), or Formula (III) exists in the R configuration.
  • the compound of Formula (I), Formula (II), or Formula (III) exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, epimeric, and tautomeric forms, as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.
  • compounds of Formula (I), Formula (II), or Formula (III) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
  • resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • Ci-C x includes Ci-C 2 , C1-C3 ... Ci-C x .
  • a group designated as "Ci-Ce” indicates that there are one to six carbon atoms in the moiety, z.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, z.e., the alkyl group is selected from among methyl, ethyl, propyl, z o-propyl, zz-butyl, zso-butyl, ec-butyl, and Z-butyl.
  • an “alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the “alkyl” group has 1 to 6 carbon atoms, z.e., a Ci-C 6 alkyl.
  • a numerical range such as “1 to 6” refers to each integer in the given range; e.g. , “ 1 to 6 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a Ci-Ce alkyl.
  • the alkyl is methyl, ethyl, propyl, z.w-propyl, zz-butyl, z o-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • alkylsulfonyl refers to an alkyl group, as previously defined, wherein one carbon atom of the alkyl group, and the carbon atom’s substituents, are replaced by a sulfur atom, and wherein the sulfur atom is further substituted with two oxo groups.
  • An alkylsulfonyl group maybe linear or branched.
  • alkylsulfonyl groups are substituted atthe alkyl portion of the alkylsulfonyl group.
  • alkylsulfonyl groups are unsubstituted at the alkyl portion of the alkylsulfonyl group.
  • alkoxy refers to an (alkyl)O- group, where alkyl is as defined herein.
  • aminoalkyl means an alkyl group which is substituted with or contains an amino group.
  • aromatic refers to a planar ring having a delocalized 7i-electron system containing 4n+2 71 electrons, where n is an integer.
  • aromatic includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine, pyrimidine).
  • aryl e.g., phenyl
  • heterocyclic aryl or “heteroaryl” or “heteroaromatic” groups
  • pyridine e.g., pyridine, pyrimidine
  • Carbocyclic refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • an aryl is a phenyl.
  • an aryl group is a monoradical or a diradical (z.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (z.e., skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • Cycloalkyl groups include groups having from 3 to 7 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • a cycloalkyl is a C3-C7 cycloalkyl.
  • a cycloalkyl is a C 3 -C 6 cycloalkyl.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to a linear or branched alkyl, alkenyl, or alkoxy, respectively, which is substituted with one or more halogen atoms.
  • Non-limiting examples of haloalkyl groups include -CHF 2 , -CH 2 F, -CF 3 , -CF 2 -, and perhaloalkyls, such as -CF 2 CF 3 .
  • Non-limiting examples of haloalkoxy groups include - OCHF 2 , -OCH 2 F, -OCF 3 , and -OCF 2 .
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a Ci-C 6 fluoroalkyl.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to two heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S, and N, wherein each heterocyclic group has from 3 to 6 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups also known as heterocycloalkyls
  • aromatic heterocyclic groups include rings having 5 to 6 atoms in its ring system.
  • non-aromatic heterocyclic groups include, but are not limited to, tetrahydropyranyl.
  • aromatic heterocyclic groups include, but are not limited to, pyridinyl and pyrimidinyl.
  • heteroaryl or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls, such as pyridinyl and pyrimidinyl
  • heterocycloalkyl refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • heterocycloalkyl groups include monocyclic heterocycloalkyls, such as tetrahydropyranyl.
  • the term “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. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • 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.
  • modulate 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.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action.
  • an “effective amount” and “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 includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating at least one symptom of a disease or condition, 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 either prophylactically and/or therapeutically.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein is 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.
  • the compounds described herein are administered either alone or in combination with one or more pharmaceutically acceptable carriers, excipients and/or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • the compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from SSTR3 agonist.
  • Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involve administration of pharmaceutical compositions that include at least one compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, in therapeutically effective amounts to said mammal.
  • the compositions containing the compound(s) described herein are administered for therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to at least partially arrest at least one of the symptoms of the disease or condition.
  • Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the amount of a given compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof that corresponds to a therapeutically effective amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 and the ED 50 .
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50 .
  • the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
  • the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
  • HPLC high performance liquid chromatography
  • MPLC medium-pressure liquid chromatography
  • Prep-HPLC preparative high performance liquid chromatography
  • Chiral-SFC chiral supercritical fluid chromatography
  • h hour or hours
  • rt room temperature
  • PhOPh PhPh phenyl ether-biphenyl eutectic
  • NBS A-bromosuccinimide
  • CO carbon monoxide gas
  • DIEA A,A-diisopropylethylamine or A-ethyl-A-isopropylpropan-2-amine;
  • PE petroleum ether
  • MeCN or ACN acetonitrile
  • Pd(dtbpf)Cl 2 [l,r-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);
  • Pd(dppf)Cl 2 [1 J'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);Pd(PPh3)Cl 2 : bis(triphenylphosphine)palladium(II) chloride;
  • NaOMe sodium methoxide
  • Ti(O/Pr) 4 titanium tetraisopropoxide
  • N 2 nitrogen gas
  • NaHCOs sodium bicarbonate
  • MgSO 4 magnesium sulfate
  • HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate;
  • TFA trifluoroacetic acid or 2,2,2-trifluoroacetic acid
  • Zn(CN) 2 zinc cyanide
  • NMP A-methylpyrrolidone
  • K 2 CO 3 potassium carbonate
  • NaOH sodium hydroxide
  • NaHSO 3 sodium bisulfite
  • Na 2 SO4 sodium sulfate
  • K 3 PO 4 potassium phosphate
  • Pd-C palladium on carbon
  • H 2 hydrogen gas
  • LiHMDS lithium bis(trimethylsilyl)amide
  • LiOH lithium hydroxide
  • Step 1 Preparation of diethyl 2-(((4-methoxyphenyl)amino)methylene)malonate:
  • Step 2 Preparation of ethyl 4-hydroxy-6-methoxyquinoline-3 -carboxylate:
  • Step 3 Preparation of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate:
  • Step 5 ethyl 2,4-dichloro-6-methoxyquinoline-3-carboxylate:
  • Step 8 (S)-2,4-dichloro-N-(l-(4-fhioro-3-methoxyphenyl)ethyl)-6-methoxyquinoline-3- carboxamide:
  • Step 9 2-chloro-N-((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-4-(L7- diazaspiro[4 ,4]nonan-7 -yl)quinoline-3 -carboxamide : [00485] An 8-mL vial was charged with a mixture of (S)-2,4-dichloro-N-(l-(4-fluoro-3- meth oxyphenyl)ethyl)-6-methoxyquinoline-3 -carboxamide (200 mg, 1 equiv, 473 pmol), 1,7- diazaspiro[4.4]nonane (119 mg, 2.00 equiv, 943 pmol), DIEA (183 mg, 247 pL, 3.00 equiv, 1.42 mmol), and ACN (2 mL). The reaction mixture was stirred at 80 °C for 16 h and used in the next step without further manipulation (
  • Step 10 tert-butyl 7-(2-chloro-3-(((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6- methoxyquinolin-4-yl)-l,7-diazaspiro[4.4]nonane-l -carboxylate:
  • Step 11 tert-butyl 7-(3-(((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy-2- morpholinoquinolin-4-yl)-l,7-diazaspiro[4.41nonane-l -carboxylate:
  • Step 12 A-((S)-l-(4-fluoro-3 -meth oxyphenyl)ethyl)-6-meth oxy -2-morpholino-4-(L7- diazaspiro[4 ,4]nonan-7 -yl)quinoline-3 -carboxamide :
  • Step 1 2-bromo-4-methoxy-5-(trifluoromethyl)aniline:
  • Step 2 methyl 2-amino-5-methoxy-4-(trifluoromethyl)benzoate:
  • Step 4 methyl 4-hydroxy-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3- carboxylate:
  • Step 5 methyl 4-chloro-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3- carboxylate: [00494] Under nitrogen atmosphere, an 8-mL vial was charged with methyl 4-hydroxy-6- methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (200 mg, 1 equiv, 630 pmol) and (COC1) 2 (10 mL). To the mixture was added DMF (18 mg, 19 pL, 0.39 equiv, 0.25 mmol) at 0 °C. The resulting solution was stirred for 5 min at 0 °C and 4 h at 40 °C thereafter.
  • Step 6 methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-L4-diazepan-l-yl)-6-methoxy-2-oxo-7- (trifluoromethyl)-l,2-dihydroquinoline-3 -carboxylate:
  • Step 7 (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-L4-diazepan-l-yl)-6-methoxy-2-oxo-7- (trifluoromethyl)-L2-dihydroquinoline-3 -carboxylic acid
  • a 40-mL vial was charged with methyl (S)-4-(4-(tert-butoxycarbonyl)-5 -methyl- 1,4- diazepan-l-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (100 mg, 1 equiv, 195 pmol), lithium hydroxide (94 mg, 20 equiv, 3.9 mmol), H 2 O (1 mL), and MeOH (2 mL).
  • Step 8 (S)-3-(l-aminoethyl)-5-fluorobenzonitrile hydrochloride:
  • Step 9 fert-butyl (S)-4-(3-(((S)-l-(3-cyano-5-fluorophenyl)ethyl)carbamoyl)-6-methoxy-2-oxo- 7-(trifluoromethyl)-l,2-dihydroquinolin-4-yl)-7-methyl-L4-diazepane-l -carboxylate:
  • Step 10 A-((S)-l-(3-cvano-5-fluorophenyl)ethyl)-6-methoxy-4-((S)-5-methyl-l,4-diazepan-l- yl)-2-oxo-7-(trifluoromethyl)-l,2-dihvdroquinoline-3 -carboxamide:
  • GPCRs Gi coupled G-protein coupled receptors
  • cAMP intracellular cyclic AMP
  • Chinese hamster ovary cells (CHO-K1, ATCC #CCL-61) stably expressing the human somatostatin receptor subtype 3 are plated two or four days prior to the assay, at 6,000 or 2,000 cells per well, respectively in a 96-well tissue culture-treated plate in Ham’s F12 growth media (ThermoFisher #10-080-CM) supplemented with 10% donor bovine serum (Gemini Bio-Products #100-506), 100 U/mL penicillin; 100 ug/mL streptomycin; 2 mM L-glutamine (Gemini Bio- Products #400-110) and 0.25 mg/mL G418 (GoldBio #G-418-5).
  • F12 growth media ThermoFisher #10-080-CM
  • donor bovine serum Gibco-Products #100-506
  • penicillin 100 ug/mL
  • streptomycin 2 mM L-glutamine
  • 0.25 mg/mL G418 GoldBio #G-418-5
  • the cells are cultured at 37 °C, 5% CO 2 and 95% humidity.
  • cAMP is measured with HTRF dynamic cAMP assay (Cisbio, #62AM5PEJ) per manufacturer’s instructions.
  • the media is aspirated and the cells are treated with 50 pL of stimulation buffer supplemented with 10.2 mM 3 -isobutyl-l- methylxanthine (IBMX, Millipore Sigma #15879) and 1.6 pM NKH477 (Tocris #1603), plus various dilutions of compounds of the present invention.
  • the cells are incubated for 20 minutes at 37 °C (the final concentration of the compounds of the invention are typically 0-10,000 nM).
  • the cells are treated with 50 pL of lysis buffer (HRTF cAMP kit, Cisbio) and incubated at room temperature for 30 minutes with rotary shaking at 600 rpm, and then diluted with 150 pL of stimulation buffer and shaken for an additional five minutes at 300 rpm.
  • the lysate is transferred to 384-well plates and incubated for 1-24 hours at room temperature, and cAMP accumulation is detected by d2-labeled cAMP and Anti-cAMP-Cryptate.
  • the time-resolved fluorescent signal is read using a ml 000 Pro (Tecan) or CLARIOStar (BMG Labtech) microplate reader, where the samples are excited with light at 340 nm and emission light is measured at 620 nm and 665 nm.
  • the data is expressed as a calculation of the fluorescence ratio (665 nm/620 nm).
  • the intracellular cAMP concentrations are calculated by regression to a standard curve and are plotted vs. the concentration of the compounds of the invention .
  • the EC50 of the compounds are calculated using standard methods. All data manipulations are in GraphPad Prism v9 (GraphPad, San Diego, CA).
  • Table 2 reports biological activity of compounds as evaluated by inhibition of cAMP activities via human SSTR3 receptor.
  • ADPKD Autosomal Dominant Polycystic Kidney Disease
  • ADPKD Mouse Model The ADPKD mouse model was generated by selective inactivation of the Pkdl gene in the kidney of Pax8 Tet-O-Cre/Pkdl flox mice (Piontek et al., Clin J Am Soc Nephrol 2004, 15 (12), 3035-3043; Piontek et al., Nat Med 2007, 13 (12), 1490-1495; Traykova-Brauch et al., //VW 2008, 14 (9), 979-984) which results in the renal cyst formation.
  • induction of Pkdl deletion in the kidney was performed by administration of doxycycline hy elate (50 mg/kg) intraperitoneally to Pax8 Tet-O-Cre/Pkdl flox mice on postnatal days (PND) 11 and 12.
  • PND20 Pax8 Tet-O-Cre/Pkdl flox mice treated with doxycycline hyclate (referred to as ADPKD mice) developed enlarged and cystic kidneys compared to control non-treated littermates.
  • SSTR3 Agonists in the ADPKD mouse model To evaluate the ability of SSTR3 agonists to reduce kidney weight and KCI in the ADPKD mouse model, studies were performed in PND12 ADPKD male and female mice. Vehicle or SSTR3 agonists were administered once daily by oral gavage from PND 12 to PND 20. Body weight and clinical signs were recorded daily. On PND20, 1-2 hours after treatment with vehicle or SSTR3 agonists, mice were anesthetized, andblood was collected by cardiac puncture to the left ventricle after performing thoracotomy using needles coated with ethylenediaminetetraacetic acid (EDTA). The blood was collected into EDTA tubes and stored on ice until processed to plasma. The plasma samples were frozen and stored.
  • EDTA ethylenediaminetetraacetic acid
  • the heart was harvested, and weight recorded to obtain the kidney to heart weight ratio.
  • the left kidney was harvested, weighed, bisected longitudinally and, placed in 4% paraformaldehyde overnight at 4°C to fix the tissue. Post fixing, the left kidney was processed and embedded in paraffin for histomorphometry. Transverse kidney sections including the cortex, medulla, and papilla were collected on a slide and the slides are stained with hematoxylin and eosin stain. Images were taken at lx and 4x, and total cystic area was measured from the images using Image J software. The kidney cystic index (KCI) was calculated using the total cystic area.
  • LKW left kidney weight
  • BW body weight
  • KCI kidney cystic index
  • SD standard deviation

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Abstract

Described herein are compounds that are somatostatin receptor subtype 3 (SSTR3) agonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of SSTR3 activity.

Description

SOMATOSTATIN SUBTYPE RECEPTOR 3 (SSTR3) AGONISTS AND USES
THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/601,948, filed on November 22, 2023 ; and U.S. Provisional Patent Application No. 63/677,136, filed on July 30, 2024; each of which is incoporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Described herein are compounds that are somatostatin receptor subtype 3 agonists (SSTR3), methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulating SSTR3 activity.
[0003] Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors (GPCRs) and inhibition of the release of numerous secondary hormones. Six subtype somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity. [0004] Somatostatin acts on five GPCRs (SSTR1 to 5). Binding to these receptors inhibits adenylyl cyclases (ACs) and mitogen-activated protein kinase, cell proliferation, and secretion of several hormones (growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin, thyroid stimulating hormone, and adrenocorticotrophic hormone) and growth factors (IGF-I and vascular endothelial growth factor). All five SSTRs are expressed in renal tubular epithelial cells and cholangiocytes. SSTR1 and SSTR2 are expressed in the thick ascending limb of Henle, distal tubule, and collecting duct. SSTR3, SSTR4, and SSTR5 are expressed in proximal tubules. In preclinical studies, somatostatin has been shown to (1) inhibit cAMP generation in MDCK cells and rat collecting ducts, (2) antagonize vasopressin effects in the toad urinary bladder and dog collecting ducts, (3) inhibit cAMP generation, fluid secretion, and cell proliferation in cholangiocytes, and (4) suppress the growth of bile ducts and periportal connective tissue in rats with extrahepatic biliary obstruction. Because somatostatin has a half- life of approximately 3 minutes, more stable synthetic peptides (octreotide, lanreotide, and pasireotide) have been developed for clinical use. [0005] In preclinical studies, octreotide (which binds to SSTR2 and SSTR5, but preferentially to SSTR2) and pasireotide (which binds with high affinity to SSTR2, SSTR3, and SSTR5) reduce cAMP levels and proliferation of cholangiocytes in vitro, expansion of liver cysts in three-dimensional collagen culture, and development of kidney and liver cysts and fibrosis in PCK rats, Pkd2WS25/ mice, and the Pkdl^crs-c model.
[0006] In clinical trials using octreotide or lanreotide (whichboth bind to SSTR2 and SSTR5, but preferentially to SSTR2), kidney growth is halted during the first year of treatment and then resumes, possibly at a lower rate than without treatment. Liver volume decreases by 4%-6% during the first year of treatment, and this reduction is sustained during the second year.
However, observation periods have been too short to assess an effect on renal function. While octreotide and lanreotide are overall well tolerated, the depot preparations of these peptide drugs are extremely expensive and require frequent doctor’ s office visits for painful injections that can lead to injection site reactions.
[0007] To the best of the inventors’ knowledge, to date, no SSTR3 selective small molecule modulator has been prepared or tested for the treatment of ciliopathies, such as polycystic kidney disease (PKD). The compounds described herein are non-peptide somatostatin agonists that selectively activate somatostatin receptor subtype 3 (SSTR3) that in turn reduce cAMP levels that can lead to the ciliopathies described herein, such as PKD.
BRIEF SUMMARY OF THE INVENTION
[0008] In one embodiment, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
wherein:
= represents a single bond or a double bond;
Z is NRZ, wherein Rz is absent or oxo or, when R7 is =0, then Rz is H or Ci-6 alkyl;
X is NRX, wherein Rx is H or Ci-6 alkyl;
L is a bond, Ci-6 alkyl, or (CRL1RL2)t, wherein RL1 and RL2 are each independently H or Ci-6 alkyl, and t is 1, 2, 3, 4, 5, or 6;
R1 is Ci-6 alkyl, C3.10 cycloalkyl, C3.6 cycloalkoxy, Ci.6 haloalkoxy, 6 to 10-membered aryl, and 4-7-membered heteroaryl, which are each optionally substituted with 1, 2, 3, 4, or 5 wherein each R1A is independently halogen, CN, Ci.6 alkyl, Ci.6 haloalkyl, OR11, C(O)ORn, or C(O)N(Rn)2, wherein each R11 is independently H or Ci.6 alkyl;
R2 is C3-7 cycloalkyl, C5-9 bicycloalkyl, or 7 to 9-membered heterocycloalkyl, which are each substituted with 1, 2, 3, 4, or 5 R2A; wherein R2A is independently H, halogen, Ci.6 alkyl, or C(O)OR21, wherein the Ci.6 alkyl is optionally substituted with 1, 2, or 3 halogen, OH, CN, or Ci-6 alkoxy; wherein R21 is H or Ci-6 alkyl; or two R2A together with the atoms to which they are attached form a C3.6 carbocycle;
R3, R4, R5, and R6 are each independently H, halogen, CN, Ci.6 alkyl, C3.6 cycloalkyl, Ci-6 alkoxy, Ci-6 haloalkyl, or C3.6 cyclohaloalkyl; and
R7 is H, halogen, Ci.6 alkyl, C3.6 heterocycloalkyl, OR71, or NR72R73; wherein R71 is absent, H, or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with 1, 2, or 3 R7A, provided that when R71 is absent, R7 is a carbonyl group;
R72 and R73 are independently H or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with 1 , 2, or 3 R7B; or R72 and R73 together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 R7C; wherein R7A, R7B, and R7C are each independently halogen, carbonyl, Ci.6 alkyl, Ci.6 alkylamine, 5 -membered heterocycle, OR7B1, C(O)OR7A1, and C(O)NR7A2R7A2, wherein the 5- membered heterocycle is optionally substituted with Ci.6 alkyl, carbonyl, or OH, and wherein the Ci-6 alkylamine is optionally substituted with a 6-membered cycloalkyl that is optionally substituted with CO2H; wherein R7A1, R7A2, R7B1, R7B2, and R7B3 are each independently H, Ci-6 alkyl, or Ci-6 alkylsulfonyl, wherein the Ci-6 alkyl and Ci-6 alkylsulfonyl are each optionally substituted with 1 or 2 R7B4; wherein R7B4 is independently OC(O)-R7B5 or 5 -membered heterocycle that is optionally substituted with Ci.6 alkyl; and wherein R7B5 is Ci.6 alkyl, which is optionally substituted with NH2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 depicts how abnormal primary cilia function triggers cystogenesis in autosomal dominant polycystic kidney disease (ADPKD).
[0010] FIG. 2 depicts interplay of calcium ions and cAMP ciliary signaling pathways in renal tissue of (A) healthy individuals and (B) individuals with ADPKD.
[0011] FIG. 3 depicts the mechanism of action by which SSTR3 activation can inhibit adenylyl cyclase activity and decrease cilio-plasma cAMP levels. [0012] FIG. 4 depicts an analysis of the mRNA expression of SSTR2, SSTR3, SSTR5, and vasopressin receptor 2 (AVPR2) in healthy and cystic tissue.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Somatostatin (SSTR), also known as somatotropin release inhibiting factor (SRIF) was initially isolated as a 14-amino acid peptide from ovine hypothalami (Brazeau etal., Science 179, 77-79, 1973). An TV-terminal extended 28-amino acid peptide with similar biological activity to 14-amino acid somatostatin was subsequently isolated (Pradayrol et, al., FEBS Leters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980).
SSTR is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SSTR acts through both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and gut and have multiple functions including modulation of secretion of growth hormone (GH), insulin, glucagon, as well as many other hormones that are anti-proliferative.
[0014] These pleiotropic actions of somatostatins are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5). The six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol Metab 8, 398-405, 1997). All the receptors are members of the class-A subgroup of the GPCR superfamily.
[0015] It is possible to selectively modulate any one of the somatostatin receptor subtypes, or combination thereof. Selectively modulating any one of the somatostatin receptor subtypes relative to other somatostatin receptor subtypes reduces unwanted side effects in a variety of clinical applications.
[0016] In some embodiments, the SSTR3 agonists described herein are used in the treatment of a variety of diseases or conditions such as, but not limited to, ciliopathic diseases, including, but not limited to, polycystic kidney disease (PKD) and polycystic liver disease (PLD) . In some embodiments, SSTR3 agonists described herein are used in the treatment of a variety of diseases or conditions associated with dysfunction of cilia such as, but not limited to, PKD, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and combinations thereof. In some embodiments, SSTR3 agonists described herein are used in the treatment of PKD. In some embodiments, the SSTR3 agonist described herein are used in the treatment of ADPKD. In some embodiments, somatostatin receptor modulators described herein are used in the treatment of PKD in a mammal. Ciliopathies
[0017] Ciliopathies are a class of developmental and degenerative single-gene disorders characterized by dysfunction of a hairlike cellular organelle called the cilium. Cilia are microtubule-based structures found on almost all vertebrate cells. They originate from a basal body, a modified centrosome, which is the organelle thatformsthe spindle poles during mitosis. Most of the proteins that are altered in the single-gene disorders that make up ciliopathies function at the cilium-centrosome complex, which represents nature’s universal system for cellular detection and management of external signals. The important role that the cilium- centrosome complex plays in the normal function of most tissues accounts for the involvement of multiple organ systems in ciliopathies. The dysfunction of cilia can cause a variety of ciliopathic diseases and conditions, including, but not limited to, PLD, PKD, ADPKD, ARPKD, and combinations thereof.
Polycystic Kidney Disease
[0018] Polycystic kidney disease (PKD), also known as polycystic kidney syndrome, is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts, non-functioning tubules filled with fluid pumped into them, within the kidney. Cysts range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well. There are two types of PKD, each having its own pathology and genetic cause: ADPKD and ARPKD. The mutated gene is expressed in all cells in the body; as a result, cysts may also occur in the liver.
[0019] Tissue levels of cAMP are increased in numerous animal models of ciliopathies, including those for PKD. In general, tissue levels of cAMP are determined by the activities of membrane-bound and soluble adenylyl cyclases (ACs) and cAMP phosphodiesterases (PDEs), which are subject to complex regulatory mechanisms. For example, in some instances, ACs can be under the positive or negative control of G protein-coupled receptors (GPCRs) and extracellular ligands. For example, somatostatin acts on the five somatostatin receptors (SSTR 1 to 5), which in turn inhibits ACs and decreases intracellular cAMP levels.
[0020] Increased cAMP levels disrupt tubulogenesis, stimulate chloride and fluid secretion within the cyst cavity, and activate proproliferative signaling pathways, including mitogen- activated protein kinase/extracellularly -regulated kinase, mTOR, and P-catenin signaling. Activated mTOR transcriptionally stimulates aerobic glycolysis, increasing ATP synthesis and lowering AMP levels, which together with B-Raf-dependent activation of LKB1, inhibits AMPK, further enhancing mTOR activity and CFTR-driven chloride and fluid secretion. Increased PKA signaling, due to increased cAMP levels, also activates a number of transcription factors, including STAT3 and cAMP response element-building protein (CREB). Activated STAT3 induces the transcription of cytokines, chemokines, and growth factors that, in turn, activates STAT3 on interstitial alternatively activated (M2) macrophages, which results in a feed forward loop between cyst-lining cells and M2 macrophages. Aberrant integrin-extracellular membrane interaction and cAMP signaling within focal adhesion complexes may also contribute to the increased adhesion of cyst-derived cells to laminin-322 and collagen. Hyperactive CREB in ADPKD medicates cAMP-dependent gene regulation that can govern a wide range of cellular processes, including metabolism, cell survival and proliferation, differentiation, apoptosis, and immune responses. The central role of cAMP in the pathogenesis of PKD provides a strong rationale for strategies to lower its levels in cystic tissues.
[0021] ADPKD is the most common genetic cause of kidney disease, affecting about 1 : 1000 individuals (Clin. Med. (Lond) 2009 Jun; 9(3): 278-283). The disease is characterized by slow and gradual bilateral kidney cyst formation, which often results in renal insufficiency usually around the fifth or sixth decade of life. The cysts that are formed in the ADPKD patient kidney originate in renal tubules where mutation in PKD1 or PKD2, genes which encode the poly cystin-1 or poly cystin-2 protein, respectively, impairs cilia functions in epithelial cells (J. Nephrol. 1997 Nov-Dec; 10(6): 295-310; AIMS Mol. Sci. 2014; 1(1): 27-46). Abnormal ciliary signaling results in incomplete differentiation and persistent proliferation of epithelial cells which leads to cyst formation (see, e.g., FIG. 1) (Int. J. Mol. Sci. 2022 Mar 19; 23(6): 3317). The cysts then grow and expand, owing to increased fluid transport into the lumen as a result of excess chloride ion secretion in the cavity. Eventually the cyst branches off from the main nephron and imposes continuous stress on the surrounding tissue, resultingin local injury. While replacement of normal renal tissue with cysts starts early in life, reductions in total nephron mass are masked by compensatory changes in glomerular filtration rate (i.e., GFR) such that total GFR remains apparently normal for many years until compensation fails years later, at which time ADPKD patients typically also experience flank pain, haematuria, urine infections, or renal colic. ADPKD often results in chronic kidney disease and end-stage renal disease (ESRD) that requires dialysis or kidney transplantation for patient survival.
[0022] The biological function of polycystins remains poorly understood. However increasing evidences point toward a model where loss of the inhibitory roles of polycystins in ciliary pathway activation might be the driver of cystogenesis observed in ADPKD. In healthy individuals, the polycystin-1 and poly cystin-2 (PC1/2) proteins directly associate to form a calcium permeable channel that is localized on primary cilia in renal epithelia (Nature Reviews Nephrology 2019; 15: 412-422). See FIG. 2(A). [0023] Cilia are nonmotile plasma membrane appendages that serve as a mechanosensor that detect changes in fluid flow in the lumen of renal tubules and transduces them into a Ca2+ signaling response. This allows the cilium to be a specialized signaling hub that holds a much higher calcium concentration than the cytoplasm (Int. J. Mol. Sci. 2020 Sept 26; 21(19): 7109). High calcium levels directly inhibit ciliary adenylyl cyclase 5 and 6 (AC5/6) which convert ATP in cAMP and stimulate phosphodiesterase (i.e., PDE), an enzyme that catalyzes the hydrolysis of cAMP. As such, functional polycystin protein complexes maintain low ciliary levels of cAMP, a second messenger that plays a role in multiple cellular processes, including cell growth and differentiation. See FIG. 2(A).
[0024] In ADPKD patients, mutation in polycystin-1 or 2 leads to the formation of nonfunctional or hypofunctional channels and causes a significant decrease in ciliary calcium levels (World J. Nephrol. 2016 Jan 6; 5(1): 76-83). Consequently, calcium-inhibitable AC5/6 activity is increased, and calcium-dependent PDE4 activity is reduced. AC5/6 and PDE4 activity dysregulation result in a significant increase in intra-ciliary cAMP levels. See FIG. 2(B).
[0025] High levels of cAMP then triggers cyst formation by stimulating the expression of cAMP dependent genes involved in proliferation as well as cyst expansion by driving chloride ions and fluid secretion in the cyst cavity via protein kinase A (PKA)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) activation. Thus, in ADPKD, dysregulated crosstalk between intraciliary calcium and the cAMP signaling pathway seems to plays a critical role in cystogenesis. Therefore, the inventors hypothesize that cyst formation observed in ADPKD should be inhibited/reduced by blocking adenylyl cyclase activity selectively within the cilia. [0026] SSTR3 is a prototypical ciliary GPCR (Neuroscience 1999 Mar; 89(3): 909-26). SSTR3 trafficking to the cilia requires a series of highly regulated processes that include the translocation of the receptor from the cytoplasm to the axoneme through the transition zone owing to a particular amino acid sequence located in the third transmembrane domain (J. Cell. Biol. 2018 May 7: 217(5): 1847-1868). As a Gi coupled receptor, SSTRR3 activation can inhibit adenylyl cyclase activity (Murthy et al., J. Biol. Chem. 1996: 271(38): 23458-23463) and decrease cilio-plasma cAMP levels, which is central to the establishment of ADPKD. See FIG. 3.
[0027] Public data set (GSE7869) from a global gene profiling study on renal cysts was reported by Song et al. (Hum. Mol. Genet. 2009; 18: 2328-2343). The data set comprises microarray expression data from cysts of different sizes from five PKD 1 -patients and from three kidneys of healthy patients. The inventors performed a reanalysis of the data using a Transcriptome Analysis Console (Thermo Fisher). Inspecting the probe covering SSTR3, SSTR3-mRNA expression was found in healthy and cystic tissue at higher levels when compared to somatostatin receptor 2 and 5 (SSTR2, SSTR5), or the vasopressin receptor 2 (AVPR2) (See FIG. 4). Thus, the inventors determined that the cellular localization and signaling capability of SSTR3 makes it an attractive target for the treatment of ADPKD. [0028] ARPKD, an important cause of ESRD and mortality in infants and children, is caused by mutations in PKD1 (encoding fibrocystin). As with ADPKD, in ARPKD cyst formation is caused by disruption of mechanisms controlling cellular differentiation, leading to excessive cell proliferation and fluid secretion, and pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages. Dy sregulation of the crosstalk between ciliary calcium and cyclic adenosine monophosphate (cAMP) signaling play central roles in the development of PKD. In some instances, the compounds described herein are somatostatin agonists that selectively activate somatostatin receptor subtype 3 (SSTR3) that in turn reduce cAMP levels and cAMP dependent signaling.
[0029] In some embodiments, somatostatin receptor modulators described herein are used to treat ciliopathies in a mammal. In some embodiments, somatostatin receptor modulators described herein lead to a decrease in cAMP levels, which is useful for the treatment of ciliopathies described herein. In some embodiments, the ciliopathic disease or condition is selected from PKD, ADPKD, ARPKD, PLD, and combinations thereof. In some embodiments, the ciliopathic disease or condition is selected from PKD, ADPKD, and ARPKD. In some embodiments, the ciliopathic disease or condition is PKD. In some embodiments, the ciliopathic disease or condition is ADPKD. In some embodiments, the ciliopathic disease or condition is ARPKD.
[0030] Also described herein is a method of treating a disease or condition in a mammal that would benefit from the modulation of somatostatin receptor subtype 3 (SSTR3) activity comprising administering to the mammal in need thereof a selective small molecule SSTR3 agonist compound.
[0031] In some embodiments, the disease or condition is any one of the diseases or conditions described herein, or combinations thereof. In some embodiments, the disease or condition is associated with dysfunction of cilia. In some embodiments, the disease or condition is a ciliopathic disease or condition. In some embodiments, the selective small molecule SSTR3 agonist is a compound described herein.
Compounds [0032] Provided are compounds of Formula (I), Formula (II), and Formula (III), including pharmaceutically acceptable salts thereof, which are somatostatin subtype 3 receptor (SSTR3) agonists.
[0033] In some embodiments, described herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof:
Figure imgf000011_0001
wherein:
= represents a single bond or a double bond;
Z is NRZ, wherein Rz is absent or oxo or, when R7 is =0, then Rz is H or Ci-6 alkyl;
X is NRX, wherein Rx is H or Ci-6 alkyl;
L is a bond, Ci.6 alkyl, or (CRL1RL2)t, wherein RL1 and RL2 are each independently H or Ci-6 alkyl, and t is 1, 2, 3, 4, 5, or 6;
R1 is Ci-6 alkyl, C3.10 cycloalkyl, C3.6 cycloalkoxy, Ci.6 haloalkoxy, 6 to 10-membered aryl, and 4-7-membered heteroaryl, which are each optionally substituted with 1, 2, 3, 4, or 5 R1A; wherein each R1A is independently halogen, CN, Ci-6 alkyl, Ci-6 haloalkyl, OR11, C(O)ORn, or C(O)N(Rn)2, wherein each R11 is independently H or Ci.6 alkyl;
R2 is C3.7 cycloalkyl, C5.9 bicycloalkyl, or 7 to 9-membered heterocycloalkyl, which are each substituted with 1, 2, 3, 4, or 5 R2A; wherein R2A is independently H, halogen, Ci.6 alkyl, or C(O)OR21, wherein the Ci.6 alkyl is optionally substituted with 1, 2, or 3 halogen, OH, CN, or Ci.6 alkoxy; wherein R21 is H or Ci-6 alkyl; or two R2A together with the atoms to which they are attached form a C3-6 carbocycle;
R3, R4, R5, and R6 are each independently H, halogen, CN, Ci.6 alkyl, C3.6 cycloalkyl, Ci-6 alkoxy, Ci.6 haloalkyl, or C3.6 cyclohaloalkyl; and
R7 is H, halogen, Ci.6 alkyl, C3.6 heterocycloalkyl, OR71, or NR72R73; wherein R71 is absent, H, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 R7A, provided that when R71 is absent, R7 is a carbonyl group;
R72 and R73 are independently H or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with 1, 2, or 3 R7B; or R72 and R73 together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 R7C; wherein R7A, R7B, and R7C are each independently halogen, carbonyl, Ci-6 alkyl, Ci-6 alkylamine, 5 -membered heterocycle, OR7B1, C(O)OR7A1, and C(O)NR7A2R7A2, wherein the 5-membered heterocycle is optionally substituted with Ci.6 alkyl, carbonyl, or OH, and wherein the Ci-6 alkylamine is optionally substituted with a 6-membered cycloalkyl that is optionally substituted with CO2H; wherein R7A1, R7A2, R7B1, R7B2, and R7B3 are each independently H, Ci-6 alkyl, or Ci-6 alkylsulfonyl, wherein the Ci.6 alkyl and Ci.6 alkylsulfonyl are each optionally substituted with 1 or2 R7B4; wherein R7B4 is independently OC(O)-R7B5 or 5-membered heterocycle that is optionally substituted with Ci.6 alkyl; and wherein R7B5 is Ci.6 alkyl, which is optionally substituted with NH2.
[0034] In some embodiments, described herein are compounds of Formula (II), compounds of Formula (III), and pharmaceutically acceptable salts of any of the foregoing:
Figure imgf000012_0001
wherein:
R2A is H, halogen, C(O)OH, C(O)OCi-6 alky( or Ci-6 alkyl optionally substituted with OH, CN, or Ci-6 alkoxy 1; m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; q is 1, 2, 3, or 4; r is 1, 2, 3, or 4; and s is 1, 2, 3, 4, or 5.
[0035] In some embodiments, in Formula (II) m is 2 and n is 2. In some emodiments, in Formula (II) m is 1 and n is 3. In some embodiments, in Formula (II) m is 3 and n is 1 . In some embodiments, in Formula (III) q is 1 and r is 2. In some embodiments, in Formula (III) q is 2 and r is 1. [0036] In some embodiments, Z is NH or NMe. In some embodiments, Z is NH. In some embodiments, Z is NMe.
[0037] In some embodiments, X is NH or NMe. In some embodiments, X is NH. In some embodiments, X is NMe.
[0038] In some embodiments, L is a bond, Ci.6 alkyl, or (CRL1RL2)t, wherein each RL1 and RL2 are independently H or Ci-6 alkyl and t is 1 or 2.
[0039] In some embodiments, L is a bond, CH2, CH2CH2,
Figure imgf000013_0001
or
^OMe
Figure imgf000013_0002
. In some embodiments, L is a bond. In some embodiments, L is CH2. In some embodiments, L is CH2CH2. In some embodiments, L is
Figure imgf000013_0003
. In some embodiments, L is ^OMe
Figure imgf000013_0006
. In some embodiments, L is
Figure imgf000013_0004
jn some embodiments, L is
Figure imgf000013_0005
[0040] In some embodiments, R1 is C3.8 cycloalkyl, phenyl, or 4 to 6-membered heteroaryl, which are each independently substituted with 1, 2, or 3 R1A. In some embodiments, R1 is C3.8 cycloalkyl, phenyl, or pyridyl, which are each independently substituted with 1, 2, or 3 R1A.
Figure imgf000013_0007
Figure imgf000014_0001
[
Figure imgf000015_0001
,
F3C.
[0043] In some embodiments, R1 is ° . In some embodiments, R1 is
Figure imgf000015_0002
Y In some embodiments, R1 is
Figure imgf000015_0004
. In some embodiments, R1 is
Figure imgf000015_0003
. In some embodiments,
R1 is
Figure imgf000015_0006
. In some embodiments, R1 is
Figure imgf000015_0007
. In some embodiments, R1 is
Figure imgf000015_0005
In some embodiments, R1 is
Figure imgf000015_0009
. In some embodiments, R1 is
Figure imgf000015_0008
. In some embodiments, R1 is
Figure imgf000015_0010
. In some embodiments, R1 is
Figure imgf000015_0011
. In some embodiments, R1
Figure imgf000015_0013
, . In some embodiments, R1 is
Figure imgf000015_0012
. In some embodiments, R1 is
Figure imgf000015_0015
. In some embodiments, R1 is
Figure imgf000015_0014
. In some embodiments, R1 is
Figure imgf000015_0016
. In some embodiments, R1 is
Figure imgf000015_0017
. In some embodiments, R1 is
Figure imgf000016_0002
. In some embodiments, R1 is
Figure imgf000016_0001
. In some embodiments, R1 is
Figure imgf000016_0003
. In some embodiments, R1 is
Figure imgf000016_0004
. In some embodiments,
Figure imgf000016_0005
some embodiments, R1 is
Figure imgf000016_0006
. In some embodiments, R1 is
Figure imgf000016_0007
. In some embodiments, R1 is
Figure imgf000016_0008
. In some embodiments, In some embodiments,
Figure imgf000016_0009
some embodiments, R1 is In some embodiments, R1 is
Figure imgf000016_0010
. In some embodiments, R1 is
. In some embodiments, R1 is
Figure imgf000016_0011
. In some embodiments, R1 is some embodiments, R1 is
Figure imgf000016_0012
. In some embodiments, R1 is
. In some embodiments, R1 is
Figure imgf000016_0014
. In some embodiments, R1 is
. In some embodiments, R1 is
Figure imgf000016_0015
. In some embodiments, R1 is
Figure imgf000016_0013
. some embodiments,
Figure imgf000016_0016
some embodiments, R1 is
Figure imgf000016_0017
. , in some embodiments, R1 is
Figure imgf000017_0001
, . In some embodiments, R1 is
. In some embodiments, R1 is
Figure imgf000017_0002
. In some embodiments, R1 is
Figure imgf000017_0003
. In some embodiments, R1
Figure imgf000017_0004
. In some embodiments, R1 is
Figure imgf000017_0005
. , . In some embodiments, R1 is
Figure imgf000017_0006
. In some embodiments, R1 is
Figure imgf000017_0007
. In some embodiments, R1 is
Figure imgf000017_0008
. In some embodiments, R1 is
Figure imgf000017_0009
. In some embodiments, R1 is
Figure imgf000017_0010
. In some embodiments, R1 is
Figure imgf000017_0011
. In some embodiments, R1 is
Figure imgf000017_0012
. In some embodiments,
R1 is
Figure imgf000017_0013
. In some embodiments, R1 is
Figure imgf000017_0014
. In some embodiments, R1 is
Figure imgf000017_0015
. , . In some embodiments, R1 is
Figure imgf000017_0016
. , . In some embodiments, R1 is
Figure imgf000017_0017
, some embodiments, R1 is
Figure imgf000018_0001
Figure imgf000019_0001
[0046] In some embodiments, R1 is
Figure imgf000019_0003
. In some embodiments, R1 is
Figure imgf000019_0002
some embodiments, R1 is
Figure imgf000019_0005
In some embodiments,
Figure imgf000019_0004
embodiments, R1 is
Figure imgf000019_0006
In some embodiments, R1 is
Figure imgf000019_0007
embodiments, R1 is
Figure imgf000019_0008
In some embodiments, R1 is
Figure imgf000019_0009
embodiments, R1 is
Figure imgf000019_0010
In some embodiments, R1 is
Figure imgf000019_0011
. in some embodiments,
Figure imgf000019_0012
embodiments,
Figure imgf000019_0013
embodiments, R1 is
Figure imgf000019_0014
. In some embodiments, R1 is
Figure imgf000019_0015
. In some embodiments,
Figure imgf000020_0001
embodiments,
Figure imgf000020_0002
embodiments,
Figure imgf000020_0003
embodiments,
Figure imgf000020_0004
embodiments,
Figure imgf000020_0005
embodiments,
Figure imgf000020_0006
embodiments,
Figure imgf000020_0007
some embodiments,
Figure imgf000020_0008
some embodiments,
Figure imgf000020_0009
some embodiments,
Figure imgf000020_0010
embodiments,
Figure imgf000020_0011
some embodiments,
Figure imgf000020_0012
embodiments,
Figure imgf000020_0013
some embodiments,
Figure imgf000020_0014
embodiments,
Figure imgf000020_0016
some embodiments,
Figure imgf000020_0015
some embodiments, R1 is
Figure imgf000021_0001
. , . In some embodiments,
Figure imgf000021_0002
some embodiments,
Figure imgf000021_0003
some
Figure imgf000021_0004
embodiments, R1 is CO2H . In some embodiments, R1 is CO2Et In some embodiments, R1 is
Figure imgf000021_0005
. In some embodiments, R1 is
Figure imgf000021_0006
. In some embodiments, R1 is
Figure imgf000021_0010
, some embodiments,
Figure imgf000021_0007
some embodiments,
Figure imgf000021_0008
some embodiments,
Figure imgf000021_0009
[0047] In some embodiments, R2 is 7 to 9-membered heterocycloalkyl, C3-7 cycloalkyl, or C5-9 bicycloalkyl which are each substituted with 1, 2, or 3 R2A;
R2A is independently H, halogen, CN, Ci.6 alkyl, C(O)OR21, or C(O)NR22R23, wherein the Ci-6 alkyl is optionally substituted with 1 or 2 OH, NH2, CN, Ci-6 alkyl, or Ci-6 alkoxy; and
R21, R22, and R23 are each independently H or Ci-6 alkyl; or two R2A together with the atoms to which they are attached form a C3.6 carbocycle. [0048] In some embodiments, R2 is 7 to 9-membered heterocycloalkyl which is substituted with 1, 2, or 3 R2A;
R2A is independently H, halogen, CN, Ci.6 alkyl, C(O)OR21, or C(O)NR22R23, wherein the Ci-6 alkyl is optionally substituted with 1 or 2 OH, NH2, CN, Ci.6 alkyl, or Ci.6 alkoxy; and
R21, R22, and R23 are each independently H or Ci-6 alkyl; or two R2A together with the atoms to which they are attached form a C3.6 carbocycle.
[0049] In some embodiments,
Figure imgf000022_0001
Figure imgf000022_0002
, which are each substituted with 1 or 2 R2A;
R2A is H, halogen, Ci-6 alkyl, or C(O)OR21, wherein the Ci-6 alkyl is optionally substituted with OH, CN, or Ci.6 alkoxy; and
R21 is H or Ci-6 alkyl.
[0050] In some embodiments,
Figure imgf000022_0003
some embodiments,
Figure imgf000022_0004
some embodiments,
Figure imgf000022_0005
some
Figure imgf000022_0006
Figure imgf000023_0012
[0052] In some embodiments,
Figure imgf000023_0002
some embodiments,
Figure imgf000023_0001
some embodiments,
Figure imgf000023_0003
some embodiments,
Figure imgf000023_0004
some embodiments, R2 is
Figure imgf000023_0006
, some embodiments,
Figure imgf000023_0005
In some embodiments,
Figure imgf000023_0007
some embodiments,
Figure imgf000023_0008
embodiments,
Figure imgf000023_0010
some embodiments,
Figure imgf000023_0009
embodiments,
Figure imgf000023_0011
Figure imgf000024_0001
embodiments, R2 is -~L- . In some embodiments, R2 is —J— . In some embodiments,
Figure imgf000024_0002
some embodiments,
Figure imgf000024_0003
some embodiments, R2 is
Figure imgf000024_0004
, some embodiments,
Figure imgf000024_0005
[0053] In some embodiments,
Figure imgf000024_0006
[0054] In some embodiments, R3 is H or F. In some embodiments, R3 is H. In some embodiments, R3 is F.
[0055] In some embodiments, R4 is H, halogen, Ci-6 alkyl, Ci-6 alkoxy, or C3-6 cycloalkyl. In some embodiments, R4 is H, F, Cl, methyl, methoxy, or cyclopropyl. In some embodiments, R4 is H. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is methyl. In some embodiments, R4 is methoxy. In some embodiments, R4 is cyclopropyl. In some embodiments, R4 is methoxy.
[0056] In some embodiments, R5 is H, halogen, CN, Ci.6 alkyl, or Ci.6 haloalkyl. In some embodiments, R5 is halogen or Ci.6 haloalkyl. In some embodiments, R5 is H, F, Cl, CN, CF3, CF2Me, OMe, or cyclopropyl. In some embodiments, R5 is Cl, CF3, or cyclopropyl. In some embodiments, R5 is H. In some embodiments, R5 is F. In some embodiments, R5 is Cl. In some embodiments, R5 is CN. In some embodiments, R5 is CF3. In some embodiments, R5 is CF2Me. In some embodiments, R5 is OMe. In some embodiments, R5 is cyclopropyl. In some
A/CF3 embodiments, R5 is CF3. In some embodiments, R5 is
[0057] In some embodiments, R6 is H, halogen, Ci.6 alkyl, or C3.6 cycloalkyl. In some embodiments, R6 is H.
[0058] In some embodiments, R7 is H, halogen, OR71, NR72R73, or Ci-6 alkyl; wherein R71 is absent, H, or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with R7A; wherein R72 and R73 are each independently H or Ci.6 alkyl, wherein the Ci.6 alkyl is each optionally substituted with R7B; or R72 and R73 together with the nitrogen atom to which they are attached form a 3 to 6 -membered heterocycloalkyl which is optionally substituted with 1 or 2 R7C; wherein R7A is independently 4 to 6-membered heterocycle, C(O)OR7A1, and C(O)NR7A2R7A2, wherein the 4 to 6-membered heterocycle is optionally substituted with carbonyl, OH, or NH2; wherein R7A1 and R7A2 are each independently H, Ci.6 alkyl, or Ci.6 alkylsulfonyl; wherein R7B is independently OR7B1, C(O)OR7B2, C(O)NR7B3R7B3, and 4 to 6- membered heterocycle, wherein the 4 to 6-membered heterocycle is optionally substituted with methyl, carbonyl, OH, orNH2; wherein R7B1, R7B2, and R7B3 are each independently H, Ci.6 alkyl, or Ci.6 alkylsulfonyl, wherein the Ci.6 alkyl and are each optionally substituted with OC(O)-R7B4 or 4 to 6-membered heterocycle that is optionally substituted with R7B4; wherein R7B4 is Ci.6 alkyl, which is optionally substituted with NH2; and
R7C is independently carbonyl, halogen, OH, Ci-6 alkoxy, CO2H, C(O)OCi-6 alkyl, Ci-6 alkyl, or Ci-6 alkylamine, wherein the Ci-6 alkylamine is optionally substituted with a 6-membered heterocycle that is optionally substituted with CO2H.
[0059] In some embodiments, R7 is H, halogen, OR71, NR72R73, or Ci-6 alkyl;
R71 is absent, H or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with R7A;
R72 and R73 are independently H or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with R7B; or
R72 and R73 together with the nitrogen atom to which they are attached form
Figure imgf000025_0001
Figure imgf000025_0002
which are each optionally substituted with 1 or 2 R7C;
R7A is independently
Figure imgf000025_0003
, C(O)OR7A1, or C(O)NR7A2R7A2;
R7A1 is independently H or Ci.6 alkyl;
R7A2 is independently H or Ci.6 alkylsulfonyl;
Figure imgf000026_0010
R7B1 is independently H or Ci.6 alkyl;
R7B2 is H or Ci-6 alkyl, wherein the Ci.6 alkyl is optionally substituted with OC(O)-R7B4
Figure imgf000026_0001
R7B3 is independently H or Ci.6 alkylsulfonyl;
R7B4 is Ci-6 alkyl, which is optionally substituted with NH2; and
R7C is independently carbonyl, halogen, OH, Ci.6 alkoxy, CO2H, C(O)OCi_6 alkyl, Ci.6 alkyl, or Ci-6 alkylamine, wherein the Ci-6 alkylamine is optionally substituted with a 6- membered heterocycle that is optionally substituted with CO2H.
Figure imgf000026_0011
Figure imgf000026_0002
. In some embodiments, R7 is H. In some embodiments, R7 is O. In some embodiments, R7 is Cl. In some embodiments, R7 is Me. In some embodiments, R7 is NH2. In some embodiments, R7 is NHMe. In some embodiments, R7 is NMe2. In some embodiments, R7 is
Figure imgf000026_0003
. In some embodiments, R7 is
Figure imgf000026_0004
. In some
Figure imgf000026_0005
embodiments, R7 is H . In some embodiments, R7 is H . In some
Figure imgf000026_0006
embodiments, R7 is H . In some embodiments, R7 is H . In some embodiments, R7 is
Figure imgf000026_0008
. In some embodiments, R7 is
Figure imgf000026_0007
. In some embodiments, R7
Figure imgf000026_0009
,
Figure imgf000027_0001
[0062] In some embodiments, R7 is H. In some embodiments, R7 is O. In some embodiments,
R7 is OH. In some embodiments, R7 is OMe. In some embodiments, R7 is NH2. In some embodiments, R7 is NHMe. In some embodiments, R7 is
Figure imgf000027_0002
. In some embodiments,
Figure imgf000028_0001
R7 is
Figure imgf000028_0002
. In some embodiments, R7 is HO2C In some embodiments, R7 is
Figure imgf000028_0003
Figure imgf000028_0004
, some embodiments, R7 is
Figure imgf000028_0005
, some embodiments, R7 is
Figure imgf000028_0006
In some embodiments, R7 is
Figure imgf000028_0007
In some embodiments, R7 is
Figure imgf000028_0008
. In some embodiments,
Figure imgf000028_0009
some embodiments, in some embodiments, R7 is
Figure imgf000028_0010
. In some embodiments, R7 is In some embodiments, R7 is
Figure imgf000028_0012
. In some embodiments, R7 is
Figure imgf000028_0011
. In some embodiments, R7 is
Figure imgf000028_0013
In some embodiments, R7 is
Figure imgf000028_0014
, some embodiments, R7 is
In some embodiments, R7 is
Figure imgf000028_0015
. In some embodiments, R7 is
Figure imgf000028_0016
. In some embodiments, R7 is
Figure imgf000028_0017
. In some embodiments, R7 is
Figure imgf000029_0001
, . In some embodiments, R7 is
Figure imgf000029_0002
. , . In some embodiments,
Figure imgf000029_0003
, embodiments,
Figure imgf000029_0004
some embodiments, R7 is
Figure imgf000029_0005
,
Figure imgf000029_0006
[0063] In some embodiments, R7 is H, O,
Figure imgf000029_0007
. In some embodiments,
R7 is H. In some embodiments, R7 is O. In some embodiments, R7 is
Figure imgf000029_0008
. In some embodiments, R7 is
Figure imgf000029_0009
In some embodiments, R7 is a carbonyl group.
[0064] Exemplary compounds described herein include the compounds described in the following Table: Table 1: Compounds of Formula (I):
Figure imgf000030_0002
Figure imgf000030_0006
Figure imgf000030_0010
Figure imgf000030_0003
Figure imgf000030_0007
Figure imgf000030_0011
Figure imgf000030_0004
Figure imgf000030_0008
Figure imgf000030_0012
Figure imgf000030_0001
Figure imgf000030_0005
Figure imgf000030_0009
Figure imgf000030_0013
Figure imgf000031_0001
Figure imgf000031_0006
Figure imgf000031_0002
Figure imgf000031_0007
Figure imgf000031_0003
Figure imgf000031_0008
Figure imgf000031_0004
Figure imgf000031_0009
Figure imgf000031_0005
Figure imgf000031_0010
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000034_0004
Figure imgf000034_0001
Figure imgf000034_0005
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0003
Figure imgf000037_0007
Figure imgf000037_0004
Figure imgf000037_0008
Figure imgf000037_0011
Figure imgf000037_0005
Figure imgf000037_0009
Figure imgf000037_0012
Figure imgf000037_0006
Figure imgf000037_0001
Figure imgf000037_0010
Figure imgf000037_0013
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0002
Figure imgf000039_0003
Figure imgf000039_0004
Figure imgf000039_0005
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000048_0006
Figure imgf000048_0002
Figure imgf000048_0007
Figure imgf000048_0003
Figure imgf000048_0008
Figure imgf000048_0004
Figure imgf000048_0009
Figure imgf000048_0005
Figure imgf000048_0010
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000051_0004
Figure imgf000051_0005
Figure imgf000052_0002
Figure imgf000052_0007
Figure imgf000052_0012
Figure imgf000052_0003
Figure imgf000052_0008
Figure imgf000052_0013
Figure imgf000052_0004
Figure imgf000052_0009
Figure imgf000052_0014
Figure imgf000052_0005
Figure imgf000052_0010
Figure imgf000052_0015
Figure imgf000052_0006
Figure imgf000052_0001
Figure imgf000052_0011
Figure imgf000052_0016
Figure imgf000053_0005
Figure imgf000053_0007
Figure imgf000053_0001
Figure imgf000053_0006
Figure imgf000053_0008
Figure imgf000053_0002
Figure imgf000053_0003
Figure imgf000053_0004
Figure imgf000054_0001
[0065] In certain embodiments, the compound of Formula (I) is compound 1.
[0066] In certain embodiments, the compound of Formula (I) is compound 2.
[0067] In certain embodiments, the compound of Formula (I) is compound 3.
[0068] In certain embodiments, the compound of Formula (I) is compound 4.
[0069] In certain embodiments, the compound of Formula (I) is compound 5.
[0070] In certain embodiments, the compound of Formula (I) is compound 6.
[0071] In certain embodiments, the compound of Formula (I) is compound 7.
[0072] In certain embodiments, the compound of Formula (I) is compound 8.
[0073] In certain embodiments, the compound of Formula (I) is compound 9.
[0074] In certain embodiments, the compound of Formula (I) is compound 10.
[0075] In certain embodiments, the compound of Formula (I) is compound 11.
[0076] In certain embodiments, the compound of Formula (I) is compound 12.
[0077] In certain embodiments, the compound of Formula (I) is compound 13.
[0078] In certain embodiments, the compound of Formula (I) is compound 14.
[0079] In certain embodiments, the compound of Formula (I) is compound 15.
[0080] In certain embodiments, the compound of Formula (I) is compound 16.
[0081] In certain embodiments, the compound of Formula (I) is compound 17.
[0082] In certain embodiments, the compound of Formula (I) is compound 18.
[0083] In certain embodiments, the compound of Formula (I) is compound 19.
[0084] In certain embodiments, the compound of Formula (I) is compound 20.
[0085] In certain embodiments, the compound of Formula (I) is compound 21.
[0086] In certain embodiments, the compound of Formula (I) is compound 22. [0087] In certain embodiments, the compound of Formula (I) is compound 23.
[0088] In certain embodiments, the compound of Formula (I) is compound 24.
[0089] In certain embodiments, the compound of Formula (I) is compound 25.
[0090] In certain embodiments, the compound of Formula (I) is compound 26.
[0091] In certain embodiments, the compound of Formula (I) is compound 27.
[0092] In certain embodiments, the compound of Formula (I) is compound 28.
[0093] In certain embodiments, the compound of Formula (I) is compound 29.
[0094] In certain embodiments, the compound of Formula (I) is compound 30.
[0095] In certain embodiments, the compound of Formula (I) is compound 31.
[0096] In certain embodiments, the compound of Formula (I) is compound 32.
[0097] In certain embodiments, the compound of Formula (I) is compound 33.
[0098] In certain embodiments, the compound of Formula (I) is compound 34.
[0099] In certain embodiments, the compound of Formula (I) is compound 35.
[00100]In certain embodiments, the compound of Formula (I) is compound 36.
[00101]In certain embodiments, the compound of Formula (I) is compound 37.
[00102]In certain embodiments, the compound of Formula (I) is compound 38.
[00103]In certain embodiments, the compound of Formula (I) is compound 39.
[00104]In certain embodiments, the compound of Formula (I) is compound 40.
[00105]In certain embodiments, the compound of Formula (I) is compound 41.
[00106]In certain embodiments, the compound of Formula (I) is compound 42.
[00107]In certain embodiments, the compound of Formula (I) is compound 43.
[00108]In certain embodiments, the compound of Formula (I) is compound 44.
[00109]In certain embodiments, the compound of Formula (I) is compound 45.
[00110]In certain embodiments, the compound of Formula (I) is compound 46.
[00111]In certain embodiments, the compound of Formula (I) is compound 47.
[00112]In certain embodiments, the compound of Formula (I) is compound 48.
[00113]In certain embodiments, the compound of Formula (I) is compound 49.
[00114]In certain embodiments, the compound of Formula (I) is compound 50.
[00115]In certain embodiments, the compound of Formula (I) is compound 51.
[00116]In certain embodiments, the compound of Formula (I) is compound 52.
[00117]In certain embodiments, the compound of Formula (I) is compound 53.
[00118]In certain embodiments, the compound of Formula (I) is compound 54.
[00119]In certain embodiments, the compound of Formula (I) is compound 55.
[00120]In certain embodiments, the compound of Formula (I) is compound 56. [00121]In certain embodiments, the compound of Formula (I) is compound 57.
[00122]In certain embodiments, the compound of Formula (I) is compound 58.
[00123]In certain embodiments, the compound of Formula (I) is compound 59.
[00124]In certain embodiments, the compound of Formula (I) is compound 60.
[00125]In certain embodiments, the compound of Formula (I) is compound 61.
[00126]In certain embodiments, the compound of Formula (I) is compound 62.
[00127]In certain embodiments, the compound of Formula (I) is compound 63.
[00128]In certain embodiments, the compound of Formula (I) is compound 64.
[00129]In certain embodiments, the compound of Formula (I) is compound 65.
[00130]In certain embodiments, the compound of Formula (I) is compound 66.
[00131]In certain embodiments, the compound of Formula (I) is compound 67.
[00132]In certain embodiments, the compound of Formula (I) is compound 68.
[00133]In certain embodiments, the compound of Formula (I) is compound 69.
[00134]In certain embodiments, the compound of Formula (I) is compound 70.
[00135]In certain embodiments, the compound of Formula (I) is compound 71.
[00136]In certain embodiments, the compound of Formula (I) is compound 72.
[00137]In certain embodiments, the compound of Formula (I) is compound 73.
[00138]In certain embodiments, the compound of Formula (I) is compound 74.
[00139]In certain embodiments, the compound of Formula (I) is compound 75.
[00140]In certain embodiments, the compound of Formula (I) is compound 76.
[00141]In certain embodiments, the compound of Formula (I) is compound 77.
[00142]In certain embodiments, the compound of Formula (I) is compound 78.
[00143]In certain embodiments, the compound of Formula (I) is compound 79.
[00144]In certain embodiments, the compound of Formula (I) is compound 80.
[00145]In certain embodiments, the compound of Formula (I) is compound 81.
[00146]In certain embodiments, the compound of Formula (I) is compound 82.
[00147]In certain embodiments, the compound of Formula (I) is compound 83.
[00148]In certain embodiments, the compound of Formula (I) is compound 84.
[00149]In certain embodiments, the compound of Formula (I) is compound 85.
[00150]In certain embodiments, the compound of Formula (I) is compound 86.
[00151]In certain embodiments, the compound of Formula (I) is compound 87.
[00152]In certain embodiments, the compound of Formula (I) is compound 88.
[00153]In certain embodiments, the compound of Formula (I) is compound 89.
[00154]In certain embodiments, the compound of Formula (I) is compound 90. [00155]In certain embodiments, the compound of Formula (I) is compound 91.
[00156]In certain embodiments, the compound of Formula (I) is compound 92.
[00157]In certain embodiments, the compound of Formula (I) is compound 93.
[00158]In certain embodiments, the compound of Formula (I) is compound 94. [00159]In certain embodiments, the compound of Formula (I) is compound 95. [00160]In certain embodiments, the compound of Formula (I) is compound 96. [00161]In certain embodiments, the compound of Formula (I) is compound 97. [00162]In certain embodiments, the compound of Formula (I) is compound 98. [00163]In certain embodiments, the compound of Formula (I) is compound 99. [00164]In certain embodiments, the compound of Formula (I) is compound 100. [00165]In certain embodiments, the compound of Formula (I) is compound 101. [00166]In certain embodiments, the compound of Formula (I) is compound 102. [00167]In certain embodiments, the compound of Formula (I) is compound 103. [00168]In certain embodiments, the compound of Formula (I) is compound 104. [00169]In certain embodiments, the compound of Formula (I) is compound 105. [00170]In certain embodiments, the compound of Formula (I) is compound 106. [00171]In certain embodiments, the compound of Formula (I) is compound 107. [00172]In certain embodiments, the compound of Formula (I) is compound 108. [00173]In certain embodiments, the compound of Formula (I) is compound 109. [00174]In certain embodiments, the compound of Formula (I) is compound 110. [00175]In certain embodiments, the compound of Formula (I) is compound 111. [00176]In certain embodiments, the compound of Formula (I) is compound 112. [00177]In certain embodiments, the compound of Formula (I) is compound 113. [00178]In certain embodiments, the compound of Formula (I) is compound 114. [00179]In certain embodiments, the compound of Formula (I) is compound 115. [00180]In certain embodiments, the compound of Formula (I) is compound 116. [00181]In certain embodiments, the compound of Formula (I) is compound 117. [00182]In certain embodiments, the compound of Formula (I) is compound 118. [00183]In certain embodiments, the compound of Formula (I) is compound 119. [00184]In certain embodiments, the compound of Formula (I) is compound 120. [00185]In certain embodiments, the compound of Formula (I) is compound 121. [00186]In certain embodiments, the compound of Formula (I) is compound 122. [00187]In certain embodiments, the compound of Formula (I) is compound 123. [00188]In certain embodiments, the compound of Formula (I) is compound 124. [00189]In certain embodiments, the compound of Formula (I) is compound 125.
[00190]In certain embodiments, the compound of Formula (I) is compound 126.
[00191]In certain embodiments, the compound of Formula (I) is compound 127.
[00192]In certain embodiments, the compound of Formula (I) is compound 128.
[00193]In certain embodiments, the compound of Formula (I) is compound 129.
[00194]In certain embodiments, the compound of Formula (I) is compound 130.
[00195]In certain embodiments, the compound of Formula (I) is compound 131.
[00196]In certain embodiments, the compound of Formula (I) is compound 132.
[00197]In certain embodiments, the compound of Formula (I) is compound 133.
[00198]In certain embodiments, the compound of Formula (I) is compound 134.
[00199]In certain embodiments, the compound of Formula (I) is compound 135.
[00200]In certain embodiments, the compound of Formula (I) is compound 136.
[00201]In certain embodiments, the compound of Formula (I) is compound 137.
[00202]In certain embodiments, the compound of Formula (I) is compound 138.
[00203]In certain embodiments, the compound of Formula (I) is compound 139.
[00204]In certain embodiments, the compound of Formula (I) is compound 140.
[00205]In certain embodiments, the compound of Formula (I) is compound 141.
[00206]In certain embodiments, the compound of Formula (I) is compound 142.
[00207]In certain embodiments, the compound of Formula (I) is compound 143.
[00208]In certain embodiments, the compound of Formula (I) is compound 144.
[00209]In certain embodiments, the compound of Formula (I) is compound 145.
[00210]In certain embodiments, the compound of Formula (I) is compound 146.
[00211]In certain embodiments, the compound of Formula (I) is compound 147.
[00212]In certain embodiments, the compound of Formula (I) is compound 148.
[00213]In certain embodiments, the compound of Formula (I) is compound 149.
[00214]In certain embodiments, the compound of Formula (I) is compound 150.
[00215]In certain embodiments, the compound of Formula (I) is compound 151.
[00216]In certain embodiments, the compound of Formula (I) is compound 152.
[00217]In certain embodiments, the compound of Formula (I) is compound 153.
[00218]In certain embodiments, the compound of Formula (I) is compound 154.
[00219]In certain embodiments, the compound of Formula (I) is compound 155.
[00220]In certain embodiments, the compound of Formula (I) is compound 156.
[00221]In certain embodiments, the compound of Formula (I) is compound 157.
[00222]In certain embodiments, the compound of Formula (I) is compound 158. [00223]In certain embodiments, the compound of Formula (I) is compound 159.
[00224]In certain embodiments, the compound of Formula (I) is compound 160.
[00225]In certain embodiments, the compound of Formula (I) is compound 161.
[00226]In certain embodiments, the compound of Formula (I) is compound 162.
[00227]In certain embodiments, the compound of Formula (I) is compound 163.
[00228]In certain embodiments, the compound of Formula (I) is compound 164.
[00229]In certain embodiments, the compound of Formula (I) is compound 165.
[00230]In certain embodiments, the compound of Formula (I) is compound 166.
[00231]In certain embodiments, the compound of Formula (I) is compound 167.
[00232]In certain embodiments, the compound of Formula (I) is compound 168.
[00233]In certain embodiments, the compound of Formula (I) is compound 169.
[00234]In certain embodiments, the compound of Formula (I) is compound 170.
[00235]In certain embodiments, the compound of Formula (I) is compound 171.
[00236]In certain embodiments, the compound of Formula (I) is compound 172.
[00237]In certain embodiments, the compound of Formula (I) is compound 173.
[00238]In certain embodiments, the compound of Formula (I) is compound 174.
[00239]In certain embodiments, the compound of Formula (I) is compound 175.
[00240]In certain embodiments, the compound of Formula (I) is compound 176.
[00241]In certain embodiments, the compound of Formula (I) is compound 177.
[00242]In certain embodiments, the compound of Formula (I) is compound 178.
[00243]In certain embodiments, the compound of Formula (I) is compound 179.
[00244]In certain embodiments, the compound of Formula (I) is compound 180.
[00245]In certain embodiments, the compound of Formula (I) is compound 181.
[00246]In certain embodiments, the compound of Formula (I) is compound 182.
[00247]In certain embodiments, the compound of Formula (I) is compound 183.
[00248]In certain embodiments, the compound of Formula (I) is compound 184.
[00249]In certain embodiments, the compound of Formula (I) is compound 185.
[00250]In certain embodiments, the compound of Formula (I) is compound 186.
[00251]In certain embodiments, the compound of Formula (I) is compound 187.
[00252]In certain embodiments, the compound of Formula (I) is compound 188.
[00253]In certain embodiments, the compound of Formula (I) is compound 189.
[00254]In certain embodiments, the compound of Formula (I) is compound 190.
[00255]In certain embodiments, the compound of Formula (I) is compound 191.
[00256]In certain embodiments, the compound of Formula (I) is compound 192. [00257]In certain embodiments, the compound of Formula (I) is compound 193.
[00258]In certain embodiments, the compound of Formula (I) is compound 194.
[00259]In certain embodiments, the compound of Formula (I) is compound 195.
[00260]In certain embodiments, the compound of Formula (I) is compound 196.
[00261]In certain embodiments, the compound of Formula (I) is compound 197.
[00262]In certain embodiments, the compound of Formula (I) is compound 198.
[00263]In certain embodiments, the compound of Formula (I) is compound 199.
[00264]In certain embodiments, the compound of Formula (I) is compound 200.
[00265]In certain embodiments, the compound of Formula (I) is compound 201.
[00266]In certain embodiments, the compound of Formula (I) is compound 202.
[00267]In certain embodiments, the compound of Formula (I) is compound 203.
[00268]In certain embodiments, the compound of Formula (I) is compound 204.
[00269]In certain embodiments, the compound of Formula (I) is compound 205.
[00270]In certain embodiments, the compound of Formula (I) is compound 206.
[00271]In certain embodiments, the compound of Formula (I) is compound 207.
[00272]In certain embodiments, the compound of Formula (I) is compound 208.
[00273]In certain embodiments, the compound of Formula (I) is compound 209.
[00274]In certain embodiments, the compound of Formula (I) is compound 210.
[00275]In certain embodiments, the compound of Formula (I) is compound 211.
[00276]In certain embodiments, the compound of Formula (I) is compound 212.
[00277]In certain embodiments, the compound of Formula (I) is compound 213.
[00278]In certain embodiments, the compound of Formula (I) is compound 214.
[00279]In certain embodiments, the compound of Formula (I) is compound 215.
[00280]In certain embodiments, the compound of Formula (I) is compound 216.
[00281]In certain embodiments, the compound of Formula (I) is compound 217.
[00282]In certain embodiments, the compound of Formula (I) is compound 218.
[00283]In certain embodiments, the compound of Formula (I) is compound 219.
[00284]In certain embodiments, the compound of Formula (I) is compound 220.
[00285]In certain embodiments, the compound of Formula (I) is compound 221.
[00286]In certain embodiments, the compound of Formula (I) is compound 222.
[00287]In certain embodiments, the compound of Formula (I) is compound 223.
[00288]In certain embodiments, the compound of Formula (I) is compound 224.
[00289]In certain embodiments, the compound of Formula (I) is compound 225.
[00290]In certain embodiments, the compound of Formula (I) is compound 226. [00291] In certain embodiments, the compound is
[00292] In certain embodiments, the compound of Formula (I) is compound 228.
[00293] In certain embodiments, the compound of Formula (I) is compound 229.
[00294] In certain embodiments, the compound of Formula (I) is compound 230.
[00295] In certain embodiments, the compound of Formula (I) is compound 231.
[00296] In certain embodiments, the compound of Formula (I) is compound 232.
[00297] In certain embodiments, the compound of Formula (I) is compound 233.
[00298] In certain embodiments, the compound of Formula (I) is compound 234.
[00299] In certain embodiments, the compound of Formula (I) is compound 235.
[00300] In certain embodiments, the compound of Formula (I) is compound 236.
[00301] In certain embodiments, the compound of Formula (I) is compound 237.
[00302] In certain embodiments, the compound of Formula (I) is compound 238.
[00303] In certain embodiments, the compound of Formula (I) is compound 239.
[00304] In certain embodiments, the compound of Formula (I) is compound 240.
[00305] In certain embodiments, the compound of Formula (I) is compound 241.
[00306] In certain embodiments, the compound of Formula (I) is compound 242.
[00307] In certain embodiments, the compound of Formula (I) is compound 243.
[00308] In certain embodiments, the compound of Formula (I) is compound 244.
[00309] In certain embodiments, the compound of Formula (I) is compound 245.
[00310] In certain embodiments, the compound of Formula (I) is compound 246.
[00311]In certain embodiments, the compound of Formula (I) is compound 247.
[00312] In certain embodiments, the compound of Formula (I) is compound 248.
[00313] In certain embodiments, the compound of Formula (I) is compound 249.
[00314] In certain embodiments, the compound of Formula (I) is compound 250.
[00315] In certain embodiments, the compound of Formula (I) is compound 251.
[00316] In certain embodiments, the compound of Formula (I) is compound 252.
[00317] In certain embodiments, the compound of Formula (I) is compound 253.
[00318] In certain embodiments, the compound of Formula (I) is compound 254.
[00319] In certain embodiments, the compound of Formula (I) is compound 255.
[00320] In certain embodiments, the compound of Formula (I) is compound 256.
[00321] In certain embodiments, the compound of Formula (I) is compound 257.
[00322] In certain embodiments, the compound of Formula (I) is compound 258.
[00323] In certain embodiments, the compound of Formula (I) is compound 259.
[00324] In certain embodiments, the compound of Formula (I) is compound 260. [00325] In certain embodiments, the compound is
[00326] In certain embodiments, the compound of Formula (I) is compound 262.
[00327] In certain embodiments, the compound of Formula (I) is compound 263.
[00328] In certain embodiments, the compound of Formula (I) is compound 264.
[00329] In certain embodiments, the compound of Formula (I) is compound 265.
[00330] In certain embodiments, the compound of Formula (I) is compound 266.
[00331] In certain embodiments, the compound of Formula (I) is compound 267.
[00332] In certain embodiments, the compound of Formula (I) is compound 268.
[00333] In certain embodiments, the compound of Formula (I) is compound 269.
[00334] In certain embodiments, the compound of Formula (I) is compound 270.
[00335] In certain embodiments, the compound of Formula (I) is compound 271.
[00336] In certain embodiments, the compound of Formula (I) is compound 272.
[00337] In certain embodiments, the compound of Formula (I) is compound 273.
[00338] In certain embodiments, the compound of Formula (I) is compound 274.
[00339] In certain embodiments, the compound of Formula (I) is compound 275.
[00340] In certain embodiments, the compound of Formula (I) is compound 276.
[00341] In certain embodiments, the compound of Formula (I) is compound 277.
[00342] In certain embodiments, the compound of Formula (I) is compound 278.
[00343] In certain embodiments, the compound of Formula (I) is compound 279.
[00344] In certain embodiments, the compound of Formula (I) is compound 280.
[00345] In certain embodiments, the compound of Formula (I) is compound 281.
[00346] In certain embodiments, the compound of Formula (I) is compound 282.
[00347] In certain embodiments, the compound of Formula (I) is compound 283.
[00348] In certain embodiments, the compound of Formula (I) is compound 284.
[00349] In certain embodiments, the compound of Formula (I) is compound 285.
[00350] In certain embodiments, the compound of Formula (I) is compound 286.
[00351] In certain embodiments, the compound of Formula (I) is compound 287.
[00352] In certain embodiments, the compound of Formula (I) is compound 288.
[00353] In certain embodiments, the compound of Formula (I) is compound 289.
[00354] In certain embodiments, the compound of Formula (I) is compound 290.
[00355] In certain embodiments, the compound of Formula (I) is compound 291.
[00356] In certain embodiments, the compound of Formula (I) is compound 292.
[00357] In certain embodiments, the compound of Formula (I) is compound 293.
[00358] In certain embodiments, the compound of Formula (I) is compound 294. [00359] In certain embodiments, the compound is
[00360] In certain embodiments, the compound of Formula (I) is compound 296.
[00361] In certain embodiments, the compound of Formula (I) is compound 297.
[00362] In certain embodiments, the compound of Formula (I) is compound 298.
[00363] In certain embodiments, the compound of Formula (I) is compound 299.
[00364] In certain embodiments, the compound of Formula (I) is compound 300.
[00365] In certain embodiments, the compound of Formula (I) is compound 301.
[00366] In certain embodiments, the compound of Formula (I) is compound 302.
[00367] In certain embodiments, the compound of Formula (I) is compound 303.
[00368] In certain embodiments, the compound of Formula (I) is compound 304.
[00369] In certain embodiments, the compound of Formula (I) is compound 305.
[00370] In certain embodiments, the compound of Formula (I) is compound 306.
[00371] In certain embodiments, the compound of Formula (I) is compound 307.
[00372] In certain embodiments, the compound of Formula (I) is compound 308.
[00373] In certain embodiments, the compound of Formula (I) is compound 309.
[00374] In certain embodiments, the compound of Formula (I) is compound 310.
[00375] In certain embodiments, the compound of Formula (I) is compound 311.
[00376] In certain embodiments, the compound of Formula (I) is compound 312.
[00377] In certain embodiments, the compound of Formula (I) is compound 313.
[00378] In certain embodiments, the compound of Formula (I) is compound 314.
[00379] In certain embodiments, the compound of Formula (I) is compound 315.
[00380] In certain embodiments, the compound of Formula (I) is compound 316.
[00381] In certain embodiments, the compound of Formula (I) is compound 317.
[00382] In certain embodiments, the compound of Formula (I) is compound 318.
[00383] In certain embodiments, the compound of Formula (I) is compound 319.
[00384] In certain embodiments, the compound of Formula (I) is compound 320.
[00385] In certain embodiments, the compound of Formula (I) is compound 321.
[00386] In certain embodiments, the compound of Formula (I) is compound 322.
[00387] In certain embodiments, the compound of Formula (I) is compound 323.
[00388] In certain embodiments, the compound of Formula (I) is compound 324.
[00389] In certain embodiments, the compound of Formula (I) is compound 325.
[00390] In certain embodiments, the compound of Formula (I) is compound 326.
[00391] In certain embodiments, the compound of Formula (I) is compound 327.
[00392] In certain embodiments, the compound of Formula (I) is compound 328. [00393] In certain embodiments, the compound is
[00394] In certain embodiments, the compound of Formula (I) is compound 330.
[00395] In certain embodiments, the compound of Formula (I) is compound 331.
[00396] In certain embodiments, the compound of Formula (I) is compound 332.
[00397] In certain embodiments, the compound of Formula (I) is compound 333.
[00398] In certain embodiments, the compound of Formula (I) is compound 334.
[00399] In certain embodiments, the compound of Formula (I) is compound 335.
[00400] In certain embodiments, the compound of Formula (I) is compound 336.
[00401] In certain embodiments, the compound of Formula (I) is compound 337.
[00402] In certain embodiments, the compound of Formula (I) is compound 338.
[00403] In certain embodiments, the compound of Formula (I) is compound 339.
[00404] In certain embodiments, the compound of Formula (I) is compound 340.
[00405] In certain embodiments, the compound of Formula (I) is compound 341.
[00406] In certain embodiments, the compound of Formula (I) is compound 342.
[00407] In certain embodiments, the compound of Formula (I) is compound 343.
[00408] In certain embodiments, the compound of Formula (I) is compound 344.
[00409] In certain embodiments, the compound of Formula (I) is compound 345.
[00410] In certain embodiments, the compound of Formula (I) is compound 346.
[00411]In certain embodiments, the compound of Formula (I) is compound 347.
[00412] In certain embodiments, the compound of Formula (I) is compound 348.
[00413] In certain embodiments, the compound of Formula (I) is compound 349.
[00414] In certain embodiments, the compound of Formula (I) is compound 350.
[00415] In certain embodiments, the compound of Formula (I) is compound 351.
[00416] In certain embodiments, the compound of Formula (I) is compound 352.
[00417] In certain embodiments, the compound of Formula (I) is compound 353.
[00418] In certain embodiments, the compound of Formula (I) is compound 354.
[00419] In certain embodiments, the compound of Formula (I) is compound 355.
[00420] In certain embodiments, the compound of Formula (I) is compound 356.
[00421] In certain embodiments, the compound of Formula (I) is compound 357.
[00422] In certain embodiments, the compound of Formula (I) is compound 358.
[00423] In certain embodiments, the compound of Formula (I) is compound 359.
[00424] In certain embodiments, the compound of Formula (I) is compound 360.
[00425] In certain embodiments, the compound of Formula (I) is compound 361.
[00426] In certain embodiments, the compound of Formula (I) is compound 362. [00427]In certain embodiments, the compound of Formula (I) is compound 363.
[00428]In certain embodiments, the compound of Formula (I) is compound 364.
[00429]In certain embodiments, the compound of Formula (I) is compound 365.
[00430]In certain embodiments, the compound of Formula (I) is compound 366.
[00431] In certain embodiments, the compound is a pharmaceutically acceptable salt of a compound described in Table 1.
[00432] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, ie., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[00433] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
[00434] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (II), or Formula (III) with an acid. In some embodiments, the free base form of the compound of Formula (I), Formula (II), or Formula (III) is basic and is reacted with an organic acid or an inorganic acid.
[00435] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (II), or Formula (III) with a base. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) is acidic and is reacted with a base. [00436] In some embodiments, the compounds of Formula (I), Formula (II), or Formula (III) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) exists in the R configuration. In some embodiments, the compound of Formula (I), Formula (II), or Formula (III) exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, epimeric, and tautomeric forms, as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
[00437] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds of Formula (I), Formula (II), or Formula (III) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
Synthesis of Compounds
[00438] Compounds of Formula (I), Formula (II), or Formula (III) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.
[00439] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.
[00440] Compounds are prepared using standard organic chemistry techniques. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.
[00441] In some embodiments, compounds of Formula (I) and Formula (II), described herein, are prepared as described in Scheme A.
Figure imgf000067_0001
Scheme A a) II, neat, 100 °C, 2 h; (b) PhOPh PhPh, 258 °C, 1.5 h; (c) POCh, 100 °C, 1 h; (d) mCPBA, DCM, 0 °C, 1 h, then rt, 16 h; (e) POC13, 100 °C, 10 min; (f) LiOH, 1 ,4-dioxane/H2O (2: 1, v/v), 80 °C, 14 h; (g) POCb, 100 °C, 1 h; (h) X, DIEA, DCM, 0 °C, 1 h; (i) XII, DIEA, MeCN, 80 °C, 16 h; (j) BOC2O, DIEA, MeCN, rt, 1 h; (k) XV, LiHMDS, THF, 0 °C, 3 h; (1) TFA, DCM, rt, 1 h.
[00442] In some embodiments, compounds of Formula (I) or Formula (III), described herein, are prepared as described in Scheme B.
Figure imgf000068_0001
Scheme B a)NBS,CCl4, 80 °C, 4 h; b) CO,Pd(dppf)Cl2, MeOH, 100 °C, 4 h; c) CF3SO3Me, HFIP, 0°C, 3.5 h; d) XXI, DIEA, DCM, 0 °C~RT, 1 h; e)NaOMe, MeOH, 80 °C, 1 h; f) (COC1)2, DMF, 40 °C, 4 h; g) XXV, DIEA, MeCN, 80 °C, 16 h; h) LiOH, MeOH/H2O (2: 1, v/v), 80 °C, 16 h; i) X, H ATU, DIEA,
DMF, rt, 1 h; j) TFA, DCM, rt, 1 h.
[00443] In some embodiments, compounds are prepared as described in the Examples.
Certain Terminology
[00444] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [00445] As used herein, Ci-Cx includes Ci-C2, C1-C3 ... Ci-Cx. By way of example only, a group designated as "Ci-Ce" indicates that there are one to six carbon atoms in the moiety, z.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, z.e., the alkyl group is selected from among methyl, ethyl, propyl, z o-propyl, zz-butyl, zso-butyl, ec-butyl, and Z-butyl.
[00446] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 6 carbon atoms, z.e., a Ci-C6 alkyl. Whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g. , “ 1 to 6 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-Ce alkyl. In one aspect the alkyl is methyl, ethyl, propyl, z.w-propyl, zz-butyl, z o-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
[00447] As used herein, the term “alkylsulfonyl” refers to an alkyl group, as previously defined, wherein one carbon atom of the alkyl group, and the carbon atom’s substituents, are replaced by a sulfur atom, and wherein the sulfur atom is further substituted with two oxo groups. An alkylsulfonyl group maybe linear or branched. In some embodiments, alkylsulfonyl groups are substituted atthe alkyl portion of the alkylsulfonyl group. In some embodiments, alkylsulfonyl groups are unsubstituted at the alkyl portion of the alkylsulfonyl group.
[00448] An “alkoxy” group refers to an (alkyl)O- group, where alkyl is as defined herein.
[00449] The term “aminoalkyl” means an alkyl group which is substituted with or contains an amino group.
[00450] The term “aromatic” refers to a planar ring having a delocalized 7i-electron system containing 4n+2 71 electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine, pyrimidine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
[00451] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls. [00452] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In some embodiments, an aryl is a phenyl. Depending on the structure, an aryl group is a monoradical or a diradical (z.e., an arylene group).
[00453] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (z.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. Cycloalkyl groups include groups having from 3 to 7 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments, a cycloalkyl is a C3-C7 cycloalkyl. In some embodiments, a cycloalkyl is a C3-C6 cycloalkyl.
[00454] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
[00455] The terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy,” as used herein, refer to a linear or branched alkyl, alkenyl, or alkoxy, respectively, which is substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyls, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include - OCHF2, -OCH2F, -OCF3, and -OCF2.
[00456] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a Ci-C6 fluoroalkyl.
[00457] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to two heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S, and N, wherein each heterocyclic group has from 3 to 6 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 6 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 6 atoms in its ring system. Examples of non-aromatic heterocyclic groups include, but are not limited to, tetrahydropyranyl. Examples of aromatic heterocyclic groups include, but are not limited to, pyridinyl and pyrimidinyl.
[00458] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls, such as pyridinyl and pyrimidinyl
[00459] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. Illustrative examples of heterocycloalkyl groups include monocyclic heterocycloalkyls, such as tetrahydropyranyl. [00460] The term “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. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
[00461] 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.
[00462] The term “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,
[00463] 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.
[00464] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.
[00465] The terms "administer, " "administering", "administration, " and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action.
[00466] The terms “effective amount” and “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 includes 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 comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
[00467] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
[00468] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, 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 either prophylactically and/or therapeutically.
Pharmaceutical Compositions
[00469] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is 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 & Wilkinsl999), herein incorporated by reference for such disclosure. [00470] In some embodiments, the compounds described herein are administered either alone or in combination with one or more pharmaceutically acceptable carriers, excipients and/or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
Methods of Dosing and Treatment Regimens
[00471] In some embodiments, the compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from SSTR3 agonist. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involve administration of pharmaceutical compositions that include at least one compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, in therapeutically effective amounts to said mammal. [00472] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
[00473] The amount of a given compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof that corresponds to a therapeutically effective amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
[00474] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
[00475] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: Abbreviations
LCMS: liquid chromatography-mass spectrometry;
HPLC: high performance liquid chromatography; MPLC: medium-pressure liquid chromatography; Prep-HPLC: preparative high performance liquid chromatography; Chiral-SFC: chiral supercritical fluid chromatography; h: hour or hours; rt: room temperature;
PhOPh PhPh: phenyl ether-biphenyl eutectic;
POCI3: phosphoryl chloride;
/77CPBA: meta-chloroperoxybenzoic acid;
NBS: A-bromosuccinimide;
(COC1)2: oxalyl chloride;
CO: carbon monoxide gas;
DIEA: A,A-diisopropylethylamine or A-ethyl-A-isopropylpropan-2-amine;
DCM: dichloromethane;
PE: petroleum ether;
EtOAc or EA: ethyl acetate;
MeCN or ACN: acetonitrile;
CC14: carbon tetrachloride;
Pd(dtbpf)Cl2: [l,r-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);
Pd(dppf)Cl2: [1 J'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);Pd(PPh3)Cl2: bis(triphenylphosphine)palladium(II) chloride;
NaOMe: sodium methoxide;
Ti(O/Pr)4: titanium tetraisopropoxide;
MeMgCl; methyl magnesium chloride;
HC1: hydrochloric acid;
Na2CO3: sodium carbonate;
THF: tetrahydrofuran;
H2O: water;
DMF: dimethylformamide;
N2: nitrogen gas;
NaHCOs: sodium bicarbonate;
MgSO4: magnesium sulfate;
HATU: l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate;
TFA: trifluoroacetic acid or 2,2,2-trifluoroacetic acid;
Zn(CN)2: zinc cyanide;
Pd2(dba)3 CHCl3: tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct;
NMP: A-methylpyrrolidone; K2CO3: potassium carbonate;
NaOH: sodium hydroxide;
MeOH: methanol;
NaHSC sodium bisulfate;
FA: formic acid;
NH3 H2O: aqueous ammonia;
Boc2O: di-tert-butyl dicarbonate;
AcOH: acetic acid;
NaHSO3: sodium bisulfite;
Na2SO4: sodium sulfate;
K3PO4: potassium phosphate;
Pd-C: palladium on carbon;
H2: hydrogen gas;
LiHMDS: lithium bis(trimethylsilyl)amide;
LiOH: lithium hydroxide;
HFIP: 1,1,1 ,3 ,3 ,3 -hexafluoroisopropanol .
EXAMPLES
[00476] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.
Example 1. Preparation of \ ((S)-1 -(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-2- morpholino-4-(l,7-diazaspiro[4.4]nonan-7-yl)quinoline-3-carboxamide (Compound 331)
Figure imgf000075_0001
Step 1 : Preparation of diethyl 2-(((4-methoxyphenyl)amino)methylene)malonate:
Figure imgf000075_0002
[00477] A 40-mL vial was charged with a mixture of 4 -meth oxy aniline (5.00 g, 1 equiv, 40.6 mmol) and diethyl 2-(ethoxymethylene)malonate (10.0 g, 1.14 equiv, 46.2 mmol). The reaction mixture was stirred at 100 °C for 2 h. The heated mixture was directly poured into PE (150 mL) and concentrated under reduced pressure to afford the crude diethyl 2-(((4- methoxyphenyl)amino)methylene)malonate (15.0 g, 41 mmol, 100 %, 80% Purity), which was directly used in the next step without additional purification. [M+H]+ = 294.1.
Step 2: Preparation of ethyl 4-hydroxy-6-methoxyquinoline-3 -carboxylate:
Figure imgf000076_0001
[00478] Into a 250-mL three-necked round bottom flask was placed with phenyl ether-biphenyl eutectic (80 g, 76 mL, 6.0 equiv, 0.25 mol). The mixture was heated to 258 °C, and diethyl 2- (((4-methoxyphenyl)amino)methylene)malonate (15.0 g, 80% Wt, 1 equiv, 40.9 mmol) was added in three portions at 258 °C. The reaction mixture was stirred at 258 °C for 1.5 h. After cooling to room temperature, the mixture was directly poured into PE (400 mL), and the resulting precipitates were collected by filtration. The filter cake was washed with PE (50 mL) and dried to afford ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (5.12 g, 20.7 mmol, 50.6 %). [M+H]+ = 248.1.
Step 3 : Preparation of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate:
Figure imgf000076_0002
[00479] Into a 40-mL vial, was placed with a mixture of ethyl 4-hydroxy-6-methoxyquinoline- 3 -carboxylate (3.0 g, 1 equiv, 12 mmol) and phosphoryl trichloride (5.6 g, 3.0 equiv, 37 mmol). The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved into 100 mL water, and the pH was adjusted to 9 by the addition of NaHCO3. The aqueous layer was extracted with EtOAc (60 mL x 2), and the combined organic phases were washed with 60 mL brine and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The so-obtained crude product was purified by MPLC (silica gel column, 20 g; Mobile Phase A: PE, Mobile Phase B: EtOAc; Flow rate: 35 mL/min; Gradient: 0% B to 60% B in 8 min;
Wavelength: 254 nm) to afford ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (2.9 g, 11 mmol, 90 %). [M+H]+= 266.1. Step 4: Preparation of 4-chloro-3-(ethoxycarbonyl)-6-methoxyquinoline 1 -oxide:
Figure imgf000077_0001
[00480] Into a 40-mL vial, was placed ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (1.5 g, 1 equiv, 5.6 mmol) in DCM (10 mL), and mCPBA (1.5 g, 1.5 equiv, 8.7 mmol) was added at 0 °C. The reaction mixture was stirred at25 °C for 16 h, quenched with 6 mL saturated NaHCCL (aq) solution and stirred for 30 min. The organic layer was separated, washed with water and brine, and dried over Na2SO4. The solution was concentrated under reduced pressure, and the crude product was purified through silica gel column chromatography, eluting with PE/EtOAc (3/1 ) to afford 4-chloro-3-(ethoxycarbonyl)-6-methoxy quinoline 1 -oxide (943 mg, 3.35 mmol, 59 %). [M+H]+ = 282.0.
Step 5: ethyl 2,4-dichloro-6-methoxyquinoline-3-carboxylate:
Figure imgf000077_0002
[00481] Into a 40-mL vial was placed 4-chloro-3-(ethoxycarbonyl)-6-methoxy quinoline 1 - oxide (930 mg, 1 equiv, 3.29 mmol) and phosphoryl trichloride (1.01 g, 2.00 equiv, 6.59 mmol). Then, the reaction mixture was stirred at 100 °C for 10 min. Subsequently, the reaction mixture was concentrated, 5 mL DCM was added, and the resulting mixture was poured into an ice- NaHCO3 mixture. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The so -obtained crude product was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford ethyl 2,4-dichloro- 6-methoxyquinoline-3-carboxylate (560 mg, 1.87 mmol, 56.7 %). [M+H]+ = 300.0.
Step 6: 2-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid:
Figure imgf000077_0003
[00482] Into a 40 mL vial were added ethyl 2, 4-dichloro-6-methoxyquinoline-3 -carboxylate (500 mg, 1 equiv, 1.67 mmol), 1,4-dioxane (5 mL), H2O (2.5 mL), and lithium hydroxide (399 mg, 10.0 equiv, 16.7 mmol). The mixture was stirred for 14 h at 80 °C. The reaction mixture was cooled to room temperature, 20 mL H2O was added, and the pH was adjusted to 5-6 with 1 M HC1 (aq) solution. The aqueous mixture was extracted with EA (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, affording 2-chloro-4-hydroxy-6-methoxyquinoline-3- carboxylic acid (466 mg, 1.6 mmol, 98 %, 89% Purity), which was used in the next step without further purification. [M+H]+ = 254.4.
Step 7: 2,4-dichloro-6-methoxyquinoline-3-carbonyl chloride:
Figure imgf000078_0001
[00483] In a 40 mL vial, a mixture of 2-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid (230 mg, 1 equiv, 907 pmol) and phosphoryl trichloride (278 mg, 2.00 equiv, 1.81 mmol) was stirred at 100 °C for 1 h. Then, the mixture was concentrated in vacuo, affording 2,4- dichloro-6-methoxyquinoline-3-carbonyl chloride (230 mg, 792 pmol, 87.3 %), which was used in next step without further purification.
Step 8: (S)-2,4-dichloro-N-(l-(4-fhioro-3-methoxyphenyl)ethyl)-6-methoxyquinoline-3- carboxamide:
Figure imgf000078_0002
[00484] An 8-mL vial was charged with a mixture of (S)-l-(4-fluoro-3-methoxyphenyl)ethan- 1 -amine hydrochloride (326 mg, 2.00 equiv, 1.59 mmol), DIEA (512 mg, 690 pL, 5.00 equiv, 3.96 mmol) and DCM(2 mL). Then, a solution of 2,4-dichloro-6-methoxyquinoline-3-carbonyl chloride (230 mg, 1 equiv, 792 pmol) in DCM (1 mL) was added at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 1 h. Subsequently, the mixture was purified directly through silica gel column chromatography, eluting with PE/EtOAc (the ratio of EtOAc increasing from 0% to 100% in 6 min) to afford (S)-2,4-dichloro-N-(l-(4-fluoro-3- methoxyphenyl)ethyl)-6-methoxyquinoline-3-carboxamide (210 mg, 496 pmol, 62.7 %). [M+H]+ = 423.0.
Step 9: 2-chloro-N-((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-4-(L7- diazaspiro[4 ,4]nonan-7 -yl)quinoline-3 -carboxamide :
Figure imgf000078_0003
[00485] An 8-mL vial was charged with a mixture of (S)-2,4-dichloro-N-(l-(4-fluoro-3- meth oxyphenyl)ethyl)-6-methoxyquinoline-3 -carboxamide (200 mg, 1 equiv, 473 pmol), 1,7- diazaspiro[4.4]nonane (119 mg, 2.00 equiv, 943 pmol), DIEA (183 mg, 247 pL, 3.00 equiv, 1.42 mmol), and ACN (2 mL). The reaction mixture was stirred at 80 °C for 16 h and used in the next step without further manipulation (in situ). [M+H]+ = 513.2.
Step 10: tert-butyl 7-(2-chloro-3-(((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6- methoxyquinolin-4-yl)-l,7-diazaspiro[4.4]nonane-l -carboxylate:
Figure imgf000079_0001
[00486] An 8-mL vial containing 2-chloro-N-((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)-6- methoxy-4-(l,7-diazaspiro[4.4]nonan-7-yl)quinoline-3-carboxamide (200 mg, 1 equiv, 390 pmol) obtained from the previous reaction was charged with Boc2O (128 mg, 135 pL, 1.50 equiv, 586 pmol) and DIEA (151 mg, 204 pL, 3.00 equiv, 1.17 mmol). The reaction mixture was stirred at 25 °C for 1 h. Then, the mixture was directly purified through MPLC (Column, C18 Column, 120 g; mobile phase, Water (0.1% FA) and ACN (30% ACN up to 98% in 7 min, 98% to 98% in 3 min); Total flow rate, 70 mL/min; Detector, UV 220 nm), affording tert-butyl 7-(2-chloro-3-(((S)-l-(4-fluoro-3 -meth oxyphenyl)ethyl)carbamoyl)-6-meth oxy quinolin-4-yl)- l,7-diazaspiro[4.4]nonane-l -carboxylate (180 mg, 294 pmol, 75.3 %). [M+H]+ = 613.2.
Step 11 : tert-butyl 7-(3-(((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy-2- morpholinoquinolin-4-yl)-l,7-diazaspiro[4.41nonane-l -carboxylate:
Figure imgf000079_0002
[00487] An 8 mL vial was charged with tert-butyl 7-(2-chloro-3-(((S)-l-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-m ethoxy quinolin -4-yl)-l,7-diazaspiro[4.4]nonane-l- carboxylate (60 mg, 1 equiv, 98 pmol) and morpholine (26mg, 3.0 equiv, 0.30mmol) in THF (1 mL). To the resulting mixture was added LiHMDS (21 mg, 1.3 equiv, 0.13 mmol) at 0 °C under nitrogen atmosphere, and the reaction mixture was stirred for 3 h from 0 °C to 25°C under nitrogen atmosphere. The crude product was purified by Prep-HPLC (Column, Cl 8; mobile phase, Water (0.1% FA) and ACN (20% ACN up to 98% in 7 min); Detector, 220 nm), affording terLbutyl 7-(3-(((S)-l-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy-2- morpholinoquinolin-4-yl)-l,7-diazaspiro[4.4]nonane-l-carboxylate (50 mg, 75 pmol, 77 %). [M+H]+ = 664.4.
Step 12: A-((S)-l-(4-fluoro-3 -meth oxyphenyl)ethyl)-6-meth oxy -2-morpholino-4-(L7- diazaspiro[4 ,4]nonan-7 -yl)quinoline-3 -carboxamide :
Figure imgf000080_0001
[00488] A 50-mL round bottom flask was charged with tert-butyl 7-(3-(((S)-l-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-m ethoxy -2-morpholinoquinolin-4-yl)- 1,7- diazaspiro[4.4]nonane-l-carboxylate (48 mg, 1 equiv, 72 pmol), DCM(3 mL), and TFA (1 mL). The reaction mixture was stirred at 25 °C for 1 h and subsequently concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column, SunFire Prep Cl 8 OBD Column, 19*150 mm 5 pm; mobile phase, Water (0.1% FA) and ACN (30.0% ACN up to 60.0% in 7 min); Total flow rate, 20 mL/min; Detector, UV 220 nm). The collected fractions were combined and concentrated under reduced pressure, affording A-((S)-l-(4-fluoro-3- methoxyphenyl)ethyl)-6-methoxy-2-morpholino-4-(l,7-diazaspiro[4.4]nonan-7-yl)quinoline-3- carboxamide (13 mg, 21 pmol, 29 %). [M+H]+ = 564.3.
[00489] The following compounds were prepared similarly to Example 1 with appropriate substitution of reagents and/or substrates and/or functional group modifications via well-known chemistry with appropriate reagents.
Figure imgf000080_0002
Figure imgf000080_0003
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000083_0005
Figure imgf000083_0004
Example 2. Preparation of -((S)-1 -(3-cyano-5-fluorophenyl)ethyl)-6-methoxy-4-((S)-5- methyl-l,4-diazepan-l-yl)-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxamide
(Compound 148)
Figure imgf000083_0001
Step 1 : 2-bromo-4-methoxy-5-(trifluoromethyl)aniline:
Figure imgf000083_0002
[00490] A 40-mL vial was charged with 4-methoxy-3-(trifluoromethyl)aniline (500 mg, 1 equiv, 2.62 mmol). Over the course of 4 h, NBS (466 mg, 1.00 equiv, 2.62 mmol) was added under nitrogen atmosphere. The resulting reaction mixture was stirred for 4 h at 80 °C. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The so- obtained residue was purified through silica gel column chromatography, eluting with PEZEA (1 :20), which afforded 2-bromo-4-methoxy-5-(trifluoromethyl)aniline (220 mg, 815 pmol, 31.1 %). [M+H]+= 268.1.
Step 2: methyl 2-amino-5-methoxy-4-(trifluoromethyl)benzoate:
Figure imgf000083_0003
[00491] A 500 mL sealed tube was charged with 2-bromo-4-methoxy-5-(trifluoromethyl)aniline (6.8 g, 1 equiv, 25 mmol), TEA (7.5 g, 10 mL, 2.9 equiv, 74 mmol), Pd(dppf)C12'DCM (2.1 g, 0.10 equiv, 2.6 mmol), and carbon monoxide (10 bar). The resulting solution was stirred for 4 h at 100 °C. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The so-obtained residue was purified through silica gel column chromatography, eluting with PE/EA (1 :10), which afforded methyl 2-amino-5-methoxy-4- (trifluoromethyl)benzoate (3.5 g, 14 mmol, 56 %). [M+H]+= 250.3. Step 3: methyl 5 -meth oxy -2-(3 -meth oxy-3 -oxopropanamido)-4- trifluoromethyl)benzoate:
Figure imgf000084_0001
[00492] Under nitrogen atmosphere, a 250-mL round bottom flask was charged with methyl 2- amino-5-methoxy-4-(trifluoromethyl)benzoate (2.5 g, 1 equiv, 10 mmol) and methyl 3-chloro-3- oxopropanoate (3.1 g, 2.3 equiv, 23 mmol). To this mixture was addedDIEA (1.4 g, 1.9 mL, 1.1 equiv, 11 mmol) at 0 °C. The resulting mixture was stirred for 5 min at 0 °C and 1 h at 25 °C thereafter. The reaction was quenched through the addition of water (50 mL). The mixture was extracted with EtOAc, and the combined organic phases were washed with brine and dried over Na2SO4. Volatiles were removed under reduced pressure, affording methyl 5 -methoxy -2-(3- meth oxy-3 -oxopropanamido)-4-(trifluoromethyl)benzoate (3.5 g, 10 mmol, 100 %). [M+H]+= 350.3.
Step 4: methyl 4-hydroxy-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3- carboxylate:
Figure imgf000084_0002
[00493] Under nitrogen atmosphere, a 250-mL round bottom flask was charged with methyl 5- methoxy -2-(3 -methoxy -3 -oxopropanamido)-4-(trifluoromethyl)benzoate (3.5 g, 1 equiv, 10 mmol) and methanol (35 mL). To this mixture was added sodium methoxide (7.7 g, 30% Wt, 4.3 equiv, 43 mmol), and the resulting solution was stirred for 1 h at 80 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, removing most methanol. To the residue was added water (50 mL), and the pH was adjusted to 5-6 with 2 M HC1 (aq) solution. The resulting precipitate was collected by filtration and dried to afford methyl 4-hydroxy-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (20 mg, 63 pmol, 0.77 %). [M+H]+= 318.1.
Step 5: methyl 4-chloro-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3- carboxylate:
Figure imgf000084_0003
[00494] Under nitrogen atmosphere, an 8-mL vial was charged with methyl 4-hydroxy-6- methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (200 mg, 1 equiv, 630 pmol) and (COC1)2 (10 mL). To the mixture was added DMF (18 mg, 19 pL, 0.39 equiv, 0.25 mmol) at 0 °C. The resulting solution was stirred for 5 min at 0 °C and 4 h at 40 °C thereafter. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 5 through the addition of a saturated NaHSCL (aq) solution. The resulting precipitate was collectedby filtration and dried to affordmethyl 4-chloro- 6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (160 mg, 477 pmol, 75.6 %). [M+H]+= 336.1.
Step 6: methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-L4-diazepan-l-yl)-6-methoxy-2-oxo-7- (trifluoromethyl)-l,2-dihydroquinoline-3 -carboxylate:
Figure imgf000085_0001
[00495] An 8-mL vial was charged with methyl 4-chloro-6-methoxy-2-oxo-7-(trifluoromethyl)- l,2-dihydroquinoline-3 -carboxylate (160 mg, 1 equiv, 477 pmol), DIEA (12 mg, 16 pL, 3.1 equiv, 93 pmol), terLbutyl (S)-7 -methyl- 1,4-diazepane-l -carb oxy late (204 mg, 2.00 equiv, 952 pmol), and ACN (3.2 mL). The mixture was stirred for 16 h at 80 °C. Sub sequently, volatiles were removed under reduced pressure, and the so-obtained residue was purified through MPLC (Column: SunFire Prep Cl 8 OBD Column, 19 mm * 150 mm, 5 pm; Mobile Phase A: Water (0.05% NH3 H2O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 25% B to 98% B in 8 min; Wavelength: 220 nm), affording methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-l,4- diazepan-l-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (100 mg, 195 pmol, 40.9 %). [M+H]+= 514.2.
Step 7: (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-L4-diazepan-l-yl)-6-methoxy-2-oxo-7- (trifluoromethyl)-L2-dihydroquinoline-3 -carboxylic acid
Figure imgf000085_0002
[00496] A 40-mL vial was charged with methyl (S)-4-(4-(tert-butoxycarbonyl)-5 -methyl- 1,4- diazepan-l-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylate (100 mg, 1 equiv, 195 pmol), lithium hydroxide (94 mg, 20 equiv, 3.9 mmol), H2O (1 mL), and MeOH (2 mL). The reaction mixture was stirred for 48 h at 80 °C and then concentrated in vacuo to remove MeOH. The residue was diluted with water and adjusted to pH 4-5 with NaHSO4 (aq). The resulting precipitate was collected by filtration and dried to afford (S)-4-(4-(tert- butoxycarbonyl)-5 -methyl- 1,4-diazepan-l-y l)-6-methoxy-2-oxo-7-(trifluoromethyl)- 1,2- dihydroquinoline-3-carboxylic acid (10 mg, 20 pmol, 100 %). [M+H]+= 500.6.
Step 8: (S)-3-(l-aminoethyl)-5-fluorobenzonitrile hydrochloride:
Figure imgf000086_0001
[00497] An 8-mL vial was charged with a mixture of (R)-N-((S)-l-(3-cyano-5- fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 1 equiv, 1.49 mmol) and HCl/Dioxane (4 mL). The reaction mixture was stirred for 1 h at 25 °C. Then, volatiles were removed under reduced pressure, affording (S)-3-(l-aminoethyl)-5-fluorobenzonitrile hydrochloride (320 mg, 1.95 mmol, 131 %). [M+H-HCl]+= 165.1.
Step 9: fert-butyl (S)-4-(3-(((S)-l-(3-cyano-5-fluorophenyl)ethyl)carbamoyl)-6-methoxy-2-oxo- 7-(trifluoromethyl)-l,2-dihydroquinolin-4-yl)-7-methyl-L4-diazepane-l -carboxylate:
Figure imgf000086_0002
[00498] An 8-mL vial was charged with (S)-4-(4-(tert-butoxycarbonyl)-5 -methyl- 1,4-diazepan- l-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinoline-3-carboxylic acid (100 mg, 1 equiv, 200 pmol), DMF (2 mL), A-ethyl-A-isopropylpropan-2-amine (129 mg, 4.99 equiv, 998 pmol), and HATU (142 mg, 1.87 equiv, 374 pmol). The reaction mixture was stirred for 15 min at 25 °C. To the above mixture was added (S)-3-(l-aminoethyl)-5-fluorobenzonitrile hydrochloride (150 mg, 3.73 equiv, 748 pmol), and the resulting mixture was stirred for 1 h at 25 °C. The mixture was directly purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, Water (0.05% NH3 H2O) and ACN (25% ACN to 25% in 2 min, 25% ACN up to 98% in 6 min, 98% ACN to 98% in 2 min; detector, UV 254 nm). The collected fractions were combined and concentrated under reduced pressure, affording tert-butyl (S)-4-(3- (((S)-l-(3-cyano-5-fluorophenyl)ethyl)carbamoyl)-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2- dihydroquinolin-4-yl)-7-methyl-l,4-diazepane-l -carboxylate (90 mg, 0.14 mmol, 70 %).
[M+H]+= 646.3.
Step 10: A-((S)-l-(3-cvano-5-fluorophenyl)ethyl)-6-methoxy-4-((S)-5-methyl-l,4-diazepan-l- yl)-2-oxo-7-(trifluoromethyl)-l,2-dihvdroquinoline-3 -carboxamide:
Figure imgf000087_0001
[00499] An 8-mL vial was charged with a mixture of tert-butyl (S)-4-(3-(((S)-l-(3-cyano-5- fluorophenyl)ethyl)carbamoyl)-6-methoxy-2-oxo-7-(trifluoromethyl)-l,2-dihydroquinolin-4-yl)- 7-methyl-l,4-diazepane-l-carboxylate (90 mg, 1 equiv, 0.14 mmol) and DCM (3 mL). TFA (1 mL) was added, and the reaction mixture was stirred for 1 h at 25 °C. The mixture was concentrated under reduced pressure, and the so -obtained residue was purified by Prep-HPLC (Column: SunFire prep OBD 19 mm * 150 mm 5 pm; Mobile Phase A: Water (0.05%
NH3 H2O); Mobile Phase B: ACN; Gradient: 25% B to 65% B in 8 min; Flow rate: 20 mL/min; Wavelength: 220 nm). The collected fractions were combined and dried through lyophilization, affording A-((S)-l-(3-cyano-5-fhrorophenyl)ethyl)-6-methoxy -4 -((S)-5-methyl-l,4-diazepan-l- yl)-2-oxo-7-(trifhroromethyl)-l,2-dihydroquinoline-3-carboxamide (50.2 mg, 92.0 pmol, 66 %). [M+H]+= 546.2.
[00500] The following compounds were prepared similarly to Example 2 with appropriate substitution of reagents and/or substrates and/or functional group modifications via well-known chemistry with appropriate reagents.
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000090_0002
Figure imgf000090_0001
Example 3. SSTR Assays
Functional Assays
[00501] General overview: All five SSTR subtypes are Gi coupled G-protein coupled receptors (GPCRs) that lead to decreases in intracellular cyclic AMP (cAMP) when activated by an agonist. Therefore, measurement of intracellular cAMP levels can be used to assess whether compounds are agonists of SSTR subtypes. One example of an intracellular cAMP assay is described below. cAMP assay protocol for SSTR3
[00502] Chinese hamster ovary cells (CHO-K1, ATCC #CCL-61) stably expressing the human somatostatin receptor subtype 3 are plated two or four days prior to the assay, at 6,000 or 2,000 cells per well, respectively in a 96-well tissue culture-treated plate in Ham’s F12 growth media (ThermoFisher #10-080-CM) supplemented with 10% donor bovine serum (Gemini Bio-Products #100-506), 100 U/mL penicillin; 100 ug/mL streptomycin; 2 mM L-glutamine (Gemini Bio- Products #400-110) and 0.25 mg/mL G418 (GoldBio #G-418-5). The cells are cultured at 37 °C, 5% CO2 and 95% humidity. cAMP is measured with HTRF dynamic cAMP assay (Cisbio, #62AM5PEJ) per manufacturer’s instructions. On the day of the assay, the media is aspirated and the cells are treated with 50 pL of stimulation buffer supplemented with 10.2 mM 3 -isobutyl-l- methylxanthine (IBMX, Millipore Sigma #15879) and 1.6 pM NKH477 (Tocris #1603), plus various dilutions of compounds of the present invention. The cells are incubated for 20 minutes at 37 °C (the final concentration of the compounds of the invention are typically 0-10,000 nM). The cells are treated with 50 pL of lysis buffer (HRTF cAMP kit, Cisbio) and incubated at room temperature for 30 minutes with rotary shaking at 600 rpm, and then diluted with 150 pL of stimulation buffer and shaken for an additional five minutes at 300 rpm. The lysate is transferred to 384-well plates and incubated for 1-24 hours at room temperature, and cAMP accumulation is detected by d2-labeled cAMP and Anti-cAMP-Cryptate. The time-resolved fluorescent signal is read using a ml 000 Pro (Tecan) or CLARIOStar (BMG Labtech) microplate reader, where the samples are excited with light at 340 nm and emission light is measured at 620 nm and 665 nm. The data is expressed as a calculation of the fluorescence ratio (665 nm/620 nm). The intracellular cAMP concentrations are calculated by regression to a standard curve and are plotted vs. the concentration of the compounds of the invention . The EC50 of the compounds are calculated using standard methods. All data manipulations are in GraphPad Prism v9 (GraphPad, San Diego, CA).
[00503] Table 2 reports biological activity of compounds as evaluated by inhibition of cAMP activities via human SSTR3 receptor.
Table 2: SSTR3 Activity of Exemplary Compounds:
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000096_0001
Figure imgf000096_0002
Example 4.
Evaluation of SSTR3 Agonists on Kidney Weight and Kidney Cystic Index in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
[00504] The following experimental protocol was used to evaluate the efficacy of SSTR3 receptor agonists in attenuating kidney size and kidney cystic index (KCI) in an autosomal dominant polycystic kidney disease (ADPKD) mouse model.
[00505] Generation of ADPKD Mouse Model. The ADPKD mouse model was generated by selective inactivation of the Pkdl gene in the kidney of Pax8 Tet-O-Cre/Pkdl flox mice (Piontek et al., Clin J Am Soc Nephrol 2004, 15 (12), 3035-3043; Piontek et al., Nat Med 2007, 13 (12), 1490-1495; Traykova-Brauch et al., //VW 2008, 14 (9), 979-984) which results in the renal cyst formation. Specifically, induction of Pkdl deletion in the kidney was performed by administration of doxycycline hy elate (50 mg/kg) intraperitoneally to Pax8 Tet-O-Cre/Pkdl flox mice on postnatal days (PND) 11 and 12. By PND20, Pax8 Tet-O-Cre/Pkdl flox mice treated with doxycycline hyclate (referred to as ADPKD mice) developed enlarged and cystic kidneys compared to control non-treated littermates.
[00506] SSTR3 Agonists in the ADPKD mouse model. To evaluate the ability of SSTR3 agonists to reduce kidney weight and KCI in the ADPKD mouse model, studies were performed in PND12 ADPKD male and female mice. Vehicle or SSTR3 agonists were administered once daily by oral gavage from PND 12 to PND 20. Body weight and clinical signs were recorded daily. On PND20, 1-2 hours after treatment with vehicle or SSTR3 agonists, mice were anesthetized, andblood was collected by cardiac puncture to the left ventricle after performing thoracotomy using needles coated with ethylenediaminetetraacetic acid (EDTA). The blood was collected into EDTA tubes and stored on ice until processed to plasma. The plasma samples were frozen and stored. The heart was harvested, and weight recorded to obtain the kidney to heart weight ratio. The left kidney was harvested, weighed, bisected longitudinally and, placed in 4% paraformaldehyde overnight at 4°C to fix the tissue. Post fixing, the left kidney was processed and embedded in paraffin for histomorphometry. Transverse kidney sections including the cortex, medulla, and papilla were collected on a slide and the slides are stained with hematoxylin and eosin stain. Images were taken at lx and 4x, and total cystic area was measured from the images using Image J software. The kidney cystic index (KCI) was calculated using the total cystic area.
[00507] Compound 8 (Study 1). Vehicle or 30, or 60 mg/kg/day Compound 8 was administered orally once daily to ADPKD mice from postnatal days (PND) 12 to 20. Left kidney weight and kidney cystic index (%) were measured and calculated post euthanasia on PND 20 (Table 1). Data are expressed as mean ± SD (n=24 for the vehicle group, n=12 for 30 mg/kg/day, and n=14 for 60 mg/kg/day Compound 8 groups).
[00508] Compound 38 (Study 2). Vehicle or 30, or 60 mg/kg/day Compound 38 was administered orally once daily to ADPKD mice from postnatal days (PND) 12 to 20. Left kidney weight and kidney cystic index (%) were measured and calculated post euthanasia on PND 20 (Table 1). Data are expressed as mean ± SD (n=l 8 for the vehicle group, n=12 for 30 mg/kg/day, and n=13 for 60 mg/kg/day Compound 38 groups). [00509] Results. Compound 8 and 38 were tested in a mouse model of ADPKD in two independent studies to evaluate its ability to decrease kidney size and kidney cystic index in this model. Kidney cystic index (KCI) and left kidney weight (LKW) by body weight (BW) after 9- day treatment with Compound 8 and 38 are summarized in Table 3 below:
Table 3:
Figure imgf000098_0001
Abbreviations: LKW = left kidney weight; BW = body weight; KCI = kidney cystic index; SD = standard deviation.
[00510] Once daily oral administration of 30 mg/kg/day of compounds 8 and 38 from postnatal day (PND) 12 to PND 20 in ADPKD model mice decreased kidney cystic index with a 13.6% and 10.7% suppression compared to the vehicle group in their respective studies (see Table 3). [00511] Once daily oral administration of 60 mg/kg/day of compounds 8 and 38 from postnatal day (PND) 12 to PND 20 in ADPKD model mice decreased kidney cystic index with a 21.6% and 25.2% suppression compared to the vehicle group in their respective studies (see Table 3). [00512] In view of these results, one would have a reasonable expectation of successfully treating PKD, including ADPKD, by administration of the SSTR3 agonists disclosed herein to a subject.

Claims

CLAIMS We Claim:
1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000099_0001
wherein:
= represents a single bond or a double bond;
Z is NRZ, wherein Rz is absent or oxo or, when R7 is =0, then Rz is H or Ci-6 alkyl;
X is NRX, wherein Rx is H or Ci-6 alkyl;
L is a bond, Ci.6 alkyl, or (CRL1RL2)t, wherein RL1 and RL2 are each independently H or Ci-6 alkyl, and t is 1, 2, 3, 4, 5, or 6;
R1 is Ci-6 alkyl, C3.10 cycloalkyl, C3.6 cycloalkoxy, Ci.6 haloalkoxy, 6 to 10-membered aryl, and 4-7-membered heteroaryl, which are each optionally substituted with 1, 2, 3, 4, or 5 R1A; wherein each R1A is independently halogen, CN, Ci.6 alkyl, Ci.6 haloalkyl, OR11, C(0)0Rn, or C(0)N(Rn)2, wherein each R11 is independently H or Ci.6 alkyl;
R2 is C3-7 cycloalkyl, C5-9 bicycloalkyl, or 7 to 9-membered heterocycloalkyl, which are each substituted with 1, 2, 3, 4, or 5 R2A; wherein R2A is H, independently H, halogen, Ci.6 alkyl, or C(0)0R21, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 halogen, OH, CN, or Ci.6 alkoxy; wherein R21 is H or Ci-6 alkyl; or two R2A together with the atoms to which they are attached form a C3.6 carbocycle;
R3, R4, R5, and R6 are each independently H, halogen, CN, Ci.6 alkyl, C3.6 cycloalkyl, Ci.6 alkoxy, Ci-6 haloalkyl, or C3.6 cyclohaloalkyl; and
R7 is H, halogen, Ci.6 alkyl, C3.6 heterocycloalkyl, OR71, or NR72R73; wherein R71 is absent, H, or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with 1, 2, or 3 R7A, provided that when R71 is absent, R7 is a carbonyl group;
R72 and R73 are independently H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with 1, 2, or 3 R7B; or R72 and R73 together with the nitrogen atom to which they are attached form a 3 to 10-membered heterocycloalkyl which is optionally substituted with 1 , 2, or 3 R7C; wherein R7A, R7B, and R7C are each independently halogen, carbonyl, Ci.6 alkyl, Ci-6 alkylamine, 5-membered heterocycle, OR7B1, C(O)OR7A1, and C(O)NR7A2R7A2, wherein the 5 -membered heterocycle is optionally substituted with Ci-6 alkyl, carbonyl, or OH, and wherein the Ci-6 alkylamine is optionally substituted with a 6-membered cycloalkyl that is optionally substituted with CO2H; and wherein R7A1, R7A2, R7B1, R7B2, and R7B3 are each independently H, Ci-6 alkyl, or Ci-6 alkylsulfonyl, wherein the Ci.6 alkyl and Ci.6 alkylsulfonyl are each optionally substituted with 1 or 2 R7B4; wherein R7B4 is independently OC(O)- R7B5 or 5-membered heterocycle that is optionally substituted with Ci-6 alkyl; and wherein R7B5 is Ci-6 alkyl, which is optionally substituted with NH2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (II) or a compound of Formula (III):
Figure imgf000100_0001
wherein:
R2A is H, halogen, C(O)OH, C(O)OCi_6 alky( or Ci_6 alkyl optionally substituted with OH, CN, or Ci-6 alkoxyl; m is 1, 2, 3, or 4; n is 1, 2, 3, or 4; q is 1, 2, 3, or 4; r is 1, 2, 3, or 4; and s is 1, 2, 3, 4, or 5.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is NH or NMe.
4. The compound of any one of claims 1 -3, or a pharmaceutically acceptable salt thereof, wherein X is NH or NMe.
The compound of any one of claims 1 -4, or a pharmaceutically acceptable salt thereof, wherein L is a bond, Ci.6 alkyl, or (CRL1RL2)t, wherein each RL1 and RL2 are independently H or Ci.6 alkyl and t is 1 or 2.
6. The compound of any one of claims 1 -5, or a pharmaceutically acceptable salt thereof, wherein L is a bond,
Figure imgf000101_0001
7. The compound of any one of claims 1 -6, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000101_0002
8. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein R1 is C3.8 cycloalkyl, phenyl, or 4 to 6-membered heteroaryl, which are each independently substituted with 1, 2, or 3 R1A.
9. The compounds of any one of claims 1 -8, or a pharmaceutically acceptable salt thereof, wherein R1 is C3.8 cycloalkyl, phenyl, or pyridyl, which are each independently substituted with 1, 2, or 3 R1A.
10. The compound of any one of claims 1 -9, or a pharmaceutically acceptable salt thereof,
Figure imgf000101_0003
Figure imgf000102_0001
11. The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof,
Figure imgf000102_0002
12. The compound of any one of claims 1 -9, or a pharmaceutically acceptable salt thereof,
Figure imgf000102_0003
Figure imgf000103_0001
13. The compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof,
Figure imgf000103_0002
14. The compound of any one of claims 1 -13, or a pharmaceutically acceptable salt thereof, wherein:
R2 is 7 to 9-membered heterocycloalkyl, C3.7 cycloalkyl, or C5.9 bicycloalkyl which are each substituted with 1, 2, or 3 R2A;
R2A is independently H, halogen, CN, Ci-6 alkyl, C(O)OR21, or C(O)NR22R23, wherein the Ci-6 alkyl is optionally substituted with 1 or 2 OH, NH2, CN, Ci-6 alkyl, or Ci-6 alkoxy; and
R21, R22, and R23 are each independently H or Ci.6 alkyl; or two R2A together with the atoms to which they are attached form a C3.6 carbocycle.
15. The compound of any one of claims 1 -14, or a pharmaceutically acceptable salt thereof, wherein:
R2 is 7 to 9-membered heterocycloalkyl which is substituted with 1, 2, or 3 R2A;
R2A is independently H, halogen, CN, Ci.6 alkyl, C(O)OR21, or C(O)NR22R23, wherein the
Ci-6 alkyl is optionally substituted with 1 or 2 OH, NH2, CN, Ci-6 alkyl, or Ci-6 alkoxy; and
R21, R22, and R23 are each independently H or Ci.6 alkyl; or two R2A together with the atoms to which they are attached form a C3.6 carbocycle.
16. The compound of any one of claims 1 -15, or a pharmaceutically acceptable salt thereof, wherein:
Figure imgf000104_0001
, which are each substituted with 1 or 2 R2A;
R2A is H, halogen, Ci-6 alkyl, or C(O)OR21, wherein the Ci-6 alkyl is optionally substituted with OH, CN, or Ci.6 alkoxy; and R21 is H or Ci-6 alkyl.
17. The compound of any one of claims 1 -16, or a pharmaceutically acceptable salt thereof,
Figure imgf000104_0002
18. The compound of any one of claims 1 -17, or a pharmaceutically acceptable salt thereof,
Figure imgf000104_0003
19. The compound of any one of claims 1 -16, or a pharmaceutically acceptable salt thereof,
Figure imgf000104_0004
Figure imgf000105_0001
20. The compound of any one of claims 1 -19, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000105_0002
21. The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof, wherein R3 is H or F.
22. The compoundof any oneof claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
23. The compound of any one of claims 1 -22, or a pharmaceutically acceptable salt thereof, wherein R4 is H, halogen, Ci.6 alkyl, Ci.6 alkoxy, or C3.6 cycloalkyl.
24. The compound of any one of claims 1 -23, or a pharmaceutically acceptable salt thereof, wherein R4 is H, F, Cl, methyl, methoxy, or cyclopropyl.
25. The compound of any one of claims 1 -24, or a pharmaceutically acceptable salt thereof, wherein R4 is methoxy.
26. The compound of any one of claims 1 -25, or a pharmaceutically acceptable salt thereof, wherein R5 is H, halogen, CN, Ci-6 alkyl, or Ci-6 haloalkyl.
27. The compound of any one of claims 1 -26, or a pharmaceutically acceptable salt thereof, wherein R5 is halogen or Ci.6 haloalkyl.
28. The compoundof any oneof claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R5 is H, F, Cl, CN, CF3, CF2Me, OMe, or cyclopropyl.
29. The compound of any one of claims 1 -28, or a pharmaceutically acceptable salt thereof, wherein R5 is Cl, CF3, or cyclopropyl.
30. The compound of any one of claims 1 -29, or a pharmaceutically acceptable salt thereof, wherein R6 is H, halogen, Ci.6 alkyl, or C3.6 cycloalkyl.
31. The compound of any one of claims 1 -30, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
32. The compound of any one of claims 1 -31, or a pharmaceutically acceptable salt thereof, wherein:
R7 is H, halogen, OR71, NR72R73, or Ci-6 alkyl; wherein R71 is absent, H, or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with R7A; wherein R72 and R73 are each independently H or Ci-6 alkyl, wherein the Ci-6 alkyl is each optionally substituted with R7B; or R72 and R73 together with the nitrogen atom to which they are attached form a 3 to 6-membered heterocycloalkyl which is optionally substituted with 1 or 2 R7C; wherein R7A is independently 4 to 6-membered heterocycle, C(O)OR7A1, and C(O)NR7A2R7A2, wherein the 4 to 6-membered heterocycle is optionally substituted with carbonyl, OH, or NH2; wherein R7A1 and R7A2 are each independently H, Ci.6 alkyl, or Ci.6 alkyl sulfonyl; wherein R7B is independently OR7B1, C(O)OR7B2, C(O)NR7B3R7B3, and 4 to 6- membered heterocycle, wherein the 4 to 6-membered heterocycle is optionally substituted with methyl, carbonyl, OH, or NH2; wherein R7B1, R7B2, and R7B3 are each independently H, Ci.6 alkyl, or Ci.6 alkyl sulfonyl, wherein the Ci.6 alkyl and are each optionally substituted with OC(O)-R7B4 or 4 to 6-membered heterocycle that is optionally substituted with R7B4; wherein R7B4 is Ci.6 alkyl, which is optionally substituted with NH2; and
R7C is independently carbonyl, halogen, OH, Ci.6 alkoxy, CO2H, C(O)OCi_6 alkyl, Ci-6 alkyl, or Ci-6 alkylamine, wherein the Ci-6 alkylamine is optionally substituted with a 6-membered heterocycle that is optionally substituted with CO2H.
33. The compound of any one of claims 1 -32, or a pharmaceutically acceptable salt thereof, wherein:
R7 is H, halogen, OR71, NR72R73, or Ci-6 alkyl;
R71 is absent, H or Ci.6 alkyl, wherein the Ci.6 alkyl is optionally substituted with R7A;
R72 and R73 are independently H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with R7B; or R72 and R73 together with the nitrogen atom to which they are attached form
Figure imgf000107_0001
Figure imgf000107_0002
, which are each optionally substituted with 1 or 2 R7C;
R7A is independently
Figure imgf000107_0003
, C(O)OR7A1, or C(O)NR7A2R7A2;
R7A1 is independently H or Ci.6 alkyl;
R7A2 is independently H or Ci-6 alkylsulfonyl;
R7B is independently
Figure imgf000107_0004
Figure imgf000107_0005
R7B1 is independently H or Ci.6 alkyl;
R7B2 is H or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with
Figure imgf000107_0006
R7B3 is independently H or Ci.6 alkylsulfonyl;
R7B4 is Ci-6 alkyl, which is optionally substituted with NH2; and
R7C is independently carbonyl, halogen, OH, Ci-6 alkoxy, CO2H, C(O)OCi-6 alkyl, Ci-6 alkyl, or Ci-6 alkylamine, wherein the Ci-6 alkylamine is optionally substituted with a 6-membered heterocycle that is optionally substituted with
CO2H.
34. The compound of any one of claims 1 -33, or a pharmaceutically acceptable salt thereof,
Figure imgf000107_0007
35. The compound of any one of claims 1 -33, or a pharmaceutically acceptable salt thereof,
Figure imgf000108_0001
36. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000108_0002
37. A compound, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
- Ill -
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
and pharmaceutically acceptable salts thereof.
38. A pharmaceutical composition comprising at least one compound of any one of claims 1 - 37, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
39. A method of treating a disorder chosen from the group consisting of polycystic kidney disease, polycystic liver disease, and ciliopathies, comprising administering to a subject in need thereof at least one compound of any one of claims 1 -37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of any one of claims 1 -37, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
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