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WO2025072265A1 - 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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Publication number
WO2025072265A1
WO2025072265A1 PCT/US2024/048313 US2024048313W WO2025072265A1 WO 2025072265 A1 WO2025072265 A1 WO 2025072265A1 US 2024048313 W US2024048313 W US 2024048313W WO 2025072265 A1 WO2025072265 A1 WO 2025072265A1
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compound
methyl
certain embodiments
ome
pharmaceutically acceptable
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Sun Hee Kim
Yunfei Zhu
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Crinetics Pharmaceuticals Inc
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Crinetics Pharmaceuticals Inc
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    • 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • 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.
  • 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 CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, X is CR 1 and Y is CR 2 ;
  • R 1 is H, halogen, or OH;
  • R 2 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or CN;
  • R 3 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or CN;
  • R 4 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, OH, or C(O)NH 2 ;
  • R 5 is H, halogen, C 1-6 alkyl, C 1-6
  • the compound of Formula (I) is selected from -compounds of Formula (Ia): ) wherein: R 2 is H, halogen, C 1-6 alkoxy, or CN; R 3 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN; R 4 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN; R 6 is H or C 1-6 alkyl; and R 8 is H or C 1-6 alkyl; - compounds of Formula (Ib): ) wherein: X is CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, then X is CR 1 and Y is CR 2 ; R 1 is H, halogen,
  • R 2 is H, halogen, C 1-6 alkoxy, or CN
  • R 3 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN
  • R 4 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN
  • R 6 is H or C 1-6 alkyl
  • R 8 is H or C 1-6 alkyl.
  • R 2 is H, halogen, C 1-3 alkoxy, or CN;
  • R 3 is H, halogen, C 1-3 alkoxy, C 1-3 haloalkyl, or CN;
  • R 4 is H, halogen, C 1-3 alkoxy, C 1-3 haloalkyl, or CN;
  • R 6 is H or C 1-3 alkyl;
  • R 8 is H or C 1-3 alkyl.
  • R 3 is halogen or C 1-3 alkoxy.
  • R 4 is C 1-3 alkoxy.
  • R 6 is H or Me.
  • R 8 is H or Me.
  • R 2 is H; R 3 is halogen or C 1-3 alkoxy; R 4 is C 1-3 alkoxy; R 6 is H or Me; and R 8 is H or Me.
  • R 2 is H, F, Cl, OMe, or CN.
  • R 3 is H, F, Cl, OMe, CF 3 , or CN.
  • R 4 is F, Cl, OMe, OEt, CF 3 , or CN.
  • R 2 is H, F, Cl, OMe, or CN; R 3 is H, F, Cl, OMe, CN, or CF 3 ; R 4 is F, Cl, OMe, OEt, CF 3 , or CN; R 6 is H or Me; and R 8 is H or Me.
  • R 2 is H.
  • R 3 is F or OMe.
  • R 4 OMe or OEt.
  • R 6 is H.
  • R 8 is H.
  • R 8 is Me.
  • the compound is selected from: , , , , , , , , d [0027]
  • R 1 is H, halogen, or OH
  • R 2 is H, halogen, C 1-3 alkyl, C 1-3 alkoxy, or CN
  • R 3 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or CN
  • R 4 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CN, OH, or C(O)NH 2
  • R 5 is H, halogen, or OH
  • R 7 is H, C 1-3 alkoxy, morpholinyl optionally substituted with C 1-3 alkyl, r
  • R 9 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyclopropyl, or cyclopropoxy
  • R 10 is C 1-3 alkyl or C 1-3 alkoxy
  • R A is C 1-3 alkyl
  • R 1 is H, F, or OH.
  • R 2 is H, F, Cl, Me, OMe, or CN.
  • R 3 is H, F, Cl, Me, CF 3 , OMe, or CN.
  • R 4 is H, F, Cl, Me, CF 3 , OMe, OEt, OCF 3 , CN, OH, or C(O)NH 2 .
  • R 5 is H, F, OH.
  • R 9 is ethyl, CF 3 , OMe, OEt, cyclopropyl, or cyclopropoxy.
  • R 10 is Me or OMe.
  • R A is Me, CH 2 OH, or CH 2 OMe and R B is H.
  • R A and R B together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group.
  • R C is H or CH 2 CH 2 F.
  • R 1 is H, F, or OH
  • R 2 is H, F, Cl, Me, OMe, or CN
  • R 3 is H, F, Cl, Me, CF 3 , OMe, or CN
  • R 4 is H, F, Cl, Me, CF 3 , OMe, OEt, OCF 3 , CN, OH, or C(O)NH 2
  • R 5 is H, r
  • R 9 is ethyl, CF 3 , OMe, OEt, cyclopropyl, or cyclopropoxy
  • R 10 is Me or OMe
  • R A is Me, CH 2 OH, or CH 2 OMe
  • R B is H; or R A and R B together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group
  • R C is H or CH 2 CH 2 F.
  • R 1 is H or OH.
  • R 2 is H or F.
  • R 3 is H, F, OMe, or CN.
  • R 4 is Cl, OMe, or CN.
  • R 5 is H.
  • R 9 is OMe or cyclopropyl.
  • R 10 is Me.
  • R A is Me and R B is H.
  • R A and R B together with the carbon atom to which they are attached form a cyclopropyl group.
  • R C is H.
  • R 1 is H or OH;
  • R 2 is H or F;
  • R 3 is H, F, OMe, or CN;
  • R 4 is Cl, OMe, r cyclopropyl;
  • R 10 is Me;
  • R A is Me;
  • R B is H; or
  • R C is H.
  • one of X, Y, or Z is N.
  • the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • a pharmaceutically acceptable salt thereof in another embodiment, described herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof: ) wherein: Z is CR 3 or N; R 2 is H, halogen, or C 1-6 alkoxy; R 3 is H, halogen, or C 1-6 alkoxy; R 4 is H, halogen, or C 1-6 alkoxy; R D is C 1-6 alkyl; and R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl.
  • R 2 is H, halogen, or C 1-3 alkoxy
  • R 3 is H, halogen, or C 1-3 alkoxy
  • R 4 is H, halogen, or C 1-3 alkoxy
  • R D is C 1-3 alkyl
  • R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl.
  • R 2 is H, F, or OMe.
  • R 3 is H, F, or OMe.
  • R 4 is F or OMe.
  • R D is Me or Et.
  • R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
  • the compound is selected from: , , , a pharmaceutically acceptable salt thereof.
  • described herein is a compound of Formula (Id), or a pharmaceutically acceptable salt thereof: ) wherein: R 2 is halogen, C 1-6 alkoxy, or CN; R 4 is halogen or C 1-6 alkoxy; and R 9 is C 1-6 alkoxy or C 3-6 cycloalkyl.
  • R 2 is halogen, C 1-3 alkoxy, or CN; R 4 is halogen or C 1-3 alkoxy; and R 9 is C 1-3 alkoxy or cyclopropyl.
  • R 2 is F, OMe, or CN.
  • R 4 is F or OMe.
  • R 9 is OMe or cyclopropyl.
  • the compound is selected from: d [0069]
  • the compound is selected from: d [0070]
  • a method of treating a disorder selected from polycystic kidney disease, polycystic liver disease, and ciliopathies comprising administering to a subject in need thereof a compound of Formula (I), Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof.
  • the disorder is polycystic kidney disease.
  • the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).
  • the disorder is polycystic kidney disease.
  • the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).
  • a compound of a compound of Formula (I), Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder selected from polycystic kidney disease, polycystic liver disease, and ciliopathies.
  • the disorder is polycystic kidney disease.
  • the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).
  • FIG.1 depicts how abnormal primary cilia function triggers cystogenesis in autosomal dominant polycystic kidney disease (ADPKD).
  • 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 et al., Science 179, 77-79, 1973). An N-terminal extended 28-amino acid peptide with similar biological activity to 14-amino acid somatostatin was subsequently isolated (Pradayrol et, al., FEBS Letters, 109, 55- 58, 1980; Esch et al., Proc. Natl. Acad. Sci. U S A, 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. [0079] It is possible to selectively modulate any one of the somatostatin receptor subtypes, or combination thereof.
  • 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).
  • ciliopathic diseases including, but not limited to, polycystic kidney disease (PKD) and polycystic liver disease (PLD).
  • 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.
  • PKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • SSTR3 agonists described herein are used in the treatment of PKD.
  • the SSTR3 agonist described herein are used in the treatment of ADPKD.
  • somatostatin receptor modulators described herein are used in the treatment of PKD in a mammal.
  • 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 that forms the 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.
  • 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 are two types of PKD, each having its own pathology and genetic cause: ADPKD and ARPKD.
  • 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.
  • 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 ⁇ -catenin signaling.
  • Increased PKA signaling due to increased cAMP levels, also activates a number of transcription factors, including STAT3 and cAMP response element-building protein (CREB).
  • 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 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.
  • ADPKD 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 polycystin- 1 or polycystin-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 cys t 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, resulting in 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.
  • ESRD end-stage renal disease
  • 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 th e 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.).
  • 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).
  • SSTR2, SSTR5 somatostatin receptor 2 and 5
  • AVPR2 vasopressin receptor 2
  • ARPKD an important cause of ESRD and mortality in infants and children, is caused by mutations in PKD1 (encoding fibrocystin).
  • 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.
  • Dysregulation 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.
  • the disease or condition is any one of the diseases or conditions described herein, or combinations thereof.
  • the disease or condition is associated with dysfunction of cilia.
  • the disease or condition is a ciliopathic disease or condition.
  • the selective small molecule SSTR3 agonist is a compound described herein.
  • Compounds [0096] Provided are compounds of Formula (I), including pharmaceutically acceptable salts thereof, which are somatostatin subtype 3 receptor (SSTR3) agonists.
  • Compounds of Formula (I) have the structure shown below: ) wherein: X is CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, X is CR 1 and Y is CR 2 ; R 1 is H, halogen, or OH; R 2 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or CN; R 3 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or CN; R 4 is H, halogen, C 1-6 alkyl, C 1-6 halo
  • the compound of Formula (I) is selected from - compounds of Formula (Ia): ) wherein: R 2 is H, halogen, C 1-6 alkoxy, or CN; R 3 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN; R 4 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN; R 6 is H or C 1-6 alkyl; and R 8 is H or C 1-6 alkyl; - compounds of Formula (Ib): ) wherein: X is CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, X is CR 1 and Y is CR 2 ; R 1 is H, halogen, or
  • X is CR 1
  • Y is CR 2
  • Z is is ula (I) are compounds of Formula (Ia).
  • the compound is a compound of Formula (Ia): ) wherein: R 2 is H, halogen, C 1-6 alkoxy, or CN; R 3 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN; R 4 is H, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, or CN; R 6 is H or C 1-6 alkyl; and R 8 is H or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof .
  • R 2 is H, halogen, C 1-3 alkoxy, or CN
  • R 3 is H, halogen, C 1-3 alkoxy, C 1-3 haloalkyl, or CN
  • R 4 is H, halogen, C 1-3 alkoxy, C 1-3 haloalkyl, or CN
  • R 6 is H or C 1- 3 alkyl
  • R 8 is H or C 1-3 alkyl.
  • R 2 is H, F, Cl, Br, I, methoxy (OMe), ethoxy (OEt), n-propoxy (O-nPr), isopropoxy (O-iPr), or CN;
  • R 3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr, C 1 haloalkyl, C 2 haloalkyl, C 3 haloalkyl, or CN;
  • R 6 is H, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr) or CN;
  • R 4 is H, F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr, C 1 haloalkyl, C 2 haloalkyl, C 3 haloalkyl, or CN;
  • R 6 is H, methyl (Me), ethyl (E
  • R 2 is H or R 4 is H.
  • R 2 is H; R 3 is halogen or C 1-3 alkoxy; R 4 is C 1-3 alkoxy; R 6 is H or Me; and R 8 is H or Me.
  • R 2 is H; R 3 is halogen or C 1-3 alkoxy; R 4 is C 1-3 alkoxy; R 6 is H; and R 8 is H or Me.
  • R 2 is H, F, Cl, OMe, or CN; R 3 is H, F, Cl, OMe, CN, or CF 3 ; R 4 is F, Cl, OMe, OEt, CF 3 , or CN; R 6 is H or Me; and R 8 is H or Me.
  • R 2 is H; R 3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R 4 is OMe, OEt, O-nPr, or O-iPr; R 6 is H or Me; and R 8 is H or Me.
  • R 2 is H; R 3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R 4 is OMe, OEt, O-nPr, or O-iPr; R 6 is H or Me; and R 8 is H or Me.
  • R 2 is H; R 3 is F or OMe; R 4 is OMe or OEt; R 6 is H; and R 8 is H or Me.
  • R 2 is H, halogen, C 1-3 alkoxy, or CN.
  • R 2 is H, F, Cl, or CN.
  • R 2 is H.
  • R 2 is F. In certain embodiments, R 2 is Cl. In certain embodiments, R 2 is OMe. In certain embodiments, R 2 is CN. [00111] In certain embodiments, R 3 is halogen or C 1-3 alkoxy. In certain embodiments, R 3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is F, Cl, Br, or I. In certain embodiments, R 3 is C 1-3 alkoxy. In certain embodiments, R 3 is OMe, OEt, O-nPr, or O-iPr.
  • R 3 is H, halogen, C 1-3 alkoxy, C 1-3 haloalkyl, or CN. In certain embodiments, R 3 is H, F, Cl, OMe, CF 3 , or CN. In certain embodiments, R 3 is F or OMe. In certain embodiments, R 3 is H. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl. In certain embodiments, R 3 is OMe. In certain embodiments, R 3 is CF 3 . In certain embodiments, R 3 is CN. [00113] In certain embodiments, R 4 is C 1-3 alkoxy.
  • R 4 is OMe, OEt, O- nPr, or O-iPr. In certain embodiments, R 4 is OMe or OEt. In certain embodiments, R 4 is OMe. In certain embodiments, R 4 is OEt. In certain embodiments, R 4 is O-nPr. In certain embodiments, R 4 is O-iPr. [00114] In certain embodiments, R 4 is H, halogen, C 1-3 alkoxy, C 1-3 haloalkyl, or CN. In certain embodiments, R 4 is F, Cl, OMe, OEt, CF 3 , or CN. In certain embodiments, R 4 is OMe or OEt. In certain embodiments, R 4 is F.
  • R 4 is Cl. In certain embodiments, R 4 is OMe. In certain embodiments, R 4 is OEt. In certain embodiments, R 4 is CF 3 . In certain embodiments, R 4 is CN. [00115] In certain embodiments, R 6 is H or C 1-3 alkyl. In certain embodiments, R 6 is H or Me. In certain embodiments, R 6 is H. In certain embodiments, R 6 is Me. [00116] In certain embodiments, R 8 is H or C 1-3 alkyl. In certain embodiments, R 8 is H or Me. In certain embodiments, R 8 is H. In certain embodiments, R 8 is Me. [00117] In certain embodiments, the compound of Formula (Ia) is selected from: , , , , , , , , , ,
  • the compound of Formula (Ia) is a compound as set forth in Table 1. [00119] In certain embodiments, the compound of Formula (Ia) is compound 1. [00120] In certain embodiments, the compound of Formula (Ia) is compound 2. [00121] In certain embodiments, the compound of Formula (Ia) is compound 3. [00122] In certain embodiments, the compound of Formula (Ia) is compound 4. [00123] In certain embodiments, the compound of Formula (Ia) is compound 5. [00124] In certain embodiments, the compound of Formula (Ia) is compound 6. [00125] In certain embodiments, the compound of Formula (Ia) is compound 7.
  • the compound of Formula (Ia) is compound 8. [00127] In certain embodiments, the compound of Formula (Ia) is compound 9. [00128] In certain embodiments, the compound of Formula (Ia) is compound 10. [00129] In certain embodiments, the compound of Formula (Ia) is compound 11. [00130] In certain embodiments, the compound of Formula (Ia) is compound 12. [00131] In certain embodiments, the compound of Formula (Ia) is compound 13. [00132] In certain embodiments, the compound of Formula (Ia) is compound 14. [00133] In certain embodiments, the compound of Formula (Ia) is compound 15. [00134] In certain embodiments, the compound of Formula (Ia) is compound 16.
  • the compound of Formula (Ia) is compound 17. [00136] In certain embodiments, the compound of Formula (Ia) is compound 18. [00137] In certain embodiments, the compound of Formula (Ia) is compound 19. [00138] In certain embodiments, the compound of Formula (Ia) is compound 20. [00139] In certain embodiments, the compound of Formula (Ia) is compound 21. [00140] In certain embodiments, the compound of Formula (Ia) is compound 22. [00141] In certain embodiments, the compound of Formula (Ia) is compound 23. [00142] In certain embodiments, the compound of Formula (Ia) is compound 24. [00143] In certain embodiments, the compound of Formula (Ia) is compound 25.
  • the compound of Formula (Ia) is compound 26. [00145] In certain embodiments, the compound of Formula (Ia) is compound 27. [00146] In certain embodiments, the compound of Formula (Ia) is compound 28. [00147] In certain embodiments, the compound of Formula (Ia) is compound 29. [00148] In certain embodiments, the compound of Formula (Ia) is compound 30. [00149] In certain embodiments, the compound of Formula (Ia) is compound 31. [00150] In certain embodiments, the compound of Formula (Ia) is compound 32. [00151] In certain embodiments, the compound of Formula (Ia) is compound 33. [00152] In certain embodiments, the compound of Formula (Ia) is compound 34.
  • the compound of Formula (Ia) is compound 35. [00154] In certain embodiments, the compound of Formula (Ia) is compound 36. [00155] In certain embodiments, the compound of Formula (Ia) is compound 168. [00156] In certain embodiments, in the compounds of Formula (I), R 6 is H; R 11 is methyl; J is n this embodiment, the compounds of Formula (I) are compounds of Formula (Ib).
  • the compound is a compound of Formula (Ib): ) wherein: X is CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, then X is CR 1 and Y is CR 2 ; R 1 is H, halogen, or OH; R 2 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or CN; R 3 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or CN; R 4 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, CN, OH, or C(O)NH 2 ; R 5
  • X is CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, then X is CR 1 and Y is CR 2 ;
  • R 1 is H, halogen, or OH;
  • R 2 is H, halogen, C 1-3 alkyl, C 1-3 alkoxy, or CN;
  • R 3 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or CN;
  • R 4 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CN, OH, or C(O)NH 2 ;
  • R 5 is H, halogen, or OH;
  • R 7 is
  • X is CR 1 or N; Y is CR 2 or N; and Z is CR 3 or N; wherein when X is N, Y is CR 2 and Z is CR 3 ; when Y is N, X is CR 1 and Z is CR 3 ; and when Z is N, then X is CR 1 and Y is CR 2 ;
  • R 1 is H, F, Cl, Br, I, or OH;
  • R 2 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr, O-iPr, or CN;
  • R 3 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, C 1 haloalkyl, C 2 haloalkyl, C 3 haloalkyl, OMe, OEt, O-nPr, O-iPr, or CN;
  • R 4 is H,
  • R 1 is H, F, or OH
  • R 2 is H, F, Cl, Me, OMe, or CN
  • R 3 is H, F, Cl, Me, CF 3 , OMe, or CN
  • R 4 is H, F, Cl, Me, CF 3 , OMe, OEt, OCF 3 , CN, OH, or C(O)NH 2
  • R 5 is r
  • R 9 is ethyl, CF 3 , OMe, OEt, cyclopropyl, or cyclopropoxy
  • R 10 is Me or OMe
  • R A is Me, CH 2 OH, or CH 2 OMe
  • R B is H; or R A and R B together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group
  • R C is H or CH 2 CH 2 F.
  • R 1 is H, F, or OH;
  • R 2 is H, F, Cl, Me, OMe, or CN;
  • R 3 is H, F, Cl, Me, CF 3 , OMe, or CN;
  • R 4 is H, F, Cl, Me, CF 3 , OMe, cyclopropoxy;
  • R 10 is Me or OMe;
  • R A is Me, CH 2 OH, or CH 2 OMe;
  • R B is H; or R A and R B together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group; and
  • R C is H or CH 2 CH 2 F.
  • one of X, Y, or Z is N;
  • R 1 is H, F, or OH;
  • R 2 is H, F, Cl, Me, OMe, or CN;
  • R 3 is H, F, Cl, Me, CF 3 , OMe, or CN;
  • R 4 is H, F, Cl, Me, CF 3 , OMe, OEt, OCF 3 , , is ethyl, CF 3 , OMe, OEt, cyclopropyl, or cyclopropoxy;
  • R 10 is Me or OMe;
  • R A is Me, CH 2 OH, or CH 2 OMe;
  • R B is H; or
  • R A and R B together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group;
  • R C is H or CH 2 CH 2 F.
  • R 1 is H or OH;
  • R 2 is H or F;
  • R 3 is H, F, OMe, or CN;
  • R 4 is Cl, r cyclopropyl;
  • R 10 is Me;
  • R A is Me;
  • R B is H; or
  • R C is H.
  • one of X, Y, or Z is N; R 1 is H or OH; R 2 is H or F; R 3 is H, F, r cyclopropyl; R 10 is Me; R A is Me; R B is H; or R A and R B together with the carbon atom to which they are attached form a cyclopropyl group; and R C is H.
  • R 1 is H, halogen, or OH.
  • R 1 is H, F, or OH.
  • R 1 is H or OH.
  • R 1 is H.
  • R 1 is F.
  • R 1 is OH.
  • R 2 is H, halogen, C 1-3 alkyl, C 1-3 alkoxy, or CN. In certain embodiments, R 2 is H, F, Cl, Me, OMe, or CN. In certain embodiments, R 2 is H or F. In certain embodiments, R 2 is H. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Cl. In certain embodiments, R 2 is Me. In certain embodiments, R 2 is OMe. In certain embodiments, R 2 is CN. [00168] In certain embodiments, R 3 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or CN.
  • R 3 is H, F, Cl, Me, CF 3 , OMe, or CN. In certain embodiments, R 3 is H, F, OMe, or CN. In certain embodiments, R 3 is H. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl. In certain embodiments, R 3 is Me. In certain embodiments, R 3 is CF 3 . In certain embodiments, R 3 is OMe. In certain embodiments, R 3 is CN. [00169] In certain embodiments, R 4 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CN, OH, or C(O)NH 2 .
  • R 4 is H, F, Cl, Me, CF 3 , OMe, OEt, OCF 3 , CN, OH, or C(O)NH 2 .
  • R 4 is Cl, OMe, or CN.
  • R 4 is H.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Me.
  • R 4 is CF 3 .
  • R 4 is OMe.
  • R 4 is OEt.
  • R 4 is OCF 3 .
  • R 4 is CN.
  • R 4 is OH.
  • R 4 is C(O)NH 2 .
  • R 5 is H, halogen, or OH.
  • R 5 is H, F, or OH.
  • R 5 is H.
  • R 5 is F.
  • R 5 is OH.
  • R 7 is H, C 1-3 alkoxy, morpholinyl optionally substituted with C 1-3 alkyl n
  • R 7 is H, OMe, n embodiments, R 7 is H, OMe, or .
  • R 7 is H. In certain embodiments, R 7 is OMe. In certain embodiments, R 7 is .
  • R 7 is . In certain embodiments, R 7 i . In certain embodiments . In certain embodiments, R 7 is . In certain embodiments, R 7 is . [00172] In certain embodiments, R 9 is C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, cyclopropyl, or cyclopropoxy. In certain embodiments, R 9 is ethyl, CF 3 , OMe, OEt, cyclopropyl, or cyclopropoxy. In certain embodiments, R 9 is OMe or cyclopropyl. In certain embodiments, R 9 is ethyl. In certain embodiments, R 9 is CF 3 .
  • R 9 is OMe. In certain embodiments, R 9 is OEt. In certain embodiments, R 9 is cyclopropyl. In certain embodiments, R 9 is cyclopropoxy. [00173] In certain embodiments, R 10 is C 1-3 alkyl or C 1-3 alkoxy. In certain embodiments, R 10 is Me or OMe. In certain embodiments, R 10 is Me. In certain embodiments, R 10 is OMe. [00174] In certain embodiments, R A is C 1-3 alkyl, CH 2 OH, or CH 2 OMe; and R B is H. In certain embodiments, R A is Me, CH 2 OH, or CH 2 OMe; and R B is H.
  • R A is Me; and R B is H. In certain embodiments, R A is CH 2 OH; and R B is H. In certain embodiments, R A is CH 2 OMe; and R B is H. [00175] In certain embodiments, R A and R B together with the carbon atom to which they are attached form a C 3-4 cycloalkyl. In certain embodiments, R A and R B together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group. In certain embodiments, R A and R B together with the carbon atom to which they are attached form a cyclopropyl group.
  • R A and R B together with the carbon atom to which they are attached form a cyclobutyl group.
  • R C is H or C 1-3 haloalkyl. In certain embodiments, R C is H or CH 2 CH 2 F. In certain embodiments, R C is H. In certain embodiments, R C is CH 2 CH 2 F.
  • X is CR 1 ; Y is CR 2 ; and Z is CR 3 .
  • one of X, Y, or Z is N. In certain embodiments, X is N. In certain embodiments, Y is N. In certain embodiments, Z is N.
  • the compound of Formula (Ib) is an N-oxide thereof.
  • the compound of Formula (Ib) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • the compound of Formula (Ib) is a compound as set forth in Table 2.
  • the compound of Formula (Ib) is compound 37.
  • the compound of Formula (Ib) is compound 38.
  • the compound of Formula (Ib) is compound 39.
  • the compound of Formula (Ib) is compound 40.
  • the compound of Formula (Ib) is compound 41.
  • the compound of Formula (Ib) is compound 42.
  • the compound of Formula (Ib) is compound 43.
  • the compound of Formula (Ib) is compound 44. [00190] In certain embodiments, the compound of Formula (Ib) is compound 45. [00191] In certain embodiments, the compound of Formula (Ib) is compound 46. [00192] In certain embodiments, the compound of Formula (Ib) is compound 47. [00193] In certain embodiments, the compound of Formula (Ib) is compound 48. [00194] In certain embodiments, the compound of Formula (Ib) is compound 49. [00195] In certain embodiments, the compound of Formula (Ib) is compound 50. [00196] In certain embodiments, the compound of Formula (Ib) is compound 51. [00197] In certain embodiments, the compound of Formula (Ib) is compound 52.
  • the compound of Formula (Ib) is compound 53. [00199] In certain embodiments, the compound of Formula (Ib) is compound 54. [00200] In certain embodiments, the compound of Formula (Ib) is compound 55. [00201] In certain embodiments, the compound of Formula (Ib) is compound 56. [00202] In certain embodiments, the compound of Formula (Ib) is compound 57. [00203] In certain embodiments, the compound of Formula (Ib) is compound 58. [00204] In certain embodiments, the compound of Formula (Ib) is compound 59. [00205] In certain embodiments, the compound of Formula (Ib) is compound 60.
  • the compound of Formula (Ib) is compound 61. [00207] In certain embodiments, the compound of Formula (Ib) is compound 62. [00208] In certain embodiments, the compound of Formula (Ib) is compound 63. [00209] In certain embodiments, the compound of Formula (Ib) is compound 64. [00210] In certain embodiments, the compound of Formula (Ib) is compound 65. [00211] In certain embodiments, the compound of Formula (Ib) is compound 66. [00212] In certain embodiments, the compound of Formula (Ib) is compound 67. [00213] In certain embodiments, the compound of Formula (Ib) is compound 68.
  • the compound of Formula (Ib) is compound 69. [00215] In certain embodiments, the compound of Formula (Ib) is compound 70. [00216] In certain embodiments, the compound of Formula (Ib) is compound 71. [00217] In certain embodiments, the compound of Formula (Ib) is compound 72. [00218] In certain embodiments, the compound of Formula (Ib) is compound 73. [00219] In certain embodiments, the compound of Formula (Ib) is compound 74. [00220] In certain embodiments, the compound of Formula (Ib) is compound 75. [00221] In certain embodiments, the compound of Formula (Ib) is compound 76.
  • the compound of Formula (Ib) is compound 77. [00223] In certain embodiments, the compound of Formula (Ib) is compound 78. [00224] In certain embodiments, the compound of Formula (Ib) is compound 79. [00225] In certain embodiments, the compound of Formula (Ib) is compound 80. [00226] In certain embodiments, the compound of Formula (Ib) is compound 81. [00227] In certain embodiments, the compound of Formula (Ib) is compound 82. [00228] In certain embodiments, the compound of Formula (Ib) is compound 83. [00229] In certain embodiments, the compound of Formula (Ib) is compound 84.
  • the compound of Formula (Ib) is compound 85. [00231] In certain embodiments, the compound of Formula (Ib) is compound 86. [00232] In certain embodiments, the compound of Formula (Ib) is compound 87. [00233] In certain embodiments, the compound of Formula (Ib) is compound 88. [00234] In certain embodiments, the compound of Formula (Ib) is compound 89. [00235] In certain embodiments, the compound of Formula (Ib) is compound 90. [00236] In certain embodiments, the compound of Formula (Ib) is compound 91. [00237] In certain embodiments, the compound of Formula (Ib) is compound 92.
  • the compound of Formula (Ib) is compound 93. [00239] In certain embodiments, the compound of Formula (Ib) is compound 94. [00240] In certain embodiments, the compound of Formula (Ib) is compound 95. [00241] In certain embodiments, the compound of Formula (Ib) is compound 96. [00242] In certain embodiments, the compound of Formula (Ib) is compound 97. [00243] In certain embodiments, the compound of Formula (Ib) is compound 98. [00244] In certain embodiments, the compound of Formula (Ib) is compound 99. [00245] In certain embodiments, the compound of Formula (Ib) is compound 100.
  • the compound of Formula (Ib) is compound 101. [00247] In certain embodiments, the compound of Formula (Ib) is compound 102. [00248] In certain embodiments, the compound of Formula (Ib) is compound 103. [00249] In certain embodiments, the compound of Formula (Ib) is compound 104. [00250] In certain embodiments, the compound of Formula (Ib) is compound 105. [00251] In certain embodiments, the compound of Formula (Ib) is compound 106. [00252] In certain embodiments, the compound of Formula (Ib) is compound 107. [00253] In certain embodiments, the compound of Formula (Ib) is compound 108.
  • the compound of Formula (Ib) is compound 109. [00255] In certain embodiments, the compound of Formula (Ib) is compound 110. [00256] In certain embodiments, the compound of Formula (Ib) is compound 111. [00257] In certain embodiments, the compound of Formula (Ib) is compound 112. [00258] In certain embodiments, the compound of Formula (Ib) is compound 113. [00259] In certain embodiments, the compound of Formula (Ib) is compound 114. [00260] In certain embodiments, the compound of Formula (Ib) is compound 115. [00261] In certain embodiments, the compound of Formula (Ib) is compound 116.
  • the compound of Formula (Ib) is compound 117. [00263] In certain embodiments, the compound of Formula (Ib) is compound 118. [00264] In certain embodiments, the compound of Formula (Ib) is compound 119. [00265] In certain embodiments, the compound of Formula (Ib) is compound 120. [00266] In certain embodiments, the compound of Formula (Ib) is compound 121. [00267] In certain embodiments, the compound of Formula (Ib) is compound 122. [00268] In certain embodiments, the compound of Formula (Ib) is compound 123. [00269] In certain embodiments, the compound of Formula (Ib) is compound 124.
  • the compound of Formula (Ib) is compound 125. [00271] In certain embodiments, the compound of Formula (Ib) is compound 126. [00272] In certain embodiments, the compound of Formula (Ib) is compound 127. [00273] In certain embodiments, the compound of Formula (Ib) is compound 128. [00274] In certain embodiments, the compound of Formula (Ib) is compound 129. [00275] In certain embodiments, the compound of Formula (Ib) is compound 130. [00276] In certain embodiments, the compound of Formula (Ib) is compound 131. [00277] In certain embodiments, the compound of Formula (Ib) is compound 132.
  • the compound of Formula (Ib) is compound 133. [00279] In certain embodiments, the compound of Formula (Ib) is compound 134. [00280] In certain embodiments, the compound of Formula (Ib) is compound 135. [00281] In certain embodiments, the compound of Formula (Ib) is compound 136. [00282] In certain embodiments, the compound of Formula (Ib) is compound 137. [00283] In certain embodiments, the compound of Formula (Ib) is compound 138. [00284] In certain embodiments, the compound of Formula (Ib) is compound 139. [00285] In certain embodiments, the compound of Formula (Ib) is compound 140.
  • the compound of Formula (Ib) is compound 141. [00287] In certain embodiments, the compound of Formula (Ib) is compound 142. [00288] In certain embodiments, the compound of Formula (Ib) is compound 143. [00289] In certain embodiments, the compound of Formula (Ib) is compound 144. [00290] In certain embodiments, the compound of Formula (Ib) is compound 145. [00291] In certain embodiments, the compound of Formula (Ib) is compound 146. [00292] In certain embodiments, the compound of Formula (Ib) is compound 147. [00293] In certain embodiments, the compound of Formula (Ib) is compound 148.
  • the compound of Formula (Ib) is compound 149. [00295] In certain embodiments, the compound of Formula (Ib) is compound 150. [00296] In certain embodiments, the compound of Formula (Ib) is compound 151. [00297] In certain embodiments, the compound of Formula (Ib) is compound 152. [00298] In certain embodiments, in the compounds of Formula (I), X is CR 1 and Y is CR 2 ; R 1 is H; R 5 is H; R 6 is H; R 11 is methyl; J is ; R 7 is H; R 9 is cyclopropyl; R 10 is methyl; and .
  • the compounds of Formula (I) are compounds of Formula (Ic).
  • the compound is a compound of Formula (Ic): ) wherein: Z is CR 3 or N; R 2 is H, halogen, or C 1-6 alkoxy; R 3 is H, halogen, or C 1-6 alkoxy; R 4 is H, halogen, or C 1-6 alkoxy; R D is C 1-6 alkyl; and R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl; or a pharmaceutically acceptable salt thereof .
  • Z is CR 3 or N;
  • R 2 is H, halogen, or C 1-3 alkoxy;
  • R 3 is H, halogen, or C 1-3 alkoxy;
  • R 4 is H, halogen, or C 1-3 alkoxy;
  • R D is C 1-3 alkyl; and
  • R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl.
  • Z is CR 3 or N;
  • R 2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R 3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R 4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R D is Me, Et, n-Pr, or i-Pr; and
  • R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl.
  • Z is CR 3 ;
  • R 2 is H, halogen, or C 1-3 alkoxy;
  • R 3 is H, halogen, or C 1-3 alkoxy;
  • R 4 is H, halogen, or C 1-3 alkoxy;
  • R D is C 1-3 alkyl; and
  • R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a C 4-5 heterocycloalkyl.
  • Z is CR 3 or N;
  • R 2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R 3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R 4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R D is Me, Et, n-Pr, or i-Pr; and
  • R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl.
  • Z is N; R 2 is H, halogen, or C 1-3 alkoxy; R 4 is H, halogen, or C 1-3 alkoxy; R D is C 1-3 alkyl; and R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a C 4-5 heterocycloalkyl.
  • Z is CR 3 or N;
  • R 2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R 3 is H, F, Cl, Br, I, OMe, OEt, O- nPr, or O-iPr;
  • R 4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr;
  • R D is Me, Et, n-Pr, or i-Pr; and
  • R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl.
  • Z is CR 3 or N;
  • R 2 is H, F, or OMe;
  • R 3 is H, F, or OMe;
  • R 4 is F or OMe;
  • R D is Me or Et;
  • R E is CH 2 OMe; or
  • R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
  • Z is CR 3 ; R 2 is H, F, or OMe; R 3 is H, F, or OMe; R 4 is F or OMe; R D is Me or Et; and R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
  • Z is CR 3 ; R 2 is H, F, or OMe; R 3 is H, F, or OMe; R 4 is F or OMe; R D is Me or Et; and R E is CH 2 OMe.
  • Z is CR 3 ; R 2 is H, F, or OMe; R 3 is H, F, or OMe; R 4 is F or OMe; and R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
  • Z is N; R 2 is H, F, or OMe; R 4 is F or OMe; R D is Me or Et; and R E is CH 2 OMe; or R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
  • Z is N; R 2 is H, F, or OMe; R 4 is F or OMe; R D is Me or Et; and R E is CH 2 OMe.
  • Z is N; R 2 is H, F, or OMe; R 4 is F or OMe; and R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
  • R 2 is H, F, or OMe.
  • R 2 is H.
  • R 2 is F.
  • R 2 is OMe.
  • R 3 is H. In certain embodiments, R 3 is F. In certain embodiments, R 3 is OMe.
  • R 4 is H, F, or OMe. In certain embodiments, R 4 is H. In certain embodiments, R 4 is F. In certain embodiments, R 4 is OMe.
  • R D is Me or Et. In certain embodiments, R D is Me. In certain embodiments, R D is Et.
  • Z is CR 3 . In certain embodiments, Z is N.
  • R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. In certain embodiments, R D and R E together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group. In certain embodiments, R D and R E together with the nitrogen and carbon atoms to which they are attached form a pyrrolidinyl group. [00316] In certain embodiments, the compound of Formula (Ic) is selected from: , , , a pharmaceutically acceptable salt thereof. [00317] In certain embodiments, the compound of Formula (Ic) is a compound as set forth in Table 3.
  • the compound of Formula (Ic) is compound 153. [00319] In certain embodiments, the compound of Formula (Ic) is compound 154. [00320] In certain embodiments, the compound of Formula (Ic) is compound 155. [00321] In certain embodiments, the compound of Formula (Ic) is compound 156. [00322] In certain embodiments, the compound of Formula (Ic) is compound 157. [00323] In certain embodiments, the compound of Formula (Ic) is compound 158. [00324] In certain embodiments, the compound of Formula (Ic) is compound 159. [00325] In certain embodiments, the compound of Formula (Ic) is compound 160.
  • the compound of Formula (Ic) is compound 161. [00327] In certain embodiments, the compound of Formula (Ic) is compound 162. [00328] In certain embodiments, the compound of Formula (Ic) is compound 163.
  • the compounds of Formula (I) are compounds of Formula [00330]
  • the compound is a compound of Formula (Id): ) wherein: R 2 is halogen, C 1-6 alkoxy, or CN; R 4 is halogen or C 1-6 alkoxy; and R 9 is C 1-6 alkoxy or C 3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof .
  • R 2 is halogen, C 1-3 alkoxy, or CN; R 4 is halogen or C 1-3 alkoxy; and R 9 is C 1-3 alkoxy or cyclopropyl.
  • R 2 is F, Cl, Br, I, OMe, OEt, O- nPr, O-iPr, or CN; R 4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; and R 9 is OMe, OEt, O-nPr, O- iPr, or cyclopropyl.
  • R 2 is F, OMe, or CN; R 4 is F or OMe; and R 9 is OMe or cyclopropyl.
  • R 2 is halogen, C 1-3 alkoxy, or CN.
  • R 2 is F, OMe, or CN.
  • R 2 is F.
  • R 2 is OMe.
  • R 2 is CN.
  • R 4 is halogen or C 1-3 alkoxy.
  • R 4 is F or OMe.
  • R 4 is F.
  • R 4 is OMe.
  • R 9 is C 1-3 alkoxy or cyclopropyl. In certain embodiments, R 9 is OMe or cyclopropyl. In certain embodiments, R 9 is OMe. In certain embodiments, R 9 is cyclopropyl. [00336] In certain embodiments, the compound of Formula (Id) is selected from: d [00337] In certain embodiments, the compound of Formula (Id) is a compound as set forth in Table 4. [00338] In certain embodiments, the compound of Formula (Id) is compound 164. [00339] In certain embodiments, the compound of Formula (Id) is compound 165.
  • the compound of Formula (Id) is compound 166.
  • the compound of Formula (Id) is compound 167.
  • Exemplary compounds of Formula (Ia) described herein include the compounds described in Table 1: (Ia)
  • Exemplary compounds of Formula (Ic) described herein include the compounds described in Table 3: (Ic) [00349] Names of the compounds in Table 3 are as follows: 153: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3- (methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 154: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3-(methylamino)- 1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 155: N-
  • Exemplary compounds of Formula (Id) described herein include the compounds described in Table 4: (Id) [00352] Names of the compounds in Table 4 are as follows: 164: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 165: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide 166: N-[(S)-1-(3,
  • a pharmaceutically acceptable salt of a compound of Formula (Id) that is described in Table 4.
  • “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, i.e., 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), (Ia), (Ib), (Ic), or (Id) with an acid.
  • the free base form of the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) 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), (Ia), (Ib), (Ic), or (Id) with a base.
  • the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) is acidic and is reacted with a base.
  • the compounds of Formula (I), (Ia), (Ib), (Ic), or (Id) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) exists in the R configuration.
  • the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) exists in the S configuration.
  • the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, epimeric, as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers tautomers, 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), (Ia), (Ib), (Ic), and (Id) 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.
  • N-H naphthyridone compounds of Formula (Ia), described herein are prepared as described in Scheme A.
  • Scheme C (a) XXVII, neat, 100 o C, 2 h; (b) PhOPh . PhPh, 258 o C, 10 min; (c) LiOH, MeOH/H 2 O (5:1), 65 o C, 1 h; (d) POCl 3 , 100 o C, 0.5-1 h; (e) X or Xa, DIEA, DCM, 0 o C, 1 h; (f) H-A-Boc, DIEA, dioxane, 110 o C, 16 h; (g) TFA, DCM, RT, 1 h. [00366] In some embodiments, compounds of Formula (Ib), described herein, have an R 7 moiety. A non-limiting example of installation of the R 7 moiety is described in Scheme D.
  • amine intermediate X is prepared as described in Scheme E.
  • Scheme E (a) i) Pd(PPh 3 ) 2 Cl 2 , toluene, 100 o C, 16 h, ii) HCl, RT, 0.5 h; (b) Ti(OiPr) 4 , toluene, 80 o C, 16 h; (c) L-Selectride, THF, -78 o C, 1 h; (d) HCl, ether, RT, 1 h. [00368] In some embodiments, amine intermediate X is prepared as described in Scheme F.
  • intermediate X is alkylated (for example, with methyliodide) to prepare intermediate Xa as described in Scheme G.
  • Scheme G (a) Boc2O, Et3N, DCM, RT, 1 h; (b) NaH, R6-I, DMF, RT, 1 h; (c) HCl, dioxane, RT, 1 h.
  • C 1 -C x includes C 1 -C 2 , C 1 -C 3 ... C 1 -C x .
  • a group designated as “C 1 -C 6 " indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • “C 1 -C 3 alkyl” indicates that there are one to three carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, and iso-propyl.
  • 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, i.e. a C 1 -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 C 1 -C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-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.
  • An “alkoxy” group refers to an (alkyl)O- group, where alkyl is as defined herein.
  • halo or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a halo atom. In one aspect, a haloalkyl is a C 1 -C 6 fluoroalkyl or C 1 -C 3 fluoroalkyl.
  • haloalkoxy refers to an alkoxy in which one or more hydrogen atoms are replaced by a halo atom.
  • a haloalkoxy is a C 1 -C 6 fluoroalkoxy or C 1 -C 3 fluoroalkoxy.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl.
  • a cycloalkyl is a C 3 - C 6 cycloalkyl.
  • a cycloalkyl is a C 3 -C 4 cycloalkyl.
  • a “cycloalkoxy” group refers to a (cycloalkyl)O- group, where cycloalkyl is as defined herein.
  • 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.
  • 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.
  • modulator 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.
  • a modulator is an agonist.
  • 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.
  • the term “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.
  • compositions [00386]
  • 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 [00387] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), and (Id), or a pharmaceutically acceptable salt thereof, described herein are formulated into pharmaceutical compositions.
  • 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.
  • 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 [00389] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), and (Id ), 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.
  • compositions that include at least one compound of Formula (I), (Ia), (Ib), (Ic), and (Id), 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.
  • 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.
  • the amount of a given compound of Formula (I), (Ia), (Ib), (Ic), and (Id), 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.
  • Example A Syntheses of Compounds Example A1. Preparation of N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4- diazepan-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3- naphthamide (Compound 13) [00396] Step A1-1, preparation of methyl 5-amino-2-chloroisonicotinate: Into a 250-mL three- necked flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of 5-amino-2-chloroisonicotinic acid (11.4 g, 1 Eq, 66.1 mmol) and methanol (114 mL)
  • the reaction mixture was stirred at 70 °C for 16 hours.
  • the reaction was concentrated under vacuum and the residue dissolved in dichloromethane (200 mL).
  • the resulting solution was adjusted to a pH of 8 with saturated NaHCO 3 solution.
  • Step A1-2 preparation of methyl 5-amino-2-methylisonicotinate: Into a 250-mL round- bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of methyl 5-amino-2-chloroisonicotinate (9.6 g, 1 Eq, 51 mmol), 1,4-dioxane (96 mL), K 2 CO 3 (21 g, 3.0 Eq, 0.15 mol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (19 g, 2.9 Eq, 0.15 mol), and PdCl 2 (dppf) (1.9 g, 0.050 Eq, 2.6 mmol).
  • Step A1-3 preparation of methyl 2-methyl-5-(methylamino)isonicotinate: Into a 250- mL round-bottom flask was placed a mixture of methyl 5-amino-2-methylisonicotinate (8.5 g, 1 Eq, 51 mmol), 1,4-dioxane (85 mL), pyridine (14 g, 14 mL, 3.5 Eq, 0.18 mol), and diacetoxycopper (23 g, 2.5 Eq, 0.13 mol).
  • reaction mixture was stirred at 25 °C for 30 minutes, after which methylboronic acid (15 g, 4.9 Eq, 0.25 mol) was added and the reaction mixture was stirred for an additional 16 hours at 100 °C.
  • methylboronic acid 15 g, 4.9 Eq, 0.25 mol
  • the reaction mixture was then filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (0% ethyl acetate up to 50% in 10 minutes).
  • Step A1-4 preparation of methyl 2-bromo-6-methyl-3-(methylamino)isonicotinate: Into a 100 mL round-bottom flask was placed a mixture of methyl 2-methyl-5- (methylamino)isonicotinate (3.3 g, 1 Eq, 18 mmol) and DMF (33 mL). To the mixture was added NBS (1.2 g, 1.2 Eq, 21 mmol) in portions at 0 °C.
  • Step 1-5 preparation of methyl 2-cyclopropyl-6-methyl-3-(methylamino)isonicotinate: Into a 250 mL vial was placed methyl 2-bromo-6-methyl-3-(methylamino)isonicotinate (3.5 g, 1 Eq, 14 mmol), Pd(OAc) 2 (0.3 g, 0.1 Eq, 1 mmol), cyclopropylboronic acid (3.5 g, 3.0 Eq, 41 mmol), potassium phosphate tribasic (8.6 g, 3.4 mL, 3.0 Eq, 41 mmol), tricyclohexylphosphine (0.76 g, 0.85 mL, 0.20 Eq, 2.7 mmol), toluene (35 mL), and water (3.5 mL).
  • Step A1-6 preparation of methyl 2-cyclopropyl-3-(3-methoxy-N-methyl-3- oxopropanamido)-6-methylisonicotinate: Into a 250-mL vial was placed a mixture of methyl 2- cyclopropyl-6-methyl-3-(methylamino)isonicotinate (2.3 g, 1 Eq, 10 mmol) and DCM (23 mL), to which was added methyl 3-chloro-3-oxopropanoate (4.3 g, 3.0 Eq, 31 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour.
  • Step A1-7 preparation of methyl 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2- dihydro-1,7-naphthyridine-3-carboxylate: Into a 250 mL vial was placed a mixture of methyl 2- cyclopropyl-3-(3-methoxy-N-methyl-3-oxopropanamido)-6-methylisonicotinate (3.1 g, 1 Eq, 9.7 mmol), sodium methoxide (2.1 g, 4.0 Eq, 39 mmol), and MeOH (30 mL). The reaction mixture was stirred at 80 °C for 1 hour.
  • Step A1-8 preparation of methyl 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2- dihydro-1,7-naphthyridine-3-carboxylate: Into a 250-mL round-bottom flask was placed a mixture of methyl 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine- 3-carboxylate (3.7 g, 1 Eq, 13 mmol), DCM (37 mL), DMF (0.94 g, 1.0 mL, 1.0 Eq, 13 mmol), and oxalyl chloride (4.9 g, 3.4 mL, 3.0 Eq, 39 mmol).
  • Step A1-9 preparation of methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4- diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate: Into a 250-mL vial was placed a mixture of methyl 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo- 1,2-dihydro-1,7-naphthyridine-3-carboxylate (3.7 g, 1 Eq, 12 mmol), DIEA (4.7 g, 6.3 mL, 3.0 Eq, 36 mmol), tert-butyl (S)-7-methyl-1,4-diazepane-1-carboxylate (4.7 g, 1.8 Eq, 22 mmol), and ACN (40 mL).
  • Step A1-10 preparation of (S)-4-(4-(tertbutoxycarbonyl)-5-methyl-1,4-diazepan-1-yl)- 8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid: Into a 250- mL round-bottom flask was placed a mixture of methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl- 1,4-diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carboxylate (4.7 g, 1 Eq, 9.7 mmol), MeOH (48 mL), water (24 mL), and LiOH (2.3 g, 9.9 Eq, 96 mmol).
  • reaction mixture was stirred at 80 °C for 1.5 hours.
  • the reaction mixture was concentrated under vacuum, and acidified to pH 5 with citric acid.
  • the resulting mixture was extracted with ethyl acetate (3 x 50 mL).
  • the combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na 2 SO 4 , and filtered.
  • Step A1-11 preparation of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(3-ethoxy-4- fluorophenyl)ethyl)carbamoyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-7- methyl-1,4-diazepane-1-carboxylate: Into a 8-mL vial was placed (S)-4-(4-(tert-butoxycarbonyl)- 5-methyl-1,4-diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carboxylic acid (150 mg, 1 Eq, 319 ⁇ mol), HATU (182 mg, 1.50 Eq, 479 ⁇ mol), DIEA (247 mg,
  • Step A1-12 preparation of N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl- 1,4-diazepan-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3- naphthamide:
  • Into a 50-mL vial was placed a mixture of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)- 1-(3-ethoxy-4-fluorophenyl)ethyl)carbamoyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridin- 4-yl)-7-methyl-1,4-diazepane-1-carboxylate (166 mg, 1 Eq, 261 ⁇ mol) and DCM (5 mL), to which was added
  • Step A2-1 preparation of methyl 3-amino-2-bromo-6-methylisonicotinate: Into a 250- mL vial was placed a mixture of methyl 5-amino-2-methylisonicotinate (3.0 g, 1 Eq, 18 mmol; prepared via Steps 1-1 to 1-2 of Example A-1) and DMF (30 mL) to which was added NBS (3.9 g, 1.2 Eq, 22 mmol) at 0 °C.
  • Step A2-2 preparation of methyl 3-amino-2-cyclopropyl-6-methylisonicotinate: Into a 8-mL vial was placed methyl 3-amino-2-bromo-6-methylisonicotinate (3.3 g, 1 Eq, 13 mmol), Pd(OAc) 2 (0.3 g, 0.1 Eq, 1 mmol), potassium phosphate tribasic (8.6 g, 3.4 mL, 3.0 Eq, 41 mmol), cyclopropylboronic acid (3 g, 3 Eq, 0.03 mol), tricyclohexylphosphine (0.76 g, 0.85 mL, 0.20 Eq, 2.7 mmol), toluene (50 mL), and H 2 O (5 mL).
  • Step A2-3, preparation of methyl 2-cyclopropyl-3-(3-ethoxy-3-oxopropanamido)-6- methylisonicotinate Into a 250-mL vial was placed a mixture of methyl 3-amino-2-cyclopropyl- 6-methylisonicotinate (1.6 g, 1 Eq, 7.8 mmol), DIEA (3.0 g, 4.0 mL, 3.0 Eq, 23 mmol), and DCM (50 mL), to which was added a mixture of ethyl 3-chloro-3-oxopropanoate (1.2 g, 1.0 Eq, 8.0 mmol) at 0 °C.
  • Step A2-4 preparation of ethyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro- 1,7-naphthyridine-3-carboxylate/methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro- 1,7-naphthyridine-3-carboxylate:
  • a mixture of methyl 2- cyclopropyl-3-(3-ethoxy-3-oxopropanamido)-6-methylisonicotinate (1.65 g, 1 Eq, 5.15 mmol)
  • sodium methoxide (1.11 g, 1.21 mL, 3.99 Eq, 20.5 mmol
  • MeOH 32 mL
  • Step A2-5 preparation of 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7- naphthyridine-3-carboxylic acid: Into a 8 mL vial were added ethyl 8-cyclopropyl-4-hydroxy-6- methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (528 mg, 1 Eq, 1.83 mmol), methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (432 mg, 0.860 Eq, 1.58 mmol), MeOH (10 mL), and H 2 O (5 mL), followed by LiOH (439 mg, 10.0 Eq, 18.3 mmol).
  • 8-cyclopropyl-4- hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid 800 mg, 1 Eq, 3.07 mmol
  • oxalyl chloride
  • reaction mixture was stirred at 25 °C for 16 hours.
  • the reaction mixture was concentrate under reduced pressure to afford 4-chloro-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonyl chloride (810 mg, 2.73 mmol), which was used directly in the next step without any purification.
  • Step A2-7 preparation of methyl (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3- methoxyphenyl)ethyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxamide:
  • Into a 40- mL vial was placed a mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethan-1-amine (923 mg, 2.00 Eq, 5.46 mmol), DIEA (1.76 g, 2.37 mL, 5.00 Eq, 13.6 mmol), and DCM (10 mL), to which was added a mixture of 4-chloro-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carbonyl chloride (810 mg, 1 Eq, 2.73 mmol) and DCM (5 mL) at
  • the reaction mixture was stirred at 80 °C for 16 hours.
  • the mixture was purified by Flash-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, Water (0.1% NH 3 .H 2 O) and ACN (20.0% ACN increased to 98.0% in 7 min); Total flow rate, 70 mL/min; Detector, UV 220 nm.
  • Step A2-9 preparation of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-(((trifluoromethyl)sulfonyl)oxy)-1,7-naphthyridin- 4-yl)-7-methyl-1,4-diazepane-1-carboxylate: Into a 40-mL vial was placed a mixture of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-oxo- 1,2-dihydro-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate (400 mg,
  • Step A2-10 preparation of tert-butyl (S)-4-(8-cyclopropyl-2-((3-ethoxy-3- oxopropyl)amino)-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7- naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate: Into a 40-mL vial was placed tert- butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2- (((trifluoromethyl)sulfonyl)oxy)-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate: Into
  • Step A2-1 preparation of ethyl 3- ⁇ 3-[N-(S)-1-(4-fluoro-3- methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6-methyl- 1,7-diaza-2-naphthylamino ⁇ propionate:
  • Into a 50-mL round-bottom flask was placed tert-butyl (S)-4-(8-cyclopropyl-2-((3-ethoxy-3-oxopropyl)amino)-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1- carboxylate (30 mg, 1 Eq, 42 ⁇ mol), D
  • Step A3-1 preparation of diethyl 2-(((2-bromo-6-methylpyridin-3- yl)amino)methylene)malonate: Into a 40-mL vial was placed a mixture of 2-bromo-6- methylpyridin-3-amine (5.00 g, 1 Eq, 26.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.94 g, 1.20 Eq, 32.1 mmol).
  • Step A3-2 preparation of diethyl 2-(((2-cyclopropyl-6-methylpyridin-3- yl)amino)methylene)malonate: Into a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of diethyl 2-(((2-bromo-6-methylpyridin-3- yl)amino)methylene)malonate (8.00 g, 1 Eq, 22.4 mmol), cyclopropylboronic acid (10.0 g, 5.20 Eq, 116 mmol), Ruphos Pd 3G (200 mg, 0.0107 Eq, 239 ⁇ mol), potassium carbonate (21.7 g, 7.01 Eq, 157 mmol), toluene (150 mL) and water (30 mL).
  • Step A3-3 preparation of ethyl 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyridine- 3-carboxylate:
  • phenyl ether- biphenyleutetic 50 g, 9.3 Eq, 0.15 mol
  • diethyl 2-(((2-cyclopropyl-6-methylpyridin-3-yl)amino)methylene)malonate 5.25 g, 1 Eq, 16.5 mmol
  • Step A3-4 preparation of 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyridine-3- carboxylic acid: Into a 40-mL vial was placed with mixture of ethyl 8-cyclopropyl-4-hydroxy-6- methyl-1,7-naphthyridine-3-carboxylate (1.00 g, 1 Eq, 3.67 mmol), LiOH (1.00 g, 11.4 Eq, 41.8 mmol) and MeOH (20 mL). Then water (4 mL) was added, and the reaction mixture was stirred at 65 °C for 1 hour.
  • Step A3-5 preparation of 4-chloro-8-cyclopropyl-6-methyl-1,7-naphthyridine-3- carbonyl chloride: Into an 8-mL vial was placed a mixture of 8-cyclopropyl-4-hydroxy-6-methyl- 1,7-naphthyridine-3-carboxylic acid (600 mg, 1 Eq, 2.46 mmol) and POCl 3 (5.0 g, 3.0 mL, 13 Eq, 33 mmol). The reaction mixture was stirred at 100 °C for 30 minutes.
  • Step A3-6 preparation of (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3- methoxyphenyl)ethyl)-6-methyl-1,7-naphthyridine-3-carboxamide:
  • Into a 8-mL vial was placed a mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethan-1-amine (100 mg, 2.1 Eq, 591 ⁇ mol), DIEA (370 mg, 499 ⁇ L, 10 Eq, 2.86 mmol), and DCM (1 mL), to which was added a mixture of 4- chloro-8-cyclopropyl-6-methyl-1,7-naphthyridine-3-carbonyl chloride (80 mg, 1 Eq, 0.28 mmol) and DCM (1 mL) at 0 °C.
  • Step A3-7 preparation of 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidin-3-amine: Into an 8-mL vial was placed tert-butyl (1-benzyl-3-(methoxymethyl)pyrrolidin-3-yl)carbamate (800 mg, 1 Eq, 2.50 mmol) and lithium aluminum(III) hydride (300 mg, 3.17 Eq, 7.91 mmol) in THF (2 mL). The resulting reaction mixture was stirred for 1 hour at 70 °C. The reaction was then quenched by water (5 mL), and the resulting solution was extracted with ethyl acetate (3 x 10 mL).
  • Step A3-8 preparation of tert-butyl (1-benzyl-3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate: A mixture of 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidin-3-amine (700 mg, 1 Eq, 2.99 mmol), di-tert-butyl dicarbonate (900 mg, 1.38 Eq, 4.12 mmol), and TEA (1000 mg, 1.38 mL, 3.31 Eq, 9.882 mmol) in DCM (10 mL) was stirred at 25 °C for 16 hours. Then water (20 mL) was added, and the reaction mixture was extracted with EtOAc (30 mL x 2).
  • Step A3-9 preparation of tert-butyl (3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate: Into a 50-mL round bottom was placed tert-butyl (1-benzyl-3- (methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate (530 mg, 1 Eq, 1.58 mmol), MeOH (10 mL), and Pd-C (200 mg, 1.19 Eq, 1.88 mmol) under a hydrogen (H 2 ) atmosphere.
  • Step A3-10 preparation of tert-butyl (1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-3- (methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate: Into an 8-mL vial was placed a mixture of (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-1,7-naphthyridine- 3-carboxamide (60 mg, 1 Eq, 0.14 mmol), tert-butyl (3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate (100 mg, 2.8 Eq, 409 ⁇ mol), DIEA (60 mg, 81 ⁇
  • the reaction mixture was stirred at 110 °C for 16 hours.
  • the mixture was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19*150mm, 5 ⁇ m; mobile phase, water (0.1% FA) and ACN (30% ACN increased to 98% in 7 mins); Total flow rate, 20 mL/min; Detector, UV 220 nm.
  • Step A3-11 preparation of N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl- 4-[3-(methoxymethyl)-3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide: Into an 8-mL vial was placed tert-butyl (1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-3- (methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate (50 mg, 1 Eq, 80 ⁇ mol), DCM (3 mL), and TFA (1 mL).
  • the resulting reaction mixture was stirred for 1 hour at 25 °C.
  • the mixture was purified by prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5 ⁇ m; mobile phase, water (0.05% NH 3 .H 2 O) and ACN (30.0% ACN increased to 50.0% in 7 mins); Total flow rate, 20 mL/min; Detector, UV 220nm.
  • Step A4-1 preparation of diethyl 2-(((2-methoxy-6-methylpyridin-3- yl)amino)methylene)malonate: Into a 100-mL flask was placed 2-methoxy-6-methylpyridin-3- amine (5 g, 1 Eq, 0.04 mol) and diethyl 2-(ethoxymethylene)malonate (15.6 g, 2 Eq, 72.1 mmol).
  • Step A4-2 preparation of ethyl 4-hydroxy-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylate: To a boiling phenyl ether-biphenyleutectic (220.0 g, 207.7 mL, 19.9 Eq, 678.1 mmol) at 252 °C was added diethyl 2-(((2-methoxy-6-methylpyridin-3- yl)amino)methylene)malonate (10.5 g, 1 Eq, 34.1 mmol) in portions, and the reaction
  • Step A4-3 preparation of ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylate: Into a 1000-mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of ethyl 4-hydroxy-8-methoxy-6-methyl-1,7- naphthyridine-3-carboxylate (8 g, 1 Eq, 0.03 mol), DMF (0.09 g, 0.1 mL, 0.04 Eq, 1 mmol), and DCM (400 mL), to which oxalyl chloride (5 g, 3 mL, 1.3 Eq, 0.04 mol) was added dropwise at 0 °C over 10 minutes.
  • oxalyl chloride 5 g, 3 mL, 1.3 Eq, 0.04 mol
  • Step A4-4 preparation of ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5- dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthyridine-3-carboxylate: Into a 250-mL vial was placed a solution of ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylate (150 mg, 1 Eq, 534 ⁇ mol) and DIEA (138 mg, 186 ⁇ L, 2.0 Eq, 1.07 mmol) in ACN (1.5 mL).
  • Step A4-5 preparation of 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1- yl)-8-methoxy-6-methyl-1,7-naphthyridine-3-carboxylic acid: Into a 40-mL vial was placed a mixture of ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6- methyl-1,7-naphthyridine-3-carboxylate (240 mg, 1 Eq, 523 ⁇ mol), lithium hydroxide (127 mg, 10.1 Eq, 5.29 mmol), MeOH (5 mL), and H 2 O (2.5 mL).
  • reaction mixture was stirred at 80 °C for 1 hour.
  • Step A4-6 preparation of tert-butyl (2S,6R)-4-(3-(((S)-1-(3,5- dimethoxyphenyl)ethyl)carbamoyl)-8-methoxy-6-methyl-1,7-naphthyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate:
  • Into a 8-mL vial was placed a solution of 4-((3S,5R)-4-(tert- butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylic acid (100 mg, 1.0 Eq, 232 ⁇ mol), DIEA (150 mg, 202 ⁇ L, 5.0 Eq, 1.16 mmol), and HATU (132 mg, 1.5 Eq, 348 ⁇ mol) in DMF (2 mL).
  • Step A4-7 preparation of N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5- dimethyl-1-piperazinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthamide:
  • Prep-HPLC-013 Column, SunFire Prep C18 OBD Column, 19*150mm 5 ⁇ m 10 nm; mobile phase, Water (0.1% NH 3 .H 2 O) and ACN (15% ACN increased to 50% in 10 mins). Total flow 20 mL/min. Detector UV 220 nm.
  • Example B-1 SSTR assays Functional Assays
  • GPCRs Gi coupled G-protein coupled receptors
  • cAMP intracellular cyclic AMP
  • cAMP assay protocol for SSTR3 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 ⁇ g/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% 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 ⁇ L of stimulation buffer supplemented with 10.2 mM 3-isobutyl-1- methylxanthine (IBMX, Millipore Sigma #I5879) and 1.6 ⁇ M 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 ⁇ L 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 ⁇ L 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 m1000 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 EC 50 of the compounds are calculated using standard methods. All data manipulations are in GraphPad Prism v9 (GraphPad, San Diego, CA). [00443] Table A reports biological activity of compounds as evaluated by inhibition of cAMP activities via human SSTR3 receptor.

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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 Application 63/585,880, filed September 27, 2023, which is herein incorporated by reference in its entirety. FIELD 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. BACKGROUND OF THE INVENTION [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 Pkd1RC/RC model. [0006] In clinical trials using octreotide or lanreotide (which both 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. BRIEF SUMMARY OF THE INVENTION [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. These compounds are compounds of Formula (I) having the general structure shown below and their pharmaceutically acceptable salts:
Figure imgf000003_0001
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R6 is H or C1-6 alkyl;
Figure imgf000004_0001
R7 is H, C1-6 alkoxy, morpholinyl optionally substituted with C1-6 alkyl,
Figure imgf000004_0002
,
Figure imgf000004_0003
; R8 is H or C1-6 alkyl; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; R11 is C1-6 alkyl;
Figure imgf000004_0004
; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; RC is H or C1-6 haloalkyl; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl. [0008] In one embodiment, the compound of Formula (I) is selected from -compounds of Formula (Ia):
Figure imgf000005_0001
) wherein: R2 is H, halogen, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R4 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R6 is H or C1-6 alkyl; and R8 is H or C1-6 alkyl; - compounds of Formula (Ib):
Figure imgf000005_0002
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, then X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R7 is H, C1-6 alkoxy, morpholinyl optionally substituted with C1-6 alkyl
Figure imgf000006_0001
, ,
Figure imgf000006_0002
; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and RC is H or C1-6 haloalkyl; - compounds of Formula (Ic):
Figure imgf000006_0003
) wherein: Z is CR3 or N; R2 is H, halogen, or C1-6 alkoxy; R3 is H, halogen, or C1-6 alkoxy; R4 is H, halogen, or C1-6 alkoxy; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl; - compounds of Formula (Id):
Figure imgf000007_0001
) wherein: R2 is halogen, C1-6 alkoxy, or CN; R4 is halogen or C1-6 alkoxy; and R9 is C1-6 alkoxy or C3-6 cycloalkyl; and pharmaceutically acceptable salts of any of the foregoing. [0009] In one embodiment, described herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0002
) wherein: R2 is H, halogen, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R4 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R6 is H or C1-6 alkyl; and R8 is H or C1-6 alkyl. [0010] In an embodiment, R2 is H, halogen, C1-3 alkoxy, or CN; R3 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN; R4 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN; R6 is H or C1-3 alkyl; and R8 is H or C1-3 alkyl. [0011] In an embodiment, R3 is halogen or C1-3 alkoxy. [0012] In an embodiment, R4 is C1-3 alkoxy. [0013] In an embodiment, R6 is H or Me. [0014] In an embodiment, R8 is H or Me. [0015] In an embodiment, R2 is H; R3 is halogen or C1-3 alkoxy; R4 is C1-3 alkoxy; R6 is H or Me; and R8 is H or Me. [0016] In an embodiment, R2 is H, F, Cl, OMe, or CN. [0017] In an embodiment, R3 is H, F, Cl, OMe, CF3, or CN. [0018] In an embodiment, R4 is F, Cl, OMe, OEt, CF3, or CN. [0019] In an embodiment, R2 is H, F, Cl, OMe, or CN; R3 is H, F, Cl, OMe, CN, or CF3; R4 is F, Cl, OMe, OEt, CF3, or CN; R6 is H or Me; and R8 is H or Me. [0020] In an embodiment, R2 is H. [0021] In an embodiment, R3 is F or OMe. [0022] In an embodiment, R4 OMe or OEt. [0023] In an embodiment, R6 is H. [0024] In an embodiment, R8 is H. [0025] In an embodiment, R8 is Me. [0026] In an embodiment, the compound is selected from: , , ,
Figure imgf000008_0001
, , , , , , ,
Figure imgf000009_0001
, d
Figure imgf000010_0001
[0027] In another embodiment, described herein is a compound of Formula (Ib), an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000010_0002
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R7 is H, C1-6 alkoxy, morpholinyl optionally substituted with C1-6 alkyl
Figure imgf000010_0003
, ,
Figure imgf000010_0004
; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and RC is H or C1-6 haloalkyl. [0028] In an embodiment, R1 is H, halogen, or OH; R2 is H, halogen, C1-3 alkyl, C1-3 alkoxy, or CN; R3 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; R4 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R7 is H, C1-3 alkoxy, morpholinyl optionally substituted with C1-3 alkyl,
Figure imgf000011_0001
r
Figure imgf000011_0002
; R9 is C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyclopropyl, or cyclopropoxy; R10 is C1-3 alkyl or C1-3 alkoxy; RA is C1-3 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-4 cycloalkyl; and RC is H or C1-3 haloalkyl. [0029] In an embodiment, R1 is H, F, or OH. [0030] In an embodiment, R2 is H, F, Cl, Me, OMe, or CN. [0031] In an embodiment, R3 is H, F, Cl, Me, CF3, OMe, or CN. [0032] In an embodiment, R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2. [0033] In an embodiment, R5 is H, F, OH. ,
Figure imgf000011_0003
[0035] In an embodiment, R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy. [0036] In an embodiment, R10 is Me or OMe. [0037] In an embodiment, RA is Me, CH2OH, or CH2OMe and RB is H. [0038] In an embodiment, RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group. [0039] In an embodiment, RC is H or CH2CH2F. [0040] In an embodiment, R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is H,
Figure imgf000012_0001
r
Figure imgf000012_0002
; R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R10 is Me or OMe; RA is Me, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group; and RC is H or CH2CH2F. [0041] In an embodiment, R1 is H or OH. [0042] In an embodiment, R2 is H or F. [0043] In an embodiment, R3 is H, F, OMe, or CN. [0044] In an embodiment, R4 is Cl, OMe, or CN. [0045] In an embodiment, R5 is H. [0046] In an embodiment
Figure imgf000012_0003
. [0047] In an embodiment, R9 is OMe or cyclopropyl. [0048] In an embodiment, R10 is Me. [0049] In an embodiment, RA is Me and RB is H. [0050] In an embodiment, RA and RB together with the carbon atom to which they are attached form a cyclopropyl group. [0051] In an embodiment, RC is H. [0052] In an embodiment, R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe,
Figure imgf000012_0004
r cyclopropyl; R10 is Me; RA is Me; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group; and RC is H. [0053] In an embodiment, X CR1; Y is CR2; and Z is CR3. [0054] In an embodiment, one of X, Y, or Z is N. [0055] In an embodiment, the compound is selected from:
Figure imgf000013_0001
, , , , , , , , , , , , , , , , , ,
Figure imgf000014_0001
, , , , , , , , ,
Figure imgf000015_0001
, , , , , , ,
Figure imgf000016_0001
, , , , , , ,
Figure imgf000017_0001
,
Figure imgf000018_0001
a pharmaceutically acceptable salt thereof . [0056] In another embodiment, described herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof:
Figure imgf000018_0002
) wherein: Z is CR3 or N; R2 is H, halogen, or C1-6 alkoxy; R3 is H, halogen, or C1-6 alkoxy; R4 is H, halogen, or C1-6 alkoxy; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl. [0057] In an embodiment, R2 is H, halogen, or C1-3 alkoxy; R3 is H, halogen, or C1-3 alkoxy; R4 is H, halogen, or C1-3 alkoxy; RD is C1-3 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl. [0058] In an embodiment, R2 is H, F, or OMe. [0059] In an embodiment, R3 is H, F, or OMe. [0060] In an embodiment, R4 is F or OMe. [0061] In an embodiment, RD is Me or Et. [0062] In an embodiment, RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. [0063] In an embodiment, the compound is selected from: , ,
Figure imgf000019_0001
,
Figure imgf000020_0001
a pharmaceutically acceptable salt thereof. [0064] In another embodiment, described herein is a compound of Formula (Id), or a pharmaceutically acceptable salt thereof:
Figure imgf000020_0002
) wherein: R2 is halogen, C1-6 alkoxy, or CN; R4 is halogen or C1-6 alkoxy; and R9 is C1-6 alkoxy or C3-6 cycloalkyl. [0065] In an embodiment, R2 is halogen, C1-3 alkoxy, or CN; R4 is halogen or C1-3 alkoxy; and R9 is C1-3 alkoxy or cyclopropyl. [0066] In an embodiment, R2 is F, OMe, or CN. [0067] In an embodiment, R4 is F or OMe. [0068] In an embodiment, R9 is OMe or cyclopropyl. [0069] In an embodiment, the compound is selected from: d
Figure imgf000020_0003
[0070] In another embodiment, also disclosed herein, is a method of treating a disorder selected from polycystic kidney disease, polycystic liver disease, and ciliopathies, comprising administering to a subject in need thereof a compound of Formula (I), Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD). [0071] In another embodiment, provided herein is a compound of Formula (I), Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from polycystic kidney disease, polycystic liver disease, and ciliopathies. In some embodiments, the disorder is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD). [0072] In another embodiment, provided herein is the use of a compound of a compound of Formula (I), Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from polycystic kidney disease, polycystic liver disease, and ciliopathies. In some embodiments, the disorder is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD). BRIEF DESCRIPTION OF THE DRAWINGS [0073] FIG.1 depicts how abnormal primary cilia function triggers cystogenesis in autosomal dominant polycystic kidney disease (ADPKD). [0074] FIG.2 depicts interplay of calcium ions and cAMP ciliary signaling pathways in renal tissue of (A) healthy individuals and (B) individuals with ADPKD. [0075] FIG.3 depicts the mechanism of action by which SSTR3 activation can inhibit adenylyl cyclase activity and decrease cilio-plasma cAMP levels. [0076] 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 [0077] Somatostatin (SSTR), also known as somatotropin release inhibiting factor (SRIF) was initially isolated as a 14-amino acid peptide from ovine hypothalami (Brazeau et al., Science 179, 77-79, 1973). An N-terminal extended 28-amino acid peptide with similar biological activity to 14-amino acid somatostatin was subsequently isolated (Pradayrol et, al., FEBS Letters, 109, 55- 58, 1980; Esch et al., Proc. Natl. Acad. Sci. U S A, 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. [0078] 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. [0079] 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. [0080] 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 [0081] 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 that forms the 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 [0082] 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. [0083] 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. [0084] 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 β-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. [0085] 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 polycystin- 1 or polycystin-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 cys t 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, resulting in 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. [0086] 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 polycystin-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). [0087] 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 Ca 2+ 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). [0088] In ADPKD patients, mutation in polycystin-1 or 2 leads to the formation of non- functional 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). [0089] 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 cross- talk 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. [0090] 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 th e 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. [0091] 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 PKD1-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. [0092] 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. Dysregulation 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. [0093] 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. [0094] 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. [0095] 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 [0096] Provided are compounds of Formula (I), including pharmaceutically acceptable salts thereof, which are somatostatin subtype 3 receptor (SSTR3) agonists. [0097] Compounds of Formula (I) have the structure shown below:
Figure imgf000026_0001
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R6 is H or C1-6 alkyl; l
Figure imgf000027_0001
, ,
Figure imgf000027_0003
R8 is H or C1-6 alkyl; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; R11 is C1-6 alkyl;
Figure imgf000027_0002
; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; RC is H or C1-6 haloalkyl; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl. [0098] In certain embodiments, the compound of Formula (I) is selected from - compounds of Formula (Ia):
Figure imgf000028_0001
) wherein: R2 is H, halogen, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R4 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R6 is H or C1-6 alkyl; and R8 is H or C1-6 alkyl; - compounds of Formula (Ib):
Figure imgf000028_0002
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R7 is H, C1-6 alkoxy, morpholinyl optionally substituted with C1-6 alkyl
Figure imgf000029_0001
, ,
Figure imgf000029_0002
; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and RC is H or C1-6 haloalkyl; - compounds of Formula (Ic):
Figure imgf000029_0003
) wherein: Z is CR3 or N; R2 is H, halogen, or C1-6 alkoxy; R3 is H, halogen, or C1-6 alkoxy; R4 is H, halogen, or C1-6 alkoxy; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl; - compounds of Formula (Id):
Figure imgf000030_0001
) wherein: R2 is halogen, C1-6 alkoxy, or CN; R4 is halogen or C1-6 alkoxy; and R9 is C1-6 alkoxy or C3-6 cycloalkyl; and pharmaceutically acceptable salts of any of the foregoing. [0099] In certain embodiments, in the compounds of Formula (I), X is CR1, Y is CR2, and Z is is
Figure imgf000030_0003
ula (I) are compounds of Formula (Ia). [00100] In certain embodiments, the compound is a compound of Formula (Ia):
Figure imgf000030_0002
) wherein: R2 is H, halogen, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R4 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R6 is H or C1-6 alkyl; and R8 is H or C1-6 alkyl; or a pharmaceutically acceptable salt thereof . [00101] In certain embodiments, R2 is H, halogen, C1-3 alkoxy, or CN; R3 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN; R4 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN; R6 is H or C1- 3 alkyl; and R8 is H or C1-3 alkyl. [00102] In certain embodiments, R2 is H, F, Cl, Br, I, methoxy (OMe), ethoxy (OEt), n-propoxy (O-nPr), isopropoxy (O-iPr), or CN; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, or CN; R6 is H, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr) or CN; R4 is H, F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, or CN; R6 is H, methyl (Me), ethyl (Et), n-propyl (nPr) or isopropyl (iPr); and R8 is R6 is H, methyl (Me), ethyl (Et), n-propyl (nPr) or isopropyl (iPr). [00103] In certain embodiments, R2 is H or R4 is H. [00104] In certain embodiments, R2 is H; R3 is halogen or C1-3 alkoxy; R4 is C1-3 alkoxy; R6 is H or Me; and R8 is H or Me. [00105] In certain embodiments, R2 is H; R3 is halogen or C1-3 alkoxy; R4 is C1-3 alkoxy; R6 is H; and R8 is H or Me. [00106] In certain embodiments, R2 is H, F, Cl, OMe, or CN; R3 is H, F, Cl, OMe, CN, or CF3; R4 is F, Cl, OMe, OEt, CF3, or CN; R6 is H or Me; and R8 is H or Me. [00107] In certain embodiments, R2 is H; R3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R4 is OMe, OEt, O-nPr, or O-iPr; R6 is H or Me; and R8 is H or Me. [00108] In certain embodiments, R2 is H; R3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R4 is OMe, OEt, O-nPr, or O-iPr; R6 is H or Me; and R8 is H or Me. [00109] In certain embodiments, R2 is H; R3 is F or OMe; R4 is OMe or OEt; R6 is H; and R8 is H or Me. [00110] In certain embodiments, R2 is H, halogen, C1-3 alkoxy, or CN. In certain embodiments, R2 is H, F, Cl, or CN. In certain embodiments, R2 is H. In certain embodiments, R2 is F. In certain embodiments, R2 is Cl. In certain embodiments, R2 is OMe. In certain embodiments, R2 is CN. [00111] In certain embodiments, R3 is halogen or C1-3 alkoxy. In certain embodiments, R3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr. In certain embodiments, R3 is halogen. In certain embodiments, R3 is F, Cl, Br, or I. In certain embodiments, R3 is C1-3 alkoxy. In certain embodiments, R3 is OMe, OEt, O-nPr, or O-iPr. [00112] In certain embodiments, R3 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN. In certain embodiments, R3 is H, F, Cl, OMe, CF3, or CN. In certain embodiments, R3 is F or OMe. In certain embodiments, R3 is H. In certain embodiments, R3 is F. In certain embodiments, R3 is Cl. In certain embodiments, R3 is OMe. In certain embodiments, R3 is CF3. In certain embodiments, R3 is CN. [00113] In certain embodiments, R4 is C1-3 alkoxy. In certain embodiments, R4 is OMe, OEt, O- nPr, or O-iPr. In certain embodiments, R4 is OMe or OEt. In certain embodiments, R4 is OMe. In certain embodiments, R4 is OEt. In certain embodiments, R4 is O-nPr. In certain embodiments, R4 is O-iPr. [00114] In certain embodiments, R4 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN. In certain embodiments, R4 is F, Cl, OMe, OEt, CF3, or CN. In certain embodiments, R4 is OMe or OEt. In certain embodiments, R4 is F. In certain embodiments, R4 is Cl. In certain embodiments, R4 is OMe. In certain embodiments, R4 is OEt. In certain embodiments, R4 is CF3. In certain embodiments, R4 is CN. [00115] In certain embodiments, R6 is H or C1-3 alkyl. In certain embodiments, R6 is H or Me. In certain embodiments, R6 is H. In certain embodiments, R6 is Me. [00116] In certain embodiments, R8 is H or C1-3 alkyl. In certain embodiments, R8 is H or Me. In certain embodiments, R8 is H. In certain embodiments, R8 is Me. [00117] In certain embodiments, the compound of Formula (Ia) is selected from: , ,
Figure imgf000032_0001
, , , , , , ,
Figure imgf000033_0001
,
Figure imgf000034_0001
d
Figure imgf000034_0002
, or a pharmaceutically acceptable salt thereof . [00118] In certain embodiments, the compound of Formula (Ia) is a compound as set forth in Table 1. [00119] In certain embodiments, the compound of Formula (Ia) is compound 1. [00120] In certain embodiments, the compound of Formula (Ia) is compound 2. [00121] In certain embodiments, the compound of Formula (Ia) is compound 3. [00122] In certain embodiments, the compound of Formula (Ia) is compound 4. [00123] In certain embodiments, the compound of Formula (Ia) is compound 5. [00124] In certain embodiments, the compound of Formula (Ia) is compound 6. [00125] In certain embodiments, the compound of Formula (Ia) is compound 7. [00126] In certain embodiments, the compound of Formula (Ia) is compound 8. [00127] In certain embodiments, the compound of Formula (Ia) is compound 9. [00128] In certain embodiments, the compound of Formula (Ia) is compound 10. [00129] In certain embodiments, the compound of Formula (Ia) is compound 11. [00130] In certain embodiments, the compound of Formula (Ia) is compound 12. [00131] In certain embodiments, the compound of Formula (Ia) is compound 13. [00132] In certain embodiments, the compound of Formula (Ia) is compound 14. [00133] In certain embodiments, the compound of Formula (Ia) is compound 15. [00134] In certain embodiments, the compound of Formula (Ia) is compound 16. [00135] In certain embodiments, the compound of Formula (Ia) is compound 17. [00136] In certain embodiments, the compound of Formula (Ia) is compound 18. [00137] In certain embodiments, the compound of Formula (Ia) is compound 19. [00138] In certain embodiments, the compound of Formula (Ia) is compound 20. [00139] In certain embodiments, the compound of Formula (Ia) is compound 21. [00140] In certain embodiments, the compound of Formula (Ia) is compound 22. [00141] In certain embodiments, the compound of Formula (Ia) is compound 23. [00142] In certain embodiments, the compound of Formula (Ia) is compound 24. [00143] In certain embodiments, the compound of Formula (Ia) is compound 25. [00144] In certain embodiments, the compound of Formula (Ia) is compound 26. [00145] In certain embodiments, the compound of Formula (Ia) is compound 27. [00146] In certain embodiments, the compound of Formula (Ia) is compound 28. [00147] In certain embodiments, the compound of Formula (Ia) is compound 29. [00148] In certain embodiments, the compound of Formula (Ia) is compound 30. [00149] In certain embodiments, the compound of Formula (Ia) is compound 31. [00150] In certain embodiments, the compound of Formula (Ia) is compound 32. [00151] In certain embodiments, the compound of Formula (Ia) is compound 33. [00152] In certain embodiments, the compound of Formula (Ia) is compound 34. [00153] In certain embodiments, the compound of Formula (Ia) is compound 35. [00154] In certain embodiments, the compound of Formula (Ia) is compound 36. [00155] In certain embodiments, the compound of Formula (Ia) is compound 168. [00156] In certain embodiments, in the compounds of Formula (I), R6 is H; R11 is methyl; J is
Figure imgf000035_0001
n this embodiment, the compounds of Formula (I) are compounds of Formula (Ib). [00157] In certain embodiments, the compound is a compound of Formula (Ib):
Figure imgf000035_0002
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, then X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH;
Figure imgf000036_0001
R7 is H, C1-6 alkoxy, morpholinyl optionally substituted with C1-6 alkyl,
Figure imgf000036_0002
,
Figure imgf000036_0003
; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and RC is H or C1-6 haloalkyl; or an N-oxide thereof or a pharmaceutically acceptable salt thereof. [00158] In certain embodiments, X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, then X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-3 alkyl, C1-3 alkoxy, or CN; R3 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; R4 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R7 is H, C1-3 alkoxy, morpholinyl optionally substituted with C1-3 alkyl, , , or ; R9 is C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyclopropyl, or cyclopropoxy; R10 is C1-3 alkyl or C1-3 alkoxy; RA is C1-3 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-4 cycloalkyl; and RC is H or C1-3 haloalkyl. [00159] In certain embodiments, X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, then X is CR1 and Y is CR2; R1 is H, F, Cl, Br, I, or OH; R2 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr, O-iPr, or CN; R3 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, OMe, OEt, O-nPr, O-iPr, or CN; R4 is H, H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, OMe, OEt, O-nPr, O-iPr, C1 haloalkoxy, C2 haloalkoxy, C3 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, ha F, Cl, Br, I, or OH; R7 is H, OMe, OEt, O-nPr, O- iPr, morpholinyl optionally substitute
Figure imgf000037_0001
e, Et, n-Pr, i-Pr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, OMe, OEt, O-nPr, O-iPr, cyclopropyl, or cyclopropoxy; R10 is Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr, or O-iPr; RA is Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr, O-iPr, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl; and RC is H or C1 haloalkyl, C2 haloalkyl, or C3 haloalkyl. [00160] In certain embodiments, R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is
Figure imgf000037_0002
r
Figure imgf000037_0003
; R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R10 is Me or OMe; RA is Me, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group; and RC is H or CH2CH2F. [00161] In certain embodiments, X is CR1; Y is CR2; and Z is CR3; R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe,
Figure imgf000037_0004
cyclopropoxy; R10 is Me or OMe; RA is Me, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group; and RC is H or CH2CH2F. [00162] In certain embodiments, one of X, Y, or Z is N; R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3,
Figure imgf000038_0001
,
Figure imgf000038_0002
is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R10 is Me or OMe; RA is Me, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group; and RC is H or CH2CH2F. [00163] In certain embodiments, R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl,
Figure imgf000038_0003
r cyclopropyl; R10 is Me; RA is Me; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group; and RC is H. [00164] In certain embodiments, X is CR1; Y is CR2; and Z is CR3; R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H; R7 is H, OMe, or ; R9 is OMe or cyclopropyl; R10 is Me; RA is Me; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group; and RC is H. [00165] In certain embodiments, one of X, Y, or Z is N; R1 is H or OH; R2 is H or F; R3 is H, F,
Figure imgf000038_0004
r cyclopropyl; R10 is Me; RA is Me; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group; and RC is H. [00166] In certain embodiments, R1 is H, halogen, or OH. In certain embodiments, R1 is H, F, or OH. In certain embodiments, R1 is H or OH. In certain embodiments, R1 is H. In certain embodiments, R1 is F. In certain embodiments, R1 is OH. [00167] In certain embodiments, R2 is H, halogen, C1-3 alkyl, C1-3 alkoxy, or CN. In certain embodiments, R2 is H, F, Cl, Me, OMe, or CN. In certain embodiments, R2 is H or F. In certain embodiments, R2 is H. In certain embodiments, R2 is F. In certain embodiments, R2 is Cl. In certain embodiments, R2 is Me. In certain embodiments, R2 is OMe. In certain embodiments, R2 is CN. [00168] In certain embodiments, R3 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN. In certain embodiments, R3 is H, F, Cl, Me, CF3, OMe, or CN. In certain embodiments, R3 is H, F, OMe, or CN. In certain embodiments, R3 is H. In certain embodiments, R3 is F. In certain embodiments, R3 is Cl. In certain embodiments, R3 is Me. In certain embodiments, R3 is CF3. In certain embodiments, R3 is OMe. In certain embodiments, R3 is CN. [00169] In certain embodiments, R4 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, CN, OH, or C(O)NH2. In certain embodiments, R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2. In certain embodiments, R4 is Cl, OMe, or CN. In certain embodiments, R4 is H. In certain embodiments, R4 is F. In certain embodiments, R4 is Cl. In certain embodiments, R4 is Me. In certain embodiments, R4 is CF3. In certain embodiments, R4 is OMe. In certain embodiments, R4 is OEt. In certain embodiments, R4 is OCF3. In certain embodiments, R4 is CN. In certain embodiments, R4 is OH. In certain embodiments, R4 is C(O)NH2. [00170] In certain embodiments, R5 is H, halogen, or OH. In certain embodiments, R5 is H, F, or OH. In certain embodiments, R5 is H. In certain embodiments, R5 is F. In certain embodiments, R5 is OH. [00171] In certain embodiments, R7 is H, C1-3 alkoxy, morpholinyl optionally substituted with C1-3 alkyl
Figure imgf000039_0001
n certain embodiments, R7 is H, OMe,
Figure imgf000039_0002
n embodiments, R7 is H, OMe, or
Figure imgf000039_0003
. In certain embodiments, R7 is H. In certain embodiments, R7 is OMe. In certain embodiments, R7 is
Figure imgf000039_0004
. In certain embodiments, R7 is
Figure imgf000040_0002
. In certain embodiments, R7 i
Figure imgf000040_0003
. In certain embodiments
Figure imgf000040_0001
.
Figure imgf000040_0004
Figure imgf000040_0005
In certain embodiments, R7 is . In certain embodiments, R7 is . [00172] In certain embodiments, R9 is C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyclopropyl, or cyclopropoxy. In certain embodiments, R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy. In certain embodiments, R9 is OMe or cyclopropyl. In certain embodiments, R9 is ethyl. In certain embodiments, R9 is CF3. In certain embodiments, R9 is OMe. In certain embodiments, R9 is OEt. In certain embodiments, R9 is cyclopropyl. In certain embodiments, R9 is cyclopropoxy. [00173] In certain embodiments, R10 is C1-3 alkyl or C1-3 alkoxy. In certain embodiments, R10 is Me or OMe. In certain embodiments, R10 is Me. In certain embodiments, R10 is OMe. [00174] In certain embodiments, RA is C1-3 alkyl, CH2OH, or CH2OMe; and RB is H. In certain embodiments, RA is Me, CH2OH, or CH2OMe; and RB is H. In certain embodiments, RA is Me; and RB is H. In certain embodiments, RA is CH2OH; and RB is H. In certain embodiments, RA is CH2OMe; and RB is H. [00175] In certain embodiments, RA and RB together with the carbon atom to which they are attached form a C3-4 cycloalkyl. In certain embodiments, RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group. In certain embodiments, RA and RB together with the carbon atom to which they are attached form a cyclopropyl group. In certain embodiments, RA and RB together with the carbon atom to which they are attached form a cyclobutyl group. [00176] In certain embodiments, RC is H or C1-3 haloalkyl. In certain embodiments, RC is H or CH2CH2F. In certain embodiments, RC is H. In certain embodiments, RC is CH2CH2F. [00177] In certain embodiments, X is CR1; Y is CR2; and Z is CR3. [00178] In certain embodiments, one of X, Y, or Z is N. In certain embodiments, X is N. In certain embodiments, Y is N. In certain embodiments, Z is N. [00179] In certain embodiments, the compound of Formula (Ib) is an N-oxide thereof. [00180] In certain embodiments, the compound of Formula (Ib) is selected from: , , , , , ,
Figure imgf000041_0001
, , , , , , ,
Figure imgf000042_0001
, , , , , , ,
Figure imgf000043_0001
, , , , , , ,
Figure imgf000044_0001
, , , , , , ,
Figure imgf000045_0001
,
Figure imgf000046_0001
a pharmaceutically acceptable salt thereof. [00181] In certain embodiments, the compound of Formula (Ib) is a compound as set forth in Table 2. [00182] In certain embodiments, the compound of Formula (Ib) is compound 37. [00183] In certain embodiments, the compound of Formula (Ib) is compound 38. [00184] In certain embodiments, the compound of Formula (Ib) is compound 39. [00185] In certain embodiments, the compound of Formula (Ib) is compound 40. [00186] In certain embodiments, the compound of Formula (Ib) is compound 41. [00187] In certain embodiments, the compound of Formula (Ib) is compound 42. [00188] In certain embodiments, the compound of Formula (Ib) is compound 43. [00189] In certain embodiments, the compound of Formula (Ib) is compound 44. [00190] In certain embodiments, the compound of Formula (Ib) is compound 45. [00191] In certain embodiments, the compound of Formula (Ib) is compound 46. [00192] In certain embodiments, the compound of Formula (Ib) is compound 47. [00193] In certain embodiments, the compound of Formula (Ib) is compound 48. [00194] In certain embodiments, the compound of Formula (Ib) is compound 49. [00195] In certain embodiments, the compound of Formula (Ib) is compound 50. [00196] In certain embodiments, the compound of Formula (Ib) is compound 51. [00197] In certain embodiments, the compound of Formula (Ib) is compound 52. [00198] In certain embodiments, the compound of Formula (Ib) is compound 53. [00199] In certain embodiments, the compound of Formula (Ib) is compound 54. [00200] In certain embodiments, the compound of Formula (Ib) is compound 55. [00201] In certain embodiments, the compound of Formula (Ib) is compound 56. [00202] In certain embodiments, the compound of Formula (Ib) is compound 57. [00203] In certain embodiments, the compound of Formula (Ib) is compound 58. [00204] In certain embodiments, the compound of Formula (Ib) is compound 59. [00205] In certain embodiments, the compound of Formula (Ib) is compound 60. [00206] In certain embodiments, the compound of Formula (Ib) is compound 61. [00207] In certain embodiments, the compound of Formula (Ib) is compound 62. [00208] In certain embodiments, the compound of Formula (Ib) is compound 63. [00209] In certain embodiments, the compound of Formula (Ib) is compound 64. [00210] In certain embodiments, the compound of Formula (Ib) is compound 65. [00211] In certain embodiments, the compound of Formula (Ib) is compound 66. [00212] In certain embodiments, the compound of Formula (Ib) is compound 67. [00213] In certain embodiments, the compound of Formula (Ib) is compound 68. [00214] In certain embodiments, the compound of Formula (Ib) is compound 69. [00215] In certain embodiments, the compound of Formula (Ib) is compound 70. [00216] In certain embodiments, the compound of Formula (Ib) is compound 71. [00217] In certain embodiments, the compound of Formula (Ib) is compound 72. [00218] In certain embodiments, the compound of Formula (Ib) is compound 73. [00219] In certain embodiments, the compound of Formula (Ib) is compound 74. [00220] In certain embodiments, the compound of Formula (Ib) is compound 75. [00221] In certain embodiments, the compound of Formula (Ib) is compound 76. [00222] In certain embodiments, the compound of Formula (Ib) is compound 77. [00223] In certain embodiments, the compound of Formula (Ib) is compound 78. [00224] In certain embodiments, the compound of Formula (Ib) is compound 79. [00225] In certain embodiments, the compound of Formula (Ib) is compound 80. [00226] In certain embodiments, the compound of Formula (Ib) is compound 81. [00227] In certain embodiments, the compound of Formula (Ib) is compound 82. [00228] In certain embodiments, the compound of Formula (Ib) is compound 83. [00229] In certain embodiments, the compound of Formula (Ib) is compound 84. [00230] In certain embodiments, the compound of Formula (Ib) is compound 85. [00231] In certain embodiments, the compound of Formula (Ib) is compound 86. [00232] In certain embodiments, the compound of Formula (Ib) is compound 87. [00233] In certain embodiments, the compound of Formula (Ib) is compound 88. [00234] In certain embodiments, the compound of Formula (Ib) is compound 89. [00235] In certain embodiments, the compound of Formula (Ib) is compound 90. [00236] In certain embodiments, the compound of Formula (Ib) is compound 91. [00237] In certain embodiments, the compound of Formula (Ib) is compound 92. [00238] In certain embodiments, the compound of Formula (Ib) is compound 93. [00239] In certain embodiments, the compound of Formula (Ib) is compound 94. [00240] In certain embodiments, the compound of Formula (Ib) is compound 95. [00241] In certain embodiments, the compound of Formula (Ib) is compound 96. [00242] In certain embodiments, the compound of Formula (Ib) is compound 97. [00243] In certain embodiments, the compound of Formula (Ib) is compound 98. [00244] In certain embodiments, the compound of Formula (Ib) is compound 99. [00245] In certain embodiments, the compound of Formula (Ib) is compound 100. [00246] In certain embodiments, the compound of Formula (Ib) is compound 101. [00247] In certain embodiments, the compound of Formula (Ib) is compound 102. [00248] In certain embodiments, the compound of Formula (Ib) is compound 103. [00249] In certain embodiments, the compound of Formula (Ib) is compound 104. [00250] In certain embodiments, the compound of Formula (Ib) is compound 105. [00251] In certain embodiments, the compound of Formula (Ib) is compound 106. [00252] In certain embodiments, the compound of Formula (Ib) is compound 107. [00253] In certain embodiments, the compound of Formula (Ib) is compound 108. [00254] In certain embodiments, the compound of Formula (Ib) is compound 109. [00255] In certain embodiments, the compound of Formula (Ib) is compound 110. [00256] In certain embodiments, the compound of Formula (Ib) is compound 111. [00257] In certain embodiments, the compound of Formula (Ib) is compound 112. [00258] In certain embodiments, the compound of Formula (Ib) is compound 113. [00259] In certain embodiments, the compound of Formula (Ib) is compound 114. [00260] In certain embodiments, the compound of Formula (Ib) is compound 115. [00261] In certain embodiments, the compound of Formula (Ib) is compound 116. [00262] In certain embodiments, the compound of Formula (Ib) is compound 117. [00263] In certain embodiments, the compound of Formula (Ib) is compound 118. [00264] In certain embodiments, the compound of Formula (Ib) is compound 119. [00265] In certain embodiments, the compound of Formula (Ib) is compound 120. [00266] In certain embodiments, the compound of Formula (Ib) is compound 121. [00267] In certain embodiments, the compound of Formula (Ib) is compound 122. [00268] In certain embodiments, the compound of Formula (Ib) is compound 123. [00269] In certain embodiments, the compound of Formula (Ib) is compound 124. [00270] In certain embodiments, the compound of Formula (Ib) is compound 125. [00271] In certain embodiments, the compound of Formula (Ib) is compound 126. [00272] In certain embodiments, the compound of Formula (Ib) is compound 127. [00273] In certain embodiments, the compound of Formula (Ib) is compound 128. [00274] In certain embodiments, the compound of Formula (Ib) is compound 129. [00275] In certain embodiments, the compound of Formula (Ib) is compound 130. [00276] In certain embodiments, the compound of Formula (Ib) is compound 131. [00277] In certain embodiments, the compound of Formula (Ib) is compound 132. [00278] In certain embodiments, the compound of Formula (Ib) is compound 133. [00279] In certain embodiments, the compound of Formula (Ib) is compound 134. [00280] In certain embodiments, the compound of Formula (Ib) is compound 135. [00281] In certain embodiments, the compound of Formula (Ib) is compound 136. [00282] In certain embodiments, the compound of Formula (Ib) is compound 137. [00283] In certain embodiments, the compound of Formula (Ib) is compound 138. [00284] In certain embodiments, the compound of Formula (Ib) is compound 139. [00285] In certain embodiments, the compound of Formula (Ib) is compound 140. [00286] In certain embodiments, the compound of Formula (Ib) is compound 141. [00287] In certain embodiments, the compound of Formula (Ib) is compound 142. [00288] In certain embodiments, the compound of Formula (Ib) is compound 143. [00289] In certain embodiments, the compound of Formula (Ib) is compound 144. [00290] In certain embodiments, the compound of Formula (Ib) is compound 145. [00291] In certain embodiments, the compound of Formula (Ib) is compound 146. [00292] In certain embodiments, the compound of Formula (Ib) is compound 147. [00293] In certain embodiments, the compound of Formula (Ib) is compound 148. [00294] In certain embodiments, the compound of Formula (Ib) is compound 149. [00295] In certain embodiments, the compound of Formula (Ib) is compound 150. [00296] In certain embodiments, the compound of Formula (Ib) is compound 151. [00297] In certain embodiments, the compound of Formula (Ib) is compound 152. [00298] In certain embodiments, in the compounds of Formula (I), X is CR1 and Y is CR2; R1 is H; R5 is H; R6 is H; R11 is methyl; J is
Figure imgf000050_0001
; R7 is H; R9 is cyclopropyl; R10 is methyl; and
Figure imgf000050_0002
. n this embodiment, the compounds of Formula (I) are compounds of Formula (Ic). [00299] In certain embodiments, the compound is a compound of Formula (Ic):
Figure imgf000050_0003
) wherein: Z is CR3 or N; R2 is H, halogen, or C1-6 alkoxy; R3 is H, halogen, or C1-6 alkoxy; R4 is H, halogen, or C1-6 alkoxy; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl; or a pharmaceutically acceptable salt thereof . [00300] In certain embodiments, Z is CR3 or N; R2 is H, halogen, or C1-3 alkoxy; R3 is H, halogen, or C1-3 alkoxy; R4 is H, halogen, or C1-3 alkoxy; RD is C1-3 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl. In certain embodiments, Z is CR3 or N; R2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; RD is Me, Et, n-Pr, or i-Pr; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl. [00301] In certain embodiments, Z is CR3; R2 is H, halogen, or C1-3 alkoxy; R3 is H, halogen, or C1-3 alkoxy; R4 is H, halogen, or C1-3 alkoxy; RD is C1-3 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a C4-5 heterocycloalkyl. In certain embodiments, Z is CR3 or N; R2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; RD is Me, Et, n-Pr, or i-Pr; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl. [00302] In certain embodiments, Z is N; R2 is H, halogen, or C1-3 alkoxy; R4 is H, halogen, or C1-3 alkoxy; RD is C1-3 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a C4-5 heterocycloalkyl. In certain embodiments, Z is CR3 or N; R2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R3 is H, F, Cl, Br, I, OMe, OEt, O- nPr, or O-iPr; R4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; RD is Me, Et, n-Pr, or i-Pr; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl. [00303] In certain embodiments, Z is CR3 or N; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; RD is Me or Et; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. [00304] In certain embodiments, Z is CR3; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; RD is Me or Et; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. [00305] In certain embodiments, Z is CR3; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; RD is Me or Et; and RE is CH2OMe. [00306] In certain embodiments, Z is CR3; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; and RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. [00307] In certain embodiments, Z is N; R2 is H, F, or OMe; R4 is F or OMe; RD is Me or Et; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. [00308] In certain embodiments, Z is N; R2 is H, F, or OMe; R4 is F or OMe; RD is Me or Et; and RE is CH2OMe. [00309] In certain embodiments, Z is N; R2 is H, F, or OMe; R4 is F or OMe; and RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. [00310] In certain embodiments, R2 is H, F, or OMe. In certain embodiments, R2 is H. In certain embodiments, R2 is F. In certain embodiments, R2 is OMe. [00311] In certain embodiments, R3 is H. In certain embodiments, R3 is F. In certain embodiments, R3 is OMe. [00312] In certain embodiments, R4 is H, F, or OMe. In certain embodiments, R4 is H. In certain embodiments, R4 is F. In certain embodiments, R4 is OMe. [00313] In certain embodiments, RD is Me or Et. In certain embodiments, RD is Me. In certain embodiments, RD is Et. [00314] In certain embodiments, Z is CR3. In certain embodiments, Z is N. [00315] In certain embodiments, RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group. In certain embodiments, RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group. In certain embodiments, RD and RE together with the nitrogen and carbon atoms to which they are attached form a pyrrolidinyl group. [00316] In certain embodiments, the compound of Formula (Ic) is selected from: , ,
Figure imgf000052_0001
,
Figure imgf000053_0001
a pharmaceutically acceptable salt thereof. [00317] In certain embodiments, the compound of Formula (Ic) is a compound as set forth in Table 3. [00318] In certain embodiments, the compound of Formula (Ic) is compound 153. [00319] In certain embodiments, the compound of Formula (Ic) is compound 154. [00320] In certain embodiments, the compound of Formula (Ic) is compound 155. [00321] In certain embodiments, the compound of Formula (Ic) is compound 156. [00322] In certain embodiments, the compound of Formula (Ic) is compound 157. [00323] In certain embodiments, the compound of Formula (Ic) is compound 158. [00324] In certain embodiments, the compound of Formula (Ic) is compound 159. [00325] In certain embodiments, the compound of Formula (Ic) is compound 160. [00326] In certain embodiments, the compound of Formula (Ic) is compound 161. [00327] In certain embodiments, the compound of Formula (Ic) is compound 162. [00328] In certain embodiments, the compound of Formula (Ic) is compound 163. [00329] In certain embodiments, in the compounds of Formula (I), X is CR1, Y is CR2, and Z is CR3; R1 is H; R3 is H; R5 is H; R6 is H; R11 is methyl
Figure imgf000053_0002
is methyl; and n this embodiment, the compounds of Formula (I) are compounds of Formula
Figure imgf000053_0003
[00330] In certain embodiments, the compound is a compound of Formula (Id):
Figure imgf000053_0004
) wherein: R2 is halogen, C1-6 alkoxy, or CN; R4 is halogen or C1-6 alkoxy; and R9 is C1-6 alkoxy or C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof . [00331] In certain embodiments, R2 is halogen, C1-3 alkoxy, or CN; R4 is halogen or C1-3 alkoxy; and R9 is C1-3 alkoxy or cyclopropyl. In certain embodiments, R2 is F, Cl, Br, I, OMe, OEt, O- nPr, O-iPr, or CN; R4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; and R9 is OMe, OEt, O-nPr, O- iPr, or cyclopropyl. [00332] In certain embodiments, R2 is F, OMe, or CN; R4 is F or OMe; and R9 is OMe or cyclopropyl. [00333] In certain embodiments, R2 is halogen, C1-3 alkoxy, or CN. In certain embodiments, R2 is F, OMe, or CN. In certain embodiments, R2 is F. In certain embodiments, R2 is OMe. In certain embodiments, R2 is CN. [00334] In certain embodiments, R4 is halogen or C1-3 alkoxy. In certain embodiments, R4 is F or OMe. In certain embodiments, R4 is F. In certain embodiments, R4 is OMe. [00335] In certain embodiments, R9 is C1-3 alkoxy or cyclopropyl. In certain embodiments, R9 is OMe or cyclopropyl. In certain embodiments, R9 is OMe. In certain embodiments, R9 is cyclopropyl. [00336] In certain embodiments, the compound of Formula (Id) is selected from: d
Figure imgf000054_0001
[00337] In certain embodiments, the compound of Formula (Id) is a compound as set forth in Table 4. [00338] In certain embodiments, the compound of Formula (Id) is compound 164. [00339] In certain embodiments, the compound of Formula (Id) is compound 165. [00340] In certain embodiments, the compound of Formula (Id) is compound 166. [00341] In certain embodiments, the compound of Formula (Id) is compound 167. [00342] Exemplary compounds of Formula (Ia) described herein include the compounds described in Table 1: (Ia)
Figure imgf000055_0001
Figure imgf000056_0001
[00343] Names of the compounds in Table 1 are as follows: 1: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 2: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 3: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 4: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 5: N-[(S)-1-(3-chloro-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 6: N-[(S)-1-(3,4-dichlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 7: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 8: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 9: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-N-methyl-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 10: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 11: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 12: N-{(S)-1-[3-cyano-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 13: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 14: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 15: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 16: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-1- methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 17: N-[(S)-1-(3,4-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-1- methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 18: N-{(S)-1-[3-cyano-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 19: N-[(S)-1-(3,5-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-1- methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 20: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 21: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 22: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 23: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 24: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 25: N-[(S)-1-(3-chloro-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 26: N-{(S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 27: N-[(S)-1-(3-chloro-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 28: N-{(S)-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 29: N-{(S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 30: N-[(S)-1-(3-chloro-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 31: N-{(S)-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 32: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 33: N-[(S)-1-(3,4-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 34: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-1- methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 35: N-[(S)-1-(3,4-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-1- methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; 36: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide; and 168: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-1- methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamide. [00344] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound of Formula (Ia) that is described in Table 1. [00345] Exemplary compounds of Formula (Ib) described herein include the compounds described in Table 2:
et No.48369-759.601 C R H H H H H H B R H H H H H H
Figure imgf000059_0001
a T 2 e R H F l C F N C M O 1 R H H H H H H 3 3 3 3 3 3 Z R R R R R R C C C C C C 2 2 2 2 2 2 Y R R R R R R C C C C C C 1 1 1 1 1 1 X R R R R R R C C C C C C dnuop 73 83 9 0 1 2 m 3 4 4 4 o C -5
ket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lb
Figure imgf000060_0001
a T 2 e R F H e e N M H M H C H M O 1 R H H H H H H H H H 3 3 3 3 3 3 Z R N N R R R R R C C N C C C C 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R C C C C C C C C C 1 1 1 1 1 1 1 1 1 X R R R R R R R R R C C C C C C C C C dnuop 34 44 5 6 7 8 9 0 1 m 4 4 4 4 4 5 5 o C -5
ocket No.48369759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lb
Figure imgf000061_0001
a O T 2 H N F l H l R C C H H H C 1 R H H H H H H H H H 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R C C C C C C C C C 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R C C C C C C C C C 1 1 1 1 1 1 1 1 1 X R R R R R R R R R C C C C C C C C C dnuop 25 35 45 5 6 7 8 9 0 m 5 5 5 5 5 6 o C -60
cket No.48369759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lb
Figure imgf000062_0001
a T 2 l R C F H N C - H F - H 1 R H H H H H H H H H 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R C C C C C C C C C 2 2 2 2 2 2 2 Y R R R R N R R R C C C C C C N C 1 1 1 1 1 1 1 1 1 X R R R R R R R R R C C C C C C C C C dnuop 16 26 3 4 5 6 7 8 9 m 6 6 6 6 6 6 6 o C -6
cket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lba T
Figure imgf000063_0001
2 R M H H H H H H H F O C 1 R H H H H H H H H H H 3 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R R C C C C C C C C C C 2 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R R C C C C C C C C C C 1 1 1 1 1 1 1 1 1 1 X R R R R R R R R R R C C C C C C C C C C dnuop 07 17 27 37 4 5 6 7 8 9 m 7 7 7 7 7 7 o C -62-
ocket No.48369759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lba T
Figure imgf000064_0001
2 R F H H H H H H H H H 1 R H H H H H H F H - H 3 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R R C C C C C C C C C C 2 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R R C C C C C C C C C C 1 1 1 1 1 1 1 1 1 X R R R R R R R R N R C C C C C C C C C dnuop 08 18 2 3 4 5 6 7 8 9 m 8 8 8 8 8 8 8 8 o C -6
cket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lb
Figure imgf000065_0001
a O T 2 R H N e C H H H H H H M H O 1 R H H H H H H H H H H 3 3 3 3 3 3 3 3 3 Z R R N R R R R R R R C C C C C C C C C 2 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R R C C C C C C C C C C 1 1 1 1 1 1 1 1 1 1 X R R R R R R R R R R C C C C C C C C C C dnuop 09 1 2 3 4 5 6 7 8 9 m 9 9 9 9 9 9 9 9 9 o C -
cket No.48369759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lb
Figure imgf000066_0001
a O O O T 2 e R H H M H H H H H H H N H O C 1 R H H H H H H H H H H H H 3 3 3 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R R R R C C C C C C C C C C C C 2 2 2 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R R R R C C C C C C C C C C C C 1 1 1 1 1 1 1 1 1 1 1 1 X R R R R R R R R R R R R C C C C C C C C C C C C dnuop 00 1 2 3 4 5 6 7 8 9 0 1 1 01 0 0 0 0 0 0 0 0 1 1 m 1 1 1 1 1 1 1 1 1 1 o C -65
ocket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lba T
Figure imgf000067_0001
R O O C C 1 R H H H H H H H H H H H H H 3 3 3 3 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R R R R R C C C C C C C C C C C C C 2 2 2 2 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R R R R R C C C C C C C C C C C C C 1 1 1 1 1 1 1 1 1 1 1 1 1 X R R R R R R R R R R R R R C C C C C C C C C C C C C dnuop 21 3 4 5 6 7 8 9 0 1 2 3 4 1 11 1 1 1 1 1 1 2 2 2 2 2 m 1 1 1 1 1 1 1 1 1 1 1 o C -
ocket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lba T
Figure imgf000068_0001
2 l l e e e R H C C H M H H F F M M H O O O 1 R H H H H H H H H H H H H 3 3 3 3 3 3 3 3 3 3 3 3 Z R R R R R R R R R R R R C C C C C C C C C C C C 2 2 2 2 2 2 2 2 2 2 2 2 Y R R R R R R R R R R R R C C C C C C C C C C C C 1 1 1 1 1 1 1 1 1 1 1 1 X R R R R R R R R R R R R C C C C C C C C C C C C dnuop 52 6 7 8 9 0 1 2 3 4 5 6 1 21 2 2 2 3 3 3 3 3 3 3 m 1 1 1 1 1 1 1 1 1 1 o C -67
Docket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e l
Figure imgf000069_0001
b R F F H H F H F Ha T 2 e R H H F F H M H N O C 1 R H H H H O O H H H H 3 3 3 3 3 3 3 3 Z R R R R R R R R C C C C C C C C 2 2 2 2 2 2 2 2 Y R R R R R R R R C C C C C C C C 1 1 1 1 1 1 1 1 X R R R R R R R R C C C C C C C C dnuop 73 83 93 04 1 2 3 4 1 1 4 4 4 4 m 1 1 1 1 1 1 o C -68-
Docket No.48369-759.601 ) b I ( a lu mroFfosdnuop mo C: 2 e lba T
Figure imgf000070_0001
R C O 1 R H H H H H H O H H 3 3 3 3 3 3 3 3 Z R R R R R R R R C C C C C C C C 2 2 2 2 2 2 2 2 Y R R R R R R R R C C C C C C C C 1 1 1 1 1 1 1 1 X R R R R R R R R C C C C C C C C dnuop 54 6 7 8 9 0 1 2 1 41 41 4 4 5 5 5 m 1 1 1 1 1 o C -69 [00346] Names of the compounds in Table 2 are as follows: 37: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 38: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 39: N-[(S)-1-(m-chlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 40: N-[(S)-1-(p-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6-methyl- 1,7-diaza-3-naphthamide; 41: N-[(S)-1-(m-cyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 42: N-[(S)-1-(m-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 43: N-[(S)-1-(3,4-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 44: N-[(S)-1-(2-methoxy-4-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 45: N-[(S)-1-(2,6-dimethyl-4-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 46: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 47: N-[(S)-1-(2-cyano-6-methyl-4-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 48: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 49: N-[(S)-1-(3-cyano-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 50: N-[(S)-1-(3,4-dichlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 51: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 52: N-{(S)-1-[m-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 53: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 54: N-[(S)-1-(3-fluoro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 55: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 56: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 57: N-[(S)-1-(m-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6-methyl-1,7- diaza-3-naphthamide; 58: N-[(S)-1-(m-trifluoromethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 59: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 60: N-[(S)-1-(3-chloro-5-cyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 61: N-[(S)-1-(3,5-dichlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 62: N-[(S)-1-(3-chloro-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 63: N-[(R)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 64: N-[(S)-1-(3,5-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 65: N-[(S)-1-(5-chloro-3-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 66: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-6,8- dimethyl-1,7-diaza-3-naphthamide; 67: N-[(S)-1-(4-chloro-3-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 68: N-[(S)-1-(5-cyano-3-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 69: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 70: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 71: N-[(S)-1-(3-fluoro-4-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 72: N-[(S)-1-(2,4-difluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 73: N-[(S)-1-(3-chloro-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 74: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[5-(hydroxymethyl)-1,4- diazepan-1-yl]-6-methyl-1,7-diaza-3-naphthamide; 75: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methoxy-1,7-diaza-3-naphthamide; 76: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy- 6-methyl-1,7-diaza-3-naphthamide; 77: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 78: N-[(S)-1-(3-fluoro-5-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 79: N-[(S)-1-(3-chloro-5-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 80: N-[(S)-1-(3,4-difluoro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 81: N-[(S)-1-(3-cyano-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 82: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-6-methyl-8- (trifluoromethyl)-1,7-diaza-3-naphthamide; 83: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 84: N-[(S)-1-(3-chloro-4-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 85: N-[(S)-1-(3-fluoro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 86: N-[(S)-1-(2,4-difluoro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 87: N-[(S)-1-(4-cyano-3-hydroxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 88: N-[(S)-1-(4-cyano-2-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 89: N-[(S)-1-(3-carbamoyl-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 90: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-4-(2-fluoroethyl)-5-methyl-1,4-diazepan- 1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 91: N-{(S)-1-[3-cyano-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 92: N-{(S)-1-[2-(trifluoromethyl)-4-pyridyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 93: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-ethyl-6- methyl-1,7-diaza-3-naphthamide; 94: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6- methyl-1,7-diaza-3-naphthamide; 95: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-ethoxy-6- methyl-1,7-diaza-3-naphthamide; 96: N-[(S)-1-(3,4-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 97: N-{(S)-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 98: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-[5-(hydroxymethyl)-1,4-diazepan-1- yl]-6-methyl-1,7-diaza-3-naphthamide; 99: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6- methyl-1,7-diaza-3-naphthamide; 100: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 101: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-6-methoxy- 8-(trifluoromethyl)-1,7-diaza-3-naphthamide; 102: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[5-(hydroxymethyl)-1,4-diazepan-1-yl]-8- methoxy-6-methyl-1,7-diaza-3-naphthamide; 103: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 104: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy- 6-methyl-1,7-diaza-3-naphthamide; 105: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy- 6-methyl-1,7-diaza-3-naphthamide; 106: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 107: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[5-(methoxymethyl)-1,4- diazepan-1-yl]-6-methyl-1,7-diaza-3-naphthamide; 108: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 109: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 110: N-[(S)-1-(3,5-dicyanophenyl)ethyl]-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 111: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 112: 3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan-1- yl]-8-cyclopropyl-6-methyl-1,7-diaza-7-naphthalenium-7-olate; 113: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropoxy-6-methyl-1,7-diaza-3-naphthamide; 114: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(R)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-3-naphthamide; 115: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 116: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 117: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy- 6-methyl-1,7-diaza-3-naphthamide; 118: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)- 6-methyl-1,7-diaza-3-naphthamide; 119: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 120: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 121: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 122: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 123: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)- 6-methyl-1,7-diaza-3-naphthamide; 124: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6- methyl-1,7-diaza-3-naphthamide; 125: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 126: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 127: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-methoxy- 6-methyl-1,7-diaza-3-naphthamide; 128: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 129: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 130: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6- methyl-1,7-diaza-3-naphthamide; 131: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-(5,8-diaza-8-spiro[3.6]decyl)-6- methyl-1,7-diaza-3-naphthamide; 132: N-[(S)-1-(3-cyano-5-fluoro-2-hydroxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 133: N-[(S)-1-(3-cyano-5-fluoro-2-hydroxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7- spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthamide; 134: N-[(S)-1-(3-cyano-2-hydroxy-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]- 8-cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 135: N-[(S)-1-(3-cyano-2-hydroxy-5-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7- spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthamide; 136: ethyl 3-{3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4- diazepan-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylamino}propionate; 137: {3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan-1- yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthyloxy}acetic acid; 138: 3-{3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan- 1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylamino}propionic acid; 139: N-[(S)-1-(5-cyano-3-fluoro-2-hydroxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 140: N-[(S)-1-(5-cyano-3-fluoro-2-hydroxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7- spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthamide; 141: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthamide; 142: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-morpholino-1,7-diaza-3-naphthamide; 143: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-2-methoxy-6-methyl-1,7-diaza-3-naphthamide; 144: N-[(S)-1-(3-cyano-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthamide; 145: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthamide; 146: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthamide; 147: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-2-morpholino-1,7-diaza-3-naphthamide; 148: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8- cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthamide; 149: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl- 6-methyl-2-morpholino-1,7-diaza-3-naphthamide; 150: N-[(S)-1-(5-cyano-2-hydroxy-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]- 8-cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 151: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-2-[(S)-3- methyl-4-morpholinyl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; and 152: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-2-[(R)-3-methyl-4-morpholinyl]-4-[(S)-5- methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthamide. [00347] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound of Formula (Ib) that is described in Table 2. [00348] Exemplary compounds of Formula (Ic) described herein include the compounds described in Table 3: (Ic)
Figure imgf000078_0001
[00349] Names of the compounds in Table 3 are as follows: 153: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3- (methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 154: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3-(methylamino)- 1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 155: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)- 6-methyl-1,7-diaza-3-naphthamide; 156: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-6- methyl-1,7-diaza-3-naphthamide; 157: N-[(S)-1-(2-methoxy-4-pyridyl)ethyl]-8-cyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-6- methyl-1,7-diaza-3-naphthamide; 158: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(ethylamino)-3- (methoxymethyl)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 159: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-[3-(ethylamino)-3-(methoxymethyl)-1- pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 160: N-[(S)-1-(2-methoxy-4-pyridyl)ethyl]-8-cyclopropyl-4-[3-(ethylamino)-3-(methoxymethyl)- 1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide; 161: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-{(R)-1,7-diaza-7-spiro[4.4]nonyl}-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide; 162: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-(1,6-diaza-6-spiro[3.4]octyl)-6- methyl-1,7-diaza-3-naphthamide; and 163: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(1,6-diaza-6-spiro[3.4]octyl)- 6-methyl-1,7-diaza-3-naphthamide. [00350] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound of Formula (Ic) that is described in Table 3. [00351] Exemplary compounds of Formula (Id) described herein include the compounds described in Table 4: (Id)
Figure imgf000079_0001
[00352] Names of the compounds in Table 4 are as follows: 164: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; 165: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-cyclopropyl- 6-methyl-1,7-diaza-3-naphthamide 166: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8- cyclopropyl-6-methyl-1,7-diaza-3-naphthamide; and 167: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-methoxy- 6-methyl-1,7-diaza-3-naphthamide. [00353] In some embodiments, provided herein is a pharmaceutically acceptable salt of a compound of Formula (Id) that is described in Table 4. [00354] “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, i.e., 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. [00355] 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. [00356] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (Ia), (Ib), (Ic), or (Id) with an acid. In some embodiments, the free base form of the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) is basic and is reacted with an organic acid or an inorganic acid. [00357] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (Ia), (Ib), (Ic), or (Id) with a base. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) is acidic and is reacted with a base. [00358] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), or (Id) 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), (Ia), (Ib), (Ic), or (Id) exists in the R configuration. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), or (Id) exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, epimeric, 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, tautomers, as well as the appropriate mixtures thereof. [00359] 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), (Ia), (Ib), (Ic), and (Id) 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 [00360] Compounds of Formula (I), (Ia), (Ib), (Ic), and (Id) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. [00361] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed. [00362] 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. [00363] In some embodiments, N-H naphthyridone compounds of Formula (Ia), described herein, are prepared as described in Scheme A.
Figure imgf000082_0001
Scheme A (a) SOCl2, MeOH, 70oC, 16 h; (b) Pd(dppf)Cl2, K2CO3, dioxane, 100oC, 2 h; (c) NBS, DMF, 0oC ^RT, 1 h; (d) Pd(OAc)2, (C6H11)3P, K3PO4, toluene/H2O= 5:1, 80oC, 1 h; (e) DIEA, DCM, 0oC, 1 h; (f) NaOMe, MeOH, 80oC, 1 h; (g) LiOH, MeOH, H2O, 60oC, 1 h; (h) (COCl)2, DMF, DCM, RT, 16 h; (i) X or Xa, DIEA, DCM, 0oC, 1 h; (j) DIEA, MeCN, 80oC, 1 h; (k) TFA, DCM, RT, 1 h. [00364] In some embodiments, N-methyl naphthyridone compounds of Formula (Ia), described herein, are prepared as described in Scheme B.
Figure imgf000083_0001
Scheme B (a) SOCl2, MeOH, 70oC, 16 h; (b) Pd(dppf)Cl2, K2CO3, dioxane, 100oC, 2 h; (c) MeB(OH)2, Pd(OAc)2, pyridine, dioxane, 100oC, 16 h; (d) NBS, DMF, 0oC ^RT, 1 h; (e) Pd(OAc)2, (C6H11)3P, K3PO4, toluene/H2O= 10:1, 80oC, 1 h; (f) DIEA, DCM, 0oC, 1 h; (g) NaOMe, MeOH, 80oC, 1 h; (h) (COCl)2, DMF, DCM, RT, 6 h; (i) DIEA, MeCN, 80oC, 1 h; (j) LiOH, MeOH, H2O, 80oC, 1.5 h; (k) X or Xa, HATU, DIEA, DMF, RT, 1 h; (l) TFA, DCM, RT, 1 h. [00365] In some embodiments, naphthyridines compounds of Formula (Ib), (Ic), or (Id), described herein, are prepared as described in Scheme C.
Figure imgf000084_0001
Scheme C (a) XXVII, neat, 100oC, 2 h; (b) PhOPh .PhPh, 258oC, 10 min; (c) LiOH, MeOH/H2O (5:1), 65oC, 1 h; (d) POCl3, 100oC, 0.5-1 h; (e) X or Xa, DIEA, DCM, 0 oC, 1 h; (f) H-A-Boc, DIEA, dioxane, 110oC, 16 h; (g) TFA, DCM, RT, 1 h. [00366] In some embodiments, compounds of Formula (Ib), described herein, have an R7 moiety. A non-limiting example of installation of the R7 moiety
Figure imgf000084_0002
is described in Scheme D.
Figure imgf000085_0001
(a) Tf2O, 2,6-lutidine, DCM, 0oC, 1 h; (b) Cs2CO3, Pd(crotyl)(tBuBrettPhose)OTf, dioxane, 80oC, 1 h; (c) TFA, DCM, RT, 1 h. [00367] In some embodiments, amine intermediate X is prepared as described in Scheme E.
Figure imgf000085_0002
Scheme E (a) i) Pd(PPh3)2Cl2, toluene, 100 oC, 16 h, ii) HCl, RT, 0.5 h; (b) Ti(OiPr)4, toluene, 80 oC, 16 h; (c) L-Selectride, THF, -78 oC, 1 h; (d) HCl, ether, RT, 1 h. [00368] In some embodiments, amine intermediate X is prepared as described in Scheme F.
Figure imgf000085_0003
(a) Ti(OiPr)4, toluene, 80 oC, 4 h; (b) MeMgCl, DCM, -40 oC, 1 h then 0-5 oC, 8 h; (c) HCl, EtOAc, RT, 3 h. [00369] In some embodiments, intermediate X is alkylated (for example, with methyliodide) to prepare intermediate Xa as described in Scheme G.
Figure imgf000086_0001
Scheme G (a) Boc2O, Et3N, DCM, RT, 1 h; (b) NaH, R6-I, DMF, RT, 1 h; (c) HCl, dioxane, RT, 1 h. [00370] In some embodiments, compounds are prepared as described in the Examples. Certain Terminology [00371] 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. [00372] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C1-C6" indicates that there are one to six carbon atoms in the moiety, i.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-C3 alkyl" indicates that there are one to three carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, and iso-propyl. [00373] 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, i.e. a C1-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 C1-C6 alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-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. [00374] An “alkoxy” group refers to an (alkyl)O- group, where alkyl is as defined herein. [00375] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. [00376] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halo atom. In one aspect, a haloalkyl is a C1-C6 fluoroalkyl or C1-C3 fluoroalkyl. [00377] The term “haloalkoxy” refers to an alkoxy in which one or more hydrogen atoms are replaced by a halo atom. In one aspect, a haloalkoxy is a C1-C6 fluoroalkoxy or C1-C3 fluoroalkoxy. [00378] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl. [00379] A “cycloalkoxy” group refers to a (cycloalkyl)O- group, where cycloalkyl is as defined herein. [00380] 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. [00381] 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. [00382] 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. [00383] 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. [00384] 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. [00385] 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. [00386] 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 [00387] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), and (Id), or a pharmaceutically acceptable salt thereof, 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 & Wilkins 1999), herein incorporated by reference for such disclosure. [00388] 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 [00389] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), and (Id ), 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), (Ia), (Ib), (Ic), and (Id), or a pharmaceutically acceptable salt thereof, in therapeutically effective amounts to said mammal. [00390] 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. [00391] The amount of a given compound of Formula (I), (Ia), (Ib), (Ic), and (Id), 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. [00392] 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. [00393] 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: SOCl2: thionyl chloride; MeOH: methanol; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride; K2CO3: potassium carbonate; MeB(OH)2: methylboronic acid; Pd(OAc)2: palladium (II) acetate; NBS: N-bromosuccinimide; DMF: dimethylformamide; RT: room temperature; (C6H11)3P: tricyclohexylphosphine; K3PO4: potassium phosphate; H2O: water; DIEA: N,N-diisopropylethylamine or N-ethyl-N-isopropylpropan-2-amine; DCM: dichloromethane; NaOMe: sodium methoxide; (COCl)2: oxalyl chloride; LiOH: lithium hydroxide; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; TFA: trifluoroacetic acid or 2,2,2-trifluoroacetic acid; Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium (II) dichloride; HCl: hydrochloric acid; Ti(OiPr)4: titanium (IV) isopropoxide; L-selectride: lithium tri-sec-butylborohydride; THF: tetrahydrofuran; h: hour; min or mins: minutes; MeMgCl: methylmagnesium chloride; EtOAc: ethyl acetate; Boc2O: di-tert-butyl dicarbonate; Et3N: triethylamine; NaH: sodium hydride; MeI: methyl iodide; NaHCO3: sodium bicarbonate; Na2SO4: sodium sulfate; ACN/MeCN: acetonitrile; Prep-HPLC: preparative high performance liquid chromatography; NH3.H2O: aqueous ammonia; PE: petroleum ether; Cs2CO3: cesium carbonate; Pd(crotyl)(tBuBrettPhos)OTf: (2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1- biphenyl)(2-buten-1-yl)palladium(II) 1,1,1-trifluoromethanesulfonate; Ruphos Pd 3G; (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate; NaHSO4: sodium bisulfate; POCl3: phosphoryl chloride; and Pd/C: palladium on carbon. EXAMPLES [00394] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. [00395] Example A: Syntheses of Compounds Example A1. Preparation of N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4- diazepan-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3- naphthamide (Compound 13)
Figure imgf000091_0001
[00396] Step A1-1, preparation of methyl 5-amino-2-chloroisonicotinate: Into a 250-mL three- necked flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of 5-amino-2-chloroisonicotinic acid (11.4 g, 1 Eq, 66.1 mmol) and methanol (114 mL) and SOCl2 (39.4 g, 24.2 mL, 5.01 Eq, 331 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 70 °C for 16 hours. The reaction was concentrated under vacuum and the residue dissolved in dichloromethane (200 mL). The resulting solution was adjusted to a pH of 8 with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3 x 200 mL), and the organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 5-amino-2-chloroisonicotinate (9.6 g, 51 mmol, 78%); (M+H)+ = 187.0. [00397] Step A1-2, preparation of methyl 5-amino-2-methylisonicotinate: Into a 250-mL round- bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of methyl 5-amino-2-chloroisonicotinate (9.6 g, 1 Eq, 51 mmol), 1,4-dioxane (96 mL), K2CO3 (21 g, 3.0 Eq, 0.15 mol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (19 g, 2.9 Eq, 0.15 mol), and PdCl2(dppf) (1.9 g, 0.050 Eq, 2.6 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (0% ethyl acetate up to 50% in 30 minutes). The collected fractions were combined and concentrated under vacuum to afford methyl 5-amino-2-methylisonicotinate (8.5 g, 51 mmol, 99%); (M+H)+ = 167.1. [00398] Step A1-3, preparation of methyl 2-methyl-5-(methylamino)isonicotinate: Into a 250- mL round-bottom flask was placed a mixture of methyl 5-amino-2-methylisonicotinate (8.5 g, 1 Eq, 51 mmol), 1,4-dioxane (85 mL), pyridine (14 g, 14 mL, 3.5 Eq, 0.18 mol), and diacetoxycopper (23 g, 2.5 Eq, 0.13 mol). The reaction mixture was stirred at 25 °C for 30 minutes, after which methylboronic acid (15 g, 4.9 Eq, 0.25 mol) was added and the reaction mixture was stirred for an additional 16 hours at 100 °C. The reaction mixture was then filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (0% ethyl acetate up to 50% in 10 minutes). The collected fractions were combined and concentrated under vacuum to afford methyl 2-methyl-5- (methylamino)isonicotinate (3.3 g, 18 mmol, 36%); (M+H)+ = 181.1. [00399] Step A1-4, preparation of methyl 2-bromo-6-methyl-3-(methylamino)isonicotinate: Into a 100 mL round-bottom flask was placed a mixture of methyl 2-methyl-5- (methylamino)isonicotinate (3.3 g, 1 Eq, 18 mmol) and DMF (33 mL). To the mixture was added NBS (1.2 g, 1.2 Eq, 21 mmol) in portions at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, and then poured into water (50 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford methyl 2-bromo-6-methyl-3-(methylamino)isonicotinate (3.5 g, 14 mmol, 74%); (M+H)+ = 259.0. [00400] Step 1-5, preparation of methyl 2-cyclopropyl-6-methyl-3-(methylamino)isonicotinate: Into a 250 mL vial was placed methyl 2-bromo-6-methyl-3-(methylamino)isonicotinate (3.5 g, 1 Eq, 14 mmol), Pd(OAc)2 (0.3 g, 0.1 Eq, 1 mmol), cyclopropylboronic acid (3.5 g, 3.0 Eq, 41 mmol), potassium phosphate tribasic (8.6 g, 3.4 mL, 3.0 Eq, 41 mmol), tricyclohexylphosphine (0.76 g, 0.85 mL, 0.20 Eq, 2.7 mmol), toluene (35 mL), and water (3.5 mL). The resulting solution was stirred for 1 hour at 80 °C. The reaction mixture was concentrated under vacuum, the organic layer was separated and washed with water and brine, dried over Na2SO4, and concentrated to give crude product. The crude product was purified by silica gel column chromatography eluted with petroleum ether/ethyl acetate (2/1) to afford methyl 2-cyclopropyl-6- methyl-3-(methylamino)isonicotinate (2.3 g, 10 mmol, 77%); (M+H)+ = 221.1. [00401] Step A1-6, preparation of methyl 2-cyclopropyl-3-(3-methoxy-N-methyl-3- oxopropanamido)-6-methylisonicotinate: Into a 250-mL vial was placed a mixture of methyl 2- cyclopropyl-6-methyl-3-(methylamino)isonicotinate (2.3 g, 1 Eq, 10 mmol) and DCM (23 mL), to which was added methyl 3-chloro-3-oxopropanoate (4.3 g, 3.0 Eq, 31 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford methyl 2-cyclopropyl-3-(3-methoxy-N-methyl-3-oxopropanamido)-6- methylisonicotinate (3.1 g, 9.7 mmol, 93%) which was used directly for the next step without any purification. [00402] Step A1-7, preparation of methyl 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2- dihydro-1,7-naphthyridine-3-carboxylate: Into a 250 mL vial was placed a mixture of methyl 2- cyclopropyl-3-(3-methoxy-N-methyl-3-oxopropanamido)-6-methylisonicotinate (3.1 g, 1 Eq, 9.7 mmol), sodium methoxide (2.1 g, 4.0 Eq, 39 mmol), and MeOH (30 mL). The reaction mixture was stirred at 80 °C for 1 hour. The crude product was concentrated under vacuum, and to the residue was added water (40 mL), and the pH of the mixture was adjusted to 3-4 with aqueous HCl (1M). The resulting precipitate was collected by filtration and dried to afford methyl 8- cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (3.7 g, 9.0 mmol, 93 %, 70% Purity); (M+H)+ = 289.1. [00403] Step A1-8, preparation of methyl 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2- dihydro-1,7-naphthyridine-3-carboxylate: Into a 250-mL round-bottom flask was placed a mixture of methyl 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine- 3-carboxylate (3.7 g, 1 Eq, 13 mmol), DCM (37 mL), DMF (0.94 g, 1.0 mL, 1.0 Eq, 13 mmol), and oxalyl chloride (4.9 g, 3.4 mL, 3.0 Eq, 39 mmol). The reaction mixture was stirred at 20 °C for 6 hours. The reaction mixture was concentrated under vacuum, and to the residue was added ice water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 4- chloro-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (3.7 g, 12 mmol, 94%); (M+H)+ = 307.1. [00404] Step A1-9, preparation of methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4- diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate: Into a 250-mL vial was placed a mixture of methyl 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo- 1,2-dihydro-1,7-naphthyridine-3-carboxylate (3.7 g, 1 Eq, 12 mmol), DIEA (4.7 g, 6.3 mL, 3.0 Eq, 36 mmol), tert-butyl (S)-7-methyl-1,4-diazepane-1-carboxylate (4.7 g, 1.8 Eq, 22 mmol), and ACN (40 mL). The reaction mixture was stirred at 80 °C for 1 hour. The resulting mixture was concentrated under vacuum and the mixture purified directly by silica gel column chromatography eluted with petroleum ether/ethyl acetate (the ratio of EtOAc was increased from 0% to 100% in 12 mins) to afford methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4- diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (4.707 g, 8.6 mmol, 97 %, 89% Purity); (M+H)+ = 485.3. [00405] Step A1-10, preparation of (S)-4-(4-(tertbutoxycarbonyl)-5-methyl-1,4-diazepan-1-yl)- 8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid: Into a 250- mL round-bottom flask was placed a mixture of methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl- 1,4-diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carboxylate (4.7 g, 1 Eq, 9.7 mmol), MeOH (48 mL), water (24 mL), and LiOH (2.3 g, 9.9 Eq, 96 mmol). The reaction mixture was stirred at 80 °C for 1.5 hours. The reaction mixture was concentrated under vacuum, and acidified to pH 5 with citric acid. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-4-(4-(tertbutoxycarbonyl)-5-methyl-1,4- diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (3.63 g, 7.71 mmol, 80%); (M+H)+ = 471.2.. [00406] Step A1-11, preparation of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(3-ethoxy-4- fluorophenyl)ethyl)carbamoyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-7- methyl-1,4-diazepane-1-carboxylate: Into a 8-mL vial was placed (S)-4-(4-(tert-butoxycarbonyl)- 5-methyl-1,4-diazepan-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carboxylic acid (150 mg, 1 Eq, 319 μmol), HATU (182 mg, 1.50 Eq, 479 μmol), DIEA (247 mg, 333 μL, 6.00 Eq, 1.91 mmol), and DMF (2 mL). The resulting reaction mixture was stirred for 10 minutes at 25 °C. Then to this reaction mixture was added (S)-1-(3-ethoxy-4-fluorophenyl)ethan- 1-amine (175 mg, 3.00 Eq, 955 μmol). The resulting reaction mixture was stirred for 1 hour at 25 °C. The mixture was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19*150mm, 5um; mobile phase, Water (0.1% NH3.H2O) and ACN (20% ACN up to 98% in 8 minutes); Total flow rate, 70 mL/min; Detector, UV 220 nm. This afforded tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(3-ethoxy-4-fluorophenyl)ethyl)carbamoyl)- 1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate (166 mg, 261 μmol, 81.9%); (M+H)+ = 636.4.. [00407] Step A1-12, preparation of N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl- 1,4-diazepan-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3- naphthamide: Into a 50-mL vial was placed a mixture of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)- 1-(3-ethoxy-4-fluorophenyl)ethyl)carbamoyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyridin- 4-yl)-7-methyl-1,4-diazepane-1-carboxylate (166 mg, 1 Eq, 261 μmol) and DCM (5 mL), to which was added TFA (1.5 mL). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and the crude product was purified by Prep- HPLC with the following conditions: Column: SunFire prep OBD 19*150mm, 5µm; Mobile Phase A: Water (0.05% NH3.H2O); Mobile Phase B: ACN; Gradient: 25% B to 65% B in 8 minutes; Flow rate: 20 mL/min; Wave Length: 220 nm. The collected fractions were dried by lyophilization to afford N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazepan- 1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthamid (68.2 mg, 127 μmol, 48.8%); (M+H)+ = 536.3. [00408] The following compounds were prepared similarly to Example A1 with appropriate substitution of reagents and/or substrates and/or functional group modifications via well-known chemistry with appropriate reagents.
Figure imgf000095_0001
Figure imgf000096_0001
Example A2. Preparation of ethyl 3-{3-[N-(S)-1-(4-fluoro-3- methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6- methyl-1,7-diaza-2-naphthylamino}propionate (Compound 136)
Figure imgf000097_0001
[00409] Step A2-1, preparation of methyl 3-amino-2-bromo-6-methylisonicotinate: Into a 250- mL vial was placed a mixture of methyl 5-amino-2-methylisonicotinate (3.0 g, 1 Eq, 18 mmol; prepared via Steps 1-1 to 1-2 of Example A-1) and DMF (30 mL) to which was added NBS (3.9 g, 1.2 Eq, 22 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was then poured into H2O (30 ml) at 0 °C and the solid was filtrated to afford methyl 3-amino-2- bromo-6-methylisonicotinate (3.4 g, 14 mmol, 77%); (M+H)+ = 244.9. [00410] Step A2-2, preparation of methyl 3-amino-2-cyclopropyl-6-methylisonicotinate: Into a 8-mL vial was placed methyl 3-amino-2-bromo-6-methylisonicotinate (3.3 g, 1 Eq, 13 mmol), Pd(OAc)2 (0.3 g, 0.1 Eq, 1 mmol), potassium phosphate tribasic (8.6 g, 3.4 mL, 3.0 Eq, 41 mmol), cyclopropylboronic acid (3 g, 3 Eq, 0.03 mol), tricyclohexylphosphine (0.76 g, 0.85 mL, 0.20 Eq, 2.7 mmol), toluene (50 mL), and H2O (5 mL). The resulting solution was stirred for 1 hour at 80 °C. The reaction mixture was extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with PE/EtOAc (2/1) to afford methyl 3-amino-2-cyclopropyl-6-methylisonicotinate (2.8 g, 14 mmol, 100%); (M+H)+ = 207.1. [00411] Step A2-3, preparation of methyl 2-cyclopropyl-3-(3-ethoxy-3-oxopropanamido)-6- methylisonicotinate: Into a 250-mL vial was placed a mixture of methyl 3-amino-2-cyclopropyl- 6-methylisonicotinate (1.6 g, 1 Eq, 7.8 mmol), DIEA (3.0 g, 4.0 mL, 3.0 Eq, 23 mmol), and DCM (50 mL), to which was added a mixture of ethyl 3-chloro-3-oxopropanoate (1.2 g, 1.0 Eq, 8.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was purified directly by silica gel column chromatography eluted with PE/EtOAc (the ratio of EtOAc increased from 0% to 65% in 8 min) to afford methyl 2-cyclopropyl-3-(3-ethoxy-3- oxopropanamido)-6-methylisonicotinate (1.75 g, 5.46 mmol, 70%); (M+H)+ = 321.2. [00412] Step A2-4, preparation of ethyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro- 1,7-naphthyridine-3-carboxylate/methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro- 1,7-naphthyridine-3-carboxylate: Into a 40-mL X2 vial was placed a mixture of methyl 2- cyclopropyl-3-(3-ethoxy-3-oxopropanamido)-6-methylisonicotinate (1.65 g, 1 Eq, 5.15 mmol), sodium methoxide (1.11 g, 1.21 mL, 3.99 Eq, 20.5 mmol), and MeOH (32 mL). The reaction mixture was stirred at 60 °C for 2 hours. The crude product was concentrated under vacuum to afford ethyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carboxylate (528 mg, 1.83 mmol, 35.6%) and methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo- 1,2-dihydro-1,7-naphthyridine-3-carboxylate (432 mg, 1.58 mmol, 30.6%); (M+H)+ = 289.1, 275.1. [00413] Step A2-5, preparation of 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7- naphthyridine-3-carboxylic acid: Into a 8 mL vial were added ethyl 8-cyclopropyl-4-hydroxy-6- methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (528 mg, 1 Eq, 1.83 mmol), methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylate (432 mg, 0.860 Eq, 1.58 mmol), MeOH (10 mL), and H2O (5 mL), followed by LiOH (439 mg, 10.0 Eq, 18.3 mmol). The mixture was stirred for 2 hours at 60 °C. The reaction was then cooled to room temperature, water (1 mL) was added, and pH was adjusted to 5-6 with aqueous HCl (1M). The reaction mixture was then extracted with DCM (3 x 20 mL), and the combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (800 mg, 3.07 mmol), which was used directly in the next step without purification; (M+H)+ = 261.0. [00414] Step A2-6, preparation of 4-chloro-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7- naphthyridine-3-carbonyl chloride: Into a 40-mL vial was placed a mixture of 8-cyclopropyl-4- hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (800 mg, 1 Eq, 3.07 mmol) and oxalyl chloride (7 g, 5 mL, 20 Eq, 0.06 mol), and then DMF (22.5 mg, 23.8 μL, 0.100 Eq, 308 μmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrate under reduced pressure to afford 4-chloro-8-cyclopropyl-6- methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonyl chloride (810 mg, 2.73 mmol), which was used directly in the next step without any purification. [00415] Step A2-7, preparation of methyl (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3- methoxyphenyl)ethyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxamide: Into a 40- mL vial was placed a mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethan-1-amine (923 mg, 2.00 Eq, 5.46 mmol), DIEA (1.76 g, 2.37 mL, 5.00 Eq, 13.6 mmol), and DCM (10 mL), to which was added a mixture of 4-chloro-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridine-3- carbonyl chloride (810 mg, 1 Eq, 2.73 mmol) and DCM (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was purified directly by silica gel column chromatography eluted with PE/EtOAc (the ratio of EtOAc was increased from 0% to 65% in 8 mins) to afford (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-2- oxo-1,2-dihydro-1,7-naphthyridine-3-carboxamide (1.04 g, 2.42 mmol, 88.7%); (M+H)+ = 432.1. [00416] Step A2-8, preparation of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-7-methyl- 1,4-diazepane-1-carboxylate: Into a 40-mL vial was placed a mixture of (S)-4-chloro-8- cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-2-oxo-1,2-dihydro-1,7- naphthyridine-3-carboxamide (1.04 g, 1 Eq, 2.42 mmol), DIEA (938 mg, 1.26 mL, 3.00 Eq, 7.26 mmol), tert-butyl (S)-7-methyl-1,4-diazepane-1-carboxylate (1.04 g, 2.01 Eq, 4.85 mmol), and ACN (10 mL). The reaction mixture was stirred at 80 °C for 16 hours. The mixture was purified by Flash-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, Water (0.1% NH3.H2O) and ACN (20.0% ACN increased to 98.0% in 7 min); Total flow rate, 70 mL/min; Detector, UV 220 nm. The collected fractions were combined and concentrated under vacuum to afford tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyridin-4-yl)-7-methyl- 1,4-diazepane-1-carboxylate (1.3 g, 2.1 mmol, 88%); (M+H)+ = 608.4. [00417] Step A2-9, preparation of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-(((trifluoromethyl)sulfonyl)oxy)-1,7-naphthyridin- 4-yl)-7-methyl-1,4-diazepane-1-carboxylate: Into a 40-mL vial was placed a mixture of tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-oxo- 1,2-dihydro-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate (400 mg, 1 Eq, 658 μmol), 2,6-lutidine (282 mg, 305 μL, 4.00 Eq, 2.63 mmol), and DCM (8 mL), to which was added a mixture of trifluoromethanesulfonic anhydride (613 mg, 365 μL, 3.30 Eq, 2.17 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford tert-butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-(((trifluoromethyl)sulfonyl)oxy)-1,7-naphthyridin- 4-yl)-7-methyl-1,4-diazepane-1-carboxylate (450 mg, 608 μmol, 92.4%), which was used directly in the next step without purification. [00418] Step A2-10, preparation of tert-butyl (S)-4-(8-cyclopropyl-2-((3-ethoxy-3- oxopropyl)amino)-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7- naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate: Into a 40-mL vial was placed tert- butyl (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2- (((trifluoromethyl)sulfonyl)oxy)-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1-carboxylate (450 mg, 1 Eq, 608 μmol), Cs2CO3 (595 mg, 3.00 Eq, 1.83 mmol), ethyl 3-aminopropanoate (143 mg, 2.01 Eq, 1.22 mmol), Pd(crotyl)(tBuBrettPhos)OTf (24.2 mg, 0.0500 Eq, 30.4 μmol), and 1,4-dioxane (5 mL). The resulting solution was stirred for 1 hour at 80 °C. The reaction mixture was concentrated under vacuum, and the crude product was purified by Prep-HPLC with the following conditions: Column, C18 Column; mobile phase, Water (0.1% NH3.H2O) and ACN (20% ACN increased to 98% in 6 mins); Total flow rate, 70 mL/min; Detector, UV 220 nm. This afforded tert-butyl (S)-4-(8-cyclopropyl-2-((3-ethoxy-3-oxopropyl)amino)-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1- carboxylate (60 mg, 85 μmol, 14%); (M+H)+ = 707.6. [00419] Step A2-11, preparation of ethyl 3-{3-[N-(S)-1-(4-fluoro-3- methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6-methyl- 1,7-diaza-2-naphthylamino}propionate: Into a 50-mL round-bottom flask was placed tert-butyl (S)-4-(8-cyclopropyl-2-((3-ethoxy-3-oxopropyl)amino)-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-7-methyl-1,4-diazepane-1- carboxylate (30 mg, 1 Eq, 42 μmol), DCM (3 mL), and TFA (1 mL). The resulting solution was stirred for 1 hour at 20 °C. The resulting mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions: Column: SunFire prep OBD 19*150mm 5um; Mobile Phase A: Water (0.05% TFA); 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 dried by lyophilization to afford ethyl 3-{3-[N-(S)-1-(4-fluoro-3- methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazepan-1-yl]-8-cyclopropyl-6-methyl- 1,7-diaza-2-naphthylamino}propionate (18.6 mg, 30.7 μmol, 72%); (M+H)+ = 607.4. [00420] The following compounds were prepared similarly to Example A2 with appropriate substitution of reagents and/or substrates and/or functional group modifications via well-known chemistry with appropriate reagents.
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0002
Example A3. Preparation of N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3- (methoxymethyl)-3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide (Compound 153)
Figure imgf000104_0001
[00421] Step A3-1, preparation of diethyl 2-(((2-bromo-6-methylpyridin-3- yl)amino)methylene)malonate: Into a 40-mL vial was placed a mixture of 2-bromo-6- methylpyridin-3-amine (5.00 g, 1 Eq, 26.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.94 g, 1.20 Eq, 32.1 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature, and diluted with PE (200 mL), and the precipitates were collected by filtration and dried to afford diethyl 2-(((2-bromo-6-methylpyridin-3- yl)amino)methylene)malonate (7.63 g, 21.4 mmol, 79.9%); (M+H)+ = 357.1. [00422] Step A3-2, preparation of diethyl 2-(((2-cyclopropyl-6-methylpyridin-3- yl)amino)methylene)malonate: Into a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of diethyl 2-(((2-bromo-6-methylpyridin-3- yl)amino)methylene)malonate (8.00 g, 1 Eq, 22.4 mmol), cyclopropylboronic acid (10.0 g, 5.20 Eq, 116 mmol), Ruphos Pd 3G (200 mg, 0.0107 Eq, 239 μmol), potassium carbonate (21.7 g, 7.01 Eq, 157 mmol), toluene (150 mL) and water (30 mL). The reaction mixture was stirred at 100 °C for 16 hours. The mixture was directly purified by flash column chromatography eluted with PE/EtOAc (3/1) to afford diethyl 2-(((2-cyclopropyl-6-methylpyridin-3- yl)amino)methylene)malonate (5.25 g, 16.5 mmol, 73.6%); (M+H)+ = 319.1. [00423] Step A3-3, preparation of ethyl 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyridine- 3-carboxylate: Into a 100-mL three-necked round bottom flask was placed phenyl ether- biphenyleutetic (50 g, 9.3 Eq, 0.15 mol), and the mixture was heated to 258 °C, to which was added diethyl 2-(((2-cyclopropyl-6-methylpyridin-3-yl)amino)methylene)malonate (5.25 g, 1 Eq, 16.5 mmol) in one portion at 258 °C. The reaction mixture was stirred at 258 °C for 20 minutes, cooled to room temperature, and diluted with PE (200 mL), and the resulting precipitates were collected by filtration and dried to afford ethyl 8-cyclopropyl-4-hydroxy-6-methyl-1,7- naphthyridine-3-carboxylate (2.85 g, 10.5 mmol, 63.5%); (M+H)+ = 273.1. [00424] Step A3-4, preparation of 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyridine-3- carboxylic acid: Into a 40-mL vial was placed with mixture of ethyl 8-cyclopropyl-4-hydroxy-6- methyl-1,7-naphthyridine-3-carboxylate (1.00 g, 1 Eq, 3.67 mmol), LiOH (1.00 g, 11.4 Eq, 41.8 mmol) and MeOH (20 mL). Then water (4 mL) was added, and the reaction mixture was stirred at 65 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (30 mL) and adjusted to pH 6.0 with a saturated NaHSO4 solution. The resulting precipitates were collected by filtration and dried to afford 8 -cyclopropyl-4- hydroxy-6-methyl-1,7-naphthyridine-3-carboxylic acid (850 mg, 3.48 mmol, 94.8%); (M+H)+ = 245.1. [00425] Step A3-5, preparation of 4-chloro-8-cyclopropyl-6-methyl-1,7-naphthyridine-3- carbonyl chloride: Into an 8-mL vial was placed a mixture of 8-cyclopropyl-4-hydroxy-6-methyl- 1,7-naphthyridine-3-carboxylic acid (600 mg, 1 Eq, 2.46 mmol) and POCl3 (5.0 g, 3.0 mL, 13 Eq, 33 mmol). The reaction mixture was stirred at 100 °C for 30 minutes. Then the reaction mixture was concentrated under reduced pressure to afford 4-chloro-8-cyclopropyl-6-methyl-1,7- naphthyridine-3-carbonyl chloride (660 mg, 2.35 mmol, 95.6%), which was used directly for next step without any purification. [00426] Step A3-6, preparation of (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3- methoxyphenyl)ethyl)-6-methyl-1,7-naphthyridine-3-carboxamide: Into a 8-mL vial was placed a mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethan-1-amine (100 mg, 2.1 Eq, 591 μmol), DIEA (370 mg, 499 μL, 10 Eq, 2.86 mmol), and DCM (1 mL), to which was added a mixture of 4- chloro-8-cyclopropyl-6-methyl-1,7-naphthyridine-3-carbonyl chloride (80 mg, 1 Eq, 0.28 mmol) and DCM (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The mixture was purified directly by silica gel column chromatography eluted with PE/EtOAc (the ratio of EtOAc was increased from 0% to 75% in 7 min) to afford (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3- methoxyphenyl)ethyl)-6-methyl-1,7-naphthyridine-3-carboxamide (60 mg, 0.14 mmol, 51%); (M+H)+ = 414.2. [00427] Step A3-7, preparation of 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidin-3-amine: Into an 8-mL vial was placed tert-butyl (1-benzyl-3-(methoxymethyl)pyrrolidin-3-yl)carbamate (800 mg, 1 Eq, 2.50 mmol) and lithium aluminum(III) hydride (300 mg, 3.17 Eq, 7.91 mmol) in THF (2 mL). The resulting reaction mixture was stirred for 1 hour at 70 °C. The reaction was then quenched by water (5 mL), and the resulting solution was extracted with ethyl acetate (3 x 10 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidin-3-amine (700 mg, 2.99 mmol), which was used in the next step without purification; (M+H)+ = 235.2. [00428] Step A3-8, preparation of tert-butyl (1-benzyl-3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate: A mixture of 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidin-3-amine (700 mg, 1 Eq, 2.99 mmol), di-tert-butyl dicarbonate (900 mg, 1.38 Eq, 4.12 mmol), and TEA (1000 mg, 1.38 mL, 3.31 Eq, 9.882 mmol) in DCM (10 mL) was stirred at 25 °C for 16 hours. Then water (20 mL) was added, and the reaction mixture was extracted with EtOAc (30 mL x 2). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl (1-benzyl-3-(methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate (530 mg, 1.58 mmol, 53.0%); (M+H)+ = 335.2. [00429] Step A3-9, preparation of tert-butyl (3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate: Into a 50-mL round bottom was placed tert-butyl (1-benzyl-3- (methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate (530 mg, 1 Eq, 1.58 mmol), MeOH (10 mL), and Pd-C (200 mg, 1.19 Eq, 1.88 mmol) under a hydrogen (H2) atmosphere. The resulting solution was stirred for 1 hour at 25 °C, then the Pd-C was filtered out, and the solution was concentrated under vacuum to afford tert-butyl (3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate (240 mg, 982 μmol, 62.0%); (M+H)+ = 245.2. [00430] Step A3-10, preparation of tert-butyl (1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-3- (methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate: Into an 8-mL vial was placed a mixture of (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-1,7-naphthyridine- 3-carboxamide (60 mg, 1 Eq, 0.14 mmol), tert-butyl (3-(methoxymethyl)pyrrolidin-3- yl)(methyl)carbamate (100 mg, 2.8 Eq, 409 μmol), DIEA (60 mg, 81 μL, 3.2, Eq, 0.46 mmol), and dioxane (1 mL). The reaction mixture was stirred at 110 °C for 16 hours. The mixture was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19*150mm, 5µm; mobile phase, water (0.1% FA) and ACN (30% ACN increased to 98% in 7 mins); Total flow rate, 20 mL/min; Detector, UV 220 nm. This afforded tert-butyl (1-(8- cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin- 4-yl)-3-(methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate (60 mg, 97 μmol, 67%); (M+H)+ = 622.4. [00431] Step A3-11, preparation of N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl- 4-[3-(methoxymethyl)-3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide: Into an 8-mL vial was placed tert-butyl (1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3- methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthyridin-4-yl)-3- (methoxymethyl)pyrrolidin-3-yl)(methyl)carbamate (50 mg, 1 Eq, 80 μmol), DCM (3 mL), and TFA (1 mL). The resulting reaction mixture was stirred for 1 hour at 25 °C. The mixture was purified by prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5µm; mobile phase, water (0.05% NH3.H2O) and ACN (30.0% ACN increased to 50.0% in 7 mins); Total flow rate, 20 mL/min; Detector, UV 220nm. The collected fractions were combined and concentrated under vacuum, then lyophilization to afford N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3- (methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthamide (32.4 mg, 62.1 μmol, 77%); (M+H)+ = 522.3. [00432] The following compounds were prepared similarly to Example A3 with appropriate substitution of reagents and/or substrates and/or functional group modifications via well-known chemistry with appropriate reagents.
Figure imgf000107_0001
Figure imgf000108_0002
Example A4. Preparation of N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl- 1-piperazinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthamide (Compound 167)
Figure imgf000108_0001
[00433] Step A4-1, preparation of diethyl 2-(((2-methoxy-6-methylpyridin-3- yl)amino)methylene)malonate: Into a 100-mL flask was placed 2-methoxy-6-methylpyridin-3- amine (5 g, 1 Eq, 0.04 mol) and diethyl 2-(ethoxymethylene)malonate (15.6 g, 2 Eq, 72.1 mmol). The resulting solution was stirred for 1 hour at 100 °C. The resulting solution was diluted with PE (50 mL) and stirred for 1 hour. The precipitate was collected to afford diethyl 2-(((2- methoxy-6-methylpyridin-3-yl)amino)methylene)malonate (8.9 g, 29 mmol, 80%); (M+H)+ = 309.1 [00434] Step A4-2, preparation of ethyl 4-hydroxy-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylate: To a boiling phenyl ether-biphenyleutectic (220.0 g, 207.7 mL, 19.9 Eq, 678.1 mmol) at 252 °C was added diethyl 2-(((2-methoxy-6-methylpyridin-3- yl)amino)methylene)malonate (10.5 g, 1 Eq, 34.1 mmol) in portions, and the reaction was stirred at 252 °C for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with PE (200 mL) to afford ethyl 4-hydroxy-8-methoxy-6-methyl-1,7- naphthyridine-3-carboxylate (4.2 g, 16 mmol, 47%); (M+H)+ = 263.1. [00435] Step A4-3, preparation of ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylate: Into a 1000-mL three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a mixture of ethyl 4-hydroxy-8-methoxy-6-methyl-1,7- naphthyridine-3-carboxylate (8 g, 1 Eq, 0.03 mol), DMF (0.09 g, 0.1 mL, 0.04 Eq, 1 mmol), and DCM (400 mL), to which oxalyl chloride (5 g, 3 mL, 1.3 Eq, 0.04 mol) was added dropwise at 0 °C over 10 minutes. Then the reaction mixture was stirred at 25 °C for 1 hour. The mixture was quenched with aqueous NaHCO3 (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by HPLC with the following conditions: Silica gel column 120 g, PE/EtOAc system, the ratio of EtOAc was increased from 0% to 50% in 15 minutes, Flow rate: 70 mL/min; Wave Length: 254 nm. The collected fractions were concentrated to afford ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthyridine-3-carboxylate (7.56 g, 26.9 mmol, 90%); (M+H)+ = 281.0. [00436] Step A4-4, preparation of ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5- dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthyridine-3-carboxylate: Into a 250-mL vial was placed a solution of ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylate (150 mg, 1 Eq, 534 μmol) and DIEA (138 mg, 186 μL, 2.0 Eq, 1.07 mmol) in ACN (1.5 mL). To this was added tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (344 mg, 3.0 Eq, 1.60 mmol). The resulting mixture was stirred at 80 °C for 16 hours. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, Water (0.1% NH3.H2O) and ACN (30% ACN increased to 98% in 4 min); Detector, UV 254 & 220 nm. The collected fractions were combined and concentrated to afford ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6- methyl-1,7-naphthyridine-3-carboxylate (240 mg, 523 μmol, 97.9%); (M+H)+ = 459.5. [00437] Step A4-5, preparation of 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1- yl)-8-methoxy-6-methyl-1,7-naphthyridine-3-carboxylic acid: Into a 40-mL vial was placed a mixture of ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6- methyl-1,7-naphthyridine-3-carboxylate (240 mg, 1 Eq, 523 μmol), lithium hydroxide (127 mg, 10.1 Eq, 5.29 mmol), MeOH (5 mL), and H2O (2.5 mL). The reaction mixture was stirred at 80 °C for 1 hour. The reaction mixture was diluted with water (50 mL), the pH was adjusted to 5.0 with saturated NaHSO4, and the resulting precipitates were collected by filtration and dried to afford 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7- naphthyridine-3-carboxylic acid (200 mg, 465 μmol, 88.8%); (M+H)+ = 431.5. [00438] Step A4-6, preparation of tert-butyl (2S,6R)-4-(3-(((S)-1-(3,5- dimethoxyphenyl)ethyl)carbamoyl)-8-methoxy-6-methyl-1,7-naphthyridin-4-yl)-2,6- dimethylpiperazine-1-carboxylate: Into a 8-mL vial was placed a solution of 4-((3S,5R)-4-(tert- butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthyridine-3- carboxylic acid (100 mg, 1.0 Eq, 232 μmol), DIEA (150 mg, 202 μL, 5.0 Eq, 1.16 mmol), and HATU (132 mg, 1.5 Eq, 348 μmol) in DMF (2 mL). The reaction mixture was stirred at 25 °C for 15 minutes. Then (S)-1-(3,5-dimethoxyphenyl)ethan-1-amine hydrochloride (152 mg, 3.0 Eq, 697 μmol) was added to the reaction mixture, which was stirred at 25 °C for 1 hour. The resulting solution was purified by Prep-HPLC with the following conditions (2#-analyse-HPLC- SHIMADZU(HPLC-0013)): Column, Kinetex EVO 21.2*150mm 5µm; mobile phase, Water (0.1% NH3.H2O) and ACN (20% ACN increased to 60.0% in 7 mins); Detector, UV 220 nm. This afforded tert-butyl (2S,6R)-4-(3-(((S)-1-(3,5-dimethoxyphenyl)ethyl)carbamoyl)-8- methoxy-6-methyl-1,7-naphthyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (80 mg, 0.13 mmol, 58%); (M+H)+ = 594.7. [00439] Step A4-7, preparation of N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5- dimethyl-1-piperazinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthamide: Into a 8-mL vial was placed tert-butyl (2S,6R)-4-(3-(((S)-1-(3,5-dimethoxyphenyl)ethyl)carbamoyl)-8-methoxy-6- methyl-1,7-naphthyridin-4-yl)-2,6-dimethylpiperazine-1-carboxylate (80 mg, 1 Eq, 0.13 mmol), TFA (2 mL), and DCM (0.4 mL). The resulting reaction mixture was stirred at 25 °C for 1.5 hours. The resulting solution was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-013): Column, SunFire Prep C18 OBD Column, 19*150mm 5µm 10 nm; mobile phase, Water (0.1% NH3.H2O) and ACN (15% ACN increased to 50% in 10 mins). Total flow 20 mL/min. Detector UV 220 nm. This afforded N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-methoxy-6- methyl-1,7-diaza-3-naphthamide (41.8 mg, 84.7 μmol, 63%); (M+H)+ = 494.6. [00440] The following compounds were prepared similarly to Example A4 with appropriate substitution of reagents and/or substrates and/or functional group modifications via well-known chemistry with appropriate reagents.
Figure imgf000110_0001
Example B-1: SSTR assays Functional Assays [00441] 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 [00442] 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 µg/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 µL of stimulation buffer supplemented with 10.2 mM 3-isobutyl-1- methylxanthine (IBMX, Millipore Sigma #I5879) and 1.6 µM 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 µL 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 µL 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 m1000 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). [00443] Table A reports biological activity of compounds as evaluated by inhibition of cAMP activities via human SSTR3 receptor.
Figure imgf000112_0001
Figure imgf000112_0002
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000114_0001
Figure imgf000114_0002
[00444] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS We Claim: 1. A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:
Figure imgf000115_0001
) wherein: R2 is H, halogen, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R4 is H, halogen, C1-6 alkoxy, C1-6 haloalkyl, or CN; R6 is H or C1-6 alkyl; and R8 is H or C1-6 alkyl.
2 The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein: R2 is H, halogen, C1-3 alkoxy, or CN; R3 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN; R4 is H, halogen, C1-3 alkoxy, C1-3 haloalkyl, or CN; R6 is H or C1-3 alkyl; and R8 is H or C1-3 alkyl.
3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R3 is halogen or C1-3 alkoxy.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-3 alkoxy.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R6 is H or Me.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R8 is H or Me.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: R2 is H; R3 is halogen or C1-3 alkoxy; R4 is C1-3 alkoxy; R6 is H or Me; and R8 is H or Me.
8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, Cl, OMe, or CN.
9. The compound of any one of claims 1-2, 4-6, or 8, or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, Cl, OMe, CF3, or CN.
10. The compound of any one of claims 1-3, 5-6, or 8-9, or a pharmaceutically acceptable salt thereof, wherein R4 is F, Cl, OMe, OEt, CF3, or CN.
11. The compound of any one of claims 1-2 or 8-10, or a pharmaceutically acceptable salt thereof, wherein: R2 is H, F, Cl, OMe, or CN; R3 is H, F, Cl, OMe, CN, or CF3; R4 is F, Cl, OMe, OEt, CF3, or CN; R6 is H or Me; and R8 is H or Me.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R2 is H.
13. The compound of any one of claim 1-12, or a pharmaceutically acceptable salt thereof, wherein R3 is F or OMe.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R4 OMe or OEt.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R8 is H.
17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R8 is Me.
18. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , ,
Figure imgf000117_0001
d
Figure imgf000118_0001
19. A compound of Formula (Ib), an N-oxide thereof, or pharmaceutically acceptable salt thereof:
Figure imgf000119_0001
) wherein: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, then X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, C1-6 alkyl, C1-6 alkoxy, or CN; R3 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or CN; R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH; R7 is H, C1-6 alkoxy, morpholinyl optionally substituted with C1-6 alkyl
Figure imgf000119_0002
, ,
Figure imgf000119_0003
; R9 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy; R10 is C1-6 alkyl or C1-6 alkoxy; RA is C1-6 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-6 cycloalkyl; and RC is H or C1-6 haloalkyl.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein: R1 is H, halogen, or OH; R2 is H, halogen, C1-3 alkyl, C1-3 alkoxy, or CN; R3 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; R4 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, CN, OH, or C(O)NH2; R5 is H, halogen, or OH;
Figure imgf000120_0001
R7 is H, C1-3 alkoxy, morpholinyl optionally substituted with C1-3 alkyl,
Figure imgf000120_0002
,
Figure imgf000120_0003
; R9 is C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, cyclopropyl, or cyclopropoxy; R10 is C1-3 alkyl or C1-3 alkoxy; RA is C1-3 alkyl, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a C3-4 cycloalkyl; and RC is H or C1-3 haloalkyl.
21. The compound of claim 19 or claim 20, or a pharmaceutically acceptable salt thereof, wherein R1 is H, F, or OH.
22. The compound of any one of claims 19-21, or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, Cl, Me, OMe, or CN.
23. The compound of any one of claims 19-22, or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, Cl, Me, CF3, OMe, or CN.
24. The compound of any one of claims 19-23, or a pharmaceutically acceptable salt thereof, wherein R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2.
25. The compound of any one of claims 19-24, or a pharmaceutically acceptable salt thereof, wherein R5 is H, F, OH.
26. The compound of any one of claims 19-25, or a pharmaceutically acceptable salt thereof, r
Figure imgf000120_0004
.
27. The compound of any one of claims 19-26, or a pharmaceutically acceptable salt thereof, wherein R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy.
28. The compound of any one of claims 19-27, or a pharmaceutically acceptable salt thereof, wherein R10 is Me or OMe.
29. The compound of any one of claims 19-28, or a pharmaceutically acceptable salt thereof, wherein RA is Me, CH2OH, or CH2OMe; and RB is H.
30. The compound of any one of claims 19-28, or a pharmaceutically acceptable salt thereof, wherein RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group.
31. The compound of any one of claims 19-30, or a pharmaceutically acceptable salt thereof, wherein RC is H or CH2CH2F.
32. The compound of any one of claims 19-31, or a pharmaceutically acceptable salt thereof, wherein: R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is H, F, or OH;
Figure imgf000121_0001
; R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R10 is Me or OMe; RA is Me, CH2OH, or CH2OMe; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group or a cyclobutyl group; and RC is H or CH2CH2F.
33. The compound of any one of claims 19-32, or a pharmaceutically acceptable salt thereof, wherein R1 is H or OH.
34. The compound of any one of claims 19-33, or a pharmaceutically acceptable salt thereof, wherein R2 is H or F.
35. The compound of any one of claims 19-34, or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, OMe, or CN.
36. The compound of any one of claims 19-35, or a pharmaceutically acceptable salt thereof, wherein R4 is Cl, OMe, or CN.
37. The compound of any one of claims 19-36, or a pharmaceutically acceptable salt thereof, wherein R5 is H.
38. The compound of any one of claims 19-37, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000122_0001
.
39. The compound of any one of claims 19-38, or a pharmaceutically acceptable salt thereof, wherein R9 is OMe or cyclopropyl.
40. The compound of any one of claims 19-39, or a pharmaceutically acceptable salt thereof, wherein R10 is Me.
41. The compound of any one of claims 19-40, or a pharmaceutically acceptable salt thereof, wherein RA is Me; and RB is H.
42. The compound of any one of claims 19-40, or a pharmaceutically acceptable salt thereof, wherein RA and RB together with the carbon atom to which they are attached form a cyclopropyl group.
43. The compound of any one of claims 19-42, or a pharmaceutically acceptable salt thereof, wherein RC is H.
44. The compound of any one of claims 19-43, or a pharmaceutically acceptable salt thereof, wherein: R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H,
Figure imgf000122_0002
; R9 is OMe or cyclopropyl; R10 is Me; RA is Me; RB is H; or RA and RB together with the carbon atom to which they are attached form a cyclopropyl group; and RC is H.
45. The compound of any one of claims 19-44, or a pharmaceutically acceptable salt thereof, wherein X is CR1; Y is CR2; and Z is CR3.
46. The compound of any one of claims 19-44, or a pharmaceutically acceptable salt thereof, wherein one of X, Y, or Z is N.
47. The compound of claim 19 or claim 20, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , ,
Figure imgf000123_0001
,
Figure imgf000124_0001
Figure imgf000125_0001
, , , , , ,
Figure imgf000126_0001
,
Figure imgf000127_0001
a
Figure imgf000128_0001
48. A compound of Formula (Ic), or a pharmaceutically acceptable salt thereof:
Figure imgf000129_0001
) wherein: Z is CR3 or N; R2 is H, halogen, or C1-6 alkoxy; R3 is H, halogen, or C1-6 alkoxy; R4 is H, halogen, or C1-6 alkoxy; RD is C1-6 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 3-6 membered heterocycloalkyl.
49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein: R2 is H, halogen, or C1-3 alkoxy; R3 is H, halogen, or C1-3 alkoxy; R4 is H, halogen, or C1-3 alkoxy; RD is C1-3 alkyl; and RE is CH2OMe; or RD and RE together with the nitrogen and carbon atoms to which they are attached form a 4-5 membered heterocycloalkyl.
50. The compound of claim 48 or claim 49, or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, or OMe.
51. The compound of any one of claims 48-50, or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, or OMe.
52. The compound of any one of claims 48-51, or a pharmaceutically acceptable salt thereof, wherein R4 is F or OMe.
53. The compound of any one of claims 48-52, or a pharmaceutically acceptable salt thereof, wherein RD is Me or Et.
54. The compound of any one of claims 48-52, or a pharmaceutically acceptable salt thereof, wherein RD and RE together with the nitrogen and carbon atoms to which they are attached form an azetidinyl group or a pyrrolidinyl group.
55. The compound of claim 48 or claim 49, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , ,
Figure imgf000130_0001
y acceptable salt thereof.
56. A compound of Formula (Id), or a pharmaceutically acceptable salt thereof:
Figure imgf000130_0002
) wherein: R2 is halogen, C1-6 alkoxy, or CN; R4 is halogen or C1-6 alkoxy; and R9 is C1-6 alkoxy or C3-6 cycloalkyl.
57. The compound of claim 56, or a pharmaceutically acceptable salt thereof , wherein: R2 is halogen, C1-3 alkoxy, or CN; R4 is halogen or C1-3 alkoxy; and R9 is C1-3 alkoxy or cyclopropyl.
58. The compound of claim 56 or claim 57, or a pharmaceutically acceptable salt thereof , wherein R2 is F, OMe, or CN.
59. The compound of any one of claims 56-58, or a pharmaceutically acceptable salt thereof , wherein R4 is F or OMe.
60. The compound of any one of claims 56-59, or a pharmaceutically acceptable salt thereof , wherein R9 is OMe or cyclopropyl.
61. The compound of claim 56 or claim 57, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: d
Figure imgf000131_0001
62. A method of treating a disorder selected from the group consisting of polycystic kidney disease, polycystic liver disease, and ciliopathies, comprising administering to a subject in need thereof a compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof. 63. The method of claim 62, wherein the disorder is polycystic kidney disease. 64. The method of claim 63, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019023278A1 (en) * 2017-07-25 2019-01-31 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
EP3689876A1 (en) * 2017-09-28 2020-08-05 Nanjing Transthera Biosciences Co. Ltd. Pde9 inhibitor and use thereof

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Publication number Priority date Publication date Assignee Title
WO2019023278A1 (en) * 2017-07-25 2019-01-31 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
EP3689876A1 (en) * 2017-09-28 2020-08-05 Nanjing Transthera Biosciences Co. Ltd. Pde9 inhibitor and use thereof

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Title
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