Somatostatin type 3 receptor (sstr3) agonists and uses thereof

Abstract

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

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 601,948, filed November 22, 2023; and U.S. Provisional Patent Application No. 63 / 677,136, filed July 30, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] This article describes compounds that are somatostatin type 3 receptor agonists (SSTR3), methods for preparing such compounds, pharmaceutical compositions and drugs comprising such compounds, and methods for treating conditions, diseases or disorders that would benefit from the regulation of SSTR3 activity using such compounds.

[0003] Somatostatin is a peptide hormone that, through interaction with G protein-coupled somatostatin receptors (GPCRs), inhibits the release of various secondary hormones, regulates the endocrine system, and affects neurotransmission and cell proliferation. Six somatostatin receptor subtypes (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5) have been identified, and they are encoded by five different somatostatin receptor genes. Regulation of specific somatostatin receptor subtypes or combinations thereof is attractive for treating conditions, diseases, or disorders that would benefit from modulating somatostatin activity.

[0004] Somatostatin acts on five GPCRs (SSTR1 through SSTR5). Binding to these receptors inhibits adenylate cyclase (AC) and mitogen-activated protein kinase, cell proliferation, and the secretion of several hormones (growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide and secretin, thyroid-stimulating hormone, and adrenocorticotropic hormone) and growth factors (IGF-I and vascular endothelial growth factor). All five SSTRs are expressed in renal tubular epithelial cells and bile duct cells. SSTR1 and SSTR2 are expressed in the thick ascending limb of Henle, the distal tubule, and the collecting duct. SSTR3, SSTR4, and SSTR5 are expressed in the proximal tubule. In preclinical studies, somatostatin has been shown to (1) inhibit cAMP production in MDCK cells and rat collecting ducts, (2) antagonize the effects of vasopressin in toad bladders and canine collecting ducts, (3) inhibit cAMP production, fluid secretion, and cell proliferation in bile duct cells, and (4) inhibit the growth of connective tissue around the bile ducts and portal vein in rats with extrahepatic biliary obstruction. Because of its half-life of approximately 3 minutes, more stable synthetic peptides (octreotide, lanreotide, and parreotide) have been developed for clinical use.

[0005] In preclinical studies, octreotide (which binds to both SSTR2 and SSTR5, but preferentially to SSTR2) and paretide (which binds to SSTR2, SSTR3, and SSTR5 with high affinity) reduced cAMP levels and in vitro bile duct cell proliferation, hepatic cyst expansion in three-dimensional collagen culture, and PCK rats. Pkd2 WS25 / – mice and Pkd1 RC / RC The development of kidney and liver cysts and fibrosis in the model.

[0006] In clinical trials using octreotide or lanreotide (both bind to SSTR2 and SSTR5, but preferentially to SSTR2), kidney growth ceased in the first year of treatment and then resumed, at a rate likely lower than the untreated rate. Liver volume decreased by 4%–6% during the first year of treatment, and this reduction persisted into the second year. However, the observation period was too short to assess the impact on renal function. While octreotide and lanreotide are generally well-tolerated, the stock formulations of these peptides are extremely expensive and require frequent, painful injections at the doctor's office, which can lead to injection site reactions.

[0007] To the best of the inventors' knowledge, no SSTR3-selective small molecule modulators have been prepared or tested for the treatment of ciliated diseases such as polycystic kidney disease (PKD). The compounds described herein are non-peptide somatostatin agonists that selectively activate the somatostatin type 3 receptor (SSTR3), thereby reducing cAMP levels that can lead to the ciliated diseases described herein, such as PKD. Summary of the Invention

[0008] In one embodiment, this document describes a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: Indicates a single bond or a double bond; Z is NR Z , where R Z It does not exist or is oxidized, or, when R 7 When R = 0, then Z Is it H or C? 1-6 alkyl; X is NR X , where R X Is it H or C? 1-6 alkyl; L is the key, C 1-6 Alkyl, or (CR L1 R L2 ) t , where R L1 and RL2 Each independently is H or C 1-6 Alkyl group, and t is 1, 2, 3, 4, 5 or 6; R 1 It is C 1-6 Alkyl, C 3-10 cycloalkyl, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 6-10 aryl, and 4-7 heteroaryl groups, each optionally bound by 1, 2, 3, 4, or 5 R groups. 1A replace; Each R 1A Independent of halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 11 C(O)OR 11 、or C(O)N(R) 11 )2, where each R 11 Independently H or C 1-6 alkyl; R 2 It is C 3-7 cycloalkyl, C 5-9 Bicycloalkyl or 7- to 9-membered heterocyclic alkyl groups, each surrounded by 1, 2, 3, 4, or 5 R groups. 2A replace; Where R 2A Independent of H, halogen, C 1-6 Alkyl, or C(O)OR 21 C 1-6 Alkyl groups are optionally surrounded by 1, 2, or 3 halogens, OH, CN, or C. 1-6 Alkyl substitution; wherein R 21 Is it H or C? 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon rings; R 3 R 4 R 5 and R 6 Each is independently H, halogen, CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, or C 3-6 Cycloalkyl groups; and R 7 H, halogen, C 1-6 Alkyl, C 3-6 Heterocyclic alkyl, OR 71 or NR 72 R73 ; Where R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. 7A Replacement, condition is when R 71 When it does not exist, R 7 It is a carbonyl group; R 72 and R 73 Independently H or C 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by 1, 2, or 3 R atoms. 7C Substituted 3- to 10-membered heterocyclic alkyl groups; Where R 7A R 7B and R 7C Each is independently a halogen, carbonyl, or C group. 1-6 Alkyl, C 1-6 Alkylamines, 5-membered heterocycles, OR 7B1 C(O)OR 7A1 and C(O)NR 7A2 R 7A2 The 5-membered heterocycle is arbitrarily selected by C 1-6 Alkyl, carbonyl, or OH substitutions, wherein C 1-6 Alkylamines may optionally be substituted with 6-membered cycloalkyl groups, which may optionally be substituted with CO2H; Where R 7A1 R 7A2 R 7B1 R 7B2 and R 7B3 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl group, wherein C 1-6 Alkyl and C 1-6 Each alkyl sulfonyl group is optionally surrounded by one or two R groups. 7B4 Replace; where R 7B4 Independently OC(O)-R 7B5 Or a 5-membered heterocycle, the 5-membered heterocycle can be arbitrarily divided by C 1-6 Alkyl substitution; and wherein R 7B5 It is C 1-6 Alkyl groups, which may optionally be substituted with NH2. Attached Figure Description

[0009] Figure 1This study describes how primary ciliary dysfunction triggers cyst formation in autosomal dominant polycystic kidney disease (ADPKD).

[0010] Figure 2 The interaction between calcium ions and the cAMP ciliary signaling pathway in the kidney tissue of (A) healthy individuals and (B) individuals with ADPKD is described.

[0011] Figure 3 The mechanism by which SSTR3 activation inhibits adenylate cyclase activity and reduces cAMP levels in ciliary plasma is described.

[0012] Figure 4 An analysis of the mRNA expression of SSTR2, SSTR3, SSTR5 and vasopressin receptor 2 (AVPR2) in healthy and cystic tissues was described. Detailed Implementation

[0013] Somatostatin (SSTR), also known as somatotropin-releasing inhibitory factor (SRIF), was originally isolated from the hypothalamus of sheep as a 14-amino acid polypeptide (Brazeau et al.). science 179, 77-79, 1973). Subsequently, a 28-amino acid peptide with an N-terminus extension was isolated, whose biological activity was similar to that of 14-amino acid somatostatin (Pradayrol et al., 1973). FEBS Letters ,109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA , 77, 6827–6831, 1980). SSTRs are regulatory peptides produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SSTRs act on their target cells through endocrine and paracrine pathways. Many of these actions involve the inhibition of the secretion of other hormones, most notably growth hormone (GH). They are produced by multiple cell types in the central nervous system (CNS) and the gut and have a variety of functions, including regulating the secretion of growth hormone (GH), insulin, glucagon, and many other antiproliferative hormones.

[0014] These pleiotropic effects of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5). These 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 receptors are members of the GPCR superfamily class A subgroup.

[0015] It is possible to selectively modulate any somatostatin receptor subtype or combination thereof. Compared to other somatostatin receptor subtypes, selectively modulating any somatostatin receptor subtype reduces undesirable side effects in various clinical applications.

[0016] In some embodiments, the SSTR3 agonists described herein are used to treat a variety of diseases or conditions, such as, but not limited to, ciliary disorders, including but not limited to, polycystic kidney disease (PKD) and polycystic liver disease (PLD). In some embodiments, the SSTR3 agonists described herein are used to treat a variety of diseases or conditions associated with ciliary dysfunction, 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, the SSTR3 agonists described herein are used to treat PKD. In some embodiments, the SSTR3 agonists described herein are used to treat ADPKD. In some embodiments, the somatostatin receptor modulators described herein are used to treat PKD in mammals.

[0017] Cialis disease Ciliary diseases are a class of developmental and degenerative monogenic disorders characterized by dysfunction of hair-like organelles called cilia. Cilia are microtubule-based structures present in almost all vertebrate cells. They originate from the basal body, a modified centrosome, an organelle that forms the spindle poles during mitosis. Most of the proteins altered in monogenic diseases constituting ciliary diseases function in the ciliary-centrosome complex, which represents a universal system in nature for cells to detect and manage external signals. The ciliary-centrosome complex plays a crucial role in the normal function of most tissues, which is why ciliary diseases involve multiple organ systems. Ciliary dysfunction can cause a variety of ciliary diseases and conditions, including but not limited to PLD, PKD, ADPKD, ARPKD, and combinations thereof.

[0018] Polycystic kidney disease Polycystic kidney disease (PKD), also known as polycystic kidney syndrome, is a genetic disorder in which the renal tubules of patients become structurally abnormal, leading to the development and growth of multiple cysts within the kidneys. These non-functional tubules fill with the fluid pumped into them. The cysts range in size from tiny to enormous, compressing adjacent normal tubules and eventually causing them to lose function. There are two types of PKD, each with its own pathological and genetic causes: ADPKD and ARPKD. The mutated gene is expressed in all cells of the body; therefore, cysts can also occur in the liver.

[0019] In many animal models of ciliated diseases, including PKD, tissue levels of cAMP are increased. Typically, tissue levels of cAMP are determined by the activity of membrane-bound and soluble adenylate cyclase (AC) and cAMP phosphodiesterase (PDE), which are influenced by complex regulatory mechanisms. For example, in some cases, AC may be positively or negatively controlled by G protein-coupled receptors (GPCRs) and extracellular ligands. For instance, somatostatin acts on five somatostatin receptors (SSTR1 to SSTR5), thereby inhibiting ACS and reducing intracellular cAMP levels.

[0020] Increased cAMP levels disrupt tubule formation, stimulate chloride and fluid secretion within the cyst lumen, and activate pro-proliferative signaling pathways, including mitogen-activated protein kinase / extracellular regulated kinase, mTOR, and β-catenin signaling. Activated mTOR stimulates aerobic glycolysis via transcription, increasing ATP synthesis and decreasing AMP levels. This, in conjunction with β-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 numerous transcription factors, including STAT3 and cAMP response element constructs (CREB). Activated STAT3 induces the transcription of cytokines, chemokines, and growth factors, thereby activating STAT3 on mesenchymal alternating activation (M2) macrophages, leading to a feedforward cycle between cyst-lining cells and M2 macrophages. Aberrant integrin-extracellular membrane interactions and cAMP signaling in focal adhesion complexes may also lead to increased adhesion of cyst-derived cells to laminin-322 and collagen. Overactive CREB in ADPKD mediates cAMP-dependent gene regulation, which controls a wide range of cellular processes, including metabolism, cell survival and proliferation, differentiation, apoptosis, and immune responses. The central role of cAMP in PKD pathogenesis provides a strong theoretical basis for strategies to reduce cAMP levels in cystic tissues.

[0021] ADPKD is the most common genetic cause of kidney disease, affecting approximately 1 in 1000 individuals (Clin. Med. (Lond) 2009 Jun; 9(3): 278-283). This disease is characterized by slow, progressive bilateral renal cyst formation, typically leading to renal insufficiency around age 50 or 60. Cysts forming in the kidneys of ADPKD patients originate in the renal tubules, where mutations in PKD1 or PKD2 (genes encoding polycystin 1 and polycystin 2, respectively) impair ciliary function in epithelial cells (J. Nephrol. 1997 Nov-Dec; 10(6): 295-310; AIMS Mol. Sci. 2014; 1(1): 27-46). Abnormal ciliary signaling leads to incomplete differentiation and persistent proliferation of epithelial cells, resulting in cyst formation (see, for example, Figure 1 (Int. J. Mol. Sci. 2022 Mar 19; 23(6): 3317). Then, due to excessive secretion of chloride ions in the lumen, the fluid transported into the lumen increases, and the cyst grows and enlarges. Eventually, the cyst branches off from the main nephron and exerts continuous stress on the surrounding tissues, causing local damage. Although normal kidney tissue begins to be replaced by the cyst early in life, the reduction in the total mass of the nephron is masked by compensatory changes in the glomerular filtration rate (GFR), which keeps the total GFR seemingly normal for many years until compensation fails after several years. At this point, ADPKD patients usually also experience flank pain, hematuria, urinary tract infection, or renal colic. ADPKD often leads to chronic kidney disease and end-stage renal disease (ESRD), requiring dialysis or kidney transplantation for survival.

[0022] The biological functions of polycystin remain poorly understood. However, mounting evidence points to a model in which the loss of polycystin's inhibitory role in ciliary pathway activation may be a driver of cyst formation observed in ADPKD. In healthy individuals, polycystin-1 and polycystin-2 (PC1 / PC2) proteins bind directly to form calcium-permeable channels located on the primary cilia of renal epithelial cells (Nature Reviews Nephrology 2019; 15: 412-422). See also Figure 2 (A)

[0023] Cilia are non-motor plasma membrane appendages that act as mechanosensors, detecting changes in fluid flow within the renal tubules and converting them into calcium. 2+Signaling response. This makes cilia a specialized signaling hub, with a much higher calcium concentration than the cytoplasm (Int. J. Mol. Sci. 2020 Sept 26; 21(19): 7109). High calcium levels directly inhibit ciliary adenylate cyclases 5 and 6 (AC5 / 6), which convert ATP in cAMP and stimulate phosphodiesterase (PDE), an enzyme that catalyzes the hydrolysis of cAMP. Thus, the functional polycystic protein complex maintains low ciliary levels of cAMP, a second messenger that plays a role in a variety of cellular processes, including cell growth and differentiation. See also Figure 2 (A)

[0024] In ADPKD patients, mutations in polycystin-1 or 2 lead to the formation of nonfunctional or hypofunctional channels, resulting in significantly reduced ciliary calcium levels (World J. Nephrol., 2016 Jan 6; 5(1): 76-83). Consequently, calcium-inhibitory AC5 / 6 activity is increased, while calcium-dependent PDE4 activity is decreased. Dysregulation of AC5 / 6 and PDE4 activity leads to a significant increase in cAMP levels within the cilia. See also Figure 2 (B)

[0025] Then, high levels of cAMP trigger cyst formation by stimulating the expression of cAMP-dependent genes associated with proliferation, and drive chloride ion and fluid secretion within the cyst cavity, triggering cyst dilation, through activation of the cystic fibrosis transmembrane transduction regulator (CFTR) stimulated by protein kinase A (PKA). Therefore, in ADPKD, dysregulation of crosstalk between intraciliary calcium and cAMP signaling pathways appears to play a key role in cyst formation. Therefore, the inventors hypothesize that cyst formation observed in ADPKD should be inhibited / reduced by selectively blocking adenylate cyclase activity within the cilia.

[0026] SSTR3 is a typical ciliary GPCR (Neuroscience 1999 Mar; 89(3): 909-26). SSTR3 transport to the cilia requires a series of highly regulated processes, including translocation of the receptor from the cytoplasm to the axonoderm via a transition region due to a specific 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 inhibits adenylate cyclase activity (Murthy et al., J. Biol. Chem., 1996:271(38):23458-23463) and reduces ciliary-plasma cAMP levels, which is crucial for the development of ADPKD. See also Figure 3 .

[0027] Song et al. reported a public dataset (GSE7869) from the Global Genomic Profiling Study of Kidney Cysts (Hum.Mol. Genet. 2009;18: 2328-2343). This dataset includes microarray expression data from cysts of different sizes in the kidneys of 5 PKD1 patients and 3 healthy patients. The inventors reanalyzed the data using a transcriptome analysis console (Thermo Fisher). Examination of probes covering SSTR3 revealed higher expression levels of SSTR3-mRNA in both healthy and cystic tissues compared to somatostatin receptors 2 and 5 (SSTR2, SSTR5) or vasopressin receptor 2 (AVPR2) (see [link to original text]). Figure 4 Therefore, the inventors determined that the cellular localization and signal transduction capabilities of SSTR3 make it an attractive target for the treatment of ADPKD.

[0028] ARPKD, a leading cause of ESRD and death in infants and children, is caused by mutations in PKD1 (encoding fibrocystin). Similar to ADPKD, cyst formation in ARPKD is caused by disruption of mechanisms controlling cell differentiation, leading to excessive cell proliferation and fluid secretion, as well as pathogenic interactions between mutated epithelial cells and abnormal extracellular matrix and alternately activated mesenchymal macrophages. Dysregulation of crosstalk between ciliary calcium and cyclic adenosine monophosphate (cAMP) signaling plays a crucial role in the development of PKD. In some cases, the compounds described herein are somatostatin agonists that selectively activate the somatostatin type 3 receptor (SSTR3), thereby reducing cAMP levels and cAMP-dependent signaling.

[0029] In some embodiments, the somatostatin receptor modulators described herein are used to treat ciliary diseases in mammals. In some embodiments, the somatostatin receptor modulators described herein cause a decrease in cAMP levels, which can be used to treat the ciliary diseases described herein. In some embodiments, the ciliary disease or condition is selected from PKD, ADPKD, ARPKD, PLD, and combinations thereof. In some embodiments, the ciliary disease or condition is selected from PKD, ADPKD, and ARPKD. In some embodiments, the ciliary disease or condition is PKD. In some embodiments, the ciliary disease or condition is ADPKD. In some embodiments, the ciliary disease or condition is ARPKD.

[0030] This article also describes a method for treating diseases or conditions in mammals that would benefit from regulation of somatostatin type 3 receptor (SSTR3) activity, comprising administering a selective small molecule SSTR3 agonist compound to the mammal in need.

[0031] In some embodiments, the disease or condition is any one of the diseases or conditions described herein, or a combination thereof. In some embodiments, the disease or condition is related to ciliary dysfunction. In some embodiments, the disease or condition is a ciliary disease or condition. In some embodiments, the selective small molecule SSTR3 agonist is a compound described herein.

[0032] compound Compounds of formula (I), formula (II) and formula (III) are provided, including their pharmaceutically acceptable salts, which are somatostatin type 3 receptor (SSTR3) agonists.

[0033] In some embodiments, this document describes compounds of formula (I) and their pharmaceutically acceptable salts: (I) in: Indicates a single bond or a double bond; Z is NR Z , where R Z It is absent or is oxygenated, or when R 7 When R = 0, then Z Is it H or C? 1-6 alkyl; X is NR X , where R X Is it H or C? 1-6 alkyl; L is the key, C 1-6 Alkyl, or (CR L1 R L2 ) t , where R L1 and R L2 Each independently is H or C 1-6 Alkyl group, and t is 1, 2, 3, 4, 5 or 6; R 1 It is C 1-6 Alkyl, C 3-10 cycloalkyl, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 6-10 aryl, and 4-7 heteroaryl groups, each optionally bound by 1, 2, 3, 4, or 5 R groups. 1A replace; Each R 1A Independent of halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 11 C(O)OR 11 、or C(O)N(R) 11 )2, where each R 11 Independently H or C1-6 alkyl; R 2 It is C 3-7 cycloalkyl, C 5-9 Bicycloalkyl or 7- to 9-membered heterocyclic alkyl groups, each surrounded by 1, 2, 3, 4, or 5 R groups. 2A replace; Where R 2A Independent of H, halogen, C 1-6 Alkyl, or C(O)OR 21 C 1-6 Alkyl groups are optionally surrounded by 1, 2, or 3 halogens, OH, CN, or C. 1-6 Alkyl substitution; wherein R 21 Is it H or C? 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon rings; R 3 R 4 R 5 and R 6 Each is independently H, halogen, CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, or C 3-6 Cycloalkyl groups; and R 7 H, halogen, C 1-6 Alkyl, C 3-6 Heterocyclic alkyl, OR 71 or NR 72 R 73 ; Where R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. 7A Replacement, condition is when R 71 When it does not exist, R 7 It is a carbonyl group; R 72 and R 73 Independently H or C 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by 1, 2, or 3 R atoms. 7C Substituted 3- to 10-membered heterocyclic alkyl groups; Where R 7A R7B and R 7C Each is independently a halogen, carbonyl, or C group. 1-6 Alkyl, C 1-6 Alkylamines, 5-membered heterocycles, OR 7B1 C(O)OR 7A1 and C(O)NR 7A2 R 7A2 The 5-membered heterocycle is arbitrarily selected by C 1-6 Alkyl, carbonyl, or OH substitutions, wherein C 1-6 Alkylamines may optionally be substituted with 6-membered cycloalkyl groups, which may optionally be substituted with CO2H; Where R 7A1 R 7A2 R 7B1 R 7B2 and R 7B3 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl group, wherein C 1-6 Alkyl and C 1-6 Each alkyl sulfonyl group is optionally surrounded by one or two R groups. 7B4 Replace; where R 7B4 Independently OC(O)-R 7B5 Or a 5-membered heterocycle, the 5-membered heterocycle can be arbitrarily divided by C 1-6 Alkyl substitution; and wherein R 7B5 It is C 1-6 Alkyl groups, which may optionally be substituted with NH2.

[0034] In some embodiments, this document describes pharmaceutically acceptable salts of compounds of formula (II), formula (III), and any of the above compounds: (II) or (III), in: R 2A It is H, halogen, C(O)OH, C(O)OC 1-6 Alkyl groups or C groups optionally substituted with OH or CN 1-6 Alkyl or C 1-6 Alkoxy; m can be 1, 2, 3, or 4; n is 1, 2, 3 or 4; q is 1, 2, 3, or 4; r is 1, 2, 3, or 4; and s can be 1, 2, 3, 4 or 5.

[0035] In some embodiments, m is 2 and n is 2 in equation (II). In some embodiments, m is 1 and n is 3 in equation (II). In some embodiments, m is 3 and n is 1 in equation (II). In some embodiments, q is 1 and r is 2 in equation (III). In some embodiments, q is 2 and r is 1 in equation (III).

[0036] In some embodiments, Z is NH or NMe. In some embodiments, Z is NH. In some embodiments, Z is NMe.

[0037] In some embodiments, X is NH or NMe. In some embodiments, X is NH. In some embodiments, X is NMe.

[0038] In some implementations, L is a key, C is a key. 1-6 Alkyl, or (CR L1 R L2 ) t , where each R L1 and R L2 Independently, it is H or C 1-6 Alkyl and t are 1 or 2.

[0039] In some implementations, L is a bond, CH2, CH2CH2, , , ,or In some implementations, L is a bond. In some implementations, L is CH2. In some implementations, L is CH2CH2. In some implementations, L is... In some implementations, L is... In some implementations, L is... In some implementations, L is... .

[0040] In some implementation schemes, R 1 It is C 3-8 Cycloalkyl, phenyl, or 4 to 6-membered heteroaryl groups, each independently bound by 1, 2, or 3 R groups. 1A Replacement. In some implementations, R 1 It is C 3-8 Cycloalkyl, phenyl, or pyridyl groups, each independently bound by one, two, or three R groups. 1A replace.

[0041] In some implementation schemes, R 1 yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, R 1 yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0042] In some implementation schemes, R 1 yes or .

[0043] In some implementation schemes, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes .

[0044] In some implementation schemes, R 1 yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0045] In some implementation schemes, R 1 yes , , ,or .

[0046] In some implementation schemes, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes In some implementations, R 1 yes .

[0047] In some implementation schemes, R 2 It is a 7- to 9-membered heterocyclic alkyl group, C 3-7 cycloalkyl or C 5-9 Bicycloalkyl groups, each surrounded by 1, 2, or 3 R groups. 2A replace; R 2A Independently, H, halogen, CN, C 1-6 Alkyl, C(O)OR 21 or C(O)NR 22 R 23 C 1-6 Alkyl groups are optionally surrounded by one or two OH, NH2, CN, or C atoms. 1-6 Alkyl or C 1-6 Alkoxy substitution; and R 21 R 22 and R 23 Each independently is H or C 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon ring.

[0048] In some implementation schemes, R 2 Is it by 1, 2 or 3 Rs? 2A Substituted 7- to 9-membered heterocyclic alkyl groups; R 2A Independently, H, halogen, CN, C 1-6 Alkyl, C(O)OR 21 or C(O)NR22 R 23 C 1-6 Alkyl groups are optionally surrounded by one or two OH, NH2, CN, or C atoms. 1-6 Alkyl or C 1-6 Alkoxy substitution; and R 21 R 22 and R 23 Each independently is H or C 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon ring.

[0049] In some implementation schemes, R 2 yes , , , , ,or They are each controlled by 1 or 2 R 2A replace; R 2A H, halogen, C 1-6 Alkyl or C(O)OR 21 C 1-6 Alkyl groups may be replaced by OH, CN, or C. 1-6 Alkoxy substitution; and R 21 Is it H or C? 1-6 alkyl.

[0050] In some implementation schemes, R 2 yes , , , or In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes .

[0051] In some implementation schemes, R 2 yes , , , , , , , , , , , , , , , , , , or .

[0052] In some implementation schemes, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes In some implementations, R 2 yes .

[0053] In some implementation schemes, R 2 yes .

[0054] In some implementation schemes, R 3 It is H or F. In some implementations, R 3 It is H. In some implementations, R 3 It is F.

[0055] In some implementation schemes, R 4 It is H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl. In some embodiments, R 4 It is H, F, Cl, methyl, methoxy, or cyclopropyl. In some embodiments, R 4 It is H. In some implementations, R 4 It is F. In some implementations, R 4 It is Cl. In some implementations, R 4 It is methyl. In some embodiments, R 4 It is a methoxy group. In some embodiments, R 4 It is cyclopropyl. In some implementations, R 4 It is a methoxy group.

[0056] In some implementation schemes, R 5 It is H, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups. In some embodiments, R 5 Is it halogen or C? 1-6 Halogenated alkyl groups. In some embodiments, R 5 It is H, F, Cl, CN, CF3, CF2Me, OMe, or cyclopropyl. In some embodiments, R 5 It is Cl, CF3, or cyclopropyl. In some embodiments, R 5 It is H. In some implementations, R 5 It is F. In some implementations, R 5 It is Cl. In some implementations, R 5 It is CN. In some implementations, R 5 It is CF3. In some implementations, R 5 It is CF2Me. In some implementations, R 5 It is OMe. In some implementations, R 5 It is cyclopropyl. In some implementations, R 5 It is CF3. In some implementations, R5 yes .

[0057] In some implementation schemes, R 6 It is H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 6 It is H.

[0058] In some implementation schemes, R 7 It is H, halogen, OR 71 NR 72 R 73 Or C 1-6 alkyl; Where R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl optional R 7A replace; Where R 72 and R 73 Each independently is H or C 1-6 Alkyl, wherein C 1-6 Alkyl groups are each optionally R 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one or two R atoms. 7C Substituted 3- to 6-membered heterocyclic alkyl groups; Where R 7A Independently 4 to 6-membered heterocyclic rings, C(O)OR 7A1 and C(O)NR 7A2 R 7A2 In which the 4- to 6-membered heterocycles are optionally substituted with carbonyl, OH, or NH2; where R 7A1 and R 7A2 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl; Where R 7B independently for OR 7B1 C(O)OR 7B2 or C(O)NR 7B3 R 7B3 and 4 to 6-membered heterocycles, wherein the 4 to 6-membered heterocycles are optionally substituted with methyl, carbonyl, OH or NH2; wherein R 7B1 R 7B2 and R 7B3 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl group, wherein C 1-6 Alkyl groups are each optionally OC(O)-R 7B4Replacement, or optional 4- to 6-membered heterocyclic rings by R 7B4 Replace; where R 7B4 It is C 1-6 Alkyl groups, optionally substituted with NH2; and R 7C Independently carbonyl, halogen, OH, C 1-6 Alkyl groups, CO2H, C(O)OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Alkylamines, wherein C 1-6 Alkylamines may be optionally substituted with a 6-membered heterocycle, which may be optionally substituted with CO2H.

[0059] In some implementation schemes, R 7 It is H, halogen, OR 71 NR 72 R 73 Or C 1-6 alkyl; R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl optional R 7A replace; R 72 and R 73 Independently H or C 1-6 Alkyl, wherein C 1-6 Alkyl optional R 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form , , or Each of them is randomly assigned to 1 or 2 R's. 7C replace; R 7A Independently C(O)OR 7A1 or C(O)NR 7A2 R 7A2 ; R 7A1 Independently H or C 1-6 alkyl; R 7A2 Independently H or C 1-6 alkylsulfonyl; R 7B Independently is OR 7B1 C(O)OR 7B2 C(O)NR 7B3 R 7B3 , , ,or ; R 7B1 Independently H or C 1-6 alkyl; R 7B2 Is it H or C? 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally OC(O)-R 7B4 or replace; R 7B3 Independently H or C 1-6 alkylsulfonyl; R 7B4 It is C 1-6 Alkyl groups, optionally substituted with NH2; and R 7C Independently carbonyl, halogen, OH, C 1-6 Alkoxy, CO2H, C(O)OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Alkylamines, wherein C 1-6 Alkylamines may optionally be substituted with a 6-membered heterocycle, which may optionally be substituted with CO2H.

[0060] In some implementation schemes, R 7 It is H, O, Cl, Me, NH2, NHMe, NMe2, , , , , , , , , or In some implementations, R 7 It is H. In some implementations, R 7 It is O. In some implementations, R 7 It is Cl. In some implementations, R 7 It is Me. In some implementations, R 7 It is NH2. In some implementations, R 7 It is NHMe. In some implementations, R 7 It is NMe2. In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes .

[0061] In some implementation schemes, R 7 It is H, O, OH, OMe, NH2, NHMe, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0062] In some implementation schemes, R 7 It is H. In some implementations, R 7 It is O. In some implementations, R 7 It is OH. In some implementations, R 7 It is OMe. In some implementations, R 7 It is NH2. In some implementations, R7 It is NHMe. In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes In some implementations, R 7 yes .

[0063] In some implementation schemes, R 7 It is H, O, or In some implementations, R 7 It is H. In some implementations, R 7 It is O. In some implementations, R 7 It is O In some implementations, R 7 yes In some implementations, R 7 It is a carbonyl group.

[0064] The exemplary compounds described herein include those listed in the following table: Table 1: Compounds of Formula (I):

[0065] In a particular embodiment, the compound of formula (I) is compound 1.

[0066] In a particular embodiment, the compound of formula (I) is compound 2.

[0067] In a particular embodiment, the compound of formula (I) is compound 3.

[0068] In a particular embodiment, the compound of formula (I) is compound 4.

[0069] In a particular embodiment, the compound of formula (I) is compound 5.

[0070] In a particular embodiment, the compound of formula (I) is compound 6.

[0071] In a particular embodiment, the compound of formula (I) is compound 7.

[0072] In a particular embodiment, the compound of formula (I) is compound 8.

[0073] In a particular embodiment, the compound of formula (I) is compound 9.

[0074] In a particular embodiment, the compound of formula (I) is compound 10.

[0075] In a particular embodiment, the compound of formula (I) is compound 11.

[0076] In a particular embodiment, the compound of formula (I) is compound 12.

[0077] In a particular embodiment, the compound of formula (I) is compound 13.

[0078] In a particular embodiment, the compound of formula (I) is compound 14.

[0079] In a particular embodiment, the compound of formula (I) is compound 15.

[0080] In a particular embodiment, the compound of formula (I) is compound 16.

[0081] In a particular embodiment, the compound of formula (I) is compound 17.

[0082] In a particular embodiment, the compound of formula (I) is compound 18.

[0083] In a particular embodiment, the compound of formula (I) is compound 19.

[0084] In a particular embodiment, the compound of formula (I) is compound 20.

[0085] In a particular embodiment, the compound of formula (I) is compound 21.

[0086] In a particular embodiment, the compound of formula (I) is compound 22.

[0087] In a particular embodiment, the compound of formula (I) is compound 23.

[0088] In a particular embodiment, the compound of formula (I) is compound 24.

[0089] In a particular embodiment, the compound of formula (I) is compound 25.

[0090] In a particular embodiment, the compound of formula (I) is compound 26.

[0091] In a particular embodiment, the compound of formula (I) is compound 27.

[0092] In a particular embodiment, the compound of formula (I) is compound 28.

[0093] In a particular embodiment, the compound of formula (I) is compound 29.

[0094] In a particular embodiment, the compound of formula (I) is compound 30.

[0095] In a particular embodiment, the compound of formula (I) is compound 31.

[0096] In a particular embodiment, the compound of formula (I) is compound 32.

[0097] In a particular embodiment, the compound of formula (I) is compound 33.

[0098] In a particular embodiment, the compound of formula (I) is compound 34.

[0099] In a particular embodiment, the compound of formula (I) is compound 35.

[0100] In a particular embodiment, the compound of formula (I) is compound 36.

[0101] In a particular embodiment, the compound of formula (I) is compound 37.

[0102] In a particular embodiment, the compound of formula (I) is compound 38.

[0103] In a particular embodiment, the compound of formula (I) is compound 39.

[0104] In a particular embodiment, the compound of formula (I) is compound 40.

[0105] In a particular embodiment, the compound of formula (I) is compound 41.

[0106] In a particular embodiment, the compound of formula (I) is compound 42.

[0107] In a particular embodiment, the compound of formula (I) is compound 43.

[0108] In a particular embodiment, the compound of formula (I) is compound 44.

[0109] In a particular embodiment, the compound of formula (I) is compound 45.

[0110] In a particular embodiment, the compound of formula (I) is compound 46.

[0111] In a particular embodiment, the compound of formula (I) is compound 47.

[0112] In a particular embodiment, the compound of formula (I) is compound 48.

[0113] In a particular embodiment, the compound of formula (I) is compound 49.

[0114] In a particular embodiment, the compound of formula (I) is compound 50.

[0115] In a particular embodiment, the compound of formula (I) is compound 51.

[0116] In a particular embodiment, the compound of formula (I) is compound 52.

[0117] In a particular embodiment, the compound of formula (I) is compound 53.

[0118] In a particular embodiment, the compound of formula (I) is compound 54.

[0119] In a particular embodiment, the compound of formula (I) is compound 55.

[0120] In a particular embodiment, the compound of formula (I) is compound 56.

[0121] In a particular embodiment, the compound of formula (I) is compound 57.

[0122] In a particular embodiment, the compound of formula (I) is compound 58.

[0123] In a particular embodiment, the compound of formula (I) is compound 59.

[0124] In a particular embodiment, the compound of formula (I) is compound 60.

[0125] In a particular embodiment, the compound of formula (I) is compound 61.

[0126] In a particular embodiment, the compound of formula (I) is compound 62.

[0127] In a particular embodiment, the compound of formula (I) is compound 63.

[0128] In a particular embodiment, the compound of formula (I) is compound 64.

[0129] In a particular embodiment, the compound of formula (I) is compound 65.

[0130] In a particular embodiment, the compound of formula (I) is compound 66.

[0131] In a particular embodiment, the compound of formula (I) is compound 67.

[0132] In a particular embodiment, the compound of formula (I) is compound 68.

[0133] In a particular embodiment, the compound of formula (I) is compound 69.

[0134] In a particular embodiment, the compound of formula (I) is compound 70.

[0135] In a particular embodiment, the compound of formula (I) is compound 71.

[0136] In a particular embodiment, the compound of formula (I) is compound 72.

[0137] In a particular embodiment, the compound of formula (I) is compound 73.

[0138] In a particular embodiment, the compound of formula (I) is compound 74.

[0139] In a particular embodiment, the compound of formula (I) is compound 75.

[0140] In a particular embodiment, the compound of formula (I) is compound 76.

[0141] In a particular embodiment, the compound of formula (I) is compound 77.

[0142] In a particular embodiment, the compound of formula (I) is compound 78.

[0143] In a particular embodiment, the compound of formula (I) is compound 79.

[0144] In a particular embodiment, the compound of formula (I) is compound 80.

[0145] In a particular embodiment, the compound of formula (I) is compound 81.

[0146] In a particular embodiment, the compound of formula (I) is compound 82.

[0147] In a particular embodiment, the compound of formula (I) is compound 83.

[0148] In a particular embodiment, the compound of formula (I) is compound 84.

[0149] In a particular embodiment, the compound of formula (I) is compound 85.

[0150] In a particular embodiment, the compound of formula (I) is compound 86.

[0151] In a particular embodiment, the compound of formula (I) is compound 87.

[0152] In a particular embodiment, the compound of formula (I) is compound 88.

[0153] In a particular embodiment, the compound of formula (I) is compound 89.

[0154] In a particular embodiment, the compound of formula (I) is compound 90.

[0155] In a particular embodiment, the compound of formula (I) is compound 91.

[0156] In a particular embodiment, the compound of formula (I) is compound 92.

[0157] In a particular embodiment, the compound of formula (I) is compound 93.

[0158] In a particular embodiment, the compound of formula (I) is compound 94.

[0159] In a particular embodiment, the compound of formula (I) is compound 95.

[0160] In a particular embodiment, the compound of formula (I) is compound 96.

[0161] In a particular embodiment, the compound of formula (I) is compound 97.

[0162] In a particular embodiment, the compound of formula (I) is compound 98.

[0163] In a particular embodiment, the compound of formula (I) is compound 99.

[0164] In a particular embodiment, the compound of formula (I) is compound 100.

[0165] In a particular embodiment, the compound of formula (I) is compound 101.

[0166] In a particular embodiment, the compound of formula (I) is compound 102.

[0167] In a particular embodiment, the compound of formula (I) is compound 103.

[0168] In a particular embodiment, the compound of formula (I) is compound 104.

[0169] In a particular embodiment, the compound of formula (I) is compound 105.

[0170] In a particular embodiment, the compound of formula (I) is compound 106.

[0171] In a particular embodiment, the compound of formula (I) is compound 107.

[0172] In a particular embodiment, the compound of formula (I) is compound 108.

[0173] In a particular embodiment, the compound of formula (I) is compound 109.

[0174] In a particular embodiment, the compound of formula (I) is compound 110.

[0175] In a particular embodiment, the compound of formula (I) is compound 111.

[0176] In a particular embodiment, the compound of formula (I) is compound 112.

[0177] In a particular embodiment, the compound of formula (I) is compound 113.

[0178] In a particular embodiment, the compound of formula (I) is compound 114.

[0179] In a particular embodiment, the compound of formula (I) is compound 115.

[0180] In a particular embodiment, the compound of formula (I) is compound 116.

[0181] In a particular embodiment, the compound of formula (I) is compound 117.

[0182] In a particular embodiment, the compound of formula (I) is compound 118.

[0183] In a particular embodiment, the compound of formula (I) is compound 119.

[0184] In a particular embodiment, the compound of formula (I) is compound 120.

[0185] In a particular embodiment, the compound of formula (I) is compound 121.

[0186] In a particular embodiment, the compound of formula (I) is compound 122.

[0187] In a particular embodiment, the compound of formula (I) is compound 123.

[0188] In a particular embodiment, the compound of formula (I) is compound 124.

[0189] In a particular embodiment, the compound of formula (I) is compound 125.

[0190] In a particular embodiment, the compound of formula (I) is compound 126.

[0191] In a particular embodiment, the compound of formula (I) is compound 127.

[0192] In a particular embodiment, the compound of formula (I) is compound 128.

[0193] In a particular embodiment, the compound of formula (I) is compound 129.

[0194] In a particular embodiment, the compound of formula (I) is compound 130.

[0195] In a particular embodiment, the compound of formula (I) is compound 131.

[0196] In a particular embodiment, the compound of formula (I) is compound 132.

[0197] In a particular embodiment, the compound of formula (I) is compound 133.

[0198] In a particular embodiment, the compound of formula (I) is compound 134.

[0199] In a particular embodiment, the compound of formula (I) is compound 135.

[0200] In a particular embodiment, the compound of formula (I) is compound 136.

[0201] In a particular embodiment, the compound of formula (I) is compound 137.

[0202] In a particular embodiment, the compound of formula (I) is compound 138.

[0203] In a particular embodiment, the compound of formula (I) is compound 139.

[0204] In a particular embodiment, the compound of formula (I) is compound 140.

[0205] In a particular embodiment, the compound of formula (I) is compound 141.

[0206] In a particular embodiment, the compound of formula (I) is compound 142.

[0207] In a particular embodiment, the compound of formula (I) is compound 143.

[0208] In a particular embodiment, the compound of formula (I) is compound 144.

[0209] In a particular embodiment, the compound of formula (I) is compound 145.

[0210] In a particular embodiment, the compound of formula (I) is compound 146.

[0211] In a particular embodiment, the compound of formula (I) is compound 147.

[0212] In a particular embodiment, the compound of formula (I) is compound 148.

[0213] In a particular embodiment, the compound of formula (I) is compound 149.

[0214] In a particular embodiment, the compound of formula (I) is compound 150.

[0215] In a particular embodiment, the compound of formula (I) is compound 151.

[0216] In a particular embodiment, the compound of formula (I) is compound 152.

[0217] In a particular embodiment, the compound of formula (I) is compound 153.

[0218] In a particular embodiment, the compound of formula (I) is compound 154.

[0219] In a particular embodiment, the compound of formula (I) is compound 155.

[0220] In a particular embodiment, the compound of formula (I) is compound 156.

[0221] In a particular embodiment, the compound of formula (I) is compound 157.

[0222] In a particular embodiment, the compound of formula (I) is compound 158.

[0223] In a particular embodiment, the compound of formula (I) is compound 159.

[0224] In a particular embodiment, the compound of formula (I) is compound 160.

[0225] In a particular embodiment, the compound of formula (I) is compound 161.

[0226] In a particular embodiment, the compound of formula (I) is compound 162.

[0227] In a particular embodiment, the compound of formula (I) is compound 163.

[0228] In a particular embodiment, the compound of formula (I) is compound 164.

[0229] In a particular embodiment, the compound of formula (I) is compound 165.

[0230] In a particular embodiment, the compound of formula (I) is compound 166.

[0231] In a particular embodiment, the compound of formula (I) is compound 167.

[0232] In a particular embodiment, the compound of formula (I) is compound 168.

[0233] In a particular embodiment, the compound of formula (I) is compound 169.

[0234] In a particular embodiment, the compound of formula (I) is compound 170.

[0235] In a particular embodiment, the compound of formula (I) is compound 171.

[0236] In a particular embodiment, the compound of formula (I) is compound 172.

[0237] In a particular embodiment, the compound of formula (I) is compound 173.

[0238] In a particular embodiment, the compound of formula (I) is compound 174.

[0239] In a particular embodiment, the compound of formula (I) is compound 175.

[0240] In a particular embodiment, the compound of formula (I) is compound 176.

[0241] In a particular embodiment, the compound of formula (I) is compound 177.

[0242] In a particular embodiment, the compound of formula (I) is compound 178.

[0243] In a particular embodiment, the compound of formula (I) is compound 179.

[0244] In a particular embodiment, the compound of formula (I) is compound 180.

[0245] In a particular embodiment, the compound of formula (I) is compound 181.

[0246] In a particular embodiment, the compound of formula (I) is compound 182.

[0247] In a particular embodiment, the compound of formula (I) is compound 183.

[0248] In a particular embodiment, the compound of formula (I) is compound 184.

[0249] In a particular embodiment, the compound of formula (I) is compound 185.

[0250] In a particular embodiment, the compound of formula (I) is compound 186.

[0251] In a particular embodiment, the compound of formula (I) is compound 187.

[0252] In a particular embodiment, the compound of formula (I) is compound 188.

[0253] In a particular embodiment, the compound of formula (I) is compound 189.

[0254] In a particular embodiment, the compound of formula (I) is compound 190.

[0255] In a particular embodiment, the compound of formula (I) is compound 191.

[0256] In a particular embodiment, the compound of formula (I) is compound 192.

[0257] In a particular embodiment, the compound of formula (I) is compound 193.

[0258] In a particular embodiment, the compound of formula (I) is compound 194.

[0259] In a particular embodiment, the compound of formula (I) is compound 195.

[0260] In a particular embodiment, the compound of formula (I) is compound 196.

[0261] In a particular embodiment, the compound of formula (I) is compound 197.

[0262] In a particular embodiment, the compound of formula (I) is compound 198.

[0263] In a particular embodiment, the compound of formula (I) is compound 199.

[0264] In a particular embodiment, the compound of formula (I) is compound 200.

[0265] In a particular embodiment, the compound of formula (I) is compound 201.

[0266] In a particular embodiment, the compound of formula (I) is compound 202.

[0267] In a particular embodiment, the compound of formula (I) is compound 203.

[0268] In a particular embodiment, the compound of formula (I) is compound 204.

[0269] In a particular embodiment, the compound of formula (I) is compound 205.

[0270] In a particular embodiment, the compound of formula (I) is compound 206.

[0271] In a particular embodiment, the compound of formula (I) is compound 207.

[0272] In a particular embodiment, the compound of formula (I) is compound 208.

[0273] In a particular embodiment, the compound of formula (I) is compound 209.

[0274] In a particular embodiment, the compound of formula (I) is compound 210.

[0275] In a particular embodiment, the compound of formula (I) is compound 211.

[0276] In a particular embodiment, the compound of formula (I) is compound 212.

[0277] In a particular embodiment, the compound of formula (I) is compound 213.

[0278] In a particular embodiment, the compound of formula (I) is compound 214.

[0279] In a particular embodiment, the compound of formula (I) is compound 215.

[0280] In a particular embodiment, the compound of formula (I) is compound 216.

[0281] In a particular embodiment, the compound of formula (I) is compound 217.

[0282] In a particular embodiment, the compound of formula (I) is compound 218.

[0283] In a particular embodiment, the compound of formula (I) is compound 219.

[0284] In a particular embodiment, the compound of formula (I) is compound 220.

[0285] In a particular embodiment, the compound of formula (I) is compound 221.

[0286] In a particular embodiment, the compound of formula (I) is compound 222.

[0287] In a particular embodiment, the compound of formula (I) is compound 223.

[0288] In a particular embodiment, the compound of formula (I) is compound 224.

[0289] In a particular embodiment, the compound of formula (I) is compound 225.

[0290] In a particular embodiment, the compound of formula (I) is compound 226.

[0291] In a particular embodiment, the compound of formula (I) is compound 227.

[0292] In a particular embodiment, the compound of formula (I) is compound 228.

[0293] In a particular embodiment, the compound of formula (I) is compound 229.

[0294] In a particular embodiment, the compound of formula (I) is compound 230.

[0295] In a particular embodiment, the compound of formula (I) is compound 231.

[0296] In a particular embodiment, the compound of formula (I) is compound 232.

[0297] In a particular embodiment, the compound of formula (I) is compound 233.

[0298] In a particular embodiment, the compound of formula (I) is compound 234.

[0299] In a particular embodiment, the compound of formula (I) is compound 235.

[0300] In a particular embodiment, the compound of formula (I) is compound 236.

[0301] In a particular embodiment, the compound of formula (I) is compound 237.

[0302] In a particular embodiment, the compound of formula (I) is compound 238.

[0303] In a particular embodiment, the compound of formula (I) is compound 239.

[0304] In a particular embodiment, the compound of formula (I) is compound 240.

[0305] In a particular embodiment, the compound of formula (I) is compound 241.

[0306] In a particular embodiment, the compound of formula (I) is compound 242.

[0307] In a particular embodiment, the compound of formula (I) is compound 243.

[0308] In a particular embodiment, the compound of formula (I) is compound 244.

[0309] In a particular embodiment, the compound of formula (I) is compound 245.

[0310] In a particular embodiment, the compound of formula (I) is compound 246.

[0311] In a particular embodiment, the compound of formula (I) is compound 247.

[0312] In a particular embodiment, the compound of formula (I) is compound 248.

[0313] In a particular embodiment, the compound of formula (I) is compound 249.

[0314] In a particular embodiment, the compound of formula (I) is compound 250.

[0315] In a particular embodiment, the compound of formula (I) is compound 251.

[0316] In a particular embodiment, the compound of formula (I) is compound 252.

[0317] In a particular embodiment, the compound of formula (I) is compound 253.

[0318] In a particular embodiment, the compound of formula (I) is compound 254.

[0319] In a particular embodiment, the compound of formula (I) is compound 255.

[0320] In a particular embodiment, the compound of formula (I) is compound 256.

[0321] In a particular embodiment, the compound of formula (I) is compound 257.

[0322] In a particular embodiment, the compound of formula (I) is compound 258.

[0323] In a particular embodiment, the compound of formula (I) is compound 259.

[0324] In a particular embodiment, the compound of formula (I) is compound 260.

[0325] In a particular embodiment, the compound of formula (I) is compound 261.

[0326] In a particular embodiment, the compound of formula (I) is compound 262.

[0327] In a particular embodiment, the compound of formula (I) is compound 263.

[0328] In a particular embodiment, the compound of formula (I) is compound 264.

[0329] In a particular embodiment, the compound of formula (I) is compound 265.

[0330] In a particular embodiment, the compound of formula (I) is compound 266.

[0331] In a particular embodiment, the compound of formula (I) is compound 267.

[0332] In a particular embodiment, the compound of formula (I) is compound 268.

[0333] In a particular embodiment, the compound of formula (I) is compound 269.

[0334] In a particular embodiment, the compound of formula (I) is compound 270.

[0335] In a particular embodiment, the compound of formula (I) is compound 271.

[0336] In a particular embodiment, the compound of formula (I) is compound 272.

[0337] In a particular embodiment, the compound of formula (I) is compound 273.

[0338] In a particular embodiment, the compound of formula (I) is compound 274.

[0339] In a particular embodiment, the compound of formula (I) is compound 275.

[0340] In a particular embodiment, the compound of formula (I) is compound 276.

[0341] In a particular embodiment, the compound of formula (I) is compound 277.

[0342] In a particular embodiment, the compound of formula (I) is compound 278.

[0343] In a particular embodiment, the compound of formula (I) is compound 279.

[0344] In a particular embodiment, the compound of formula (I) is compound 280.

[0345] In a particular embodiment, the compound of formula (I) is compound 281.

[0346] In a particular embodiment, the compound of formula (I) is compound 282.

[0347] In a particular embodiment, the compound of formula (I) is compound 283.

[0348] In a particular embodiment, the compound of formula (I) is compound 284.

[0349] In a particular embodiment, the compound of formula (I) is compound 285.

[0350] In a particular embodiment, the compound of formula (I) is compound 286.

[0351] In a particular embodiment, the compound of formula (I) is compound 287.

[0352] In a particular embodiment, the compound of formula (I) is compound 288.

[0353] In a particular embodiment, the compound of formula (I) is compound 289.

[0354] In a particular embodiment, the compound of formula (I) is compound 290.

[0355] In a particular embodiment, the compound of formula (I) is compound 291.

[0356] In a particular embodiment, the compound of formula (I) is compound 292.

[0357] In a particular embodiment, the compound of formula (I) is compound 293.

[0358] In a particular embodiment, the compound of formula (I) is compound 294.

[0359] In a particular embodiment, the compound of formula (I) is compound 295.

[0360] In a particular embodiment, the compound of formula (I) is compound 296.

[0361] In a particular embodiment, the compound of formula (I) is compound 297.

[0362] In a particular embodiment, the compound of formula (I) is compound 298.

[0363] In a particular embodiment, the compound of formula (I) is compound 299.

[0364] In a particular embodiment, the compound of formula (I) is compound 300.

[0365] In a particular embodiment, the compound of formula (I) is compound 301.

[0366] In a particular embodiment, the compound of formula (I) is compound 302.

[0367] In a particular embodiment, the compound of formula (I) is compound 303.

[0368] In a particular embodiment, the compound of formula (I) is compound 304.

[0369] In a particular embodiment, the compound of formula (I) is compound 305.

[0370] In a particular embodiment, the compound of formula (I) is compound 306.

[0371] In a particular embodiment, the compound of formula (I) is compound 307.

[0372] In a particular embodiment, the compound of formula (I) is compound 308.

[0373] In a particular embodiment, the compound of formula (I) is compound 309.

[0374] In a particular embodiment, the compound of formula (I) is compound 310.

[0375] In a particular embodiment, the compound of formula (I) is compound 311.

[0376] In a particular embodiment, the compound of formula (I) is compound 312.

[0377] In a particular embodiment, the compound of formula (I) is compound 313.

[0378] In a particular embodiment, the compound of formula (I) is compound 314.

[0379] In a particular embodiment, the compound of formula (I) is compound 315.

[0380] In a particular embodiment, the compound of formula (I) is compound 316.

[0381] In a particular embodiment, the compound of formula (I) is compound 317.

[0382] In a particular embodiment, the compound of formula (I) is compound 318.

[0383] In a particular embodiment, the compound of formula (I) is compound 319.

[0384] In a particular embodiment, the compound of formula (I) is compound 320.

[0385] In a particular embodiment, the compound of formula (I) is compound 321.

[0386] In a particular embodiment, the compound of formula (I) is compound 322.

[0387] In a particular embodiment, the compound of formula (I) is compound 323.

[0388] In a particular embodiment, the compound of formula (I) is compound 324.

[0389] In a particular embodiment, the compound of formula (I) is compound 325.

[0390] In a particular embodiment, the compound of formula (I) is compound 326.

[0391] In a particular embodiment, the compound of formula (I) is compound 327.

[0392] In a particular embodiment, the compound of formula (I) is compound 328.

[0393] In a particular embodiment, the compound of formula (I) is compound 329.

[0394] In a particular embodiment, the compound of formula (I) is compound 330.

[0395] In a particular embodiment, the compound of formula (I) is compound 331.

[0396] In a particular embodiment, the compound of formula (I) is compound 332.

[0397] In a particular embodiment, the compound of formula (I) is compound 333.

[0398] In a particular embodiment, the compound of formula (I) is compound 334.

[0399] In a particular embodiment, the compound of formula (I) is compound 335.

[0400] In a particular embodiment, the compound of formula (I) is compound 336.

[0401] In a particular embodiment, the compound of formula (I) is compound 337.

[0402] In a particular embodiment, the compound of formula (I) is compound 338.

[0403] In a particular embodiment, the compound of formula (I) is compound 339.

[0404] In a particular embodiment, the compound of formula (I) is compound 340.

[0405] In a particular embodiment, the compound of formula (I) is compound 341.

[0406] In a particular embodiment, the compound of formula (I) is compound 342.

[0407] In a particular embodiment, the compound of formula (I) is compound 343.

[0408] In a particular embodiment, the compound of formula (I) is compound 344.

[0409] In a particular embodiment, the compound of formula (I) is compound 345.

[0410] In a particular embodiment, the compound of formula (I) is compound 346.

[0411] In a particular embodiment, the compound of formula (I) is compound 347.

[0412] In a particular embodiment, the compound of formula (I) is compound 348.

[0413] In a particular embodiment, the compound of formula (I) is compound 349.

[0414] In a particular embodiment, the compound of formula (I) is compound 350.

[0415] In a particular embodiment, the compound of formula (I) is compound 351.

[0416] In a particular embodiment, the compound of formula (I) is compound 352.

[0417] In a particular embodiment, the compound of formula (I) is compound 353.

[0418] In a particular embodiment, the compound of formula (I) is compound 354.

[0419] In a particular embodiment, the compound of formula (I) is compound 355.

[0420] In a particular embodiment, the compound of formula (I) is compound 356.

[0421] In a particular embodiment, the compound of formula (I) is compound 357.

[0422] In a particular embodiment, the compound of formula (I) is compound 358.

[0423] In a particular embodiment, the compound of formula (I) is compound 359.

[0424] In a particular embodiment, the compound of formula (I) is compound 360.

[0425] In a particular embodiment, the compound of formula (I) is compound 361.

[0426] In a particular embodiment, the compound of formula (I) is compound 362.

[0427] In a particular embodiment, the compound of formula (I) is compound 363.

[0428] In a particular embodiment, the compound of formula (I) is compound 364.

[0429] In a particular embodiment, the compound of formula (I) is compound 365.

[0430] In a particular embodiment, the compound of formula (I) is compound 366.

[0431] In a particular embodiment, the compound is a pharmaceutically acceptable salt of the compounds described in Table 1.

[0432] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, i.e., the material is applied to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing it.

[0433] The term "pharmaceutically acceptable salt" refers to a form of therapeutic agent consisting of a cationic therapeutic agent combined with a suitable anion, or, in an alternative embodiment, a combination of an anionic therapeutic agent with a suitable cation.

[0434] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), formula (II), or formula (III) with an acid. In some embodiments, the compound of formula (I), formula (II), or formula (III) in its free basic form is basic and reacts with an organic or inorganic acid.

[0435] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), formula (II), or formula (III) with a base. In some embodiments, the compound of formula (I), formula (II), or formula (III) is acidic and reacts with a base.

[0436] In some embodiments, the compounds of formula (I), (II), or (III) have one or more stereocenters, and each stereocenter exists independently in an R or S configuration. In some embodiments, the compounds of formula (I), (II), or (III) exist in an R configuration. In some embodiments, the compounds of formula (I), (II), or (III) exist in an S configuration. The compounds provided herein include all diastereomers, individual enantiomers, trans-isomers, epi-isomers, and tautomers, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entiger (E), and zusammen (Z) isomers, as well as suitable mixtures thereof.

[0437] If desired, individual stereoisomers are obtained by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography or separation of diastereomers by achiral or chiral chromatography, or by crystallization and recrystallization in a suitable solvent or solvent mixture. In a particular embodiment, compounds of formula (I), (II), or (III) are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomer compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the separation of individual enantiomers is performed using covalent diastereomer derivatives of the compounds described herein. In another embodiment, diastereomers are separated by a separation / resolution technique based on solubility differences. In other embodiments, the separation of stereoisomers is carried out by chromatography or by forming diastereomer salts and then recrystallizing or chromatography, or any combination thereof.

[0438] Compound Synthesis The compounds of formula (I), formula (II) or formula (III) described herein are synthesized using standard synthetic techniques or by combining methods known in the art with those described herein.

[0439] Unless otherwise specified, use conventional mass spectrometry, NMR, or HPLC methods.

[0440] Compounds are prepared using standard organic chemistry techniques. Optional reaction conditions for the synthetic transformations described herein can be employed, such as variations in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions.

[0441] In some embodiments, compounds of formula (I) and formula (II) described herein are prepared as described in scheme A.

[0442]

[0443] Option A (a) II, pure, 100°C, 2 hours; (b) PhOPh . PhPh, 258°C, 1.5 hours; (c) POCl3, 100°C, 1 hour; (d) m CPBA, DCM, 0°C, 1 hour, then room temperature, 16 hours; (e) POCl3, 100°C, 10 minutes; (f) LiOH, 1,4-dioxane / H2O (2:1, v / v), 80°C, 14 hours; (g) POCl3, 100°C, 1 hour; (h) X, DIEA, DCM, 0°C, 1 hour; (i) XII, DIEA, MeCN, 80°C, 16 hours; (j) Boc2O, DIEA, MeCN, room temperature, 1 hour; (k) XV, LiHMDS, THF, 0°C, 3 hours; (l) TFA, DCM, room temperature, 1 hour.

[0444] In some embodiments, compounds of formula (I) or formula (III) described herein are prepared as described in scheme B.

[0445]

[0446] Option B a) NBS, CCl4, 80°C, 4 hours; b) Co, Pd(dppf)Cl2, MeOH, 100°C, 4 hours; c) CF3SO3Me, HFIP, 0 o C) 3.5 hours; d) XXI, DIEA, DCM, 0°C to room temperature, 1 hour; e) NaOMe, MeOH, 80 oC, 1 hour; f) (COCl)2, DMF, 40°C, 4 hours; g) XXV, DIEA, MeCN, 80°C, 16 hours; h) LiOH, MeOH / H2O (2:1, v / v), 80°C, 16 hours; i) X, HATU, DIEA, DMF, room temperature, 1 hour; j) TFA, DCM, room temperature, 1 hour.

[0447] In some implementations, the compound is prepared as described in the examples.

[0448] Specific terms Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "comprising" and other forms such as "including," "containing," and "included in" is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0449] As used in this article, C1-C x Including C1-C2, C1-C3…C1-C x By way of example only, groups specified as "C1-C6" indicate the presence of 1 to 6 carbon atoms in the part, i.e., groups containing 1, 2, 3, 4, 5, or 6 carbon atoms. Therefore, by way of example only, "C1-C4 alkyl" indicates that the alkyl group contains 1 to 4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0450] “Alkyl” refers to an aliphatic hydrocarbon group. Alkyl groups are branched or straight-chain. In some embodiments, an “alkyl” group has 1 to 6 carbon atoms, i.e., C1-C6 alkyl. Whenever it appears herein, numerical ranges such as “1 to 6” refer to each integer within a given range; for example, “1 to 6 carbon atoms” means an alkyl group consisting of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 6 carbon atoms, although this definition also covers the occurrence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0451] As used herein, the term "alkylsulfonyl" refers to an alkyl group as defined above, wherein one carbon atom and a substituent on the carbon atom are substituted with a sulfur atom, and wherein the sulfur atom is further substituted with two oxo groups. The alkylsulfonyl group can be straight-chain or branched. In some embodiments, the alkyl portion of the alkylsulfonyl group is substituted. In some embodiments, the alkyl portion of the alkylsulfonyl group is not substituted.

[0452] "Alkoxy" refers to an (alkyl) O- group, where the alkyl group is as defined herein.

[0453] The term "aminoalkyl" refers to an alkyl group that is substituted with an amino group or contains an amino group.

[0454] The term "aromatic family" refers to a family containing 4n+2 elements. electron delocalization - A planar ring in an electronic system, where n is an integer. The term "aromatic" includes carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") (e.g., pyridine, pyrimidine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0455] The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which all atoms forming the ring skeleton are carbon atoms. Therefore, this term distinguishes a carbocyclic ring from a "heterocyclic" ring or "heterocyclic" ring, in which the ring skeleton contains at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocyclic ring is aromatic. In some embodiments, both rings of a bicyclic carbocyclic ring are aromatic. Carbocyclic rings include aryl and cycloalkyl groups.

[0456] As used herein, the term "aryl" refers to an aromatic ring, in which each atom forming the ring is a carbon atom. In some embodiments, the aryl group is phenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene).

[0457] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic group in which each atom forming the ring (i.e., the skeleton atom) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. Cycloalkyl includes groups having 3 to 7 ring atoms. In some embodiments, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the cycloalkyl is a C3-C7 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl.

[0458] The terms "halogen," "halogenated," or "halide" refer to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0459] As used herein, the terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy” refer to straight-chain or branched alkyl, alkenyl, or alkoxy groups substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include -CHF2, -CH2, -CF3, -CF2-, and perhaloalkyl groups, such as -CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2.

[0460] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one respect, fluoroalkyl is a C1-C6 fluoroalkyl group.

[0461] The term "heterocyclic" or "heterocyclic" refers to a heteroaromatic ring (also called a heteroaryl) and a heterocyclic alkyl ring containing one or two heteroatoms, wherein each heteroatom in the ring is selected from O, S, or N, and each heterocyclic group has 3 to 6 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also called heterocyclic alkyl) include rings having 3 to 6 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 6 atoms in their ring system. Examples of non-aromatic heterocyclic groups include, but are not limited to, tetrahydropyranyl. Examples of aromatic heterocyclic groups include, but are not limited to, pyridyl and pyrimidinyl.

[0462] The term "heteroaryl" or "aromatic heterocycle" refers to an aryl group that comprises one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryl groups, such as pyridyl and pyrimidinyl.

[0463] "Heterocyclic alkyl" means a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Illustrative examples of heterocyclic alkyl groups include monocyclic heterocyclic alkyl groups, such as tetrahydropyranyl.

[0464] The term "bond" refers to a chemical bond between two atoms, or a chemical bond between two parts when the atoms connected by a bond are considered part of a larger substructure. In one aspect, when the group described herein is a bond, the group is absent, thereby allowing bonds to form between the remaining identified groups.

[0465] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0466] As used herein, the term "acceptable" in relation to formulations, compositions, or ingredients means that it does not have a lasting harmful effect on the overall health of the person being treated. As used in this article, the term "modulation" refers to interacting with a target directly or indirectly to alter the target's activity, including, by way of example only, enhancing, inhibiting, limiting, or prolonging the target's activity.

[0467] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0468] As used in this article, the terms “administration,” “application,” “giving,” etc., refer to methods that can be used to deliver a compound or composition to the desired site of biological action.

[0469] As used herein, the terms “effective amount” and “therapeutic effective amount” refer to an adequate quantity of a drug or compound that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. Results include a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an “effective amount” for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of a disease. In any individual case, the appropriate “effective” amount may optionally be determined using techniques such as dose escalation studies.

[0470] The terms “subject” or “patient” include mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is human.

[0471] As used herein, the terms “treatment,” “management,” or “curing” include relieving, reducing, or improving at least one symptom of a disease or condition, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, relieving symptoms caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0472] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: Pharmaceutical Science and Practice, 19th edition (Easton, Pa.: Mack Publishing, 1995); Hoover, John E., Remington Pharmaceutical Sciences, Mack Publishing, Easton, PA, 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, NY, 1980; Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the disclosure of which is incorporated herein by reference.

[0473] In some embodiments, the compounds described herein are administered 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 achieved by any method capable of delivering the compounds to the site of action.

[0474] Administration method and treatment regimen In some embodiments, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, is used to prepare a medicament for treating a disease or condition in a mammal that will benefit from an SSTR3 agonist. In mammals requiring such treatment, a method of treating any of the diseases or conditions described herein includes administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof.

[0475] In certain embodiments, a composition containing the compounds described herein is administered for therapeutic treatment. In a particular therapeutic application, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to at least partially inhibit at least one symptom of the disease or condition, such amount being sufficient to at least partially prevent at least one symptom of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, prior treatment, the patient's health status, weight and response to the drug, and the judgment of the treating physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0476] The amount of a given compound of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof corresponding to a therapeutically effective amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0477] The toxicity and efficacy of these treatment regimens were determined using standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining LD50. 50 and ED 50 The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as LD50. 50 and ED 50 The ratio between. In certain embodiments, data obtained from cell culture experiments and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range of ED with minimal toxicity. 50 Within the cyclic concentration range. In certain embodiments, the daily dose range and / or the amount of unit dose vary within this range, depending on the dosage form and route of administration used.

[0478] As used above, throughout this specification, unless otherwise stated, the following abbreviations shall be understood to have the following meanings: Abbreviations LCMS: Liquid Chromatography-Mass Spectrometry; HPLC: High Performance Liquid Chromatography; MPLC: Medium-pressure liquid chromatography; Prep-HPLC: Preparative high-performance liquid chromatography; Chiral-SFC: Chiral supercritical fluid chromatography; h: time or hour; rt: room temperature; PhOPh . PhPh: Phenyl ether-biphenyl eutectic; POCl3: phosphoryl chloride; m CPBA ： m-chloroperoxybenzoic acid; NBS: N - Bromosuccinimide; (COCl)2: Oxaloyl chloride; CO: Carbon monoxide gas; DIEA: N,N -Diisopropylethylamine orN -Ethyl- N -Isopropylpropyl-2-amine; DCM: Dichloromethane; PE: Petroleum ether; EtOAc or EA: Ethyl acetate; MeCN or ACN: Acetonitrile; CCl4: Carbon tetrachloride; Pd(dtbpf)Cl2:[1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloro(II); Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloro(II); Pd(PPh3)Cl2: Bis(triphenylphosphine)palladium(II) chloride; NaOMe: Sodium methoxide; Ti(O i Pr)4: Tetraisopropoxytitanium; MeMgCl: Methyl magnesium chloride; HCl: hydrochloric acid; Na2CO3: Sodium carbonate; THF: Tetrahydrofuran; H2O: water; DMF: Dimethylformamide; N2: Nitrogen gas; NaHCO3: Sodium bicarbonate; MgSO4: Magnesium sulfate; 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; Zn(CN)2: Zinc cyanide; Pd2(dba)3·CHCl3: tris(dibenzylideneacetone)dipalladium(O)-chloroform adduct; NMP: N 1-Methylpyrrolidone; K2CO3: Potassium carbonate; NaOH: Sodium hydroxide; MeOH: Methanol; NaHSO4: Sodium bisulfate; FA: Formic acid; NH3·H2O: ammonia solution; Boc2O: Ditert-butyl dicarbonate; AcOH: Acetic acid; NaHSO3: Sodium bisulfite; Na2SO4: Sodium sulfate; K3PO4: Potassium phosphate; Pd-C: Palladium supported on carbon; H2: Hydrogen gas; LiHMDS: Lithium bis(trimethylsilyl)amino; LiOH: Lithium hydroxide; HFIP: 1,1,1,3,3,3-Hexafluoroisopropanol.

[0479] Example The following examples are for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0480] Example 1. Preparation of N-((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-2-morpholino-4-(1,7-diazaspiro[4.4]nonane-7-yl)quinoline-3-carboxamide (compound 331)

[0481] Step 1: Preparation of diethyl 2-(((4-methoxyphenyl)amino)methylene)malonate:

[0482] A mixture of 4-methoxyaniline (5.00 g, 1 equivalent, 40.6 mmol) and diethyl 2-(ethoxymethylene)malonate (10.0 g, 1.14 equivalent, 46.2 mmol) was placed in a 40 mL vial. The reaction mixture was stirred at 100 °C for 2 hours. The heated mixture was poured directly into PE (150 mL) and concentrated under reduced pressure to give crude diethyl 2-(((4-methoxyphenyl)amino)methylene)malonate (15.0 g, 41 mmol, 100%, 80% purity), which was used directly in the next step without further purification. [M+H] + =294.1.

[0483] Step 2: Preparation of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate:

[0484] A phenyl ether-biphenyl eutectic (80 g, 76 mL, 6.0 equivalent, 0.25 mol) was placed in a 250 mL three-necked round-bottom flask. The mixture was heated to 258 °C, and 2-(((4-methoxyphenyl)amino)methylene)diethyl malonate (15.0 g, 80% wt, 1 equivalent, 40.9 mmol) was added in three portions at 258 °C. The reaction mixture was stirred at 258 °C for 1.5 hours. After cooling to room temperature, the mixture was poured directly into a PE container (400 mL), and the precipitate was collected by filtration. The filter cake was washed with a PE container (50 mL) and dried to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (5.12 g, 20.7 mmol, 50.6%). [M+H] + =248.1.

[0485] Step 3: Preparation of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate:

[0486] A mixture of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (3.0 g, 1 equivalent, 12 mmol) and phosphorus oxychloride (5.6 g, 3.0 equivalent, 37 mmol) was placed in a 40 mL vial. The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 100 mL of water, and the pH was adjusted to 9 by adding NaHCO3. The aqueous layer was extracted with EtOAc (60 mL × 2), the combined organic phases were washed with 60 mL of brine, and then dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product thus obtained was purified by MPLC (silica gel column, 20 g; mobile phase A: PE, mobile phase B: EtOAc; flow rate: 35 mL / min; gradient: from 0%B to 60%B over 8 min; wavelength: 254 nm) to give ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (2.9 g, 11 mmol, 90%). [M+H]+=266.1.

[0487] Step 4: Preparation of 4-chloro-3-(ethoxycarbonyl)-6-methoxyquinoline 1-oxide:

[0488] Ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (1.5 g, 1 equivalent, 5.6 mmol) was added to a 40-mL vial containing 10 mL of DCM, and the mixture was added at 0°C. mCPBA (1.5 g, 1.5 equivalents, 8.7 mmol). The reaction mixture was stirred at 25 °C for 16 h, quenched with 6 mL of saturated NaHCO3(aq) solution, and stirred for 30 min. The organic layer was separated, washed with water and brine, and dried over Na2SO4. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography, eluting with PE / EtOAc (3 / 1) to give 4-chloro-3-(ethoxycarbonyl)-6-methoxyquinoline 1-oxide (943 mg, 3.35 mmol, 59%). [M+H] + =282.0.

[0489] Step 5: Ethyl 2,4-dichloro-6-methoxyquinoline-3-carboxylate:

[0490] 4-Chloro-3-(ethoxycarbonyl)-6-methoxyquinoline 1-oxide (930 mg, 1 equivalent, 3.29 mmol) and phosphorus oxychloride (1.01 g, 2.00 equivalent, 6.59 mmol) were placed in a 40 mL vial. The reaction mixture was then stirred at 100 °C for 10 min. Subsequently, the reaction mixture was concentrated by adding 5 mL of DCM, and the resulting mixture was poured into an ice-NaHCO3 mixture. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography, eluting with PE / EtOAc (3 / 1) to give ethyl 2,4-dichloro-6-methoxyquinoline-3-carboxylate (560 mg, 1.87 mmol, 56.7%). [M+H] + =300.0.

[0491] Step 6: 2-Chloro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid:

[0492] Ethyl 2,4-dichloro-6-methoxyquinoline-3-carboxylic acid (500 mg, 1 equivalent, 1.67 mmol), 1,4-dioxane (5 mL), H₂O (2.5 mL), and lithium hydroxide (399 mg, 10.0 equivalent, 16.7 mmol) were added to a 40 mL vial. The mixture was stirred at 80 °C for 14 hours. The reaction mixture was cooled to room temperature, 20 mL of H₂O was added, and the pH was adjusted to 5–6 with 1 M HCl (aq) solution. The aqueous mixture was extracted with EA (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid (466 mg, 1.6 mmol, 98%, 89% purity), which was used in the next step without further purification. [M+H]+ =254.4.

[0493] Step 7: 2,4-Dichloro-6-methoxyquinoline-3-carbonyl chloride:

[0494] In a 40 mL vial, a mixture of 2-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid (230 mg, 1 equivalent, 907 μmol) and phosphorus oxychloride (278 mg, 2.00 equivalent, 1.81 mmol) was stirred at 100 °C for 1 h. The mixture was then concentrated under vacuum to give 2,4-dichloro-6-methoxyquinoline-3-carbonyl chloride (230 mg, 792 μmol, 87.3%), which was used in the next step without further purification.

[0495] Step 8: (S)-2,4-dichloro-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxyquinoline-3-formyl amine:

[0496] A mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-amine hydrochloride (326 mg, 2.00 equivalent, 1.59 mmol), DIEA (512 mg, 690 μL, 5.00 equivalent, 3.96 mmol), and DCM (2 mL) was added to an 8 mL vial. Then, a solution of 2,4-dichloro-6-methoxyquinoline-3-carbonyl chloride (230 mg, 1 equivalent, 792 μmol) in DCM (1 mL) was added at 0 °C, and the resulting reaction mixture was stirred at 0 °C for 1 h. The mixture was then directly purified by silica gel column chromatography, eluting with PE / EtOAc (EtOAc ratio increased from 0% to 100% over 6 minutes) to give (S)-2,4-dichloro-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxyquinoline-3-carboxamide (210 mg, 496 μmol, 62.7%). [M+H]+ = 423.0.

[0497] Step 9: 2-Chloro-N-((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-4-(1,7-diazaspiro) [4.4]Nonan-7-yl)quinoline-3-carboxamide:

[0498] A mixture of (S)-2,4-dichloro-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxyquinoline-3-carboxamide (200 mg, 1 equivalent, 473 μmol), 1,7-diazaspiro[4.4]nonane (119 mg, 2.00 equivalent, 943 μmol), DIEA (183 mg, 247 μL, 3.00 equivalent, 1.42 mmol), and ACN (2 mL) was placed in an 8 mL vial. The reaction mixture was stirred at 80 °C for 16 hours and used for the next step without further processing (in situ). [M+H] + =513.2.

[0499] Step 10: 7-(2-chloro-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy Quinolino-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester:

[0500] Boc₂O (128 mg, 135 μL, 1.50 equivalence, 586 μmol) and DIEA (151 mg, 204 μL, 3.00 equivalence, 1.17 mmol) were added to an 8-mL vial containing 2-chloro-N-((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-4-(1,7-diazaspiro[4.4]nonane-7-yl)quinoline-3-carboxamide (200 mg, 1 equivalent, 390 μmol) obtained from the previous reaction. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was then directly purified by MPLC (column, C18, 120 g; mobile phase, water (0.1% FA) and ACN (30% ACN reaching 98% within 7 min, maintaining 98% within 3 min); total flow rate, 70 mL / min; detector, UV 220 nm) to obtain 7-(2-chloro-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxyquinoline-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (180 mg, 294 μmol, 75.3%). [M+H] + =613.2.

[0501] Step 11: 7-(3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy-2-methoxy Phylogenin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester:

[0502] A THF (1 mL) solution of 7-(2-chloro-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxyquinoline-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (60 mg, 1 equivalent, 98 μmol) and morpholine (26 mg, 3.0 equivalent, 0.30 mmol) was placed in an 8 mL vial. LiHMDS (21 mg, 1.3 equivalent, 0.13 mmol) was added to the resulting mixture at 0 °C under a nitrogen atmosphere, and the reaction mixture was stirred from 0 °C to 25 °C for 3 hours under a nitrogen atmosphere. The crude product was subjected to Prep-HPLC (column, C18; mobile phase, water (0.1% FA) and ACN (20% ACN to 98% within 7 min); detector, 220 nm) to give 7-(3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy-2-morpholinoquinolino-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (50 mg, 75 μmol, 77%). [M+H] + =664.4.

[0503] Step 12: N -((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-2-morpholino-4-(1,7-di) Azaspiro[4.4]nonane-7-yl)quinoline-3-carboxamide:

[0504] In a 50 mL round-bottom flask, 7-(3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methoxy-2-morpholinoquinoline-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (48 mg, 1 equivalent, 72 μmol), DCM (3 mL), and TFA (1 mL) were added. The reaction mixture was stirred at 25 °C for 1 h and then concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column, SunFire Prep C18 OBD column, 19*150 mm 5 μm; mobile phase, water (0.1% FA) and ACN (30.0% ACN to 60.0% within 7 min); total flow rate, 20 mL / min; detector, UV 220 nm). The collected fractions were combined and concentrated under reduced pressure to obtain N -((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methoxy-2-morpholino-4-(1,7-diazaspiro[4.4]nonane-7-yl)quinoline-3-carboxamide (13 mg, 21 μmol, 29%). [M+H]+ = 564.3.

[0505] The following compounds were prepared in a similar manner to Example 1, wherein the reagents and / or substrates were appropriately substituted and / or functionalized using known chemical methods with appropriate reagents.

[0506]

[0507] Example 2. N Preparation of -((S)-1-(3-cyano-5-fluorophenyl)ethyl)-6-methoxy-4-((S)-5-methyl-1,4-diazaphen-1-yl)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxamide (compound 148)

[0508] Step 1: 2-Bromo-4-methoxy-5-(trifluoromethyl)aniline:

[0509] 4-Methoxy-3-(trifluoromethyl)aniline (500 mg, 1 equivalent, 2.62 mmol) was added to a 40 mL vial. NBS (466 mg, 1.00 equivalent, 2.62 mmol) was added over a nitrogen atmosphere over 4 hours. The resulting reaction mixture was stirred at 80 °C for 4 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with PE / EA (1:20) to give 2-bromo-4-methoxy-5-(trifluoromethyl)aniline (220 mg, 815 μmol, 31.1%). [M+H] + =268.1.

[0510] Step 2: Methyl 2-amino-5-methoxy-4-(trifluoromethyl)benzoate:

[0511] 2-Bromo-4-methoxy-5-(trifluoromethyl)aniline (6.8 g, 1 equivalent, 25 mmol), TEA (7.5 g, 10 mL, 2.9 equivalent, 74 mmol), PD(dppf)Cl2·DCM (2.1 g, 0.10 equivalent, 2.6 mmol), and carbon monoxide (10 bar) were added to a 500 mL sealed tube. The resulting solution was stirred at 100 °C for 4 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with PE / EA (1:10) to give methyl 2-amino-5-methoxy-4-(trifluoromethyl)benzoate (3.5 g, 14 mmol, 56%). [M+H] + =250.3.

[0512] Step 3: Methyl 5-methoxy-2-(3-methoxy-3-oxopropamido)-4-(trifluoromethyl)benzoate:

[0513] Under a nitrogen atmosphere, methyl 2-amino-5-methoxy-4-(trifluoromethyl)benzoate (2.5 g, 1 equivalent, 10 mmol) and methyl 3-chloro-3-oxopropionic acid (3.1 g, 2.3 equivalent, 23 mmol) were placed in a 250 mL round-bottom flask. DIEA (1.4 g, 1.9 mL, 1.1 equivalent, 11 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 5 min, then at 25 °C for 1 h. The reaction was quenched by adding water (50 mL). The mixture was extracted with EtOAc, and the combined organic phases were washed with brine and dried over Na₂SO₄. The volatiles were removed under reduced pressure to give methyl 5-methoxy-2-(3-methoxy-3-oxopropamido)-4-(trifluoromethyl)benzoate (3.5 g, 10 mmol, 100%). [M+H] + =350.3.

[0514] Step 4: Methyl 4-hydroxy-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid:

[0515] Under a nitrogen atmosphere, methyl 5-methoxy-2-(3-methoxy-3-oxopropamido)-4-(trifluoromethyl)benzoate (3.5 g, 1 equivalent, 10 mmol) and methanol (35 mL) were added to a 250 mL round-bottom flask. Sodium methoxide (7.7 g, 30% by weight, 4.3 equivalent, 43 mmol) was added to the mixture, and the resulting solution was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the methanol. Water (50 mL) was added to the residue, and the pH was adjusted to 5–6 with 2 M HCl (aq) solution. The precipitate was collected by filtration and dried to give methyl 4-hydroxy-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (20 mg, 63 μmol, 0.77%). [M+H]+ = 318.1.

[0516] Step 5: Methyl 4-chloro-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid ester:

[0517] Under a nitrogen atmosphere, methyl 4-hydroxy-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (200 mg, 1 equivalent, 630 μmol) and (COCl)₂ (10 mL) were added to an 8-mL vial. DMF (18 mg, 19 μL, 0.39 equivalent, 0.25 mmol) was added to the mixture at 0 °C. The resulting solution was stirred at 0 °C for 5 minutes, then at 40 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 5 by adding a saturated NaHSO₄(aq) solution. The resulting precipitate was collected by filtration and dried to give methyl 4-chloro-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (160 mg, 477 μmol, 75.6%). [M+H] + =336.1.

[0518] Step 6: (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazaphen-1-yl)-6-methoxy-2- Oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid methyl ester:

[0519] Add methyl 4-chloro-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (160 mg, 1 equivalent, 477 μmol), DIEA (12 mg, 16 μL, 3.1 equivalent, 93 μmol), (S)-7-methyl-1,4-diazaphen-1-carboxylate tert-butyl ester (204 mg, 2.00 equivalent, 952 μmol), and ACN (3.2 mL) to an 8 mL vial. Stir the mixture at 80 °C for 16 hours. Subsequently, volatiles were removed under reduced pressure, and the residue was purified by MPLC (column: Sunfire Prep C18 OBD column, 19 mm × 150 mm, 5 μm; mobile phase A: water (0.05% NH3·H2O), mobile phase B: ACN; flow rate: 20 ml / min; gradient: from 25% B to 98% B over 8 minutes; wavelength: 220 nm) to give (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazaphen-1-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid methyl ester (100 mg, 195 μmol, 40.9%). [M+H] + =514.2.

[0520] Step 7: (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazaphen-1-yl)-6-methoxy-2- oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid

[0521] Methyl (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazaphen-1-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 1 equivalent, 195 μmol), lithium hydroxide (94 mg, 20 equivalent, 3.9 mmol), H₂O (1 mL), and MeOH (2 mL) were placed in a 40 mL vial. The reaction mixture was stirred at 80 °C for 48 hours, and then concentrated under vacuum to remove MeOH. The residue was diluted with water and adjusted to pH 4–5 with NaHSO₄ (aq). The precipitate was collected by filtration and dried to give (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazaphen-1-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (10 mg, 20 μmol, 100%). [M+H + =500.6.

[0522] Step 8: (S)-3-(1-aminoethyl)-5-fluorobenzyl nitrile hydrochloride:

[0523] A mixture of (R)-N-((S)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 1 equivalent, 1.49 mmol) and HCl / dioxane (4 mL) was placed in an 8 mL vial. The reaction mixture was stirred at 25 °C for 1 hour. The volatiles were then removed under reduced pressure to give (S)-3-(1-aminoethyl)-5-fluorobenzyl nitrile hydrochloride (320 mg, 1.95 mmol, 131%). [M+H-HCl] + =165.1.

[0524] Step 9: (S)-4-(3-(((S)-1-(3-cyano-5-fluorophenyl)ethyl)carbamoyl)-6-methoxy-2- oxo-7-(trifluoromethyl)-1,2-dihydroquinolin-4-yl)-7-methyl-1,4-diazaphen-1-carboxylic acid tert-butyl ester:

[0525] Add (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazaphen-1-yl)-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 1 equivalent, 200 μmol) and DMF (2 mL) to an 8 mL vial. N -Ethyl- N- Isopropylpropyl-2-amine (129 mg, 4.99 equivalents, 998 μmol) and HATU (142 mg, 1.87 equivalents, 374 μmol). The reaction mixture was stirred at 25°C for 15 minutes. (S)-3-(1-aminoethyl)-5-fluorobenzyl nitrile hydrochloride (150 mg, 3.73 equivalents, 748 μmol) was added to the above mixture, and the resulting mixture was stirred at 25°C for 1 hour. The mixture was directly purified by reversed-phase rapid chromatography (column, C18 silica gel; mobile phase, water (0.05% NH3·H2O) and ACN (25% acetonitrile to 25% within 2 min, 25% acetonitrile to 98% within 6 min, 98% acetonitrile to 98% within 2 min; detector, UV 254 nm). The collected fractions were combined and concentrated under reduced pressure to give (S)-4-(3-(((S)-1-(3-cyano-5-fluorophenyl)ethyl)carbamoyl)-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinolin-4-yl)-7-methyl-1,4-diazaphen-1-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol, 70%). [M+H]+ = 646.3.

[0526] Step 10: N -((S)-1-(3-cyano-5-fluorophenyl)ethyl)-6-methoxy-4-((S)-5-methyl-1,4-di- (Zepazol-1-yl)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxamide:

[0527] A mixture of (S)-4-(3-((S)-1-(3-cyano-5-fluorophenyl)ethyl)carbamoyl)-6-methoxy-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinolin-4-yl)-7-methyl-1,4-diazaphen-1-carboxylic acid tert-butyl ester (90 mg, 1 equivalent, 0.14 mmol) and DCM (3 mL) was placed in an 8 mL vial. TFA (1 mL) was added, and the reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (column: SunFire prepOBD 19 mm × 150 mm 5 μm; mobile phase A: water (0.05% NH3·H2O); mobile phase B: CAN; gradient: from 25% B to 65% B over 8 minutes; flow rate: 20 mL / min; wavelength: 220 nm). The collected fractions were combined and dried by freeze-drying to obtain N -((S)-1-(3-cyano-5-fluorophenyl)ethyl)-6-methoxy-4-((S)-5-methyl-1,4-diazaphen-1-yl)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxamide (50.2 mg, 92.0 μmol, 66%). [M+H]+=546.2.

[0528] The following compounds were prepared similarly to those in Example 2, wherein the reagents and / or substrates were appropriately substituted and / or functionalized using known chemical methods with appropriate reagents.

[0529]

[0530] Example 3. SSTR determination Functional testing Overview: All five SSTR isoforms are Gi-coupled G protein-coupled receptors (GPCRs), which, when activated by agonists, lead to a decrease in intracellular cyclic AMP (cAMP). Therefore, the measurement of intracellular cAMP levels can be used to assess whether a compound is an agonist of an SSTR isoform. An example of intracellular cAMP assay is described below.

[0531] SSTR3 cAMP assay protocol Chinese hamster ovary cells (CHO-K1, ATCC#) stably expressing human somatostatin type 3 receptor Two or four days prior to analysis, CCL-61 cells were seeded at 6,000 or 2,000 cells per well in 96-well tissue culture plates prepared for culture. The plates were cultured in Ham's F12 growth medium (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). Cells were cultured at 37°C, 5% CO2, and 95% humidity. cAMP was measured using the HTRF dynamic cAMP assay (Cisbio, #62AM5PEJ) according to the manufacturer's instructions. On the day of assay, culture medium was aspirated and cells were treated with 50 µL of stimulation buffer containing 10.2 mM 3-isobutyl-1-methylxanthine (IBMX, Millipore Sigma#I5879) and 1.6 µM NKH477 (Tocris#1603), along with various dilutions of the compounds of this invention. Cells were incubated at 37°C for 20 min (the final concentration of the compounds of this invention is typically 0-10,000 nM). Cells were treated with 50 µL of lysis buffer (HRTF cAMP kit, Cisbio) and incubated at 600 rpm for 30 min at room temperature, then diluted with 150 µL of stimulation buffer and vortexed at 300 rpm for another 5 min. The lysates were transferred to 384-well plates and incubated at room temperature for 1-24 h. cAMP accumulation was detected by d2-labeled cAMP and anti-cAMP-Cryptate. Time-resolved fluorescence signals were read using an m1000 Pro (Tecan) or CLARIOStar (BMG Labtech) microplate reader, with samples excited at 340 nm and emission measured at 620 nm and 665 nm. Data are expressed as calculated fluorescence ratios (665 nm / 620 nm). Intracellular cAMP concentrations were calculated using a regression standard curve and plotted against the concentrations of the compounds of this invention. The EC50 of the compounds was calculated using standard methods. 50 All data operations are performed in GraphPad Prismv9 (GraphPad, San Diego, CA).

[0532] Table 2 reports the evaluation of the bioactivity of compounds by inhibiting cAMP activity using the human SSTR3 receptor.

[0533] Table 2: SSTR3 activity of exemplary compounds:

[0534] Example 4. Evaluate the effects of SSTR3 agonists on kidney weight and renal cyst index in an autosomal dominant polycystic kidney disease (ADPKD) mouse model. The following experimental protocol was used to evaluate the efficacy of SSTR3 receptor agonists in reducing kidney size and kidney cyst index (KCI) in an autosomal dominant polycystic kidney disease (ADPKD) mouse model.

[0535] Establishment of an ADPKD mouse model. This was achieved through selective inactivation. Pax8 Tet-O-Cre / Pkd1 flox mouse kidneys Pkd1 Genes were used to generate an ADPKD mouse model (Piontek et al., Clin J Am Soc Nephrol 2004, 15(12), 3035–3043; Piotek et al. Nat Med 2007, 13(12), 1490–1495; Traykova-Brauch et al. Nat Med 2008, 14(9), 979–984), which leads to the formation of renal cysts. Specifically, by on days 11 and 12 after birth (PND) Pax8 Tet-O-Cre / Pkd1 flox Intraperitoneal injection of doxycycline hydrochloride (50 mg / kg) into mice to induce renal... Pkd1 Missing. By day 20 after birth (PND 20), compared with untreated control mice born in the same littermate, mice treated with doxycycline hydrochloride... Pax8 Tet-O-Cre / Pkd1 flox The kidneys of the mice (called ADPKD mice) are enlarged and cysts have appeared.

[0536] SSTR3 agonist in ADPKD mouse model. To evaluate the ability of SSTR3 agonists to reduce kidney weight and KCI in ADPKD mouse model, studies were conducted in male and female ADPKD mice at day 12 postnatal. From day 12 to day 20 postnatal, either the carrier or the SSTR3 agonist was administered orally once daily. Body weight and clinical signs were recorded daily. On day 20 postnatal, mice were anesthetized 1–2 hours after treatment with the carrier or the SSTR3 agonist, and blood was collected by cardiac puncture of the left ventricle following an open-chest procedure using an EDTA-coated needle. Blood was collected in EDTA tubes and stored on ice until processed into plasma. Plasma samples were cryopreserved. The heart was removed, and its weight was recorded to obtain the kidney-to-heart weight ratio. The left kidney was removed, weighed, bisected longitudinally, and placed overnight in 4% paraformaldehyde at 4ºC for tissue fixation. After fixation, the left kidney was processed and embedded in paraffin for histomorphological analysis. Renal transverse sections, including the cortex, medulla, and renal papillae, were collected on glass slides and stained with hematoxylin and eosin. Images were taken at 1X and 4X, and the total cyst area was measured from the images using ImageJ software. The renal cyst index (KCI) was calculated using the total cyst area.

[0537] Compound 8 (Study 1). ADPKD mice were orally administered the carrier or 30 mg / kg / day or 60 mg / kg / day once daily from day 12 to day 20 postnatal day. After euthanasia on day 20 postnatal day, left kidney weight and renal cyst index (%) were measured and calculated (Table 1). Data are presented as mean ± SD (carrier group n=24, 30 mg / kg / day compound 8 group n=12, 60 mg / kg / day compound 8 group n=14).

[0538] Compound 38 (Study 2). ADPKD mice were orally administered the carrier or 30 mg / kg / day or 60 mg / kg / day once daily from day 12 (PND) to day 20. After euthanasia on day 20, left kidney weight and renal cyst index (%) were measured and calculated (Table 1). Data are presented as mean ± SD (carrier group n=18, 30 mg / kg / day compound 38 group n=12, 60 mg / kg / day compound 38 group n=13).

[0539] Results. In two independent studies, compounds 8 and 38 were tested in an ADPKD mouse model to evaluate their ability to reduce kidney size and renal cyst index in this model. The renal cyst index (KCI) and left kidney weight (LKW) / body weight (BW) after 9 days of treatment with compounds 8 and 38 are summarized in Table 3 below: Table 3: Abbreviations: LKW = Left kidney weight; BW = Body weight; KCI = Kidney cyst index; SD = Standard deviation.

[0540] In ADPKD model mice, oral administration of compounds 8 and 38 at 30 mg / kg / day once daily from day 12 to day 20 after birth resulted in a 13.6% and 10.7% reduction in the renal cyst index, respectively, compared to the carrier groups in their respective studies (see Table 3).

[0541] In ADPKD model mice, oral administration of compounds 8 and 38 at 60 mg / kg / day once daily from day 12 to day 20 after birth resulted in a 21.6% and 25.2% reduction in the renal cyst index, respectively, compared to the carrier groups in their respective studies (see Table 3).

[0542] Given these results, it is reasonable to expect successful treatment of PKD (including ADPKD) by administering the SSTR3 agonist disclosed herein to subjects.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: Indicates a single bond or a double bond; Z is NR Z , where R Z It does not exist or is oxidized, or, when R 7 When R = 0, then Z Is it H or C? 1-6 alkyl; X is NR X , where R X Is it H or C? 1-6 alkyl; L is a key, C 1-6 Alkyl or (CR) L1 R L2 ) t , where R L1 and R L2 Each independently is H or C 1-6 Alkyl group, and t is 1, 2, 3, 4, 5 or 6; R 1 It is C 1-6 Alkyl, C 3-10 cycloalkyl, C 3-6 Cycloalkoxy, C 1-6 Haloalkoxy, 6-10 aryl, and 4-7 heteroaryl groups, each optionally bound by 1, 2, 3, 4, or 5 R groups. 1A replace; Each R 1A Independent of halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 11 C(O)OR 11 、or C(O)N(R) 11 )2, where each R 11 Independently H or C 1-6 alkyl; R 2 It is C 3-7 cycloalkyl, C 5-9 Bicycloalkyl or 7- to 9-membered heterocyclic alkyl groups, each surrounded by 1, 2, 3, 4, or 5 R groups. 2A replace; Where R 2A Independent of H, halogen, C 1-6 Alkyl or C(O)OR 21 C 1-6 Alkyl groups are optionally surrounded by 1, 2, or 3 halogens, OH, CN, or C. 1-6 Alkyl substitution; wherein R 21 Is it H or C? 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon rings; R 3 R 4 R 5 and R 6 Each is independently H, halogen, CN, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, or C 3-6 Cycloalkyl groups; and R 7 H, halogen, C 1-6 Alkyl, C 3-6 Heterocyclic alkyl, OR 71 or NR 72 R 73 ; Where R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. 7A Replacement, condition is when R 71 When it does not exist, R 7 It is a carbonyl group; R 72 and R 73 Independently H or C 1-6 Alkyl, wherein C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by 1, 2, or 3 R atoms. 7C Substituted 3- to 10-membered heterocyclic alkyl groups; Where R 7A R 7B and R 7C Each is independently a halogen, carbonyl, or C group. 1-6 Alkyl, C 1-6 Alkylamines, 5-membered heterocycles, OR 7B1 C(O)OR 7A1 、 and C(O)NR 7A2 R 7A2 The 5-membered heterocycle is arbitrarily selected by C 1-6 Alkyl, carbonyl, or OH substitutions, wherein C 1-6 The alkylamine may optionally be substituted with a 6-membered cycloalkyl group, wherein the 6-membered cycloalkyl group may optionally be substituted with CO2H; and Where R 7A1 R 7A2 R 7B1 R 7B2 and R 7B3 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl group, wherein C 1-6 Alkyl and C 1-6 Each alkyl sulfonyl group is optionally surrounded by one or two R groups. 7B4 Replace; where R 7B4 Independently OC(O)-R 7B5 Or a 5-membered heterocycle, wherein the 5-membered heterocycle is optionally C 1-6 Alkyl substitution; and wherein R 7B5 It is C 1-6 Alkyl groups, which may optionally be substituted with NH2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (II) or a compound of formula (III): (II) or (III), in: R 2A It is H, halogen, C(O)OH, C(O)OC 1-6 Alkyl or C 1-6 Alkyl, the C 1-6 Alkyl groups may be replaced by OH, CN, or C. 1-6 Alkyl substitution; m can be 1, 2, 3, or 4; n is 1, 2, 3 or 4; q is 1, 2, 3, or 4; r is 1, 2, 3, or 4; and s can be 1, 2, 3, 4 or 5.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Z is NH or NMe.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein X is NH or NMe.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is a bond, C is a carbon ... 1-6 Alkyl or (CR) L1 R L2 ) t , where each R L1 and R L2 Independently, it is H or C 1-6 Alkyl group, and t is 1 or 2.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein L is a bond, CH2, CH2CH2, , , or .

7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein L is... .

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 3-8 Cycloalkyl, phenyl, or 4 to 6-membered heteroaryl groups, each independently bound by 1, 2, or 3 R groups. 1A replace.

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 3-8 Cycloalkyl, phenyl, or pyridyl groups, each independently bound by one, two, or three R groups. 1A replace.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or 。 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R 1 for or .

12. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

13. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-10, wherein R 1 for , , or .

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein: R 2 It is a 7- to 9-membered heterocyclic alkyl group, C 3-7 cycloalkyl, or C 5-9 Bicycloalkyl groups, each surrounded by 1, 2, or 3 R groups. 2A replace; R 2A Independently, H, halogen, CN, C 1-6 Alkyl, C(O)OR 21 or C(O)NR 22 R 23 C 1-6 Alkyl groups are optionally surrounded by one or two OH, NH2, CN, or C atoms. 1-6 Alkyl or C 1-6 Alkoxy substitution; and R 21 R 22 and R 23 Each independently is H or C 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon ring.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein: R 2 Is it by 1, 2 or 3 Rs? 2A Substituted 7- to 9-membered heterocyclic alkyl groups; R 2A Independently, H, halogen, CN, C 1-6 Alkyl, C(O)OR 21 or C(O)NR 22 R 23 C 1-6 Alkyl groups are optionally surrounded by one or two OH, NH2, CN, or C atoms. 1-6 Alkyl or C 1-6 Alkoxy substitution; and R 21 R 22 and R 23 Each independently is H or C 1-6 Alkyl; or Two Rs 2A Together with the atoms they are attached to, they form C 3-6 Carbon ring.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein: R 2 yes , , , , or Each of them is controlled by 1 or 2 R 2A replace; R 2A H, halogen, C 1-6 Alkyl or C(O)OR 21 C 1-6 Alkyl groups may be replaced by OH, CN, or C. 1-6 Alkoxy substitution; and R 21 Is it H or C? 1-6 alkyl.

17. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 2 yes , , , or .

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R 2 yes , or .

19. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 2 yes , , , , , , , , , , , , , , , , , , or .

20. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, wherein R 2 yes .

21. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H or F.

22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein R 3 It is H.

23. The compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof, wherein R 4 It is H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl.

24. The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, wherein R 4 It is H, F, Cl, methyl, methoxy, or cyclopropyl.

25. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methoxy group.

26. The compound of any one of claims 1-25 or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, halogen, CN, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

27. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, wherein R 5 Is it halogen or C? 1-6 Halogenated alkyl groups.

28. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, F, Cl, CN, CF3, CF2Me, OMe or cyclopropyl.

29. The compound of any one of claims 1-28 or a pharmaceutically acceptable salt thereof, wherein R 5 It is Cl, CF3, or cyclopropyl.

30. The compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, wherein R 6 It is H, halogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R 6 It is H.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein: R 7 It is H, halogen, OR 71 NR 72 R 73 Or C 1-6 alkyl; Where R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl optional R 7A replace; Where R 72 and R 73 Each independently is H or C 1-6 Alkyl, wherein C 1-6 Alkyl groups are each optionally R 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one or two R atoms. 7C Substituted 3- to 6-membered heterocyclic alkyl groups; Where R 7A Independently 4 to 6-membered heterocyclic rings, C(O)OR 7A1 or C(O)NR 7A2 R 7A2 The 4- to 6-membered heterocycle is optionally substituted with a carbonyl group, OH, or NH2; wherein R 7A1 and R 7A2 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl; Where R 7B independently for OR 7B1 C(O)OR 7B2 C(O)NR 7B3 R 7B3 Or a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is optionally substituted with a methyl group, a carbonyl group, an OH group, or an NH2 group; wherein R 7B1 R 7B2 and R 7B3 Each independently represents H and C. 1-6 Alkyl or C 1-6 alkylsulfonyl group, wherein C 1-6 Alkyl groups are each optionally OC(O)-R 7B4 Replacement or optional 4- to 6-membered heterocyclic rings by R 7B4 Replace; where R 7B4 It is C 1-6 Alkyl groups, optionally substituted with NH2; and R 7C Independently carbonyl, halogen, OH, C 1-6 Alkoxy, CO2H, C(O)OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Alkylamine, wherein the C 1-6 The alkylamine may optionally be substituted with a 6-membered heterocycle, which may optionally be substituted with CO2H.

33. The compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof, wherein: R 7 It is H, halogen, OR 71 NR 72 R 73 Or C 1-6 alkyl; R 71 It does not exist, and is H or C. 1-6 Alkyl, wherein C 1-6 Alkyl optional R 7A replace; R 72 and R 73 Independently H or C 1-6 Alkyl, wherein the C 1-6 Alkyl optional R 7B Replace; or R 72 and R 73 Together with the nitrogen atoms they are attached to, they form , , ,or Each of them can be arbitrarily assigned to 1 or 2 Rs. 7C replace; R 7A Independently C(O)OR 7A1 or C(O)NR 7A2 R 7A2 ; R 7A1 Independently H or C 1-6 alkyl; R 7A2 Independently H or C 1-6 alkylsulfonyl; R 7B independently for OR 7B1 C(O)OR 7B2 C(O)NR 7B3 R 7B3 , , or ; R 7B1 Independently H or C 1-6 alkyl; R 7B2 For H or C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally OC(O)-R 7B4 or replace; R 7B3 Independently H or C 1-6 alkylsulfonyl; R 7B4 It is C 1-6 Alkyl groups, optionally substituted with NH2; and R 7C Independently carbonyl, halogen, OH, C 1-6 Alkoxy, CO2H, C(O)OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Alkylamine, wherein the C 1-6 The alkylamine may optionally be substituted with a 6-membered heterocycle, which may optionally be substituted with CO2H.

34. The compound of any one of claims 1-33 or a pharmaceutically acceptable salt thereof, wherein R 7 It is H, O, Cl, Me, NH2, NHMe, NMe2, , , , , , , , , or .

35. The compound of any one of claims 1-33 or a pharmaceutically acceptable salt thereof, wherein R 7 It is H, O, OH, OMe, NH2, NHMe, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

36. The compound of any one of claims 1-33 or a pharmaceutically acceptable salt thereof, wherein R 7 It is H, O, or .

37. A compound or a pharmaceutically acceptable salt thereof, selected from: And its pharmaceutically acceptable salts.

38. A pharmaceutical composition comprising at least one compound of any one of claims 1-37 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

39. A method of treating a disease selected from the group consisting of polycystic kidney disease, polycystic liver disease, and ciliary disorders, the method comprising administering to a subject in need at least one compound of any one of claims 1-37 or a pharmaceutically acceptable salt thereof, or administering a pharmaceutical composition comprising at least one compound of any one of claims 1-37 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

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