Somatostatin subtype receptor 3 (SSTR3) agonists and their use

Abstract

Compounds that are somatostatin receptor subtype 3 (SSTR3) agonists, methods for producing such compounds, pharmaceutical compositions and agents comprising such compounds, and methods for using such compounds in the treatment of conditions, diseases, or disorders for which modulation of SSTR3 activity would be beneficial are described herein.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 513,599, filed on 14 July 2023, which is incorporated in its entirety by reference herein.

[0002] Compounds that are somatostatin receptor subtype 3 agonists (SSTR3), methods for producing such compounds, pharmaceutical compositions and agents comprising such compounds, and methods for using such compounds in the treatment of conditions, diseases, or disorders for which modulation of SSTR3 activity would be beneficial are described herein. [Background technology]

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

[0004] Somatostatin acts on five GPCRs (SSTR1-5). Binding to these receptors inhibits the secretion of adenylyl cyclase (AC) and mitogen-activated protein kinase, cell proliferation, and several hormones (growth hormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive gastrointestinal peptides and seretins, 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 cholangiocarcinoma cells. SSTR1 and SSTR2 are expressed in the broad ascending limb of Henle, distal tubule, and collecting duct. SSTR3, SSTR4, and SSTR5 are expressed in the proximal tubule. Preclinical studies have shown that somatostatin inhibits cAMP production in MDCK cells and rat collecting ducts, antagonizes the vasopressin effect in toad bladder and canine collecting ducts, inhibits cAMP production, fluid secretion, and cell proliferation in bile duct cells, and suppresses the growth of bile ducts and periportal connective tissue in rats with extrahepatic biliary obstruction. Because somatostatin has a half-life of approximately 3 minutes, more stable synthetic peptides (octreotide, lanreotide, and pasireotide) are being developed for clinical use.

[0005] In preclinical studies, octreotide (which binds to SSTR2 and SSTR3, but preferentially to SSTR2) and pasireotide (which binds to SSTR1, SSTR2, SSTR3, and SSTR5 with high affinity) were shown to increase cAMP levels and bile duct cell proliferation in vitro, enlarge hepatic cysts in 3D collagen culture, and in PCK rats and Pkd2 WS25 / - Mouse, and Pkd1 RC / RC To reduce the development of renal and hepatic cysts and fibrosis in the model.

[0006] In clinical trials using octreotide or lanreotide (both bind to SSTR2 and SSTR3, but preferentially to SSTR2), kidney growth halted in the first year of treatment and then resumed, possibly at a slower rate than without treatment. Liver volume decreased by 4%–6% during the first year of treatment, and this reduction persisted throughout 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, depot preparations of these peptide drugs are very expensive and require frequent physician visits due to painful injections that can lead to injection site reactions.

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

[0008] In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is described herein.

[0009] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-6 The elements are alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted 6-membered heterocycloalkyl, unsubstituted or substituted C5-7 bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, and if R1 is substituted, R1 is substituted with 1 to 3 X members, each X independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 fluoroalkyl, C1-6 fluoroalkoxy, C3-6 cycloalkoxy, CN, and OH. L is a bond or CR2R3, where R2 is H or C1-6 alkyl, R3 is H, C1-6 alkyl, C1-6 alkoxy, CH2OCH3, or C1-6 fluoroalkyl, or R2 and R3 together with the carbon to which they are attached form a C 3-6 cycloalkyl, Z is

[0010]

Chemical formula

[0011]

Chemical formula

[0012] In one embodiment, L is a bond.

[0013] In one embodiment, L is CR2R3. In some embodiments, R2 is H or methyl. In some embodiments, R3 is H, methyl, ethyl, trifluoromethyl, or CH2OCH3. In some embodiments, R2 and R3, together with the carbon to which they are bonded, are C 3-6 It forms a cycloalkyl group. In some embodiments, L is CH2,

[0014] [ka] Selected from.

[0015] In one embodiment, R1 is either unsubstituted or substituted C 1-4 It is alkyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is

[0016] [ka] Selected from.

[0017] In one embodiment, R1 is either unsubstituted or substituted C 3-6 It is a cycloalkyl group. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X groups, each X independently selected from the group consisting of fluoromethyl and trifluoromethyl groups. In some embodiments, R1 is

[0018] [ka] Selected from.

[0019] In one embodiment, R1 is an unsubstituted or substituted phenyl compound. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 3 X compounds, each X independently selected from the group consisting of fluoro, chloro, methyl, methoxy, and CN compounds. In some embodiments, R1 is

[0020] [ka] Selected from.

[0021] In one embodiment, R1 is an unsubstituted or substituted pyridinyl, or an unsubstituted or substituted pyrimidinyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is

[0022] [ka] Selected from.

[0023] In one embodiment, R1 is an unsubstituted or substituted C5-7 bicycloalkyl. In some embodiments, if R1 is substituted, R1 is substituted with fluoro or trifluoromethyl. In some embodiments, one or more carbon atoms of the C5-7 bicycloalkyl are bridging carbons. In some embodiments, R1 is

[0024] [ka] Selected from.

[0025] In one embodiment, m is 1 and n is 1.

[0026] In one embodiment, R A H is H.

[0027] In one embodiment, RB H is R C H is R D H is H.

[0028] In one embodiment, Z is

[0029] [ka] That is the case.

[0030] In one embodiment, Z is

[0031] [ka] That is the case.

[0032] In another embodiment, a compound of formula (Ia) or a pharmaceutically acceptable salt thereof is described herein,

[0033] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-4 The compounds are alkyl, unsubstituted or substituted C3-6 cycloalkyl, tetrahydropyran, unsubstituted or substituted C5-7 bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1-2 X molecules, each X independently selected from F, Cl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, OCH2CF3, CN, and OH. L is a bond or CR2R3, R2 is H or methyl, R3 is H, methyl, ethyl, trifluoromethyl, or -CH2OCH3, or R2 and R3 together with the carbon to which they are bonded to form a cyclopropyl group. Z is

[0034] [ka] And, R4 is H, F, or Cl; R5 is H or F; and R6 is H, F, Cl, CN, methyl, or methoxy. R7 is H or

[0035] [ka] And, R8 is H, NH2, or methyl.

[0036] In one embodiment, L is a bond.

[0037] In one embodiment, L is CR2R3. In some embodiments, L is CH2,

[0038] [ka] Selected from.

[0039] In one embodiment, R1 is either unsubstituted or substituted C 1-4 It is alkyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In some embodiments, R1 is

[0040] [ka] Selected from.

[0041] In one embodiment, R1 is either unsubstituted or substituted C 3-6It is a cycloalkyl group. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X groups, each X independently selected from the group consisting of fluoromethyl and trifluoromethyl groups. In some embodiments, R1 is

[0042] [ka] Selected from.

[0043] In one embodiment, R1 is an unsubstituted or substituted phenyl compound. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X compounds, each X independently selected from the group consisting of fluoro, chloro, methyl, methoxy, and CN compounds. In some embodiments, R1 is

[0044] [ka] Selected from.

[0045] In one embodiment, R1 is an unsubstituted or substituted pyridinyl, or an unsubstituted or substituted pyrimidinyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is

[0046] [ka] Selected from.

[0047] In one embodiment, R1 is an unsubstituted or substituted C5-7 bicycloalkyl. In some embodiments, if R1 is substituted, R1 is substituted with a fluorocarbon. In some embodiments, one or more carbon atoms of the C5-7 bicycloalkyl are bridging carbons. In some embodiments, R1 is

[0048] [ka] Selected from.

[0049] In one embodiment, R1 is tetrahydropyran. In some embodiments, R1 is

[0050] [ka] That is the case.

[0051] In one embodiment, Z is

[0052] [ka] In some embodiments, R4 and R6 are fluorocarbons.

[0053] In one embodiment, Z is

[0054] [ka] That is the case.

[0055] In one embodiment, the compound is

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka] Selected from.

[0062] In another embodiment, compounds of formula (Ib) or formula (Ic), or pharmaceutically acceptable salts thereof, are described herein.

[0063] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-3 Alkyl, unsubstituted, or substituted C 3-4 A cycloalkyl, unsubstituted or substituted C5 bicycloalkyl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1 to 2 X molecules, each X independently selected from F, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, CN, and OH. L is a bond or CR2R3, R2 is H, and R3 is H, methyl, or -CH2OCH3. R5 is either H or F. R7 is either H or CN. R8 is H, D, OH, methoxy, or -NH(CH2)2OH.

[0064] In one embodiment, the compound is the compound of formula (Ib), or a pharmaceutically acceptable salt thereof.

[0065] [ka]

[0066] In one embodiment, L is a bond.

[0067] In one embodiment, L is CR2R3. In some embodiments, L is CH2,

[0068] [ka] Selected from.

[0069] In one embodiment, R1 is either unsubstituted or substituted C 1-3 It is alkyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH. In some embodiments, R1 is

[0070] [ka] Selected from.

[0071] In one embodiment, R1 is either unsubstituted or substituted C 3-4 It is a cycloalkyl group. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X groups, each X independently selected from the group consisting of fluoromethyl and trifluoromethyl groups. In some embodiments, R1 is

[0072] [ka] Selected from.

[0073] In one embodiment, R1 is an unsubstituted or substituted pyridinyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of fluoro, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is

[0074] [ka] Selected from.

[0075] In one embodiment, R1 is an unsubstituted or substituted C5 bicycloalkyl. In some embodiments, one or more carbon atoms of the C5 bicycloalkyl are bridging carbons. In some embodiments, if R1 is substituted, R1 is substituted with trifluoromethyl. In some embodiments, R1 is

[0076] [ka] That is the case.

[0077] In one embodiment, the compound is

[0078] [ka]

[0079] [ka] Selected from.

[0080] In one embodiment, R7 is H, and R8 is H.

[0081] In another embodiment, a compound of formula (Id), or a pharmaceutically acceptable salt thereof, is described herein.

[0082] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-4 Alkyl, unsubstituted, or substituted C 3-5 A cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1 to 3 X molecules, each X independently selected from F, Cl, methyl, ethyl, trifluoromethoxy, and CN. L is a bond or CR2R3, R2 is H, and R3 is H or methyl. R4 is H, F, or Cl. R5 is either H or F. R6 is H, F, or Cl. R A is H, C(O)OEt, or C(O)Me, R B is H, D, or methyl, R C is either H or D, R D is either H or F, m is an integer selected from 0 or 1. n is an integer selected from 0, 1, and 2.

[0083] In one embodiment, L is a bond.

[0084] In one embodiment, L is CR2R3. In some embodiments, L is CH2 and

[0085] [ka] Selected from.

[0086] In one embodiment, R1 is either unsubstituted or substituted C 1-4 It is alkyl. In some embodiments, if R1 is substituted, R1 is substituted with methyl or trifluoromethoxy. In some embodiments, R1 is

[0087] [ka] Selected from.

[0088] In one embodiment, R1 is either unsubstituted or substituted C 3-5It is a cycloalkyl group. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X groups, each X independently selected from the group consisting of fluoromethyl and trifluoromethyl groups. In some embodiments, R1 is

[0089] [ka] Selected from.

[0090] In one embodiment, R1 is an unsubstituted or substituted phenyl compound. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 3 X compounds, each X independently selected from the group consisting of fluoro, chloro, and CN compounds. In some embodiments, R1 is

[0091] [ka] Selected from.

[0092] In one embodiment, R1 is an unsubstituted or substituted pyridinyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group consisting of methyl and CN. In some embodiments, R1 is

[0093] [ka] Selected from.

[0094] In one embodiment, the compound is

[0095] [ka]

[0096] [ka] Selected from.

[0097] In another embodiment, a compound of formula (II), or a pharmaceutically acceptable salt thereof, is described herein.

[0098] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-6 Alkyl, unsubstituted, or substituted C 3-6 A cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1 to 2 X molecules, each X independently selected from the group consisting of halogens, C1-6 alkyl, C1-6 alkoxy, C1-6 fluoroalkyl, C1-6 fluoroalkoxy, and CN. L is a bond or CR2R3, R2 is H, and R3 is H or methyl.

[0099] In one embodiment, the compound is the compound of formula (IIa) or a pharmaceutically acceptable salt thereof.

[0100] [ka]

[0101] In one embodiment, L is a bond.

[0102] In one embodiment, L is CH2 or

[0103] [ka] Selected from.

[0104] In one embodiment, R1 is unsubstituted or substituted ethyl. In some embodiments, if R1 is substituted, R1 is substituted with 1 to 2 X, each X independently selected from the group of methoxy and trifluoromethoxy. In some embodiments, R1 is

[0105] [ka] Selected from.

[0106] In one embodiment, R1 is either unsubstituted or substituted C 4-5 It is a cycloalkyl group. In some embodiments, R1 is substituted, or R1 is substituted with a fluoropolymer. In some embodiments, R1 is

[0107] [ka] Selected from.

[0108] In one embodiment, R1 is an unsubstituted or substituted phenyl. In some embodiments, if R1 is substituted, R1 is substituted with CN. In some embodiments, R1 is

[0109] [ka] That is the case.

[0110] In one embodiment, R1 is an unsubstituted or substituted pyridinyl. In some embodiments, if R1 is substituted, R1 is substituted with methyl. In some embodiments, R1 is

[0111] [ka] That is the case.

[0112] In one embodiment, the compound is

[0113] [ka] Selected from.

[0114] In one embodiment, the compound is

[0115] [ka] Selected from.

[0116] In another embodiment, methods for treating disorders selected from the group consisting of polycystic kidney disease, polycystic liver disease, and ciliopathy are also disclosed herein, the methods comprising administering to a subject in need any one of the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa), or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is polycystic kidney disease. In some embodiments, polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

[0117] In another embodiment, pharmaceutical compositions comprising any one compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are also disclosed herein. [Brief explanation of the drawing]

[0118] [Figure 1] This study demonstrates how abnormal primary ciliary function leads to cyst formation in autosomal dominant polycystic kidney disease (ADPKD). [Figure 2-1] (A) shows the interaction between calcium ions and the cAMP ciliary signaling pathway in the kidney tissue of healthy individuals and (B) individuals with ADPKD. [Figure 2-2] (A) shows the interaction between calcium ions and the cAMP ciliary signaling pathway in the kidney tissue of healthy individuals and (B) individuals with ADPKD. [Figure 3] This study demonstrates a mechanism in which SSTR3 activation inhibits adenylyl cyclase activity, thereby reducing ciliary-plasma cAMP levels. [Figure 4] This paper presents an analysis of mRNA expression of SSTR2, SSTR3, SSTR5, and vasopressin receptor 2 (AVPR2) in healthy and cystic tissue. [Figure 5] The effects of compound 105 (A) and compound 108 (B) in an in vitro three-dimensional cyst formation model are shown. [Figure 6] This shows the effects of oral administration of compound 108 on (A) left kidney weight and (B) renal cyst index in ADPKD mice. [Modes for carrying out the invention]

[0119] Somatostatin (SSTR), also known as a somatotropin release inhibitor (SRIF), was initially isolated as a 14-amino acid peptide from the sheep hypothalamus (Brazeau et al., Science 179, 77-79, 1973). A 28-amino acid peptide with N-terminal elongation possessing biological activity similar to 14-amino acid somatostatin was subsequently isolated (Pradayrol et al., FEBS Letters, 109, 55-58, 1980; Esch et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980). SSTR is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SSTR acts via both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of the secretion of other hormones, most notably growth hormone (GH). These are produced by a wide variety of cell types in the central nervous system (CNS) and the gut, and have multiple functions, including regulating the secretion of growth hormone (GH), insulin, glucagon, and many other antiproliferative hormones.

[0120] These multifaceted 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 distinct 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 class A subgroup of the GPCR superfamily.

[0121] It is possible to selectively modulate one or a combination of somatostatin receptor subtypes. Selectively modulating one somatostatin receptor subtype relative to other somatostatin receptor subtypes reduces undesirable side effects in various clinical applications.

[0122] In some embodiments, the SSTR3 agonists described herein are used in the treatment of various diseases or conditions, including but not limited to polycystic kidney disease and polycystic liver disease, including but not limited to ciliary disorders. In some embodiments, the SSTR3 agonists described herein are used in the treatment of various diseases or conditions related to ciliary dysfunction, including but not limited to polycystic kidney disease (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 in the treatment of polycystic kidney disease (PKD). In some embodiments, the SSTR3 agonists described herein are used in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In some embodiments, the somatostatin receptor modulators described herein are used in the treatment of polycystic kidney disease (PKD) in mammals.

[0123] Ciliosis Ciliopathy is a class of developmental and degenerative monogenic disorders characterized by dysfunction of cilia, which are organelles of hair-like cells. Cilia are microtubule-based structures found in almost all vertebrate cells. They derive from basal bodies, modified centrosomes, which are organelles that form the spindle poles during mitosis. Most of the proteins altered in the monogenic disorders that constitute ciliopathy function in the cili-centrosome complex, which represents a naturally universal system for cell detection and the management of external signals. The crucial role that the cili-centrosome complex plays in the normal function of most tissues explains the involvement of multiple organ systems in ciliopathy. Dysfunction of cilia can cause a variety of ciliary diseases and conditions, including, but are not limited to, polycystic liver disease, polycystic kidney disease (PKD), autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and combinations thereof.

[0124] Polycystic kidney disease Polycystic kidney disease (PKD), also known as polycystic kidney syndrome, is a genetic disorder in which the renal tubules within the kidneys become structurally abnormal, leading to the development and growth of multiple cysts, which are non-functional tubules filled with fluid. The cysts range in size from microscopic to gigantic and crush adjacent normal tubules, ultimately rendering them non-functional. There are two types of PKD, each with its own pathology and genetic causes: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The mutated gene is expressed in all cells in the body, and as a result, cysts can also occur in the liver.

[0125] Tissue levels of cAMP are elevated in numerous animal models of ciliopathy, including those for polycystic kidney disease (PKD). Generally, tissue levels of cAMP are determined by the activity of membrane-bound and soluble adenylyl cyclase (AC) and cAMP phosphodiesterase (PDE), which are subject to complex regulatory mechanisms. For example, in some cases, AC may be under positive or negative control of G protein-coupled receptors (GPCRs) and extracellular ligands. For instance, somatostatin acts on five somatostatin receptors (SSTR1-5), which then inhibit AC and reduce intracellular cAMP levels.

[0126] Increased cAMP levels disrupt tubule formation, stimulate chloride and fluid secretion within cystic cavities, and activate proliferative signaling pathways including mitogenic factor-activated protein kinase / extracellular regulatory kinase, mTOR, and β-catenin signaling. Activated mTOR transcriptionally stimulates aerobic glycolysis, increasing ATP synthesis, decreasing AMP levels, inhibiting AMPK along with B-Raf-dependent activation of LKB1, further enhancing mTOR activity and CFTR-driven chloride and fluid secretion. Increased PKA signaling due to elevated cAMP levels also activates several transcription factors, including STAT3 and cAMP response element-binding protein (CREB). Activated STAT3 induces transcription of cytokines, chemokines, and growth factors, and subsequently activates STAT3 on interstitially alternatingly activated (M2) macrophages, resulting in a feedforward loop between cyst-lining cells and M2 macrophages. Abnormal integrin-extracellular membrane interactions and cAMP signaling within focal adhesion complexes may also contribute to increased adhesion of cyst-derived cells to laminin-322 and collagen. Highly active CREBs in ADPKD drug therapy regulate cAMP-dependent genes, which can control a wide range of cellular processes, including metabolism, cell survival and proliferation, differentiation, apoptosis, and immune responses. The central role of cAMP in the pathogenesis of PKD provides strong evidence for strategies to reduce its levels in cystic tissue.

[0127] ADPKD is the most common genetic cause of kidney disease, affecting approximately 1 in 1,000 individuals (Clin. Med. (Lond) 2009 Jun;9(3):278-283). The disease is characterized by slow, stepwise bilateral renal cystic formation, which often leads to renal failure, usually in the 40s or 50s. The cysts that form in the kidneys of ADPKD patients originate from renal tubules in which mutations in PKD1 or PKD2 (genes encoding polycystin-1 or polycystin-2 proteins, respectively) impair the ciliary function of 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, e.g., Figure 1) (Int.J.Mol.Sci.2022 Mar 19;23(6):3317). The cyst then grows and enlarges due to increased fluid transport into the lumen as a result of excessive chloride ion secretion within the cavity. Eventually, the cyst branches off from the major nephron, causing continuous stress on the surrounding tissue and resulting in local damage. The replacement of normal kidney tissue with cysts begins early in life, but the reduction in total nephron mass is masked by compensatory changes in glomerular filtration rate (i.e., GFR), and as a result, total GFR remains normal for many years until the compensation fails after several years, at which point ADPKD patients typically also experience flank pain, hematuria, urinary tract infections, or renal colic. ADPKD often leads to chronic kidney disease and end-stage renal disease (ESRD) requiring dialysis or kidney transplantation for the patient's survival.

[0128] The biological function of polycystin remains poorly understood. However, increasing evidence points to a model in which the loss of polycystin's inhibitory role in ciliary pathway activation may be a driving factor for cyst formation observed in ADPKD. In healthy individuals, polycystin-1 and polycystin-2 (PC1 / 2) proteins directly associate to form calcium-permeable channels that localize on primary cilia of renal epithelium (Nature Reviews Nephrology 2019;15:412-422). See Figure 2(A).

[0129] Cilia detect changes in the fluid flow within the lumen of the renal tubules and convert them into Ca 2+ Cilia are non-motile plasma membrane appendages that function as mechanosensors that transduce signaling responses. This makes cilia specialized signaling hubs that maintain significantly higher calcium concentrations than the cytoplasm (Int.J.Mol.Sci.2020 Sept 26;21(19):7109). High calcium levels directly inhibit ciliary adenylyl cyclases 5 and 6 (AC5 / 6), which stimulate phosphodiesterases (i.e., PDEs), enzymes that convert ATP in cAMP and catalyze the hydrolysis of cAMP. Therefore, the functional polycystin protein complex maintains low ciliary levels of cAMP, a second messenger that plays a role in multiple cellular processes, including cell growth and differentiation. See Figure 2(A).

[0130] In ADPKD patients, mutations in polycystin-1 or 2 lead to the formation of non-functional or impaired channels, causing a significant decrease in ciliary calcium levels (WorldJ.Nephrol.2016 Jan 6;5(1):76-83). This results in increased calcium-inhibitory AC5 / 6 activity and decreased calcium-dependent PDE4 activity. Dysregulation of AC5 / 6 and PDE4 activity leads to a significant increase in intracilar cAMP levels. See Figure 2(B).

[0131] Subsequently, high levels of cAMP induce cystophylloid formation by stimulating the expression of cAMP-dependent genes involved in proliferation and cystophylloidization, thereby driving chloride ion and fluid secretion within cystic cavities via protein kinase A (PKA)-stimulated transmembrane conductance regulator (CFTR) activation. Therefore, in ADPKD, dysregulation of crosstalk between intraciliary calcium and the cAMP signaling pathway appears to play a crucial role in cystophylloid formation. Accordingly, we hypothesize that cystophylloid formation observed in ADPKD should be inhibited / reduced by selectively blocking adenylyl cyclase activity within the cilia.

[0132] SSTR3 is a prototype ciliary GPCR (Neuroscience 1999 Mar;89(3):909-26). Transport of SSTR3 to cilia requires a series of highly regulated processes, including translocation of the receptor from cytoplasm to axoneme via a transition zone, 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, SSTR3 activation can inhibit adenylyl cyclase activity (Murthy et al., J.Biol.Chem.1996:271(38):23458-23463), and can reduce ciliary-plasma cAMP levels, which are central to the establishment of ADPKD. See Figure 3.

[0133] A publicly available dataset (GSE7869) from a global gene profiling study on renal cysts was reported by Song et al. (Hum.Mol.Genet.2009;18:2328-2343). The dataset includes microarray expression data from cysts of different sizes from five PKD1 patients and from three kidneys of healthy patients. The inventors reanalyzed the data using the Transcriptome Analysis Console (Thermo Fisher). Examination of probes covering SSTRR3 (SSTR3) revealed higher levels of SSTRR3-mRNA expression in healthy and cystic tissues compared to somatostatin receptors 2 and 5 (SSTR2, SSTR5) or vasopressin receptor 2 (AVPR2) (see Figure 4). Therefore, the inventors determined that the cellular localization and signaling capacity of SSTR3 make it an attractive target for the treatment of ADPKD.

[0134] Autosomal recessive polycystic kidney disease (ARPKD), a significant cause of ESRD and death in infants and children, is caused by mutations in PKHD1 (encoding fibrocystin). Similar to ADPKD, in ARPKD, cyst formation is triggered by disruption of mechanisms controlling cell differentiation, resulting in excessive cell proliferation and fluid secretion, as well as pathogenic interactions between mutant epithelial cells and abnormal extracellular matrix and alternatively activated stromal macrophages. Dysregulation of crosstalk between ciliated calcium and cyclic adenosine monophosphate (cAMP) signaling plays a central role in the development of PKD. In some cases, the compounds described herein are somatostatin agonists that selectively activate somatostatin receptor subtype 3 (SSTR3) and subsequently reduce cAMP levels and cAMP-dependent signaling.

[0135] In some embodiments, the somatostatin receptor modulators described herein are used to treat ciliopathy in mammals. In some embodiments, the somatostatin receptor modulators described herein result in a reduction of cAMP levels, which is useful for the treatment of ciliopathy as described herein. In some embodiments, the ciliopathy-related disease or condition is selected from polycystic kidney disease (PKD), autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), polycystic liver disease, and combinations thereof. In some embodiments, the ciliopathy-related disease or condition is selected from polycystic kidney disease (PKD), autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). In some embodiments, the ciliopathy-related disease or condition is polycystic kidney disease (PKD). In some embodiments, the ciliopathy-related disease or condition is autosomal dominant polycystic kidney disease (ADPKD). In some embodiments, the ciliary disorder or condition is autosomal recessive polycystic kidney disease (ARPKD).

[0136] Methods for treating diseases or conditions in mammals that would benefit from modulation of somatostatin receptor subtype 3 (SSTR3) activity are also described herein, the methods comprising administering a selective small molecule SSTR3 agonist compound to a mammal in need thereof.

[0137] In some embodiments, the disease or condition is one or a combination of the diseases or conditions described herein. 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.

[0138] compound Compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (II), and (IIa) (including pharmaceutically acceptable salts thereof) are provided as somatostatin subtype 3 receptor (SSTR3) agonists.

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

[0140] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R1 is either unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted 6-membered heterocycloalkyl, unsubstituted or substituted C5-7 bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, If R1 is substituted, R1 is substituted with 1 to 3 X atoms, each X independently selected from the group consisting of halogens, C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 fluoroalkyl groups, C1-6 fluoroalkoxy groups, C3-6 cycloalkoxy groups, CN groups, and OH groups. L is a bond or CR2R3, R2 is H or C1-6 alkyl, R3 is H, C1-6 alkyl, C1-6 alkoxy, CH2OCH3, or C1-6 fluoroalkyl, or R2 and R3 together with the carbon to which they are bonded, C 3-6 Forming a cycloalkyl group, Z is

[0141] [ka] And, R4 is H or halogen, R5 is H or halogen, and R6 is H, halogen, CN, C1-6 alkyl, or C1-6 alkoxy. R7 is H, D, CN, or

[0142] [ka] And, R8 is H, D, OH, C1-6 alkyl, C1-6 alkoxy, NH2, or -NH(CH2)2OH, R A is H, C(O)OC 1-6 alkyl, or C(O)C 1-6 alkyl, R B is H, D, or C1-6 alkyl, R C is H or D, R D is H or halogen, m is an integer selected from 0 and 1, n is an integer selected from 0, 1, and 2.

[0143] In certain embodiments, L is a bond.

[0144] In certain embodiments, L is CR2R3. In certain embodiments, L is CR2R3 and R2 is H or methyl. In certain embodiments, L is CR2R3 and R2 is H. In certain embodiments, L is CR2R3 and R2 is methyl. In certain embodiments, L is CR2R3 and R3 is H, methyl, ethyl, trifluoromethyl, or CH2OCH3. In certain embodiments, L is CR2R3 and R3 is H. In certain embodiments, L is CR2R3 and R3 is methyl. In certain embodiments, L is CR2R3 and R3 is ethyl. In certain embodiments, L is CR2R3 and R3 is trifluoromethyl. In certain embodiments, L is CR2R3 and R3 is CH2OCH3. In certain embodiments, L is CR2R3 and R2 is H and R3 is H. In certain embodiments, L is CR2R3 and R2 is H and R3 is methyl.

[0145] In certain embodiments, L is CR2R3, and R2 and R3 together with the carbon to which they are attached form a C 3-6It forms a cycloalkyl. In certain embodiments, L is CR2R3, and R2 and R3 together with the carbon to which they are attached form a cyclopropyl moiety.

[0146] In certain embodiments, L is CH2,

[0147]

Chemical formula

[0148] In certain embodiments, R1 is unsubstituted or substituted C 1-4 alkyl. In certain embodiments, R1 is unsubstituted C 1-4 alkyl. In certain embodiments, R1 is substituted C 1-4 alkyl. In certain embodiments, R1 is C substituted with 1 to 2 Xs 1-4 alkyl, and each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is C substituted with X 1-4 alkyl, and X is selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is C substituted with 2 Xs 1-4 alkyl, and each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0149] In certain embodiments, R1 is an unsubstituted or substituted methyl molecule. In certain embodiments, R1 is an unsubstituted methyl molecule. In certain embodiments, R1 is a substituted methyl molecule. In certain embodiments, R1 is a methyl molecule substituted with 1 to 2 X molecules, each X independently selected from trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is a methyl molecule substituted with X molecules, where X is independently selected from trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is a methyl molecule substituted with 2 X molecules, each X independently selected from trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0150] In certain embodiments, R1 is unsubstituted or substituted ethyl. In certain embodiments, R1 is unsubstituted ethyl. In certain embodiments, R1 is substituted ethyl. In certain embodiments, R1 is substituted ethyl with 1 to 2 X, each X independently selected from methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is ethyl substituted with X, each X independently selected from methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is ethyl substituted with 2 X, each X independently selected from methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0151] In certain embodiments, R1 is unsubstituted or substituted n-propyl. In certain embodiments, R1 is unsubstituted n-propyl. In certain embodiments, R1 is substituted n-propyl. In certain embodiments, R1 is n-propyl substituted with 1 to 2 X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is n-propyl substituted with X, where X is selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is an n-propyl substituted with two X's, where each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0152] In certain embodiments, R1 is an unsubstituted or substituted isopropyl. In certain embodiments, R1 is an unsubstituted isopropyl. In certain embodiments, R1 is a substituted isopropyl. In certain embodiments, R1 is an isopropyl substituted with 1 to 2 X's, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is an isopropyl substituted with X's, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is an isopropyl substituted with 2 X's, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0153] In certain embodiments, R1 is unsubstituted or substituted n-butyl. In certain embodiments, R1 is unsubstituted n-butyl. In certain embodiments, R1 is substituted n-butyl. In certain embodiments, R1 is n-butyl substituted with 1 to 2 X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is n-butyl substituted with X, where X is selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is n-butyl substituted with two X's, where each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0154] In certain embodiments, R1 is unsubstituted or substituted isobutyl. In certain embodiments, R1 is unsubstituted isobutyl. In certain embodiments, R1 is substituted isobutyl. In certain embodiments, R1 is isobutyl substituted with 1 to 2 X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is isobutyl substituted with X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is isobutyl substituted with 2 X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0155] In certain embodiments, R1 is unsubstituted or substituted sec-butyl. In certain embodiments, R1 is unsubstituted sec-butyl. In certain embodiments, R1 is substituted sec-butyl. In certain embodiments, R1 is substituted sec-butyl with 1 to 2 X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is substituted sec-butyl with X, each X selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In a particular embodiment, R1 is sec-butyl substituted with two X's, where each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0156] In certain embodiments, R1 is unsubstituted or substituted tert-butyl. In certain embodiments, R1 is unsubstituted tert-butyl. In certain embodiments, R1 is substituted tert-butyl. In certain embodiments, R1 is substituted tert-butyl with 1 to 2 X, each X independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is substituted tert-butyl with X, each X selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In certain embodiments, R1 is tert-butyl substituted with two X's, where each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0157] In a particular embodiment, R1 is

[0158] [ka] Selected from.

[0159] In certain embodiments, R1 is either unsubstituted or substituted C 3-6 It is a cycloalkyl. In certain embodiments, R1 is an unsubstituted C 3-6 It is a cycloalkyl. In certain embodiments, R1 is a substituted C 3-6 It is a cycloalkyl group. In certain embodiments, R1 is a C group substituted with 1-2 X groups. 3-6 It is a cycloalkyl group, where each X is independently selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl. In a particular embodiment, R1 is a C substituted with X. 3-6It is a cycloalkyl group, where X is selected from fluoromethyl, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is a C substituted with two X's. 3-6 It is a cycloalkyl group, where each X is independently selected from fluoromethyl, methyl, difluoromethyl, and trifluoromethyl.

[0160] In certain embodiments, R1 is an unsubstituted or substituted cyclopropyl. In certain embodiments, R1 is an unsubstituted cyclopropyl. In certain embodiments, R1 is a substituted cyclopropyl. In certain embodiments, R1 is a cyclopropyl substituted with 1 to 2 X's, each X independently selected from the group consisting of fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is a cyclopropyl substituted with X's, where X's are independently selected from fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is a cyclopropyl substituted with 2 X's, each X independently selected from fluoro, methyl, difluoromethyl, and trifluoromethyl.

[0161] In certain embodiments, R1 is unsubstituted or substituted cyclobutyl. In certain embodiments, R1 is unsubstituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl with 1 to 2 X, each X independently selected from the group consisting of fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is substituted cyclobutyl with X, where X is independently selected from fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is substituted cyclobutyl with 2 X, each X independently selected from fluoro, methyl, difluoromethyl, and trifluoromethyl.

[0162] In certain embodiments, R1 is unsubstituted or substituted cyclopentyl. In certain embodiments, R1 is unsubstituted cyclopentyl. In certain embodiments, R1 is substituted cyclopentyl. In certain embodiments, R1 is cyclopentyl substituted with 1 to 2 Xs, where each X is independently selected from the group consisting of fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is cyclopentyl substituted with X, where X is selected from fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is cyclopentyl substituted with 2 Xs, where each X is independently selected from fluoro, methyl, difluoromethyl, and trifluoromethyl.

[0163] In certain embodiments, R1 is unsubstituted or substituted cyclohexyl. In certain embodiments, R1 is unsubstituted cyclohexyl. In certain embodiments, R1 is substituted cyclohexyl. In certain embodiments, R1 is cyclohexyl substituted with 1 to 2 Xs, where each X is independently selected from the group consisting of fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is cyclohexyl substituted with X, where X is selected from fluoro, methyl, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is cyclohexyl substituted with 2 Xs, where each X is independently selected from fluoro, methyl, difluoromethyl, and trifluoromethyl.

[0164] In certain embodiments, R1 is

[0165] [[ID=十三]]

Chemical Structure

[0166] It should be noted that in the translation, "

化

Chemical Structure

[0167] In a particular embodiment, R1 is

[0168] [ka] Selected from.

[0169] In a particular embodiment, R1 is

[0170] [ka] Selected from.

[0171] In a particular embodiment, R1 is

[0172] [ka] Selected from.

[0173] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl or an unsubstituted or substituted pyrimidinyl.

[0174] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl. In certain embodiments, R1 is an unsubstituted pyridinyl. In certain embodiments, R1 is a pyridinyl substituted with 1 to 2 X, each X independently selected from fluoro, methyl, trifluoromethyl, methoxy, and CN. In certain embodiments, R1 is a pyridinyl substituted with X, each X independently selected from fluoro, methyl, trifluoromethyl, methoxy, and CN. In certain embodiments, R1 is a pyridinyl substituted with 2 X, each X independently selected from fluoro, methyl, trifluoromethyl, methoxy, and CN.

[0175] In certain embodiments, R1 is an unsubstituted or substituted pyrimidinyl. In certain embodiments, R1 is an unsubstituted pyrimidinyl. In certain embodiments, R1 is a pyrimidinyl substituted with X, where X is methyl.

[0176] In a particular embodiment, R1 is

[0177] [ka] Selected from.

[0178] In a particular embodiment, R1 is

[0179] [ka] Selected from.

[0180] In a particular embodiment, R1 is

[0181] [ka] Selected from.

[0182] In a particular embodiment, R1 is

[0183] [ka] Selected from.

[0184] In a particular embodiment, R1 is

[0185] [ka] Selected from.

[0186] In certain embodiments, R1 is an unsubstituted or substituted C5-7 bicycloalkyl group. In certain embodiments, R1 is an unsubstituted C5-7 bicycloalkyl group. In certain embodiments, R1 is a substituted C5-7 bicycloalkyl group. In certain embodiments, R1 is a C5-7 bicycloalkyl group substituted with fluoromethyl or trifluoromethyl. In certain embodiments, R1 is a C5-7 bicycloalkyl group substituted with fluoromethyl. In certain embodiments, R1 is a C5-7 bicycloalkyl group substituted with trifluoromethyl. In certain embodiments, one or more carbon atoms of the C5-7 bicycloalkyl group are crosslinked carbon atoms. In certain embodiments, one of the carbon atoms of the C5-7 bicycloalkyl group is a crosslinked carbon atom.

[0187] In certain embodiments, R1 is an unsubstituted or substituted C5 bicycloalkyl. In certain embodiments, R1 is an unsubstituted C5 bicycloalkyl. In certain embodiments, R1 is a substituted C5 bicycloalkyl. In certain embodiments, R1 is a C5 bicycloalkyl substituted with fluoro or trifluoromethyl. In certain embodiments, R1 is a C5 bicycloalkyl substituted with fluoro. In certain embodiments, R1 is a C5 bicycloalkyl substituted with trifluoromethyl. In certain embodiments, one or more carbon atoms of the C5 bicycloalkyl are bridged carbons. In certain embodiments, one of the carbon atoms of the C5 bicycloalkyl is a bridged carbon.

[0188] In certain embodiments, R1 is an unsubstituted or substituted C6 bicycloalkyl. In certain embodiments, R1 is an unsubstituted C6 bicycloalkyl. In certain embodiments, R1 is a substituted C6 bicycloalkyl. In certain embodiments, R1 is a C6 bicycloalkyl substituted with fluoro or trifluoromethyl. In certain embodiments, R1 is a C6 bicycloalkyl substituted with fluoro. In certain embodiments, R1 is a C6 bicycloalkyl substituted with trifluoromethyl. In certain embodiments, one or more carbon atoms of the C6 bicycloalkyl are bridged carbons. In certain embodiments, one of the carbon atoms of the C6 bicycloalkyl is a bridged carbon.

[0189] In certain embodiments, R1 is an unsubstituted or substituted C7 bicycloalkyl group. In certain embodiments, R1 is an unsubstituted C7 bicycloalkyl group. In certain embodiments, R1 is a substituted C7 bicycloalkyl group. In certain embodiments, R1 is a C7 bicycloalkyl group substituted with fluoromethyl or trifluoromethyl. In certain embodiments, R1 is a C7 bicycloalkyl group substituted with fluoromethyl. In certain embodiments, R1 is a C7 bicycloalkyl group substituted with trifluoromethyl. In certain embodiments, one or more carbon atoms of the C7 bicycloalkyl group are bridged carbon atoms. In certain embodiments, one of the carbon atoms of the C7 bicycloalkyl group is a bridged carbon atom.

[0190] In a particular embodiment, R1 is

[0191] [ka] Selected from.

[0192] In a particular embodiment, R1 is tetrahydropyran.

[0193] In certain embodiments, m is 1 and n is 1. In some embodiments, m is 0 and n is 2.

[0194] In a particular embodiment, R A It is hydrogen.

[0195] In a particular embodiment, R B is hydrogen, and R C is hydrogen, and R D It is hydrogen.

[0196] In a particular embodiment, R A is hydrogen, and R B is hydrogen, and R C is hydrogen, and R D It is hydrogen.

[0197] In a particular embodiment, Z is

[0198] [ka] That is the case.

[0199] In a particular embodiment, Z is

[0200] [ka] That is the case.

[0201] In a particular embodiment, the compound is the compound of formula (Ia),

[0202] [ka] or a pharmaceutically acceptable salt thereof, in the formula, R1 is either unsubstituted or substituted C 1-4The compounds are alkyl, unsubstituted or substituted C3-6 cycloalkyl, tetrahydropyran, unsubstituted or substituted C5-7 bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1-2 X molecules, each X independently selected from F, Cl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, OCH2CF3, CN, and OH. L is a bond or CR2R3, R2 is H or methyl, R3 is H, methyl, ethyl, trifluoromethyl, or -CH2OCH3, or R2 and R3 together with the carbon to which they are bonded to form a cyclopropyl group. Z is

[0203] [ka] And, R4 is H, F, or Cl; R5 is H or F; and R6 is H, F, Cl, CN, methyl, or methoxy. R7 is H or

[0204] [ka] And, R8 is H, NH2, or methyl.

[0205] In a particular embodiment, L is a bond.

[0206] In certain embodiments, L is CR2R3. In certain embodiments, L is CR2R3 and R2 is H or methyl. In certain embodiments, L is CR2R3 and R2 is H. In certain embodiments, L is CR2R3 and R2 is methyl. In certain embodiments, L is CR2R3 and R3 is H, methyl, ethyl, trifluoromethyl, or -CH2OCH3. In certain embodiments, L is CR2R3, R2 is H, and R3 is H. In certain embodiments, L is CR2R3, R2 is H, and R3 is methyl. In certain embodiments, L is CR2R3, and R2 and R3, together with the carbons to which they are bonded, form a cyclopropyl moiety.

[0207] In a particular embodiment, L is CH2,

[0208] [ka] Selected from.

[0209] In certain embodiments, R1 is either unsubstituted or substituted C 1-4 It is alkyl. In certain embodiments, R1 is unsubstituted C 1-4 It is alkyl. In certain embodiments, R1 is substituted C 1-4 It is alkyl. In certain embodiments, R1 is C substituted with 1-2 X. 1-4 The alkyl group is independently selected from methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In certain embodiments, R1 is a C substituted with X. 1-4 The alkyl group is selected from methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In certain embodiments, R1 is a C substituted with two X groups. 1-4The alkyl group is independently selected from methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy.

[0210] In certain embodiments, R1 is an unsubstituted or substituted methyl molecule. In certain embodiments, R1 is an unsubstituted methyl molecule. In certain embodiments, R1 is a substituted methyl molecule. In certain embodiments, R1 is a methyl-substituted trifluoromethoxy molecule.

[0211] In certain embodiments, R1 is unsubstituted or substituted ethyl. In certain embodiments, R1 is unsubstituted ethyl. In certain embodiments, R1 is substituted ethyl. In certain embodiments, R1 is substituted ethyl with 1 to 2 X, each X independently selected from methyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In certain embodiments, R1 is ethyl substituted with X, where X is independently selected from trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In certain embodiments, R1 is ethyl substituted with 2 X, each X independently selected from methyl and trifluoromethoxy.

[0212] In certain embodiments, R1 is unsubstituted or substituted n-propyl. In certain embodiments, R1 is unsubstituted n-propyl. In certain embodiments, R1 is substituted n-propyl. In certain embodiments, R1 is n-propyl substituted with 1 to 2 X, each X independently selected from methyl and trifluoromethyl. In certain embodiments, R1 is n-propyl substituted with X, where X is selected from methyl and trifluoromethyl. In certain embodiments, R1 is n-propyl substituted with 2 X, each X is methyl.

[0213] In certain embodiments, R1 is unsubstituted or substituted n-butyl. In certain embodiments, R1 is unsubstituted n-butyl. In certain embodiments, R1 is substituted n-butyl, where X is selected from methyl and ethyl.

[0214] In a particular embodiment, R1 is

[0215] [ka] Selected from.

[0216] In certain embodiments, R1 is either unsubstituted or substituted C 3-6 It is a cycloalkyl. In certain embodiments, R1 is an unsubstituted C 3-6 It is a cycloalkyl group. In certain embodiments, R1 is an unsubstituted or substituted C 3-6 It is a cycloalkyl group. In certain embodiments, R1 is a C group substituted with 1-2 X groups. 3-6 It is a cycloalkyl group, where each X is independently selected from the group consisting of fluoro, methyl, and trifluoromethyl. In a particular embodiment, R1 is a C substituted with X. 3-6 It is a cycloalkyl group, where X is selected from the group consisting of fluoromethyl and trifluoromethyl. In a particular embodiment, R1 is a C substituted with two X's. 3-6 It is a cycloalkyl group, where each X is independently selected from the group consisting of fluoro, methyl, and trifluoromethyl.

[0217] In certain embodiments, R1 is an unsubstituted or substituted cyclopropyl. In certain embodiments, R1 is an unsubstituted cyclopropyl. In certain embodiments, R1 is a substituted cyclopropyl. In certain embodiments, R1 is a cyclopropyl substituted with 1 to 2 X's, each X independently selected from the group consisting of fluoro, methyl, and trifluoromethyl. In certain embodiments, R1 is a cyclopropyl substituted with X's, where X's are selected from methyl and trifluoromethyl. In certain embodiments, R1 is a cyclopropyl substituted with 2 X's, each X's fluoro.

[0218] In certain embodiments, R1 is unsubstituted or substituted cyclobutyl. In certain embodiments, R1 is unsubstituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl with 1 to 2 X, each X independently selected from the group consisting of fluoro, methyl, and trifluoromethyl. In certain embodiments, R1 is substituted cyclobutyl with X, where X is selected from fluoro and trifluoromethyl. In certain embodiments, R1 is substituted cyclobutyl with 2 X, each X independently selected from fluoro and methyl.

[0219] In certain embodiments, R1 is an unsubstituted or substituted cyclopentyl. In certain embodiments, R1 is an unsubstituted cyclopentyl. In certain embodiments, R1 is a substituted cyclopentyl. In certain embodiments, R1 is a cyclopentyl substituted with 1 to 2 X's, each X independently selected from the group consisting of fluoro and trifluoromethyl. In certain embodiments, R1 is a cyclopentyl substituted with X's, where X's are selected from fluoro and trifluoromethyl. In certain embodiments, R1 is a cyclopentyl substituted with 2 X's, each X's fluoro.

[0220] In certain embodiments, R1 is an unsubstituted or substituted cyclohexyl. In certain embodiments, R1 is an unsubstituted cyclohexyl. In certain embodiments, R1 is a substituted cyclohexyl. In certain embodiments, R1 is a cyclohexyl substituted with 1 to 2 X's, where X is a fluoro. In certain embodiments, R1 is a cyclohexyl substituted with X's, where X is a fluoro. In certain embodiments, R1 is a cyclohexyl substituted with 2 X's, where X is a fluoro.

[0221] In a particular embodiment, R1 is

[0222] [ka] Selected from.

[0223] In certain embodiments, R1 is an unsubstituted or substituted phenyl. In certain embodiments, R1 is an unsubstituted phenyl. In certain embodiments, R1 is a substituted phenyl. In certain embodiments, R1 is a phenyl substituted with 1 to 2 X's, each X independently selected from fluoro, chloro, methyl, methoxy, and CN. In certain embodiments, R1 is a phenyl substituted with X's, where X's are independently selected from fluoro, chloro, methyl, methoxy, and CN. In certain embodiments, R1 is a phenyl substituted with 2 X's, each X independently selected from fluoro, chloro, methyl, methoxy, and CN.

[0224] In a particular embodiment, R1 is

[0225] [ka] Selected from.

[0226] In a particular embodiment, R1 is

[0227] [ka] Selected from.

[0228] In a particular embodiment, R1 is

[0229] [ka] Selected from.

[0230] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl. In certain embodiments, R1 is an unsubstituted pyridinyl. In certain embodiments, R1 is a pyridinyl substituted with 1 to 2 X, each X independently selected from methyl, methoxy, and CN. In certain embodiments, R1 is a pyridinyl substituted with X, where X is selected from methyl, methoxy, and CN. In certain embodiments, R1 is a pyridinyl substituted with 2 X, each X is methyl.

[0231] In certain embodiments, R1 is an unsubstituted or substituted pyrimidinyl. In certain embodiments, R1 is an unsubstituted pyrimidinyl. In certain embodiments, R1 is a pyrimidinyl substituted with X, where X is methyl.

[0232] In a particular embodiment, R1 is

[0233] [ka] Selected from.

[0234] In a particular embodiment, R1 is

[0235] [ka] Selected from.

[0236] In a particular embodiment, R1 is

[0237] [ka] Selected from.

[0238] In a particular embodiment, R1 is

[0239] [ka] Selected from.

[0240] In certain embodiments, R1 is an unsubstituted or substituted C5-7 bicycloalkyl group. In certain embodiments, R1 is an unsubstituted C5-7 bicycloalkyl group. In certain embodiments, R1 is a substituted C5-7 bicycloalkyl group. In certain embodiments, R1 is a fluorosubstituted C5-7 bicycloalkyl group. In certain embodiments, one or more carbon atoms of the C5-7 bicycloalkyl group are bridged carbon atoms. In certain embodiments, one of the carbon atoms of the C5-7 bicycloalkyl group is a bridged carbon atom.

[0241] In certain embodiments, R1 is an unsubstituted or substituted C5 bicycloalkyl. In certain embodiments, R1 is an unsubstituted C5 bicycloalkyl. In certain embodiments, R1 is a substituted C5 bicycloalkyl. In certain embodiments, R1 is a C5 bicycloalkyl substituted with X, where X is fluoro. In certain embodiments, one or more carbon atoms of the C5 bicycloalkyl are bridging carbons. In certain embodiments, one of the carbon atoms of the C5 bicycloalkyl is a bridging carbon.

[0242] In certain embodiments, R1 is an unsubstituted or substituted C6 bicycloalkyl group. In certain embodiments, R1 is an unsubstituted C6 bicycloalkyl group. In certain embodiments, one or more carbon atoms of the C6 bicycloalkyl group are bridging carbon atoms. In certain embodiments, one of the carbon atoms of the C6 bicycloalkyl group is bridging carbon atoms.

[0243] In certain embodiments, R1 is an unsubstituted or substituted C7 bicycloalkyl. In certain embodiments, R1 is an unsubstituted C7 bicycloalkyl. In certain embodiments, R1 is a substituted C7 bicycloalkyl. In certain embodiments, R1 is a C7 bicycloalkyl substituted with X, where X is fluoro. In certain embodiments, one or more carbon atoms of the C7 bicycloalkyl are bridging carbons. In certain embodiments, one of the carbon atoms of the C7 bicycloalkyl is a bridging carbon.

[0244] In a particular embodiment, R1 is

[0245] [ka] Selected from.

[0246] In a particular embodiment, R1 is tetrahydropyran.

[0247] In a particular embodiment, R1 is

[0248] [ka] That is the case.

[0249] In a particular embodiment, Z is

[0250] [ka] That is the case.

[0251] In a particular embodiment, Z is

[0252] [ka] That is the case.

[0253] In a particular embodiment, the compound of formula (Ia) is

[0254] [ka]

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka] Selected from.

[0260] In a particular embodiment, the compound of formula (Ia) is one of the compounds shown in Table 1.

[0261] In a particular embodiment, the compound of formula (Ia) is compound 1.

[0262] In a particular embodiment, the compound of formula (Ia) is compound 2.

[0263] In a particular embodiment, the compound of formula (Ia) is compound 3.

[0264] In a particular embodiment, the compound of formula (Ia) is compound 4.

[0265] In a particular embodiment, the compound of formula (Ia) is compound 5.

[0266] In a particular embodiment, the compound of formula (Ia) is compound 6.

[0267] In a particular embodiment, the compound of formula (Ia) is compound 7.

[0268] In a particular embodiment, the compound of formula (Ia) is compound 8.

[0269] In a particular embodiment, the compound of formula (Ia) is compound 9.

[0270] In a particular embodiment, the compound of formula (Ia) is compound 10.

[0271] In a particular embodiment, the compound of formula (Ia) is compound 11.

[0272] In a particular embodiment, the compound of formula (Ia) is compound 12.

[0273] In a particular embodiment, the compound of formula (Ia) is compound 13.

[0274] In a particular embodiment, the compound of formula (Ia) is compound 14.

[0275] In a particular embodiment, the compound of formula (Ia) is compound 15.

[0276] In a particular embodiment, the compound of formula (Ia) is compound 16.

[0277] In a particular embodiment, the compound of formula (Ia) is compound 17.

[0278] In a particular embodiment, the compound of formula (Ia) is compound 18.

[0279] In a particular embodiment, the compound of formula (Ia) is compound 19.

[0280] In a particular embodiment, the compound of formula (Ia) is compound 20.

[0281] In a particular embodiment, the compound of formula (Ia) is compound 21.

[0282] In a particular embodiment, the compound of formula (Ia) is compound 22.

[0283] In a particular embodiment, the compound of formula (Ia) is compound 23.

[0284] In a particular embodiment, the compound of formula (Ia) is compound 24.

[0285] In a particular embodiment, the compound of formula (Ia) is compound 25.

[0286] In a particular embodiment, the compound of formula (Ia) is compound 26.

[0287] In a particular embodiment, the compound of formula (Ia) is compound 27.

[0288] In a particular embodiment, the compound of formula (Ia) is compound 28.

[0289] In a particular embodiment, the compound of formula (Ia) is compound 29.

[0290] In a particular embodiment, the compound of formula (Ia) is compound 30.

[0291] In a particular embodiment, the compound of formula (Ia) is compound 31.

[0292] In a particular embodiment, the compound of formula (Ia) is compound 32.

[0293] In a particular embodiment, the compound of formula (Ia) is compound 33.

[0294] In a particular embodiment, the compound of formula (Ia) is compound 34.

[0295] In a particular embodiment, the compound of formula (Ia) is compound 35.

[0296] In a particular embodiment, the compound of formula (Ia) is compound 36.

[0297] In a particular embodiment, the compound of formula (Ia) is compound 37.

[0298] In a particular embodiment, the compound of formula (Ia) is compound 38.

[0299] In a particular embodiment, the compound of formula (Ia) is compound 39.

[0300] In a particular embodiment, the compound of formula (Ia) is compound 40.

[0301] In a particular embodiment, the compound of formula (Ia) is compound 41.

[0302] In a particular embodiment, the compound of formula (Ia) is compound 42.

[0303] In a particular embodiment, the compound of formula (Ia) is compound 43.

[0304] In a particular embodiment, the compound of formula (Ia) is compound 44.

[0305] In a particular embodiment, the compound of formula (Ia) is compound 45.

[0306] In a particular embodiment, the compound of formula (Ia) is compound 46.

[0307] In a particular embodiment, the compound of formula (Ia) is compound 47.

[0308] In a particular embodiment, the compound of formula (Ia) is compound 48.

[0309] In a particular embodiment, the compound of formula (Ia) is compound 49.

[0310] In a particular embodiment, the compound of formula (Ia) is compound 50.

[0311] In a particular embodiment, the compound of formula (Ia) is compound 51.

[0312] In a particular embodiment, the compound of formula (Ia) is compound 52.

[0313] In a particular embodiment, the compound of formula (Ia) is compound 53.

[0314] In a particular embodiment, the compound of formula (Ia) is compound 54.

[0315] In a particular embodiment, the compound of formula (Ia) is compound 55.

[0316] In a particular embodiment, the compound of formula (Ia) is compound 56.

[0317] In a particular embodiment, the compound of formula (Ia) is compound 57.

[0318] In a particular embodiment, the compound of formula (Ia) is compound 58.

[0319] In a particular embodiment, the compound of formula (Ia) is compound 59.

[0320] In a particular embodiment, the compound of formula (Ia) is compound 60.

[0321] In a particular embodiment, the compound of formula (Ia) is compound 61.

[0322] In a particular embodiment, the compound of formula (Ia) is compound 62.

[0323] In a particular embodiment, the compound of formula (Ia) is compound 63.

[0324] In a particular embodiment, the compound of formula (Ia) is compound 64.

[0325] In a particular embodiment, the compound of formula (Ia) is compound 65.

[0326] In a particular embodiment, the compound of formula (Ia) is compound 66.

[0327] In a particular embodiment, the compound of formula (Ia) is compound 67.

[0328] In a particular embodiment, the compound of formula (Ia) is compound 68.

[0329] In a particular embodiment, the compound of formula (Ia) is compound 69.

[0330] In a particular embodiment, the compound of formula (Ia) is compound 70.

[0331] In a particular embodiment, the compound of formula (Ia) is compound 71.

[0332] In a particular embodiment, the compound of formula (Ia) is compound 72.

[0333] In a particular embodiment, the compound of formula (Ia) is compound 73.

[0334] In a particular embodiment, the compound of formula (Ia) is compound 74.

[0335] In a particular embodiment, the compound of formula (Ia) is compound 75.

[0336] In a particular embodiment, the compound of formula (Ia) is compound 76.

[0337] In a particular embodiment, the compound of formula (Ia) is compound 77.

[0338] In a particular embodiment, the compound of formula (Ia) is compound 78.

[0339] In a particular embodiment, the compound of formula (Ia) is compound 79.

[0340] In a particular embodiment, the compound of formula (Ia) is compound 80.

[0341] In a particular embodiment, the compound of formula (Ia) is compound 81.

[0342] In a particular embodiment, the compound of formula (Ia) is compound 82.

[0343] In a particular embodiment, the compound of formula (Ia) is compound 83.

[0344] In a particular embodiment, the compound of formula (Ia) is compound 84.

[0345] In a particular embodiment, the compound of formula (Ia) is compound 85.

[0346] In a particular embodiment, the compound of formula (Ia) is compound 86.

[0347] In a particular embodiment, the compound of formula (Ia) is compound 87.

[0348] In a particular embodiment, the compound of formula (Ia) is compound 88.

[0349] In a particular embodiment, the compound of formula (Ia) is compound 89.

[0350] In a particular embodiment, the compound of formula (Ia) is compound 90.

[0351] In a particular embodiment, the compound of formula (Ia) is compound 100.

[0352] In a particular embodiment, the compound of formula (Ia) is compound 101.

[0353] In a particular embodiment, the compound of formula (Ia) is compound 102.

[0354] In a particular embodiment, the compound of formula (Ia) is compound 103.

[0355] In a particular embodiment, the compound of formula (Ia) is compound 104.

[0356] In a particular embodiment, the compound of formula (Ia) is compound 105.

[0357] In a particular embodiment, the compound of formula (Ia) is compound 106.

[0358] In a particular embodiment, the compound of formula (Ia) is compound 107.

[0359] In certain embodiments, R4, R5, and R6 are halogens.

[0360] In certain embodiments, R4 and R6 are halogens. In certain embodiments, R4 and R6 are halogens, and R5 is hydrogen.

[0361] In certain embodiments, R4 and R6 are fluorocarbons. In certain embodiments, R4 and R6 are fluorocarbons, and R5 is hydrogen.

[0362] In certain embodiments, the compound is a compound of formula (Ib) or formula (Ic), or a pharmaceutically acceptable salt thereof.

[0363] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-3 Alkyl, unsubstituted, or substituted C 3-4 A cycloalkyl, unsubstituted or substituted C5 bicycloalkyl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1 to 2 X molecules, each X independently selected from F, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, CN, and OH. L is a bond or CR2R3, R2 is H, and R3 is H, methyl, or -CH2OCH3. R5 is either H or F. R7 is H, D, or CN. R8 is H, D, OH, methoxy, or -NH(CH2)2OH.

[0364] In certain embodiments, the compound is the compound of formula (Ib), or a pharmaceutically acceptable salt thereof.

[0365] [ka]

[0366] In a particular embodiment, L is a bond.

[0367] In certain embodiments, L is CR2R3. In certain embodiments, L is CR2R3 and R3 is H. In certain embodiments, L is CR2R3 and R3 is methyl. In certain embodiments, L is CR2R3 and R3 is CH2OCH3.

[0368] In a particular embodiment, L is CH2,

[0369] [ka] Selected from.

[0370] In certain embodiments, R1 is either unsubstituted or substituted C 1-3 It is alkyl. In certain embodiments, R1 is unsubstituted C 1-3 It is alkyl. In certain embodiments, R1 is substituted C 1-3 It is alkyl. In certain embodiments, R1 is C substituted with 1-2 X. 1-3 It is an alkyl group, and each X is independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH. In a particular embodiment, R1 is a C substituted with X. 1-3 It is alkyl, and X is selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH. In certain embodiments, R1 is C substituted with two X's. 1-3 It is an alkyl group, and each X is independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH.

[0371] In certain embodiments, R1 is unsubstituted or substituted ethyl. In certain embodiments, R1 is unsubstituted ethyl. In certain embodiments, R1 is substituted ethyl. In certain embodiments, R1 is substituted ethyl with 1 to 2 X molecules, each X independently selected from methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, and OH. In certain embodiments, R1 is substituted ethyl with X, where X is independently selected from difluoromethoxy and trifluoromethoxy. In certain embodiments, R1 is substituted ethyl with 2 X molecules, each X independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH.

[0372] In certain embodiments, R1 is unsubstituted or substituted n-propyl. In certain embodiments, R1 is unsubstituted n-propyl. In certain embodiments, R1 is substituted n-propyl. In certain embodiments, R1 is n-propyl substituted with 1 to 2 Xs, where each X is independently selected from methyl and trifluoromethyl. In certain embodiments, R1 is n-propyl substituted with X, where X is trifluoromethyl. In certain embodiments, R1 is n-propyl substituted with 2 Xs, where each X is independently selected from methyl and trifluoromethyl.

[0373] In certain embodiments, R1 is

[0374]

Chemical formula

[0375] In certain embodiments, R1 is unsubstituted or substituted C 3-4 cycloalkyl. In certain embodiments, R1 is unsubstituted C 3-4 cycloalkyl. In certain embodiments, R1 is substituted C 3-6 cycloalkyl. In certain embodiments, R1 is C 3-4 cycloalkyl substituted with 1 to 2 Xs, where each X is independently selected from the group consisting of fluoro, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is C 3-4 cycloalkyl substituted with X, where X is selected from fluoro, difluoromethyl, and trifluoromethyl. In certain embodiments, R1 is C 3-4 cycloalkyl substituted with 2 Xs, where each X is independently selected from fluoro, difluoromethyl, and trifluoromethyl.

[0376] In certain embodiments, R1 is an unsubstituted or substituted cyclopropyl. In certain embodiments, R1 is an unsubstituted cyclopropyl. In certain embodiments, R1 is a substituted cyclopropyl. In certain embodiments, R1 is a cyclopropyl substituted with X, where X is selected from difluoromethyl or trifluoromethyl.

[0377] In certain embodiments, R1 is unsubstituted or substituted cyclobutyl. In certain embodiments, R1 is unsubstituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl with 1 to 2 X, each X independently selected from the group consisting of fluoro and trifluoromethyl. In certain embodiments, R1 is substituted cyclobutyl with X, where X is trifluoromethyl. In certain embodiments, R1 is substituted cyclobutyl with 2 X, where X is fluoro.

[0378] In a particular embodiment, R1 is

[0379] [ka] Selected from.

[0380] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl. In certain embodiments, R1 is an unsubstituted pyridinyl. In certain embodiments, R1 is a pyridinyl substituted with 1 to 2 X, each X independently selected from fluoro, methyl, trifluoromethyl, methoxy, and CN. In certain embodiments, R1 is a pyridinyl substituted with X, where X is independently selected from trifluoromethyl, methoxy, and CN. In certain embodiments, R1 is a pyridinyl substituted with 2 X, each X independently selected from fluoro, methyl, and CN.

[0381] In a particular embodiment, R1 is

[0382] [ka] Selected from.

[0383] In a particular embodiment, R1 is

[0384] [ka] Selected from.

[0385] In certain embodiments, R1 is an unsubstituted or substituted C5 bicycloalkyl. In certain embodiments, R1 is an unsubstituted C5 bicycloalkyl. In certain embodiments, R1 is a substituted C5 bicycloalkyl. In certain embodiments, R1 is a C5 bicycloalkyl substituted with X, where X is trifluoromethyl. In certain embodiments, one or more carbon atoms of the C5 bicycloalkyl are bridging carbons. In certain embodiments, one of the carbon atoms of the C5 bicycloalkyl is a bridging carbon.

[0386] In a particular embodiment, R1 is

[0387] [ka] Selected from.

[0388] In certain embodiments, the compound of formula (Ib) or formula (Ic) is one of the compounds shown in Table 2.

[0389] In a particular embodiment, the compound of formula (Ib) is

[0390] [ka]

[0391] [ka] Selected from.

[0392] In a particular embodiment, the compound of formula (Ic) is

[0393] [ka] Selected from.

[0394] In a particular embodiment, the compound of formula (Ib) is compound 108.

[0395] In a particular embodiment, the compound of formula (Ic) is compound 109.

[0396] In a particular embodiment, the compound of formula (Ic) is compound 110.

[0397] In a particular embodiment, the compound of formula (Ib) is compound 111.

[0398] In a particular embodiment, the compound of formula (Ib) is compound 112.

[0399] In a particular embodiment, the compound of formula (Ib) is compound 113.

[0400] In a particular embodiment, the compound of formula (Ib) is compound 114.

[0401] In a particular embodiment, the compound of formula (Ib) is compound 115.

[0402] In a particular embodiment, the compound of formula (Ib) is compound 116.

[0403] In a particular embodiment, the compound of formula (Ib) is compound 117.

[0404] In a particular embodiment, the compound of formula (Ib) is compound 118.

[0405] In a particular embodiment, the compound of formula (Ib) is compound 119.

[0406] In a particular embodiment, the compound of formula (Ib) is compound 120.

[0407] In a particular embodiment, the compound of formula (Ib) is compound 121.

[0408] In a particular embodiment, the compound of formula (Ib) is compound 122.

[0409] In a particular embodiment, the compound of formula (Ib) is compound 123.

[0410] In a particular embodiment, the compound of formula (Ib) is compound 124.

[0411] In a particular embodiment, the compound of formula (Ib) is compound 125.

[0412] In a particular embodiment, the compound of formula (Ib) is compound 126.

[0413] In a particular embodiment, the compound of formula (Ib) is compound 127.

[0414] In a particular embodiment, the compound of formula (Ib) is compound 128.

[0415] In a particular embodiment, the compound of formula (Ib) is compound 129.

[0416] In a particular embodiment, the compound of formula (Ib) is compound 130.

[0417] In a particular embodiment, the compound of formula (Ib) is compound 131.

[0418] In a particular embodiment, the compound of formula (Ib) is compound 132.

[0419] In a particular embodiment, the compound of formula (Ib) is compound 133.

[0420] In a particular embodiment, the compound of formula (Ib) is compound 134.

[0421] In a particular embodiment, the compound of formula (Ib) is compound 135.

[0422] In a particular embodiment, the compound of formula (Ib) is compound 136.

[0423] In a particular embodiment, the compound of formula (Ib) is compound 137.

[0424] In a particular embodiment, the compound of formula (Ib) is compound 138.

[0425] In a particular embodiment, the compound of formula (Ib) is compound 139.

[0426] In a particular embodiment, the compound of formula (Ib) is compound 140.

[0427] In a particular embodiment, the compound of formula (Ib) is compound 141.

[0428] In a particular embodiment, the compound of formula (Ib) is compound 142.

[0429] In a particular embodiment, the compound of formula (Ib) is compound 143.

[0430] In a particular embodiment, the compound of formula (Ib) is compound 144.

[0431] In a particular embodiment, the compound of formula (Ib) is compound 145.

[0432] In a particular embodiment, the compound of formula (Ib) is compound 146.

[0433] In a particular embodiment, the compound of formula (Ib) is compound 147.

[0434] In a particular embodiment, the compound of formula (Ib) is compound 148.

[0435] In a particular embodiment, the compound of formula (Ib) is compound 149.

[0436] In a particular embodiment, the compound of formula (Ib) is compound 150.

[0437] In a particular embodiment, the compound of formula (Ib) is compound 151.

[0438] In a particular embodiment, the compound of formula (Ib) is compound 152.

[0439] In a particular embodiment, R5 is hydrogen.

[0440] In a particular embodiment, R7 is hydrogen and R8 is hydrogen.

[0441] In a particular embodiment, R5 is hydrogen, R7 is hydrogen, and R8 is hydrogen.

[0442] In certain embodiments, the compound is a compound of formula (Id), or a pharmaceutically acceptable salt thereof.

[0443] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-4 Alkyl, unsubstituted, or substituted C 3-5 A cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1 to 3 X molecules, each X independently selected from F, Cl, methyl, ethyl, trifluoromethoxy, and CN. L is a bond or CR2R3, where R2 is H, and R3 is H or methyl. R4 is H, F, or Cl. R5 is H or F. R6 is H, F, or Cl. R A is H, C(O)OEt, or C(O)Me. R B is H, D, or methyl. R C is H or D. R D is H or F. m is an integer selected from 0 or 1. n is an integer selected from 0, 1, and 2.

[0444] In certain embodiments, L is a bond.

[0445] <\ In certain embodiments, L is CR2R3. In certain embodiments, L is CR2R3 and R3 is H. In certain embodiments, L is CR2R3 and R3 is methyl.

[0446] In certain embodiments, L is CH2 and

[0447]

Chemical formula

[0448] In certain embodiments, R is unsubstituted or substituted C 1-4 alkyl. In certain embodiments, R is unsubstituted C 1-4 alkyl. In certain embodiments, R is substituted C 1-4 alkyl. In certain embodiments, R is C 1-4 alkyl substituted with X, where X is methyl or trifluoromethyloxy.

[0449] In certain embodiments, R1 is unsubstituted or substituted ethyl. In certain embodiments, R1 is unsubstituted ethyl. In certain embodiments, R1 is substituted ethyl, where X is trifluoromethyloxy.

[0450] In certain embodiments, R1 is unsubstituted or substituted n-butyl. In certain embodiments, R1 is unsubstituted n-butyl. In certain embodiments, R1 is substituted n-butyl, where X is methyl.

[0451] In a particular embodiment, R1 is

[0452] [ka] Selected from.

[0453] In certain embodiments, R1 is either unsubstituted or substituted C 3-5 It is a cycloalkyl. In certain embodiments, R1 is an unsubstituted C 3-5 It is a cycloalkyl. In certain embodiments, R1 is a substituted C 3-5 It is a cycloalkyl group. In certain embodiments, R1 is a C group substituted with 1-2 X groups. 3-5 It is a cycloalkyl group, where each X is independently selected from the group consisting of fluoromethyl and trifluoromethyl groups. In a particular embodiment, R1 is a C substituted with X. 3-5 It is a cycloalkyl group, where X is selected from fluoro and trifluoromethyl groups. In certain embodiments, R1 is a C group substituted with two X groups. 3-5 It is a cycloalkyl compound, where each X is independently selected from fluoromethyl and trifluoromethyl compounds.

[0454] In certain embodiments, R1 is an unsubstituted or substituted cyclopropyl. In certain embodiments, R1 is an unsubstituted cyclopropyl. In certain embodiments, R1 is a substituted cyclopropyl. In certain embodiments, R1 is a cyclopropyl substituted with X, where X is trifluoromethyl.

[0455] In certain embodiments, R1 is unsubstituted or substituted cyclobutyl. In certain embodiments, R1 is unsubstituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl. In certain embodiments, R1 is substituted with two X's, where X is fluoro.

[0456] In certain embodiments, R1 is an unsubstituted or substituted cyclopentyl. In certain embodiments, R1 is an unsubstituted cyclopentyl. In certain embodiments, R1 is a substituted cyclopentyl. In certain embodiments, R1 is a cyclopentyl substituted with two X's, where X is a fluoropolymer.

[0457] In a particular embodiment, R1 is

[0458] [ka] Selected from.

[0459] In certain embodiments, R1 is an unsubstituted or substituted phenyl. In certain embodiments, R1 is an unsubstituted phenyl. In certain embodiments, R1 is a substituted phenyl. In certain embodiments, R1 is a phenyl substituted with 1 to 3 X's, each X independently selected from fluoro, chloro, and CN. In certain embodiments, R1 is a phenyl substituted with X's, where X's are independently selected from fluoro, chloro, and CN. In certain embodiments, R1 is a phenyl substituted with 2 X's, each X independently selected from fluoro and chloro. In certain embodiments, R1 is a phenyl substituted with 3 X's, each X's fluoro.

[0460] In a particular embodiment, R1 is

[0461] [ka] Selected from.

[0462] In a particular embodiment, R1 is

[0463] [ka] Selected from.

[0464] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl. In certain embodiments, R1 is an unsubstituted pyridinyl. In certain embodiments, R1 is a pyridinyl substituted with 1 to 2 X atoms, each X independently selected from methyl and CN. In certain embodiments, R1 is a pyridinyl substituted with X atoms, where X is selected from CN. In certain embodiments, R1 is a pyridinyl substituted with 2 X atoms, each X independently selected from methyl and CN.

[0465] In a particular embodiment, R1 is

[0466] [ka] Selected from.

[0467] In certain embodiments, the compound of formula (Id) is one of the compounds shown in Table 3.

[0468] In a particular embodiment, the compound of formula (Id) is

[0469] [ka]

[0470] [ka] Selected from.

[0471] In a particular embodiment, the compound of formula (Id) is compound 153.

[0472] In a particular embodiment, the compound of formula (Id) is compound 154.

[0473] In a particular embodiment, the compound of formula (Id) is compound 155.

[0474] In a particular embodiment, the compound of formula (Id) is compound 156.

[0475] In a particular embodiment, the compound of formula (Id) is compound 157.

[0476] In a particular embodiment, the compound of formula (Id) is compound 158.

[0477] In a particular embodiment, the compound of formula (Id) is compound 159.

[0478] In a particular embodiment, the compound of formula (Id) is compound 160.

[0479] In a particular embodiment, the compound of formula (Id) is compound 161.

[0480] In a particular embodiment, the compound of formula (Id) is compound 162.

[0481] In a particular embodiment, the compound of formula (Id) is compound 163.

[0482] In a particular embodiment, the compound of formula (Id) is compound 164.

[0483] In a particular embodiment, the compound of formula (Id) is compound 165.

[0484] In a particular embodiment, the compound of formula (Id) is compound 166.

[0485] In a particular embodiment, the compound of formula (Id) is compound 167.

[0486] In a particular embodiment, the compound of formula (Id) is compound 168.

[0487] In a particular embodiment, the compound of formula (Id) is compound 169.

[0488] In a particular embodiment, the compound of formula (Id) is compound 170.

[0489] In a particular embodiment, the compound of formula (Id) is compound 171.

[0490] In a particular embodiment, the compound of formula (Id) is compound 172.

[0491] In a particular embodiment, the compound of formula (Id) is compound 173.

[0492] In a particular embodiment, the compound of formula (Id) is compound 174.

[0493] In a particular embodiment, the compound of formula (Id) is compound 175.

[0494] In a particular embodiment, the compound of formula (Id) is compound 176.

[0495] In a particular embodiment, the compound of formula (Id) is compound 177.

[0496] In a particular embodiment, the compound of formula (Id) is compound 178.

[0497] In a particular embodiment, the compound of formula (Id) is compound 179.

[0498] In a particular embodiment, the compound of formula (Id) is compound 180.

[0499] In a particular embodiment, the compound of formula (Id) is compound 181.

[0500] In a particular embodiment, the compound of formula (Id) is compound 182.

[0501] In a particular embodiment, the compound of formula (Id) is compound 183.

[0502] In a particular embodiment, the compound of formula (Id) is compound 184.

[0503] In a particular embodiment, the compound of formula (Id) is compound 185.

[0504] In a particular embodiment, the compound of formula (Id) is compound 186.

[0505] In a particular embodiment, the compound of formula (Id) is compound 187.

[0506] In a particular embodiment, the compound of formula (Id) is compound 188.

[0507] In a particular embodiment, the compound of formula (Id) is compound 189.

[0508] In a particular embodiment, the compound of formula (Id) is compound 190.

[0509] In a particular embodiment, the compound of formula (Id) is compound 191.

[0510] In certain embodiments, the compound is the compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0511] [ka] During the ceremony, R1 is either unsubstituted or substituted C 1-6 Alkyl, unsubstituted, or substituted C 3-6 A cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, where if R1 is substituted, R1 is substituted with 1 to 2 X molecules, each X independently selected from the group consisting of halogens, C1-6 alkyl, C1-6 alkoxy, C1-6 fluoroalkyl, C1-6 fluoroalkoxy, and CN. L is a bond or CR2R3, R2 is H, and R3 is H or methyl.

[0512] In certain embodiments, the compound is the compound of formula (IIa) or a pharmaceutically acceptable salt thereof.

[0513] [ka]

[0514] In a particular embodiment, L is a bond.

[0515] In certain embodiments, L is CR2R3. In certain embodiments, L is CR2R3 and R3 is H. In certain embodiments, L is CR2R3 and R3 is methyl.

[0516] In a particular embodiment, L is CH2 or

[0517] [ka] Selected from.

[0518] In certain embodiments, R1 is unsubstituted or substituted ethyl. In certain embodiments, R1 is unsubstituted ethyl. In certain embodiments, R1 is substituted ethyl with 1 to 2 X, each X independently selected from methoxy and trifluoromethoxy. In certain embodiments, R1 is ethyl substituted with X, where X is trifluoromethoxy. In certain embodiments, R1 is ethyl substituted with 2 X, each X independently selected from methoxy and trifluoromethoxy.

[0519] In a particular embodiment, R1 is

[0520] [ka] Selected from.

[0521] In certain embodiments, R1 is either unsubstituted or substituted C 4-5 It is a cycloalkyl. In certain embodiments, R1 is an unsubstituted C 4-5 It is a cycloalkyl. In certain embodiments, R1 is a substituted C 4-5 It is a cycloalkyl group. In certain embodiments, R1 is a fluorosubstituted C 4-5 It is a cycloalkyl group.

[0522] In certain embodiments, R1 is unsubstituted or substituted cyclobutyl. In certain embodiments, R1 is unsubstituted cyclobutyl. In certain embodiments, R1 is substituted cyclobutyl. In certain embodiments, R1 is substituted with two X's, where X is fluoro.

[0523] In certain embodiments, R1 is an unsubstituted or substituted cyclopentyl. In certain embodiments, R1 is an unsubstituted cyclopentyl. In certain embodiments, R1 is a substituted cyclopentyl. In certain embodiments, R1 is a cyclopentyl substituted with two X's, where X is a fluoropolymer.

[0524] In a particular embodiment, R1 is

[0525] [ka] Selected from.

[0526] In certain embodiments, R1 is an unsubstituted or substituted phenyl. In certain embodiments, R1 is an unsubstituted phenyl. In certain embodiments, R1 is a substituted phenyl. In certain embodiments, R1 is a phenyl substituted with X, where X is CN.

[0527] In a particular embodiment, R1 is

[0528] [ka] That is the case.

[0529] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl.

[0530] In certain embodiments, R1 is an unsubstituted or substituted pyridinyl. In certain embodiments, R1 is an unsubstituted pyridinyl. In certain embodiments, R1 is a pyridinyl substituted with two X's, where X is methyl.

[0531] In a particular embodiment, R1 is

[0532] [ka] That is the case.

[0533] In certain embodiments, the compound of formula (II) or formula (IIa) is one of the compounds shown in Table 4.

[0534] In a particular embodiment, the compound of formula (II) is

[0535] [ka] Selected from.

[0536] In a particular embodiment, the compound of formula (IIa) is

[0537] [ka] Selected from.

[0538] In a particular embodiment, the compound of formula (II) is compound 192.

[0539] In a particular embodiment, the compound of formula (II) is compound 193.

[0540] In a particular embodiment, the compound of formula (II) is compound 194.

[0541] In a particular embodiment, the compound of formula (II) is compound 195.

[0542] In a particular embodiment, the compound of formula (IIa) is compound 196.

[0543] In a particular embodiment, the compound of formula (IIa) is compound 197.

[0544] In a particular embodiment, the compound of formula (IIa) is compound 198.

[0545] In a particular embodiment, the compound of formula (IIa) is compound 199.

[0546] In a particular embodiment, the compound of formula (IIa) is compound 200.

[0547] In a particular embodiment, the compound of formula (IIa) is compound 201.

[0548] The exemplary compounds described herein include the compounds listed in the following table.

[0549] [Table 1-1]

[0550] [Table 1-2]

[0551] [Table 1-3]

[0552] [Table 1-4]

[0553] [Table 1-5]

[0554] [Table 1-6]

[0555] [Table 1-7]

[0556] [Table 1-8]

[0557] [Table 1-9]

[0558] [Table 1-10]

[0559] [Table 1-11]

[0560] [Table 1-12]

[0561] The names of the compounds in Table 1 are as follows: 1:N-2-ethylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 2: N-isobutyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 3:N-Cyclopentylmethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 4:N-butyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 5:N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 6:N-neopentyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 7:N-(1-methylcyclopropyl)methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 8:N-3,3-dimethylcyclobutyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 9: No-Tolyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 10:N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 11:N-3,3-difluorocyclobutyl-5-(3-chloro-5-fluorophenyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)nicotinamide, 12:N-3,3-difluorocyclobutyl-5-(3-cyano-5-fluorophenyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)nicotinamide, 13:N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3-fluoro-5-tolyl)nicotinamide, 14:N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3-fluoro-5-methoxyphenyl)nicotinamide, 15:N-[(R)-1-cyclopropylethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 16:N-(bicyclo[3.1.0]hexa-3-yl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 17:N-[(R)-2,2,2-trifluoro-1-methylethyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 18: N-[1-(trifluoromethyl)cyclopropyl]methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 19:N-2,2,2-trifluoroethyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 20:N-3,3,3-trifluoropropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 21:N-2-trifluoromethoxyethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 22:N-[(R)-2,2,2-trifluoro-1-methylethyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,4-difluorophenyl)nicotinamide, 23:N-[(R)-2,2,2-trifluoro-1-methylethyl]-5-(3-chloro-4-fluorophenyl)-4-(1,7-diaza-7-spiro[4,4]nonyl)nicotinamide, 24:N-[(R)-2,2,2-trifluoro-1-methylethyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(p-fluorophenyl)nicotinamide, 25:N-[(R)-2,2,2-trifluoro-1-methylethyl]-5-(3-chloro-5-cyanophenyl)-4-(1,7-diaza-7-spiro[4,4]nonyl)nicotinamide, 26:N-[(S)-2,2,2-trifluoro-1-methylethyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 27:N-[(R)-1-(trifluoromethyl)propyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 28: N-(1-cyclopropyl-2,2,2-trifluoroethyl)-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 29: N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-2-methylnicotinamide, 30:N-2-ethoxyethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 31:N-2-isopropoxyethyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 32:N-(tetrahydro-2H-pyran-4-yl)-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 33: N-cyclopentyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 34:N-[(S)-1-cyclopropylethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 35:N-(3-fluorobicyclo[1.1.1]penta-1-yl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 36:N-1-norbornyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 37:N-[(R)-3,3-difluorocyclopentyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 38:N-[(S)-3,3-difluorocyclopentyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 39:N-4,4-difluorocyclohexyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 40:N-2-trifluoromethoxyethyl-2-amino-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 41:N-2-trifluoromethoxyethyl-5-(m-chlorophenyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)nicotinamide, 42:N-2-trifluoromethoxyethyl-5-(3-chloro-5-fluorophenyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)nicotinamide, 43:N-2-trifluoromethoxyethyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,4,5-trifluorophenyl)nicotinamide, 44:N-2-trifluoromethoxyethyl-5-(3-chloro-4-fluorophenyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)nicotinamide, 45:N-[(R)-1-methyl-2-trifluoromethoxyethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 46:N-[(S)-1-methyl-2-trifluoromethoxyethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 47:N-2-cyclopropoxyethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 48:N-2-trifluoromethoxyethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,4-difluorophenyl)nicotinamide, 49:N-[2-(2,2,2-trifluoroethoxy)ethyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 50:N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,4,5-trifluorophenyl)nicotinamide, 51:N-3,3-difluorocyclobutyl-5-(3-chloro-4-fluorophenyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)nicotinamide, 52:N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,4-difluorophenyl)nicotinamide, 53:N-[(R)-3,3-difluorocyclopentyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,4,5-trifluorophenyl)nicotinamide, 54:N-[(R)-3,3-difluorocyclopentyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,4-difluorophenyl)nicotinamide, 55:N-[(1s,3s)-3-fluorocyclobutyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 56:N-[(1r,3r)-3-fluorocyclobutyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 57: N-(3-methyl-4-pyridyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 58: N-(2-methyl-3-pyridyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 59: N-(4-methyl-3-pyridyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 60: N-(3-methyl-2-pyridyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 61:N-(4-fluoro-1-norbornyl)-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 62:N-[(1R,2S)-2-fluorocyclohexyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 63:N-[(1R,2R)-2-fluorocyclohexyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 64:N-(bicyclo[2.1.1]hexa-1-yl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 65:N-1-(trifluoromethyl)cyclopentyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 66: N-(3,3-difluorocyclobutyl)methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 67:N-[(1R,3R)-3-fluorocyclopentyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 68:N-[(1R,3S)-3-fluorocyclopentyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 69:N-[(1s,4s)-4-fluorocyclohexyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 70:N-[(1r,4r)-4-fluorocyclohexyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 71: N-benzyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 72:N-[(R)-1-phenylethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 73: No-Methoxyphenyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 74:N-(2,6-dimethyl-3-pyridyl)-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 75:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 76:N-[(4-fluoro-3-methoxyphenyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 77: N-(m-methoxyphenyl)methyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 78: N-(2,2-difluorocyclopropyl)methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 79: N-[(2-methoxy-4-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 80: No-fluorophenyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 81:N-(6-methyl-3-pyridyl)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 82: N-(m-cyanophenyl)methyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 83: N-(m-fluorophenyl)methyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 84:N-[(R)-1-(m-methoxyphenyl)ethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 85:N-[(3-fluoro-5-methoxyphenyl)methyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 86:N-[(S)-2-methoxy-1-phenylethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 87:N-[(R)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 88:N-1-phenylcyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 89:N-[(6-methoxy-2-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 90:N-3,3-difluorocyclobutyl-6-(cyclopropylmethoxy)-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 91:N-[(5-methoxy-3-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 92:N-[(5-cyano-3-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 93:N-[1-(trifluoromethyl)cyclobutyl]methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 94:N-[1-(trifluoromethyl)cyclopentyl]methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 95:N-[(2-fluoro-5-methoxyphenyl)methyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 96:N-[(2-fluoro-3-methoxyphenyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 97:N-[1-(3,3-difluorocyclobutyl)cyclopropyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 98:N-[(6-methyl-4-pyrimidinyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 99:N-[(2-methyl-4-pyrimidinyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 100: N-(3,5-difluorophenyl)methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 101:N-[(3-chloro-5-fluorophenyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 102:N-{1-[1-(trifluoromethyl)cyclopropyl]ethyl}-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 103:N-(1-methyl-1-phenylethyl)-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 104:N-[(4-cyano-2-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 105:N-[(6-cyano-2-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 106:N-[(2-cyano-4-pyridyl)methyl]-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)nicotinamide, and 107: N-cyclopentyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(4-methyl-1H-1,3-benzimidazole-2-yl)nicotinamide.

[0562] In some embodiments, pharmaceutically acceptable salts of the compounds listed in Table 1 are provided herein.

[0563] [Table 2-1]

[0564] [Table 2-2]

[0565] [Table 2-3]

[0566] [Table 2-4]

[0567] The names of the compounds in Table 2 are as follows: 108:N-2-trifluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 109:N-2-trifluoromethoxyethyl-4-{(R)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 110:N-[(5-methoxy-3-pyridyl)methyl]-4-{(R)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 111:N-[(5-methoxy-3-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 112:N-[(2-cyano-4-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 113:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 114:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 115:N-[(R)-1-(2-cyano-4-pyridyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 116: N-[1-(trifluoromethyl)cyclopropyl]methyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 117:N-{[2-(trifluoromethyl)-4-pyridyl]methyl}-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 118:N-[(R)-3,3,3-trifluoro-1-methylpropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 119:N-[(2-cyano-5-fluoro-4-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 120:N-[(R)-1-(2,6-dimethyl-4-pyridyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 121:N-[(R)-1-(2-cyano-5-fluoro-4-pyridyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 122:N-[(R)-1-cyclopropylethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-6-cyano-5-(3,5-difluorophenyl)nicotinamide, 123:N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-2-(2-hydroxyethylamino)nicotinamide, 124:N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 125:N-[(1r,3S)-3-(trifluoromethyl)cyclobutyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 126:N-{3-(trifluoromethyl)bicyclo[1.1.1]penta-1-yl}-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 127:N-(3,3,3-trifluoro-2-methylpropyl)-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 128:N-2-(trifluoromethyl)cyclopropyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 129:N-[(2-cyano-6-methyl-4-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 130:N-(4,4,4-trifluoro-2-methylbutyl)-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 131:N-[(S)-1-(2,6-dimethyl-4-pyridyl)-2-methoxyethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 132:N-[(R)-1-(2-cyano-6-methyl-4-pyridyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 133:N-[(1S,2S)-2-(trifluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 134:N-[(1S,2R)-2-(trifluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 135:N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-2-methoxynicotinamide, 136:N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-2-oxo-1,2-dihydronicotinamide, 137:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-2-oxo-1,2-dihydronicotinamide, 138:N-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 139:N-[3,3,3-trifluoro-2-(trifluoromethyl)propyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 140:N-(3,3,3-trifluoro-2-methoxypropyl)-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 141:N-(3,3,3-trifluoro-2-hydroxypropyl)-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 142:N-[(R)-3,3,3-trifluoro-2-methoxypropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 143:N-[(S)-3,3,3-trifluoro-2-methoxypropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 144:N-[(S)-1-(2,6-dimethyl-4-pyridyl)-2-methoxyethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,4,5-trifluorophenyl)nicotinamide, 145:N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2- 2 H) Nicotinamide, 146:N-[(S)-1-(3,3-difluorocyclobutyl)-2-methoxyethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide. 147:N-2-trifluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2- 2 H) Nicotinamide, 148:N-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2- 2 H) Nicotinamide, 149:N-2-difluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2- 2 H) Nicotinamide, 150:N-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 151:N-[(1R,2R)-2-(difluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2- 2 H) Nicotinamide, 152:N-2-difluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2,6- 2 H2) Nicotinamide.

[0568] In some embodiments, pharmaceutically acceptable salts of the compounds listed in Table 2 are provided herein.

[0569] [Table 3-1]

[0570] [Table 3-2]

[0571] [Table 3-3]

[0572] [Table 3-4]

[0573] The names of the compounds in Table 3 are as follows: 153: N-2-methylbutyl-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 154: N-[1-(trifluoromethyl)cyclopropyl]methyl-5-(3-chloro-5-fluorophenyl)-4-(1,6-diaza-6-spiro[3,4]octyl)nicotinamide, 155:N-2-trifluoromethoxyethyl-5-(3-chloro-5-fluorophenyl)-4-(1,6-diaza-6-spiro[3,4]octyl)nicotinamide, 156:N-2-trifluoromethoxyethyl-4-(2,5-diaza-2-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 157:N-2-trifluoromethoxyethyl-4-(2,5-diaza-2-spiro[3.5]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 158:N-3,3-difluorocyclobutyl-4-(2,5-diaza-2-spiro[3.5]nonyl)-5-(3,5-difluorophenyl)nicotinamide, 159: N-[(R)-3,3-difluorocyclopentyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 160:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 161:N-[(R)-1-(m-cyanophenyl)ethyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 162:N-[(2-cyano-4-pyridyl)methyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 163:N-[(2-cyano-4-pyridyl)methyl]-4-{(S)-1,6-diaza-6-spiro[3,4]octyl}-5-(3,5-difluorophenyl)nicotinamide, 164: N-[(2,6-dimethyl-4-pyridyl)methyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 165:N-[(R)-1-(2,6-dimethyl-4-pyridyl)ethyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 166:N-[(R)-1-(m-chlorophenyl)ethyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 167: N-(m-chlorophenyl)methyl-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 168: N-(m-fluorophenyl)methyl-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 169: N-[(3-chloro-5-fluorophenyl)methyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 170:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,4,5-trifluorophenyl)nicotinamide, 171:N-[(2,6-dimethyl-4-pyridyl)methyl]-5-(3-chloro-5-fluorophenyl)-4-(1,6-diaza-6-spiro[3,4]octyl)nicotinamide, 172:N-[(2,6-dimethyl-4-pyridyl)methyl]-5-(3-chloro-4-fluorophenyl)-4-(1,6-diaza-6-spiro[3,4]octyl)nicotinamide, 173: N-(3,5-difluorophenyl)methyl-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 174: N-(2,3,5-trifluorophenyl)methyl-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 175:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-{(2,2- 2 H2)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 176:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(2,2- 2 H2)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 177:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(3R)-3-fluoro-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 178:N-[(2-cyano-6-methyl-4-pyridyl)methyl]-4-(1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, 179: N-[(2-cyano-4-pyridyl)methyl]-4-{(3R)-3-fluoro-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 180:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-{(3R)-3-fluoro-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 181:N-2-trifluoromethoxyethyl-4-{(3R)-3-fluoro-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 182:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(2S,5R)-2-methyl-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 183:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(2S,5S)-2-methyl-1,7-diaza-7-spiro[4,4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 184:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-{(2S,5R)-2-methyl-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 185:N-[(R)-1-(3,3-difluorocyclobutyl)ethyl]-4-{(2S,5S)-2-methyl-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 186:N-3,3-difluorocyclobutyl-4-{(2S,5R)-2-methyl-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 187:N-3,3-difluorocyclobutyl-4-{(2S,5S)-2-methyl-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 188:N-[(2-cyano-4-pyridyl)methyl]-4-{(2S,5R)-2-methyl-1,7-diaza-7-spiro[4,4]nonyl}-5-(3,5-difluorophenyl)nicotinamide, 189: Ethyl 6-(5-{[(2,6-dimethyl-4-pyridyl)methyl]carbamoyl}-3-(3,4,5-trifluorophenyl)-4-pyridyl)-1,6-diaza-1-spiro[3,4]octanecarboxylate, 190:N-[(2-cyano-6-methyl-4-pyridyl)methyl]-4-(1-acetyl-1,6-diaza-6-spiro[3,4]octyl)-5-(3,5-difluorophenyl)nicotinamide, and 191:N-[(2-cyano-4-pyridyl)methyl]-4-{(2S,5S)-2-methyl-1,7-diaza-7-spiro[4,4]nonyl}-5-(3,5-difluorophenyl)nicotinamide.

[0574] In some embodiments, pharmaceutically acceptable salts of the compounds listed in Table 3 are provided herein.

[0575] [Table 4]

[0576] The names of the compounds in Table 4 are as follows: 192:N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 193:N-[(R)-3,3-difluorocyclopentyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 194:N-2-trifluoromethoxyethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 195: N-(m-cyanophenyl)methyl-4-(1,7-diaza-7-spiro[4,4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 196:N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 197:N-[(R)-1-(2,6-dimethyl-4-pyridyl)ethyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 198:N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 199:N-2-trifluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, 200:N-[(R)-3,3,3-trifluoro-2-methoxypropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide, and 201:N-[(S)-3,3,3-trifluoro-2-methoxypropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide.

[0577] In some embodiments, pharmaceutically acceptable salts of the compounds listed in Table 4 are provided herein.

[0578] As used herein, “pharmaceutically acceptable” means a material such as a carrier or diluent that does not inhibit the biological activity or properties of a compound and is relatively non-toxic; that is, the material is administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0579] The term "pharmaceutically acceptable salt" refers to a cationic form of the therapeutic activator combined with a suitable anion, or, in an alternative embodiment, a form of the therapeutic activator consisting of an anionic form of the therapeutic activator combined with a suitable cation.

[0580] In some embodiments, pharmaceutically acceptable salts are obtained by reacting compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) with an acid. In some embodiments, the free base form of compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) is basic and reacts with organic or inorganic acids.

[0581] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) with a base. In some embodiments, the compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) is acidic and reacts with a base.

[0582] In some embodiments, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) have one or more stereocenters, each stereocenter independently existing in either the R or S configuration. In some embodiments, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) exist in the R configuration. In some embodiments, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) exist in the S configuration. The compounds presented herein include all diastereomers, individual enantiomers, atropisomers, epimers, and tautomers, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entogen (E), and tussamen (Z) isomers, as well as suitable mixtures thereof.

[0583] If necessary, individual stereoisomers can be obtained by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns, separation of diastereomers by either non-chiral or chiral chromatography columns, or crystallization and recrystallization in a suitable solvent or mixture of solvents. In certain embodiments, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active decomposition agent to form diastereomer compound / salt pairs, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the decomposition of individual enantiomers is carried out using covalently bonded diastereomer derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / decomposition techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is carried out by chromatography or by the formed diastereomer salts, and by recrystallization, or chromatography, or any combination thereof.

[0584] Compound synthesis The compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa) described herein are synthesized using standard synthetic techniques or by methods known in the art in combination with the methods described herein.

[0585] Unless otherwise specified, conventional mass spectrometry methods, NMR, and HPLC are used.

[0586] The compounds are prepared using standard organic chemistry techniques. Alternative reaction conditions for the synthetic transformations described herein may involve variations in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions.

[0587] In some embodiments, the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), and formula (Id) described herein are prepared as described in Scheme A.

[0588] [ka] Scheme A a) i) iPrMgCl, THF, -40℃~RT; ii) Dry ice, 6 hours; b) MeI, K2CO3, DMF, RT, 1 hour; c) IV, MeCN, DIEA, 100℃, 2 hours; d) VI, Pd(dtbpf)Cl2, K3PO4, Toluene / H2O=10:1, 70℃, 1 hour; e) LiOH . H2O, MeOH / H2O=2:1, 60°C, 16 hours; f) IX, HATU, DIEA, DMF, RT, 30 minutes; g) TFA, DCM, RT, 30 minutes.

[0589] In some other embodiments, compounds of formula (II) or formula (IIa) described herein are prepared as described in scheme B.

[0590] [ka] Scheme B a) XIII, DIEA, MeCN, RT, 2 hours; b) XV, AcOH, DCM, RT, 30 minutes; c) XVII, Pd(dppf)Cl2, K2CO3, Toluene / H2O (5:1), 70°C, 3 hours; d) Pd / C, MeOH, RT, 2 hours; e) LiOH . H2O, MeOH / H2O=2:1, 60℃, 1 hour; f) XXI, HATU, DIEA, NMP, RT, 1 hour; g) TFA, DCM, RT, 1 hour

[0591] In some embodiments, the compounds are prepared as described in the examples.

[0592] Specific terms Unless otherwise specified, the following terms used in this application have the definitions set forth below. The term "including," as well as other forms such as "include," "includes," and "included," are not limiting. Section headings used herein are for structural purposes only and should not be construed as limiting the subject matter described herein.

[0593] When used herein, C1-C x C1-C2, C1-C3...C1-C x This includes. As a simple example, a group indicated as "C1-C6" indicates the presence of a group containing 1 to 6 carbon atoms in part, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Therefore, as a simple example, "C1-C4 alkyl" indicates the presence of 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0594] The “alkyl” group refers to an aliphatic hydrocarbon group. Alkyl groups can be branched or linear. In some embodiments, the “alkyl” group has 1 to 6 carbon atoms, i.e., a C1-C6 alkyl group. 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 that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to 6 carbon atoms. However, this definition also includes occurrences of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one embodiment, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0595] The "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0596] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl," e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine, pyrimidine). This term includes monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups.

[0597] The term "carbocyclic" refers to a ring or ring system in which all atoms forming the ring's framework are carbon atoms. Therefore, this term distinguishes a carbocyclic from a "heterocyclic" ring or "heterocycle" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocyclic is aromatic. In some embodiments, both rings in a bicyclic carbocyclic are aromatic. Carbocyclics include aryl and cycloalkyl groups.

[0598] As used herein, the term “aryl” refers to an aromatic ring in which each of the ring-forming atoms is a carbon atom. In some embodiments, the aryl is phenyl. Depending on the structure, the aryl group is a monoradical or a diradical (i.e., an arylene group).

[0599] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. Cycloalkyl groups include groups having 3 to 7 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the cycloalkyl group is a C3-C7 cycloalkyl group. In some embodiments, the cycloalkyl group is a C3-C6 cycloalkyl group. In some embodiments, the cycloalkyl group is a bicyclic cycloalkyl group, or "bicycloalkyl group." In some embodiments, the cycloalkyl group is a spirocyclic or crosslinked compound.

[0600] The "cycloalkoxy" group refers to a (cycloalkyl)O- group, where cycloalkyl is as defined herein.

[0601] The terms "halo" or, alternatively, "halogen" or "halide" mean fluoro, chloro, bromo, or iodine. In some embodiments, the halo is fluoro, chloro, or bromo.

[0602] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, a fluoroalkyl group is a C1-C6 fluoroalkyl group.

[0603] The "fluoroalkoxy" group refers to a (fluoroalkyl)O- group, where fluoroalkyl is as defined herein.

[0604] The term "heterocyclic" or "heterocyclic formula" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one or two heteroatoms within the ring, where each heteroatom is selected from O, S, and 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 known as heterocycloalkyls) contain rings with 3 to 6 atoms in their ring system, while aromatic heterocyclic groups contain rings with 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, pyridinyl and pyrimidinyl.

[0605] The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic heteroaryls such as pyridinyl and pyrimidinyl.

[0606] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl groups include monocyclic heterocycloalkyls such as tetrahydropyranyl.

[0607] The term "bond" refers to a chemical bond between two atoms, or two parts where the atoms linked by the bond are considered to be part of a larger substructure. In one embodiment, when the group described herein is a bond, there is no reference group, thereby allowing a bond to be formed between the remaining identified groups.

[0608] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is often recognized as a chemical substance embedded in or attached to a molecule.

[0609] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that it does not have any lasting adverse effects on the general health of the subject being treated.

[0610] As used herein, the term “modulate” means to directly or indirectly interact with the activity of a target in such a way as to alter the activity of the target, including, but not limited to, enhancing, inhibiting, limiting, or prolonging the activity of the target.

[0611] As used herein, the term “modulator” refers to a molecule that interacts directly or indirectly with a target. These interactions include, but are not limited to, agonist, partial agonist, reverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0612] When used herein, terms such as “administer,” “give administration,” and “give administration” refer to methods that may be used to enable the delivery of a compound or composition to a desired biological site of action.

[0613] The terms “effective dose” and “therapeutic effective dose,” as used herein, refer to a sufficient amount of an agent or compound administered that reduces, to some extent, one or more of the symptoms of the disease or condition being treated. The result may include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compound disclosed herein that is necessary to produce a clinically significant reduction in the symptoms of the disease. The appropriate “effective” dose in any individual case may, at their discretion, be determined using techniques such as dose-escalation studies.

[0614] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class, humans, non-human primates such as chimpanzees, and other apes and monkey species, farm animals such as cattle, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals such as rats, mice, and guinea pigs. In one embodiment, a mammal is a human.

[0615] The terms “to treat,” “to treat,” or “treatment” as used herein include alleviating, reducing, or improving at least one symptom of a disease or condition, inhibiting a disease or condition, for example, preventing the onset of a disease or condition, reducing a disease or condition, causing regression of a disease or condition, reducing a condition caused by a disease or condition, or stopping the symptoms of a disease or condition, either preventively or therapeutically.

[0616] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert components that facilitate the treatment of the active compound into a preparation for pharmaceutical use. The appropriate formulation depends on the chosen route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0617] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with one or more pharmaceutically acceptable carriers, excipients, and / or diluents. Administration of the compounds and compositions described herein can be carried out by any method that enables the compound to be delivered to the site of action.

[0618] In some embodiments, pharmaceutical compositions comprising any one of the compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising the compound of formula (Ia), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising the compound of formula (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising the compound of formula (Ic), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising a compound of formula (Id) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are disclosed herein. In some embodiments, pharmaceutical compositions comprising a compound of formula (IIa) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are disclosed herein.

[0619] Methods of administration and treatment regimens In some embodiments, compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa), or pharmaceutically acceptable salts thereof, are used to prepare agents for the treatment of diseases or conditions in mammals that would benefit from SSTR3 agonists. A method for treating a mammal in need of treatment for a disease or condition described herein includes administering to the mammal a therapeutically effective dose of a pharmaceutical composition comprising at least one compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa), or a pharmaceutically acceptable salt thereof.

[0620] In certain embodiments, compositions containing the compounds described herein are administered for therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to at least partially cessate at least one of the symptoms of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, previous therapies, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective dose may be determined at a discretionary rate by methods including, but are not limited to, dose escalation and / or dose range clinical trials.

[0621] The amount of a given compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), or formula (IIa), or a pharmaceutically acceptable salt thereof, corresponding to a therapeutically effective dose varies depending on factors such as the specific compound, the disease state and its severity, and the identity of the subject or host requiring treatment (e.g., body weight, sex). Nevertheless, it is determined according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0622] The toxicity and therapeutic efficacy of such treatment regimens are LD 50 and ED 50 This is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to the determination of the LD50. The dose ratio between toxic effects and therapeutic effects is the therapeutic index, LD50. 50 and ED 50 It is expressed as a ratio between [value] and [value]. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dose ranges and / or therapeutically effective unit dosage forms for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is ED with minimal toxicity. 50 It is within the range of circulating concentrations, including [the specified substance]. In certain embodiments, the range of daily doses and / or the amount of the unit dose varies within this range depending on the dosage form used and the route of administration utilized.

[0623] As used above and throughout this description of the present invention, unless otherwise indicated, the following abbreviations should be understood to have the following meanings. Abbreviation: LCMS: Liquid chromatography-mass spectrometry HPLC: High-performance liquid chromatography, Preparative HPLC: Preparative high-performance liquid chromatography, Chiral-SFC: Chiral supercritical fluid chromatography, POCl3: Phosphoryl chloride, DIEA: N,N-diisopropylethylamine or N-ethyl-N-isopropylpropan-2-amine, DCM: Dichloromethane, PE: Petroleum ether, alkyl or EA: ethyl acetate, MeCN: Acetonitrile, Pd(dtbpf)Cl2:[1,1'-bis(di-tert-butylphosphinone)ferrocene]dichloropalladium(II), 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(0)-chloroform adduct, NMP: N-methylpyrrolidone, K2CO3: Potassium carbonate, NaOH: Sodium hydroxide, MeOH: methanol, NaHSO4: Sodium bicarbonate, FA: Formic acid, NH3.H2O: Aqueous ammonia solution, Boc2O: Di-tert-butyl dicarbonate, AcOH: Acetic acid, NaHSO3: Sodium sulfite, Na2SO4: Sodium sulfate, K3PO4: Potassium phosphate, Pd-C: Palladium-carbon, H2: Hydrogen gas, LiOH: Lithium hydroxide.

[0624] The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

[0625] Compound synthesis Example A-1. Preparation of N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide (compound 5)

[0626] [ka] Step 1-1, Preparation of 5-bromo-4-chloronicotinoyl chloride: A mixture of 5-bromo-4-chloronicotinic acid (2.50 g, 1 equivalent, 10.6 mmol; prepared as disclosed in Example 2, Step 2-1) and POCl3 (25 g, 15 mL, 15 equivalents, 0.16 mol) was placed in a 50 mL round-bottom flask. The resulting reaction mixture was stirred at 100 °C for 1 hour. The crude product was concentrated under reduced pressure to obtain 5-bromo-4-chloronicotinoyl chloride (2.85 g, 10 mmol, 95%, purity 90%).

[0627] Steps 1-2, Preparation of 5-bromo-4-chloro-N-(2-methylbutyl)nicotinamide: 2-methylbutan-1-amine (1.71 g, 2.00 equivalents, 19.6 mmol), DIEA (10.0 g, 13.5 mL, 7.88 equivalents, 77.4 mmol), and DCM (50 mL) were placed in a 100 mL round-bottom flask. Then, 5-bromo-4-chloronicotinoyl chloride (2.78 g, 90% by weight, 1 equivalent, 9.82 mmol) in DCM (10 mL) was added, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was purified by silica gel column (PE / siRNA system, the amount of siRNA was increased from 0% to 65% over 20 minutes). This results in 5-bromo-4-chloro-N-(2-methylbutyl)nicotinamide (1.60g, 5.24 mmol, 53.3%); LCMS(M+H) + We obtained values ​​of 305.0 and 307.0.

[0628] Steps 1-3, Preparation of tert-butyl 7-(3-bromo-5-((2-methylbutyl)carbamoyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: In a 50 mL round-bottom flask, 5-bromo-4-chloro-N-(2-methylbutyl)nicotinamide (1.60 g, 1.18 equivalents, 5.24 mmol), tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate (1.00 g, 1 equivalent, 4.42 mmol), DIEA (1.50 g, 2.02 mL, 2.63 equivalents, 11.6 mmol), and MeCN (20 mL) were added. The resulting reaction mixture was stirred at 70°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column elution with PE / SiO(1:1) to obtain tert-butyl7-(3-bromo-5-((2-methylbutyl)carbamoyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (1.88 g, 3.79 mmol, 85.9%); LCMS(M+H) + We obtained values ​​of 495.2 and 497.2.

[0629] Steps 1-4, Preparation of tert-butyl 7-(3-(3,5-difluorophenyl)-5-((2-methylbutyl)carbamoyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: In a 50 mL round-bottom flask, prepare tert-butyl 7-(3-bromo-5-((2-methylbutyl)carbamoyl)pyridine in toluene (30 mL) and water (3 mL). -4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (1.88 g, 1 equivalent, 3.79 mmol), (3,5-difluorophenyl)boronic acid (3.00 g, 5.01 equivalents, 19.0 mmol), Pd(dtbpf)Cl2 (124 mg, 0.0501 equivalents, 190 μmol), and potassium phosphate (4.00 g, 4.97 equivalents, 18.8 mmol) were added. The resulting mixture was stirred at 70°C for 5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column elution with PE / SiO(1:1-1:5) to obtain tert-butyl7-(3-(3,5-difluorophenyl)-5-((2-methylbutyl)carbamoyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (1.80 g, 3.40 mmol, 89.7%); LCMS(M+H) + = 529.3 was obtained.

[0630] Steps 1-5, Preparation of N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide dihydrochloride: In an 8 mL vial, add tert-butyl7-(3-(3,5-difluorophenyl)-5-((2-methylbutyl)carbamoyl)pyridine-4-yl)-1,7-

[0631] A mixture of diazaspiro[4.4]nonane-1-carboxylate (100 mg, 1 equivalent, 189 μmol) and HCl / ether (2.0 M HCl in ether; 2 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure and dried by lyophilization to obtain N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide dihydrochloride (80 mg, 0.16 mmol, 84%); LCMS(M+H) + = 429.3 was obtained.

[0632] Steps 1-6, Preparation of N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide: In an 8 mL vial, N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide dihydrochloride (30 mg, 1 equivalent, 60 μmol) was added, dissolved in water (5 mL), the pH was adjusted to 9 with Na2CO3, and extracted with DCM (2 × 7 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 5-(3,5-difluorophenyl)-N-(2-methylbutyl)-4-(1,7-diazaspiro[4.4]nonan-7-yl)nicotinamide (20 mg, 47 μmol, 78%); LCMS(M+H) + = 429.3 was obtained.

[0633] The following compounds were prepared in the same manner as in Example 1 using appropriate reagents and / or substitutions of reagents and / or substrates and / or functional group modifications via well known chemicals.

[0634] [Table 5-1]

[0635] [Table 5-2]

[0636] Example A-2. Preparation of N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide (compound 124)

[0637] [ka] Step 2-1, Preparation of 5-bromo-4-chloronicotinic acid: In a 500 mL three-necked round-bottom flask, purged and maintained under an inert nitrogen atmosphere, 150 mL of THF and 15.0 g of 3,5-dibromo-4-chloropyridine (15.0 g, 1 equivalent, 55.3 mmol) were added. Subsequently, isopropyl magnesium chloride (6.82 g, 30 mL, 2 M, 1.2 equivalents, 66.3 mmol) was added dropwise while stirring at -40°C. The temperature was allowed to rise naturally to 20°C. The resulting reaction solution was stirred at 20°C for 30 minutes. 300 g of dry ice was washed with 200 ml of THF, and then the THF was decanted. The reaction solution was immediately poured onto the dry ice and stirred for 3 hours. The reactants were then quenched with 150 ml of H2O. The resulting solution was extracted with ethyl acetate (2 × 100 mL). The aqueous phase was adjusted to pH 1-2 and extracted with ethyl acetate (3 × 100 mL). The organic phase was added and washed with 200 mL of brine. The resulting mixture was concentrated under vacuum to obtain 5-bromo-4-chloronicotinic acid (9.6 g, 32 mmol, 59%, purity 80%).

[0638] Step 2-2, Preparation of methyl 5-bromo-4-chloronicotinate: 5-bromo-4-chloronicotinic acid (1 g, 1 equivalent, 4 mmol) and DMF (10 mL) were added to a 40 mL vial. Subsequently, potassium carbonate (2 g, 3 equivalents, 0.01 mol) was added. The resulting reaction mixture was stirred at 25°C for 3 hours to obtain methyl 5-bromo-4-chloronicotinate (800 mg, 3.19 mmol, 80%).

[0639] Steps 2-3, Preparation of tert-butyl(S)-7-(3-bromo-5-(methoxycarbonyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: N-ethyl-N-isopropylpropan-2-amine (519.3 mg, 700 μL, 2 equivalents, 4.018 mmol) was added to a solution of methyl 5-bromo-4-chloronicotinate (503.2 mg, 1 equivalent, 2.009 mmol) and tert-butyl(S)-1,7-diazaspiro[4.4]nonane-1-carboxylate (500.1 mg, 1.1 equivalents, 2.210 mmol) in MeCN (5 mL). The mixture was heated at 100 °C for 16 hours. The mixture was concentrated under vacuum until dry, and the residue was purified by silica gel column chromatography (eluted with 40% ethyl acetate in hexane). The pure fractions were combined, concentrated in vacuum until dry, and dried under high vacuum to obtain tert-butyl(S)-7-(3-bromo-5-(methoxycarbonyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (866.0 mg, 1.967 mmol, 97.90%); LCMS(M+H) + We obtained values ​​of 440.1 and 442.4.

[0640] Steps 2-4, Preparation of tert-butyl(S)-7-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate in sealed tubes: tert-butyl(S)-7-(3-bromo-5-(methoxycarbonyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate in sealed tubes A mixture of voxylate (866.0 mg, 1 equivalent, 1.967 mmol), (3,5-difluorophenyl)boronic acid (465.8 mg, 1.5 equivalents, 2.950 mmol), Pd(dtbpf)Cl2 (256.4 mg, 0.2 equivalents, 393.3 μmol), and potassium phosphate (1.252 g, 3 equivalents, 5.900 mmol) was mixed with toluene (10 mL) and water (1.0 mL). N2 (g) was passed through the mixture and bubbling for 5 minutes. The resulting mixture was heated at 70°C for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by reverse-phase column chromatography. The pure fractions were combined, neutralized with saturated NaHCO3 (aqueous solution), concentrated, and MeCN was removed. The aqueous residue was extracted with ethyl acetate (twice), the combined organic matter was dried with anhydrous MgSO4, and concentrated in vacuum until dry to obtain tert-butyl(S)-7-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (706.5 mg, 1.492 mmol, 75.87%); LCMS(M+H) + = 474.1 was obtained.

[0641] Step 2-5, Preparation of (S)-4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)nicotinic acid: To a solution of tert-butyl(S)-7-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (649.0 mg, 1 equivalent, 1.371 mmol) in a mixed solvent of methanol (10 mL) and water (5.0 mL), lithium hydroxide hydrate (575.1 mg, 10 equivalents, 13.71 mmol) was added. The mixture was heated at 60°C for 5 hours. The mixture was concentrated under vacuum to remove methanol. Ice water was added to the aqueous residue and neutralized to pH 6-7 with 1N HCl (aqueous solution). The solution was extracted with ethyl acetate (3 times) and 20% isopropyl alcohol / dichloromethane (1 time). The combined organic matter was dried over anhydrous MgSO4 and concentrated under vacuum until dry to obtain (S)-4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4,4]nonan-7-yl)-5-(3,5-difluorophenyl)nicotinic acid (564.2 mg, 1.228 mmol, 89.59%); LCMS(M+H) + = 460.2 was obtained.

[0642] Steps 2-6, Preparation of tert-butyl(S)-7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate in DMF (1 mL): (S)-4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)nico To a solution of tinic acid (564.2 mg, 1 equivalent, 1.228 mmol) and 3-((dimethylamino)(dimethylimino)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine 1-oxide hexafluorophosphate (V) (887.1 mg, 1.9 equivalents, 2.333 mmol), N-ethyl-N-isopropylpropan-2-amine (793.5 mg, 1.07 mL, 5 equivalents, 6.139 mmol) was added. The mixture was stirred at 25°C for 5 minutes. To this HATU-activated solution, 3,3-difluorocyclobutane-1-amine hydrochloride (352.5 mg, 2 equivalents, 2.456 mmol) was added. The mixture was stirred at 25°C for 10 minutes. The crude mixture was directly purified by reverse-phase column chromatography. The pure fractions were combined, neutralized with saturated NaHCO3 (aqueous solution), concentrated under vacuum, and MeCN removed. The aqueous residue was extracted twice with ethyl acetate. The combined organic matter was dried over anhydrous MgSO4, filtered, and concentrated under vacuum until dry to obtain tert-butyl(S)-7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (487.5 mg, 888.7 μmol, 72.37%); LCMS(M+H) + = 549.6 was obtained.

[0643] Step 2-7, Preparation of N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide: To a solution of tert-butyl(S)-7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (487.5 mg, 1 equivalent, 888.7 μmol) in dichloromethane (1 mL), 2,2,2-trifluoroacetic acid (2.026 g, 1.360 mL, 20 equivalents, 17.77 mmol) was added. The mixture was stirred at 25°C for 30 minutes. The mixture was concentrated under vacuum until dry, and the residue was purified by reverse-phase column chromatography. The pure fractions were combined, neutralized with saturated NaHCO3 (aqueous solution), concentrated under vacuum, and MeCN was removed. The aqueous residue was extracted with ethyl acetate (twice), the combined organic matter was dried over anhydrous MgSO4, concentrated under vacuum until dry, and dried under high vacuum to obtain N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide (331.17 mg, 738.44 μmol, 83.10%); LCMS(M+H) + = 449.4 was obtained.

[0644] The following compounds were prepared in the same manner as in Example 2 using appropriate reagents and appropriate substitutions of reagents and / or substrates and / or functional group modifications via well known chemicals.

[0645] [Table 6]

[0646] Example A-3. Preparation of N-[(2-cyano-4-pyridyl)methyl]-4-{(S)-1,6-diaza-6-spiro[3,4]octyl}-5-(3,5-difluorophenyl)nicotinamide (compound 163)

[0647] [ka] Step 3-1, Preparation of tert-butyl((2-cyanopyridine-4-yl)methyl)carbamate: In a 250 mL flask under an inert nitrogen atmosphere, tert-butyl((2-bromopyridine-4-yl)methyl)carbamate (5.0 g, 1 equivalent, 17 mmol), Zn(CN)2 (5.0 g, 2.4 equivalents, 43 mmol), Pd2(dba)3.CH3Cl (1.8 g, 0.10 equivalents, 1.7 mmol), and xanthophos (2.0 g, 0.20 equivalents, 3.5 mmol) were added in 100 mL of NMP. The mixture was stirred at 120 °C for 2 hours. Next, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to obtain tert-butyl((2-cyanopyridine-4-yl)methyl)carbamate (3.0 g, 13 mmol, 74%); LCMS(M+H) + =234.1 was obtained.

[0648] Step 3-2, Preparation of 4-(aminomethyl)picolinonitrile hydrochloride: In a 100 mL flask, tert-butyl((2-cyanopyridine-4-yl)methyl)carbamate (3.0 g, 1 equivalent, 13 mmol) and 4-(aminomethyl)picolinonitrile hydrochloride (2.0 g, 12 mmol, 92%) were added. The mixture was stirred at 25°C for 1 hour. The solution was concentrated under reduced pressure. Water and MeCN were added, and the mixture was freeze-dried under vacuum to obtain 4-(aminomethyl)picolinonitrile hydrochloride (2.0 g, 12 mmol, 92%).

[0649] Step 3-3, Preparation of tert-butyl 6-(3-bromo-5-(methoxycarbonyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate: Methyl 5-bromo-4-chloronicotinate (3.0 g, 1 equivalent, 12 mmol; prepared as disclosed in Example 2, Steps 2-1 to 2-2), tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate oxalate (3.0 g, 0.83 equivalents, 9.9 mmol), and DIEA (6.0 g, 8.1 mL, 3.9 equivalents, 46 mmol) were added to a 250 mL flask in MeCN (40 mL). The mixture was stirred at 60°C for 5 hours. The solution was concentrated under reduced pressure, the residue was applied to a silica gel column, and eluted with ethyl acetate / PE (1:3) to obtain tert-butyl 6-(3-bromo-5-(methoxycarbonyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (3.5 g, 8.2 mmol, 69%); LCMS(M+H) + We obtained values ​​of 426.1 and 428.1.

[0650] Steps 3-4, Preparation of tert-butyl 6-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octan-1-carboxylate: In a 250 mL flask under an inert atmosphere of nitrogen, add 1,4-dioxane (60 mL) and tert-butyl 6-(3-bromo-5-(methoxycarbonyl) in water (6 mL). Rubonyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (3.5 g, 1 equivalent, 8.2 mmol), Pd(dtbpf)Cl2 (500 mg, 0.093 equivalents, 767 μmol), (3,5-difluorophenyl)boronic acid (2.6 g, 2.0 equivalents, 16 mmol), and K2CO3 (3.5 g, 3.1 equivalents, 25 mmol) were added. The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, the residue was applied to a silica gel column, and eluted with ethyl acetate / PE (2:1) to obtain tert-butyl 6-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (3.5 g, 7.6 mmol, 93%); LCMS(M+H) + = 461.1 was obtained.

[0651] Steps 3-5: Preparation of 4-(1-(tert-butoxycarbonyl)-1,6-diazaspiro[3.4]octane-6-yl)-5-(3,5-difluorophenyl)nicotinic acid: In a 250 mL flask, tert-butyl6-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (3.5 g, 1 equivalent, 7.6 mmol) and NaOH (3.0 g, 9.8 equivalents, 75 mmol) were added in MeOH (60 mL) and water (6 mL). The mixture was stirred at 80°C for 1 hour. The mixture solution was concentrated under vacuum and diluted with water. The pH of the solution was adjusted to 5-6 with saturated NaHSO4 aqueous solution. The resulting solution was extracted with DCM (3 × 40 mL). The organic layers were combined, washed with brine, dried, and concentrated under vacuum to obtain 4-(1-(tert-butoxycarbonyl)-1,6-diazaspiro[3,4]octan-6-yl)-5-(3,5-difluorophenyl)nicotinic acid (3.0 g, 6.7 mmol, 88%); LC-MS(M+H) + = 446.1 was obtained.

[0652] Steps 3-6, Preparation of tert-butyl(R)-6-(3-(((2-cyanopyridine-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octan-1-carboxylate: 4-(1-(tert-butoxycarbonyl)-1,6-diazaspiro[3.4]octan-6-yl)-5-(3,5-difluorophenyl)nicotinic acid (2.5 g, 1 equivalent, 5.6 mmol), DIEA (3.0 g, 4.0 mL, 4.1 equivalents, 23 mmol), and HATU (2.5 g, 1.2 equivalents, 6.6 mmol) in DMF (40 mL) were added to a 100 mL flask. The mixture was stirred at room temperature for 10 minutes, then 4-(aminomethyl)picolinonitrile hydrochloride (2.0 g, 2.1 equivalents, 12 mmol; from step 3-2) was added. The mixture was stirred at 25°C for 1 hour. The crude product was purified by preparative HPLC under the following conditions (2#-Analysis-HPLC-SHIMADZU(HPLC-01)): Column, SunFine prep OBD 19×150 mm 5 μm C-01; Mobile phase, water (0.05% FA) and MeCN (27% MeCN over 7 minutes - max 47%); Detectors 254 nm and 220 nm. Flow rate was set to 80 mL / min. The purified solution was concentrated under vacuum to obtain 1.8 g of the product. The product was purified by Chiral-SFC to obtain two diastereomers. The first peak (t=2.69 min) was tert-butyl(S)-6-(3-(((2-cyanopyridine-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (830 mg, 1.48 mmol, 26%); LCMS(M+H) + It was identified as =561.4. The second peak (t=3.35 min) was tert-butyl(R)-6-(3-(((2-cyanopyridine-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridine-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (740 mg, 1.32 mmol, 24%);LCMS(M+H) + It was identified as =561.3.

[0653] Steps 3-7, Preparation of N-[(2-cyano-4-pyridyl)methyl]-4-{(S)-1,6-diaza-6-spiro[3.4]octyl}-5-(3,5-difluorophenyl)nicotinamide: In a 100 mL flask, tert-butyl(R)-6-(3-(((2-cyanopyridin-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate (740 mg, 1 equivalent, 1.32 mmol) was added to a mixture of TFA (2 mL) and DCM (10 mL). The mixture was stirred at 25°C for 1 hour. The solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (2#-Analysis-HPLC SHIMADZU(HPLC-01)): Column, XBridge prep OBD 19×150 mm 5 μm C-01; Mobile phase, water (0.05% NH3, H2O) and MeCN (26% MeCN over 7 minutes - max 48%); Detector, 254 nm and 220 nm. Flow rate was 80 mL / min. This yielded N-[(2-cyano-4-pyridyl)methyl]-4-{(S)-1,6-diaza-6-spiro[3,4]octyl}-5-(3,5-difluorophenyl)nicotinamide (367.4 mg, 797.8 μmol, 60.4%); LCMS(M+H) + = 461.3 was obtained.

[0654] The following compounds were prepared in the same manner as in Example 3 using appropriate reagents and appropriate substitution of reagents and / or substrates and / or functional group modifications via well known chemicals.

[0655] [Table 7]

[0656] Example A-4. Preparation of N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide (compound 192)

[0657] [ka] Step 4-1, Preparation of tert-butyl 7-(6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: Methyl 4,6-dichloropyridazin-3-carboxylate (1.0 g, 1 equivalent, 4.8 mmol), 1,7-diazaspiro[4.4]nonane dihydrochloride (1.4 g, 1 equivalent, 7.0 mmol), and DIEA (3.1 g, 4.2 mL, 5 equivalents, 24 mmol) were added to a 40 mL vial in MeCN (10 mL). The resulting solution was stirred at 25°C for 2 hours. Then, Boc2O (1.6 g, 1.7 mL, 1.8 equivalents, 7.3 mmol) was added, and the resulting solution was stirred at 25°C for 1 hour. The resulting solution was concentrated under reduced pressure and purified by silica gel column chromatography eluted with PE / SiO(3:1) to obtain tert-butyl7-(6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (1.5g, 3.8 mmol, 93%); LCMS(M+H) + =397.2 was obtained.

[0658] Step 4-2, Preparation of tert-butyl 7-(5-bromo-6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: 1.5 g, 1 equivalent, 3.8 mmol of tert-butyl 7-(6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate, 2.8 mL of DCM, and 14 mL of AcOH were added to a 40 mL vial. Then, 1,3,5-tribromo-1,3,5-triazinan-2,4,6-trione (1.4 g, 1.0 equivalent, 3.8 mmol) was added at 0°C, and the solution was stirred at 25°C for 30 minutes. The resulting solution was quenched with NaHSO3 (10 mL) and the pH was adjusted to 7 with NaHCO3. The reaction mixture was extracted with ethyl acetate (3 × 30 mL), the organic layers were combined, washed with brine (2 × 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with PE / siRNA (5:1) to obtain tert-butyl7-(5-bromo-6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (1.4 g, 2.9 mmol, 78%); LCMS(M+H) + We obtained values ​​of 475.1 and 477.1.

[0659] Step 4-3, Preparation of tert-butyl7-(6-chloro-5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: In a 40 mL vial, add 1,4-dioxane (7 mL) and water (0.7 mL) to tert-butyl7-(5-bromo-6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate. Ridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (750 mg, 1 equivalent, 1.58 mmol), (3,5-difluorophenyl)boronic acid (300 mg, 1.21 equivalents, 1.90 mmol), Pd(dtbpf)Cl2 (103 mg, 0.100 equivalents, 158 μmol), and K3PO4 (1.00 g, 2.99 equivalents, 4.71 mmol) were added. The resulting mixture was stirred at 70°C for 1 hour under a nitrogen atmosphere. The resulting mixture was quenched with water (20 ml) and extracted with SiO2 (3 × 30 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with PE / siRNA (1:3) to obtain tert-butyl 7-(6-chloro-5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (350 mg, 688 μmol, 43.6%); LCMS(M+H) + We obtained values ​​of 509.4 and 511.4.

[0660] Step 4-4, Preparation of tert-butyl 7-(5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: In a 50 mL round-bottom flask, tert-butyl 7-(6-chloro-5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (350 mg, 1 equivalent, 688 μmol) and Pd-C (35 mg, 0.48 equivalents, 0.33 mmol; 10 wt%) were added in MeOH (10 mL). The reaction mixture was stirred at 25 °C for 1 hour under H2 (3 bar). Next, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain tert-butyl 7-(5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (250 mg, 527 μmol, 76.6%); LCMS(M+H) + = 475.2 was obtained.

[0661] Steps 4-5, Preparation of lithium 4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)pyridazine-3-carboxylate: In an 8 mL vial, tert-butyl 7-(5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (50 mg, 1 equivalent, 0.11 mmol), MeOH (0.2 mL), and water (0.04 mL) were added, followed by LiOH (4 mg, 2 equivalents, 0.2 mmol). The mixture was stirred at 60°C for 1 hour. The resulting mixture was concentrated under vacuum to obtain lithium 4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)pyridazine-3-carboxylate (50 mg, 92 μmol, 87%, purity 86%).

[0662] Steps 4-6, Preparation of tert-butyl 7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate: Lithium 4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)pyridazin-3-carboxylate (50 mg, 1 equivalent, 0.11 mmol), HATU (49 mg, 1.2 equivalents, 0.13 mmol), and DIEA (70 mg, 94 μL, 5.1 equivalents, 0.54 mmol) in DMF (1 mL) were added. The resulting reaction mixture was stirred at 25°C for 10 minutes. Next, 3,3-difluorocyclobutan-1-amine hydrochloride (23 mg, 1.5 equivalents, 0.16 mmol) was added. The resulting reaction mixture was stirred at 25°C for 1 hour. The mixture was purified by preparative HPLC under the following conditions: Column, SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; Mobile phase, water (0.1% TFA) and MeCN (30% MeCN - max 75%) over 7 minutes; Total flow rate, 20 mL / min; Detector, UV 220 nm. This yielded tert-butyl 7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (30 mg, 55 μmol, 51%); LC-MS(M+H) + = 550.4 was obtained.

[0663] Steps 4-7, Preparation of N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide: In a 50 mL round-bottom flask, tert-butyl7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridazine-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylate (30 mg, 1 equivalent, 55 μmol), DCM (3 mL), and TFA (1 mL) were added. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC under the following conditions (2#-Analysis-HPLC-SHIMADZU(HPLC-0013)): Column, Kinetex EVO 21.2×150 mm 5 μm; Mobile phase, water (0.1% TFA) and MeCN (25% MeCN over 15 minutes - max 55.0%); Detector, 220 nm. This extracted N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazinecarboxamide bis(2,2,2-trifluoroacetate) (32.1 mg, 47.4 μmol, 87%); LC-MS(M+H) += I obtained 450.2.

[0664] The following compounds were prepared in the same manner as in Example 4 using appropriate reagents and appropriate substitution of reagents and / or substrates and / or functional group modifications via well known chemicals.

[0665] [Table 8]

[0666] Example B-1: SSTR assay Functional assay General Overview: All five SSTR subtypes are Gi-coupled G protein-coupled receptors (GPCRs) that result in a decrease in intracellular cyclic AMP (cAMP) when activated by an agonist. Therefore, measuring intracellular cAMP levels can be used to assess whether a compound is an agonist of an SSTR subtype. An example of an intracellular cAMP assay is described below.

[0667] SSTR3 cAMP assay protocol Two or four days prior to the assay, Chinese hamster ovary cells (CHO-K1, ATCC #CCL-61) stably expressing human somatostatin receptor subtype 3 are plated at a rate of 6,000 or 2,000 cells per well in 96-well tissue culture plates 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 ug / mL streptomycin, 2 mM L-glutamine (Gemini Bio-Products #400-110), and 0.25 mg / mL G418 (GoldBio #G-418-5), respectively. Cells are cultured at 37°C, 5% CO2, and 95% humidity. cAMP is measured using the HTRF dynamic cAMP assay (Cisbio, #62AM5PEJ) according to the manufacturer's instructions. On the day of the assay, the culture medium is aspirated and the cells are treated with various dilutions of the compound of the present invention in 50 μL of stimulating buffer supplemented with 10.2 mM 3-isobutyl-1-methylxanthine (IBMX, Millipore Sigma #I5879) and 1.6 μM NKH477 (Tocris #1603). The cells are incubated at 37°C for 20 minutes (the final concentration of the compound of the present invention is typically 0–10,000 nM). The cells are treated with 50 μL of lysis buffer (HRTF cAMP kit, Cisbio) and incubated at room temperature for 30 minutes with rotational shaking at 600 rpm, then diluted with 150 μL of stimulating buffer and shaken for a further 5 minutes at 300 rpm. The lysate is transferred to a 384-well plate and incubated at room temperature for 1–24 hours. cAMP accumulation is detected by d2-labeled cAMP and anti-cAMP-cryptate. Time-resolved fluorescence signals are read using an m1000 Pro (Tecan) or CLARIOStar (BMG Labtech) microplate reader. The sample is excited with 340 nm light, and the emitted light is measured at 620 nm and 665 nm. The data is expressed as a calculated fluorescence ratio (665 nm / 620 nm). Intracellular cAMP concentration is calculated by regression to a standard curve and plotted against the concentration of the compound of the present invention. EC of the compound50 It is calculated using standard methods. All data manipulation is done in GraphPad Prism v9 (GraphPad, San Diego, CA).

[0668] Table A reports the biological activity of compounds evaluated by inhibition of cAMP activity via the human SSTR3 receptor.

[0669] [Table 9-1]

[0670] [Table 9-2]

[0671] [Table 9-3]

[0672] [Table 9-4]

[0673] Example B-2: In vitro 3D cyst formation model Maidin Darby canine kidney (MDCK) cells were resuspended in complete medium as single-cell suspensions in ice-cold collagen type I (Sigma-Aldrich) and plated in 96-well plates at a density of 250 cells per well (5-8 wells per condition). The plates were incubated at 37°C for 1 hour to polymerize the gel. To promote cyst growth, 100 μM of the panphosphodiesterase inhibitor IBMX (3-isobutyl-1-methylxanthine) was added to the complete medium on the plating day. Simultaneously, various concentrations of compound 5 or compound 108 were added to the wells. The medium was changed every 48-72 hours over a 9-day span. On day 9, the effect of each treatment on the cysts was evaluated. Random fields were selected, and multiple z-planes were imaged using an inverse-phase contrast microscope (Olympus CK2) at 40x magnification to account for all cysts within the field. The cyst area of ​​all captured cysts was measured using ImageJ V.2.9.0, and the data was analyzed using GraphPad Prism software. For each culture condition, the data (mean ± standard error) was expressed as um 2 The results were expressed as cyst area per unit. For each experiment, n=2. Statistical analysis using a two-tailed t-test: *P<0.05. See Figure 5.

[0674] Results: MDCK cells, derived from canine renal collecting ducts, are widely used to study cyst formation in vitro. When seeded on collagen gel, MDCK cells spontaneously form cysts, maintaining apical to basolateral polarity. Similarly, intracellular cAMP production drives cystic swelling in this system, as is observed in ADPKD patients.

[0675] Using this system, a three-dimensional culture system was developed to test the potential efficacy of the SSTR3 agonists disclosed herein. In this assay, cells were seeded in collagen in a 96-well plate, and cystic growth was promoted by the addition of IBMX, a pan-PDE inhibitor. IBMX was used to increase cAMP levels, as it was found that this treatment preferentially increased cAMP levels in the cilia rather than in the cytoplasm. As shown in Figure 5, the addition of IBMX resulted in a significant increase in cyst size. Importantly, the IBMX-induced cystic swelling was attenuated in a concentration-dependent manner by treatment with compound 5 (see Figure 5(A)) and compound 108 (see Figure 5(B)).

[0676] These results support the hypothesis that SSTR3 receptor activation reduces ciliary cAMP levels and cyst enlargement observed in ADPKD.

[0677] Example B-3: Evaluation of SSTR3 agonists on kidney weight and renal cyst index in a mouse model of autosomal dominant polycystic kidney disease (ADPKD) The efficacy of SSTR3 receptor agonists in attenuating kidney size and renal cyst index (KCI) in an autosomal dominant polycystic kidney disease (ADPKD) mouse model was evaluated using the following experimental protocol.

[0678] Generation of ADPKD mouse models. ADPKD mouse models were generated by selective inactivation of the Pkd1 gene in the kidneys of Pax8 Tet-O-Cre / Pkd1 flox mice, which result in renal cyst formation (Piontek et al., Clin J Am Soc Nephrol 2004, 15(12), 3035-3043; Piontek et al., Nat Med 2007, 13(12), 1490-1495; Traykova-Brauch et al., Nat Med 2008, 14(9), 979-984). Specifically, Pkd1 deletion in the kidneys was induced in Pax8 Tet-O-Cre / Pkd1 flox mice by intraperitoneal administration of doxycycline hicrat (50 mg / kg) on ​​postnatal days (PND) 11 and 12. PND20 showed that Pax8 Tet-O-Cre / Pkd1 flox mice (referred to as ADPKD mice) treated with doxycycline hicrat developed enlarged cystic kidneys compared to untreated control littermates.

[0679] SSTR3 agonists in ADPKD mouse models. To evaluate the ability of SSTR3 agonists to reduce kidney weight and KCI in ADPKD mouse models, studies were conducted in PND12 ADPKD male and female mice. Vehicles or SSTR3 agonists were administered once daily by forced oral administration from PND12 to PND20. Body weight and clinical signs were recorded daily. In PND20, 1-2 hours after treatment with vehicle or SSTR3 agonist, mice were anesthetized, and blood was collected by cardiac puncture into the left ventricle after thoracotomy using an ethylenediaminetetraacetic acid (EDTA) coated needle. Blood was collected in EDTA tubing and stored on ice until processed into plasma. Plasma samples were frozen and stored. The heart was harvested and its weight recorded to obtain the kidney-to-heart weight ratio. The left kidney was harvested, weighed, bisected longitudinally, and fixed overnight in 4% paraformaldehyde at 4°C. After fixation, the left kidney was processed and paraffin-embedded for histological morphometrics. Transverse sections of the kidney, including the cortex, medulla, and papilla, were collected on slides, and the slides were stained with hematoxylin and eosin. Images were taken at 1x and 4x magnification, and the total cystic area was measured from the images using ImageJ software. The renal cystic index (KCI) was calculated using the total cystic area.

[0680] Compound 108 was administered orally once daily to ADPKD mice from postnatal days (PND) 12 to 20, either as a vehicle or at doses of 10, 30, or 100 mg / kg / day. Left kidney weight (A) and renal cyst index (%) (B) were measured and calculated after euthanasia at PND20. Data are expressed as mean ± SEM (n=17 for the vehicle group, n=14 for the 10 mg / kg / day compound 108 group, n=15 for the 30 mg / kg / day group, and n=13 for the 100 mg / kg / day group). All data were analyzed using one-way analysis of variance (ANOVA), followed by a post-hoc test (Dunnett's test) to compare the treatment groups with the vehicle group. *p<0.5, ns: not significant. See Figure 6.

[0681] Results. Compound 108 was tested in a mouse model of ADPKD to evaluate its ability to reduce kidney size and renal cyst index in this model. The renal cyst index (KCI) after 9 days of treatment with compound 108 is summarized in Table B below.

[0682] [Table 10]

[0683] In ADPKD model mice, once-daily oral administration of compound 108 at a dose of 100 mg / kg / day from postnatal day 12 to postnatal day 20 significantly reduced the renal cyst index by 13.3% compared to the vehicle group (see Figure 6(B)), but had no significant effect on kidney weight (see Figure 6(A)).

[0684] Considering these results, there is a reasonable expectation that administering the SSTR3 agonists disclosed herein to the target population will lead to successful treatment of PKD, including ADPKD.

[0685] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes proposed to those skilled in the art should be included in the spirit and scope of this application and the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, R １ is unsubstituted or substituted C １－６ alkyl, unsubstituted or substituted C ３ - ６ cycloalkyl, unsubstituted or substituted 6-membered heterocycloalkyl, unsubstituted or substituted C ５ - ７ bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, and when R １ is substituted, R １ is substituted with 1 to 3 Xs, and each X is independently halogen, C １ - ６ alkyl, C １ - ６ alkoxy, C １ - ６ fluoroalkyl, C １ - ６ fluoroalkoxy, C ３ - ６ cycloalkoxy, CN, and OH, and is selected from the group consisting of L is combined or CR ２ R ３ And R ２ However, H or C １ - ６ It is alkyl, R ３ However, H, C １ - ６ Alkyl, C １ - ６ Alkoxy, CH ２ OCH ３ , or C １ - ６ It is either fluoroalkyl or R ２ and R ３ However, together with the carbon atoms to which they are bonded, C ３－６ Forming a cycloalkyl group, Z is 【Chemistry 2】 And, R ４ However, H is a halogen, and R ５ However, H is a halogen, and R ６ However, H, halogen, CN, C １ - ６ Alkyl, or C １ - ６ It is an alkoxy, R ７ However, H, D, CN, or 【Transformation 3】 And, R ８ However, H, D, OH, C １ - ６ Alkyl, C １ - ６ Alkoxy, NH ２ , or -NH(CH ２ ) ２ OH, R Ａ ,H,C(O)OC １－６ Alkyl, or C(O)C １－６ It is alkyl, R Ｂ However, H, D, or C １ - ６ It is alkyl, R Ｃ However, it is H or D, R Ｄ However, it is H or halogen, m is an integer selected from 0 and 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, where n is an integer selected from 0, 1, and 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

3. L is CR ２ R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R ２ The compound according to claim 1 or 3, wherein the compound is H or methyl, or a pharmaceutically acceptable salt thereof.

5. R ３ However, H, methyl, ethyl, trifluoromethyl, or CH ２ OCH ３ The compound according to claim 1, 3, or 4, or a pharmaceutically acceptable salt thereof.

6. R ２ and R ３ However, together with the carbon atoms to which they are bonded, C ３－６ A compound according to claim 1 or 3 that forms a cycloalkyl group, or a pharmaceutically acceptable salt thereof.

7. L, CH ２ 、 【Chemistry 4】 A compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

8. R １ However, non-substituted or substituted C １－４ A compound according to any one of claims 1 to 7, which is alkyl, or a pharmaceutically acceptable salt thereof.

9. R １ However, if it is substituted, R １ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X groups, each X being independently selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

10. R １ but, 【Transformation 5】 A compound according to any one of claims 1 to 9, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

11. R １ However, non-substituted or substituted C ３－６ A compound according to any one of claims 1 to 7, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

12. R １ However, if it is substituted, R １ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl.

13. R １ but, 【Transformation 6】 A compound according to any one of claims 1 to 7, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

14. R １ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted phenyl.

15. R １ However, if it is substituted, R １ The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with 1 to 3 X molecules, each X being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, and CN.

16. R １ but, 【Transformation 7】 A compound according to any one of claims 1 to 7, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

17. R １ The compound according to any one of claims 1 to 7, which is an unsubstituted or substituted pyridinyl, or an unsubstituted or substituted pyrimidinyl, or a pharmaceutically acceptable salt thereof.

18. R １ However, if it is substituted, R １ The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl, trifluoromethyl, methoxy, and CN.

19. R １ but, 【Transformation 8】 A compound according to any one of claims 1 to 7, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

20. R １ is unsubstituted or substituted C ５ - ７ -bicycloalkyl, a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

21. R １ However, if it is substituted, R １ The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with fluoro or trifluoromethyl.

22. Said C ５ - ７ The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein one or more of the carbon atoms of the bicycloalkyl group are crosslinking carbons.

23. R １ but, 【Chemistry 9】 A compound according to any one of claims 1 to 7, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

25. R Ａ A compound according to any one of claims 1 to 24, wherein H is present, or a pharmaceutically acceptable salt thereof.

26. R Ｂ is H, and R Ｃ is H, and R Ｄ is H, the compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

27. Z is 【Chemistry 10】 The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

28. Z is 【Chemistry 11】 A compound according to any one of claims 1 to 7 and 11 to 13, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound is the compound of formula (Ia), or a pharmaceutically acceptable salt thereof. 【Chemistry 12】 During the ceremony, R １ However, non-substituted or substituted C １－４ Alkyl, unsubstituted, or substituted C ３ - ６ Cycloalkyl, tetrahydropyran, unsubstituted or substituted C ５ - ７ Bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, R １ However, if it is substituted, R １ However, it is substituted with 1-2 X, and each X independently is F, Cl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, or OCH ２ CF ３ Selected from CN and OH, L is combined or CR ２ R ３ And R ２ However, it is H or methyl, and R ３ However, H, methyl, ethyl, trifluoromethyl, or -CH ２ OCH ３ is or R ２ and R ３ However, together with the carbon atoms to which they are bonded, they form a cyclopropyl group. Z is 【Chemistry 13】 And, R ４ However, it is H, F, or Cl, and R ５ However, it is H or F, and R ６ However, it is H, F, Cl, CN, methyl, or methoxy. R ７ However, H or 【Chemistry 14】 And, R ８ However, H, NH ２ The compound according to claim 1, which is methyl or methyl.

30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

31. L is CR ２ R ３ The compound according to claim 29, or a pharmaceutically acceptable salt thereof.

32. L, CH ２ 、 【Chemistry 15】 A compound according to claim 29 or 31, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

33. R １ However, non-substituted or substituted C １－４ A compound according to any one of claims 29 to 32, which is alkyl, or a pharmaceutically acceptable salt thereof.

34. R １ However, if it is substituted, R １ The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy.

35. R １ but, 【Chemistry 16】 A compound according to any one of claims 29 to 34, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

36. R １ However, non-substituted or substituted C ３－６ A compound according to any one of claims 29 to 32, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

37. R １ However, if it is substituted, R １ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl and trifluoromethyl.

38. R １ but, 【Chemistry 17】 A compound according to any one of claims 29 to 32, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

39. R １ The compound according to any one of claims 29 to 32, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted phenyl.

40. R １ However, if it is substituted, R １ The compound according to claim 39, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X, each X being independently selected from the group consisting of fluoro, chloro, methyl, methoxy, and CN.

41. R １ but, [Chemistry 18] A compound according to any one of claims 29-32 and 39-40, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

42. R １ The compound according to any one of claims 29 to 32, which is an unsubstituted or substituted pyridinyl, or an unsubstituted or substituted pyrimidinyl, or a pharmaceutically acceptable salt thereof.

43. R １ However, if it is substituted, R １ The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl, trifluoromethyl, methoxy, and CN.

44. R １ but, 【Chemistry 19】 A compound according to any one of claims 29 to 32, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

45. R １ However, non-substituted or substituted C ５ - ７ A compound according to any one of claims 29 to 32, which is a bicycloalkyl compound, or a pharmaceutically acceptable salt thereof.

46. Said C ５ - ７ The compound according to claim 45, or a pharmaceutically acceptable salt thereof, wherein one or more of the carbon atoms of the bicycloalkyl group are crosslinking carbons.

47. R １ However, if it is substituted, R １ The compound according to claim 45 or 46, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with a fluoropolymer.

48. R １ but, 【Chemistry 20】 A compound according to any one of claims 29 to 32, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

49. R １ The compound according to any one of claims 29 to 32, which is tetrahydropyran, or a pharmaceutically acceptable salt thereof.

50. R １ but, 【Chemistry 21】 The compound according to any one of claims 29 to 32 and 49, or a pharmaceutically acceptable salt thereof.

51. Z is 【Chemistry 22】 The compound according to any one of claims 29 to 50, or a pharmaceutically acceptable salt thereof.

52. Z is 【Chemistry 23】 The compound according to any one of claims 29 to 32 and 36 to 37, or a pharmaceutically acceptable salt thereof.

53. The aforementioned compound, 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 【Chemistry 24-4】 【Chemistry 24-5】 【Chemistry 24-6】 A compound according to claim 29, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

54. R ４ and R ６ A compound according to any one of claims 1 to 27 and 29 to 51, or a pharmaceutically acceptable salt thereof, wherein the compound is fluoro.

55. The compound is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt thereof. 【Chemistry 25】 During the ceremony, R １ However, non-substituted or substituted C １－３ Alkyl, unsubstituted, or substituted C ３－４ Cycloalkyl, unsubstituted, or substituted C ５ Bicycloalkyl, or unsubstituted or substituted 6-membered heteroaryl, R １ However, if it is substituted, R １ However, it is substituted with 1 to 2 X molecules, each X being independently selected from F, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, CN, and OH. L is bonded or CR ２ R ３ And R ２ However, H is R ３ However, H, methyl, or -CH ２ OCH ３ And, R ５ However, it is H or F, R ７ However, it is H, D, or CN, R ８ However, H, D, OH, methoxy, or -NH(CH ２ ) ２ The compound according to claim 1, wherein it is an OH group.

56. The compound according to claim 55, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

57. L is CR ２ R ３ The compound according to claim 55, or a pharmaceutically acceptable salt thereof.

58. L, CH ２ 、 【Chemistry 26】 A compound according to claim 55 or 57, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

59. R １ However, non-substituted or substituted C １－３ A compound according to any one of claims 55 to 58, which is alkyl, or a pharmaceutically acceptable salt thereof.

60. R １ However, if it is substituted, R １ The compound according to claim 59, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X groups, each X being independently selected from the group consisting of methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, and OH.

61. R １ but, 【Chemistry 27】 A compound according to any one of claims 55 to 60, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

62. R １ However, non-substituted or substituted C ３－４ A compound according to any one of claims 55 to 59, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

63. R １ However, if it is substituted, R １ The compound according to claim 62, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl, difluoromethyl, and trifluoromethyl.

64. R １ but, 【Chemistry 28】 A compound according to any one of claims 55 to 59, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

65. R １ The compound according to any one of claims 55 to 59, or a pharmaceutically acceptable salt thereof, wherein the compound is unsubstituted or substituted pyridinyl.

66. R １ However, if it is substituted, R １ The compound according to claim 65, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl, trifluoromethyl, methoxy, and CN.

67. R １ but, 【Chemistry 29】 A compound according to any one of claims 55 to 59, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

68. R １ However, non-substituted or substituted C ５ A compound according to any one of claims 55 to 59, which is a bicycloalkyl compound, or a pharmaceutically acceptable salt thereof.

69. Said C ５ The compound according to claim 68, or a pharmaceutically acceptable salt thereof, wherein one or more of the carbon atoms of the bicycloalkyl group are crosslinking carbons.

70. R １ However, if it is substituted, R １ The compound according to claim 68 or 69, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with trifluoromethyl.

71. R １ but, 【Transformation 30】 The compound according to any one of claims 55 to 59, or a pharmaceutically acceptable salt thereof.

72. The compound is the compound of formula (Ib), or a pharmaceutically acceptable salt thereof. 【Chemistry 31】 The compound according to any one of claims 55 to 71, or a pharmaceutically acceptable salt thereof.

73. The aforementioned compound, 【Chemistry 32-1】 【Chemistry 32-2】 【Chemistry 32-3】 A compound according to claim 55, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

74. The aforementioned compound is a compound of formula (Ib). 【Transformation 33】 The compound according to claim 73, or a pharmaceutically acceptable salt thereof.

75. R ７ However, H is R ８ A compound according to any one of claims 1 to 52, 54 to 72, and 74, or a pharmaceutically acceptable salt thereof, wherein H is present.

76. The aforementioned compound is the compound of formula (Id), or a pharmaceutically acceptable salt thereof. 【Transformation 34】 During the ceremony, R １ However, non-substituted or substituted C １－４ Alkyl, unsubstituted, or substituted C ３－５ A cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, R １ However, if it is substituted, R １ However, it is substituted with 1 to 3 X molecules, each X independently selected from F, Cl, methyl, ethyl, trifluoromethoxy, and CN. L is bonded or CR ２ R ３ And R ２ However, H is R ３ However, it is H or methyl, R ４ However, it is H, F, or Cl, R ５ However, it is H or F, R ６ However, it is H, F, or Cl, R Ａ However, it is H, C(O)OEt, or C(O)Me, R Ｂ However, it is H, D, or methyl, R Ｃ However, it is H or D, R Ｄ However, it is H or F, m is an integer selected from 0 or 1. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0, 1, and 2.

77. The compound according to claim 76, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

78. L is CR ２ R ３ The compound according to claim 76, or a pharmaceutically acceptable salt thereof.

79. L, CH ２ and 【Chemistry 35】 A compound according to claim 76 or 78, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

80. R １ However, non-substituted or substituted C １－４ A compound according to any one of claims 76 to 79, which is alkyl, or a pharmaceutically acceptable salt thereof.

81. R １ However, if it is substituted, R １ The compound according to claim 80, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with methyl or trifluoromethoxy.

82. R １ but, 【Transformation 36】 A compound according to any one of claims 76 to 81, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

83. R １ However, non-substituted or substituted C ３－５ A compound according to any one of claims 76 to 79, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

84. R １ However, if it is substituted, R １ The compound according to claim 83, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of fluoromethyl and trifluoromethyl molecules.

85. R １ but, 【Chemistry 37】 A compound according to any one of claims 76 to 79, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

86. R １ The compound according to any one of claims 76 to 79, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted phenyl.

87. R １ However, if it is substituted, R １ The compound according to claim 86, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with 1 to 3 X, each X being independently selected from the group consisting of fluoro, chloro, and CN.

88. R １ but, 【Transformation 38】 A compound according to any one of claims 76 to 79, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

89. R １ The compound according to any one of claims 76 to 79, or a pharmaceutically acceptable salt thereof, wherein the compound is unsubstituted or substituted pyridinyl.

90. R １ However, if it is substituted, R １ The compound according to claim 89, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X molecules, each X being independently selected from the group consisting of methyl and CN.

91. R １ but, 【Chemistry 39】 A compound according to any one of claims 76 to 79, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

92. The aforementioned compound, 【Chemistry 40-1】 【Chemistry 40-2】 【Chemistry 40-3】 A compound according to claim 76, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

93. A compound of formula (II), or a pharmaceutically acceptable salt thereof, 【Chemistry 41】 During the ceremony, R １ However, non-substituted or substituted C １－６ Alkyl, unsubstituted, or substituted C ３－６ A cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl, R １ However, if it is substituted, R １ However, it is substituted with 1-2 X, and each X independently acts as a halogen, C １ - ６ Alkyl, C １ - ６ Alkoxy, C １ - ６ Fluoroalkyl, C １ - ６ Selected from the group consisting of fluoroalkoxys and CN, L is bonded or CR ２ R ３ And R ２ However, H is R ３ A compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is H or methyl.

94. The compound according to claim 93, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

95. L is CH ２ or 【Chemistry 42】 The compound according to claim 93, or a pharmaceutically acceptable salt thereof.

96. R １ The compound according to any one of claims 93 to 95, or a pharmaceutically acceptable salt thereof, wherein the compound is unsubstituted or substituted ethyl.

97. R １ However, if it is substituted, R １ The compound according to claim 96, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or two X, each X being independently selected from the group consisting of methoxy and trifluoromethoxy.

98. R １ but, 【Chemistry 43】 A compound according to any one of claims 93 to 97, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

99. R １ However, non-substituted or substituted C ４－５ A compound according to any one of claims 93 to 95, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

100. R １ However, if it is substituted, R １ The compound according to claim 99, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with a fluoropolymer.

101. R １ but, 【Chemistry 44】 A compound according to any one of claims 93 to 95, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

102. R １ The compound according to any one of claims 93 to 95, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted phenyl.

103. R １ However, if it is substituted, R １ The compound according to claim 102, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with CN.

104. R １ but, 【Chemistry 45】 The compound according to any one of claims 93 to 95, or a pharmaceutically acceptable salt thereof.

105. R １ The compound according to any one of claims 93 to 95, or a pharmaceutically acceptable salt thereof, wherein the compound is an unsubstituted or substituted pyridinyl.

106. R １ However, if it is substituted, R １ The compound according to claim 105, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with methyl.

107. R １ but, 【Chemistry 46】 The compound according to any one of claims 93 to 95, or a pharmaceutically acceptable salt thereof.

108. The aforementioned compound, 【Chemistry 47】 A compound according to claim 93, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

109. The aforementioned compound is a compound of formula (IIa). 【Chemistry 48】 The compound according to any one of claims 93 to 107, or a pharmaceutically acceptable salt thereof.

110. The aforementioned compound, 【Chemistry 49】 A compound according to claim 109, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

111. A method for treating a disorder selected from the group consisting of polycystic kidney disease, polycystic liver disease, and ciliopathy, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof.

112. The method according to claim 111, wherein the disorder is polycystic kidney disease.

113. The method according to claim 111 or 112, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

114. A pharmaceutical composition comprising a compound according to any one of claims 1 to 110, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Images