Somatostatin subtype receptor 3 (SSTR3) agonists and uses thereof

Abstract

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

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 513,599, filed on July 14, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This article describes somatostatin receptor subtype 3 (SSTR3) agonist compounds, methods for preparing such compounds, pharmaceutical compositions and agents containing such compounds, and methods for treating conditions, diseases, or disorders that would benefit from the modulation of SSTR3 activity using such compounds. Background Technology

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

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

[0005] In preclinical studies, octreotide (binds to SSTR2 and SSTR3, but preferentially to SSTR2) and paretide (binds with high affinity to SSTR1, SSTR2, SSTR3, and SSTR5) reduced cAMP levels and proliferation in in vitro bile duct epithelial cells, inhibited the expansion of liver cysts in three-dimensional collagen culture, and inhibited the growth of PCK rats and Pkd2 cells. WS25 / – Mice and Pkd1 RC / RC The model shows the occurrence of kidney and liver cysts and fibrosis.

[0006] In clinical trials using octreotide or lanreotide (both bind to SSTR2 and SSTR3, but preferentially to SSTR2), kidney growth ceased in the first year of treatment and then resumed, though at a slower rate than in the untreated group. Liver volume decreased by 4%–6% in the first year of treatment, and this reduction was maintained in the second year. However, the observation period was too short to assess its impact on renal function. While octreotide and lanreotide are generally well tolerable, the long-acting formulations of these peptides are extremely expensive and require frequent, painful injections, which may lead to injection site reactions.

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

[0008] In one embodiment, the present invention describes a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R1 is unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted 6-membered heterocyclic alkyl, unsubstituted or substituted C 5-7 Bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl; wherein, if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 3-6 The group consisting of cycloalkoxy groups, CN, and OH; L is a bond or CR2R3, where R2 is H or C. 1-6Alkyl group, and R3 is H or C. 1-6 Alkyl, C 1-6 Alkoxy, CH2OCH3 or C 1-6 Fluoroalkyl groups; or R2 and R3 together with the carbon atoms to which they are attached to form C2+. 3-6 cycloalkyl; Z is or , R4 is H or a halogen; R5 is H or a halogen; and R6 is H, a halogen, CN, or C. 1-6 Alkyl or C 1-6 Alkoxy; R7 is H, CN, or ; R8 represents H, D, OH, and C. 1-6 Alkyl, C 1-6 alkoxy group, NH2 or -NH(CH2)2OH; R A H, C(O)OC 1-6 Alkyl or C(O)C 1-6 alkyl; R B For H, D or C 1-6 alkyl; R C For H or D; R D It is H or halogen; m is an integer selected from 0 and 1; and n is an integer selected from 0, 1, and 2.

[0009] In one implementation, L is a key.

[0010] 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 attached form C. 3-6 Cycloalkyl groups. In some embodiments, L is selected from: CH2、 , , , , , , , , as well as .

[0011] On the one hand, R1 is unsubstituted or substituted C. 1-4Alkyl group. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X groups, wherein each X is independently selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is selected from: , , , , , , , , , , , , , , , , , , , , , , as well as .

[0012] On the one hand, R1 is unsubstituted or substituted C. 3-6 Cycloalkyl. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine, methyl, and trifluoromethyl. In some embodiments, R1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0013] In one aspect, R1 is an unsubstituted or substituted phenyl group. In some embodiments, if R1 is substituted, then R1 is substituted by 1-3 X groups, wherein each X is independently selected from groups consisting of fluorine, chlorine, methyl, methoxy, and CN. In some embodiments, R1 is selected from: , , , , , , , , , , , , , as well as .

[0014] In one aspect, R1 is an unsubstituted or substituted pyridinyl group, or an unsubstituted or substituted pyrimidinyl group. In some embodiments, if R1 is substituted, R1 is substituted by 1-2 X groups, wherein each X is independently selected from the group consisting of fluorine, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is selected from: , , , , , , , , , , , , , , , , , as well as .

[0015] In one respect, R1 is unsubstituted or substituted C 5-7 Bicycloalkyl. In some embodiments, if R1 is substituted, R1 is substituted with fluorine or trifluoromethyl. In some embodiments, C 5-7 One or more carbon atoms of the bicycloalkyl group are bridging carbons. In some embodiments, R1 is selected from: , , , , as well as .

[0016] In one respect, m is 1 and n is 1.

[0017] In one respect, R A For H.

[0018] In one respect, R B For H; R C For H; R D For H.

[0019] In one respect, Z is .

[0020] In one respect, Z is .

[0021] On the other hand, this article describes compounds of formula (Ia) or pharmaceutically acceptable salts thereof: (Ia) in: R1 is unsubstituted 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 six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from F, Cl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, OCH2CF3, CN and OH. L is a bond or CR2R3, where R2 is H or methyl, and R3 is H, methyl, ethyl, trifluoromethyl, or -CH2OCH3; or R2 and R3 together with the carbon attached to them form a cyclopropyl group; Z is or , Where R4 is H, F, or Cl; R5 is H or F; R6 is H, F, Cl, CN, methyl, or methoxy. R7 is H or ; R8 can be H, NH2, or methyl.

[0022] In one respect, L is the key.

[0023] In one aspect, L is CR2R3. In some implementations, L is selected from: CH2、 , , , , , , , , as well as .

[0024] In one respect, R1 is unsubstituted or substituted C 1-4 Alkyl group. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X groups, wherein each X is independently selected from the group consisting of methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In some embodiments, R1 is selected from: , , , , , , , , , , , , , , , as well as .

[0025] In one respect, R1 is unsubstituted or substituted C 3-6 Cycloalkyl. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine, methyl, and trifluoromethyl. In some embodiments, R1 is selected from: , , , , , , , , , , , , , , , , , , , , as well as .

[0026] In one aspect, R1 is an unsubstituted or substituted phenyl group. In some embodiments, R1 is substituted by one or two X's, wherein each X is independently selected from the group consisting of fluorine, chlorine, methyl, methoxy, and CN. In some embodiments, R1 is selected from: , , , , , , , , , , , as well as .

[0027] In one aspect, R1 is an unsubstituted or substituted pyridinyl group, or an unsubstituted or substituted pyrimidinyl group. In some embodiments, if R1 is substituted, R1 is substituted by 1-2 X groups, wherein each X is independently selected from the group consisting of fluorine, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is selected from: , , , , , , , , , , , , , as well as .

[0028] In one respect, R1 is unsubstituted or substituted C 5-7 Bicycloalkyl. In some embodiments, if R1 is substituted, then R1 is substituted with fluorine. In some embodiments, C 5-7 One or more carbon atoms of the bicycloalkyl group are bridging carbons. In some embodiments, R1 is selected from: , , , as well as .

[0029] In one aspect, R1 is tetrahydropyran. In some embodiments, R1 is... .

[0030] In one respect, Z is In some implementations, R4 and R6 are fluorine.

[0031] In one respect, Z is .

[0032] In one respect, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0033] On the other hand, this article describes compounds of formula (Ib) or formula (Ic), or pharmaceutically acceptable salts thereof: (Ib) (Ic) in: R1 is unsubstituted or substituted C 1-3 Alkyl, unsubstituted or substituted C 3-4 Cycloalkyl, unsubstituted or substituted C5 bicycloalkyl, or unsubstituted or substituted 6-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from F, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, CN, and OH. L is a bond or CR2R3, where R2 is H and R3 is H, methyl, or -CH2OCH3; R5 is either H or F; R7 is either H or CN; and R8 can be H, D, OH, methoxy, or -NH(CH2)2OH.

[0034] In one respect, the compound is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: (Ib).

[0035] In one respect, L is the key.

[0036] In one aspect, L is CR2R3. In some implementations, L is selected from: CH2、 as well as .

[0037] In one respect, R1 is unsubstituted or substituted C 1-3 Alkyl group. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X groups, wherein each X group is independently selected from the group consisting of methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH. In some embodiments, R1 is selected from: , , , , , , , as well as .

[0038] In one respect, R1 is unsubstituted or substituted C 3-4 Cycloalkyl. In one embodiment, if R1 is substituted, then R1 is substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine and trifluoromethyl. In some embodiments, R1 is selected from: , , , , , , , as well as .

[0039] In one aspect, R1 is an unsubstituted or substituted pyridinyl group. In some embodiments, if R1 is substituted, R1 is substituted by 1-2 X groups, wherein each X is independently selected from the group consisting of fluorine, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is selected from: , , , , , as well as .

[0040] In one aspect, R1 is an unsubstituted or substituted C5 bicycloalkyl group. In some embodiments, one or more carbon atoms of the R5 bicycloalkyl group are bridging carbons. In some embodiments, if R1 is substituted, R1 is substituted with a trifluoromethyl group. In one embodiment, R1 is: .

[0041] In one respect, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0042] In one respect, R7 is H and R8 is H.

[0043] On the other hand, this article describes compounds of formula (Id) or pharmaceutically acceptable salts thereof:

[0044] Formula(Id) in: R1 is unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is 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 a methyl group; R4 is H, F, or Cl; R5 is either H or F; R6 is H, F, or Cl; R A For H, C(O)OEt or C(O)Me; R B It can be H, D, or methyl; R C For H or D; R D For H or F; m is an integer selected from 0 or 1; and n is an integer selected from 0, 1, and 2.

[0045] In one respect, L is the key.

[0046] In one aspect, L is CR2R3. In some implementations, L is selected from: CH2 and .

[0047] In one respect, R1 is unsubstituted or substituted C 1-4 Alkyl group. In some embodiments, if R1 is substituted, R1 is substituted with methyl or trifluoromethoxy. In some embodiments, R1 is selected from: and .

[0048] In one respect, R1 is unsubstituted or substituted C 3-5 Cycloalkyl. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine and trifluoromethyl. In some embodiments, R1 is selected from: , as well as .

[0049] In one aspect, R1 is an unsubstituted or substituted phenyl group. In some embodiments, if R1 is substituted, then R1 is substituted by 1-3 X's, wherein each X is independently selected from the group consisting of fluorine, chlorine, and CN. In some embodiments, R1 is selected from: , , , , as well as .

[0050] In one aspect, R1 is an unsubstituted or substituted pyridyl group. In some embodiments, if R1 is substituted, then R1 is substituted by 1-2 X groups, wherein each X group is independently selected from the group consisting of methyl and CN. In one embodiment, R1 is selected from: , as well as .

[0051] In one respect, the compounds are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0052] On the other hand, this article describes compounds of formula (II) or pharmaceutically acceptable salts thereof: (II) in: R1 is unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 fluoroalkyl, C 1-6 The group consisting of fluoroalkoxy groups and CN; and L is a bond or CR2R3, where R2 is H and R3 is H or methyl.

[0053] In one respect, the compound is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof: (IIa).

[0054] In one respect, L is a bond or CR2R3.

[0055] In one respect, L is selected from: CH2 or .

[0056] In one aspect, R1 is an unsubstituted or substituted ethyl group. In some embodiments, if R1 is substituted, then R1 is substituted with 1-2 X groups, wherein each X group is independently selected from methoxy and trifluoromethoxy groups. In some embodiments, R1 is selected from: , as well as .

[0057] In one respect, R1 is unsubstituted or substituted C 4-5 Cycloalkyl groups. In some embodiments, if R1 is substituted, then R1 is substituted with fluorine. In some embodiments, R1 is selected from: and .

[0058] In one aspect, R1 is an unsubstituted or substituted phenyl group. In some embodiments, if R1 is substituted, then R1 is substituted with CN. In some embodiments, R1 is: .

[0059] In one aspect, R1 is an unsubstituted or substituted pyridinyl group. In some embodiments, if R1 is substituted, then R1 is substituted with a methyl group. In some embodiments, R1 is: .

[0060] In one respect, the compound is selected from: , , as well as .

[0061] In one respect, the compound is selected from: , , , , as well as .

[0062] In another aspect disclosed herein, there is a method for treating a disease selected from polycystic kidney disease, polycystic liver disease, and cilia, comprising administering to a subject requiring treatment any one of formulas (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) a pharmaceutically acceptable salt thereof. In some embodiments, the disease is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

[0063] This document also discloses another aspect, a pharmaceutical composition 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. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 This study describes how abnormal primary ciliary function in autosomal dominant polycystic kidney disease (ADPKD) triggers cyst formation.

[0065] FIG. 2 The interaction between calcium ions and the cAMP ciliary signaling pathway in the kidney tissue of (A) healthy individuals and (B) individuals with ADPKD was depicted.

[0066] FIG. 3 The mechanism by which SSTR3 activates and inhibits adenylate cyclase activity and reduces cAMP levels in ciliated plasma was described.

[0067] Figure 4 illustrates the analysis of mRNA expression of SSTR2, SSTR3, SSTR5, and angiotensin receptor 2 (AVPR2) in healthy and cystic tissues.

[0068] FIG. 5 The roles of (A) compound 105 and (B) compound 108 in an in vitro 3D cyst formation model were described.

[0069] Figure 6 illustrates the effects of oral administration of compound 108 on (A) left kidney weight and (B) renal cyst index in ADPKD mice. Detailed Implementation

[0070] Somatostatin (SSTR), also known as growth hormone-releasing inhibitory factor (SRIF), was initially isolated from the hypothalamus of sheep as a 14-amino acid peptide (Brazeau et al., Science 179, 77-79, 1973). Subsequently, a 28-amino acid peptide with an N-terminal extension was isolated, whose biological activity was similar to that of the 14-amino acid somatostatin (Pradayrol et al., FEBS Letters, 109, 55-58, 1980; Esch et al., Proceedings of the National Academy of Sciences, 77, 6827–6831, 1980). SSTR is a regulatory peptide produced by various cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SSTR affects its target cells through endocrine and paracrine pathways. Many of its effects are related to the inhibition of the secretion of other hormones, especially growth hormone (GH). SSTRs are produced by multiple cell types in the central nervous system (CNS) and the gut and have a variety of functions, including regulating the secretion of growth hormone (GH), insulin, glucagon, and many other hormones with antiproliferative effects.

[0071] The pleiotropic effects of somatostatin are mediated by six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, and SSTR5). These six somatostatin receptor proteins are encoded by five different somatostatin receptor genes (Reisine and Bell, Endocr Rev. 16, 427-442, 1995; Patel and Srikant, TrendsEndocrinol Metab 8, 398-405, 1997). All of these receptors belong to the A subgroup of the GPCR superfamily.

[0072] Any somatostatin receptor subtype or combination thereof can be selectively modulated. Selective modulation of any somatostatin receptor subtype, compared to other somatostatin receptor subtypes, can reduce adverse side effects in a variety of clinical applications.

[0073] In some embodiments, the SSTR3 agonists described herein are used to treat a variety of diseases or conditions, such as, but not limited to, ciliary disorders, including but not limited to polycystic kidney disease and polycystic liver disease. In some embodiments, the SSTR3 agonists described herein are used to treat a variety of diseases or conditions associated with ciliary dysfunction, such as, but not limited to, 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 to treat polycystic kidney disease (PKD). In some embodiments, the SSTR3 agonists described herein are used to treat autosomal dominant polycystic kidney disease (ADPKD). In one embodiment, the somatostatin receptor modulator described herein is used to treat polycystic kidney disease (PKD) in mammals.

[0074] Fibrosis Ciliopathy is a group of developmental and degenerative monogenic disorders characterized by dysfunction of hair-like organelles called cilia. Cilia are microtubule structures present on cells of almost all vertebrates. They originate from the basal body (modified centrosome), organelles that form the spindle poles during mitosis. Most of the altered proteins in monogenic ciliopathy function at the ciliate-centrosome complex, which represents a universal system in nature for cells to detect and manage external signals. The ciliate-centrosome complex plays a crucial role in the normal function of most tissues, explaining why ciliopathy can affect multiple organ systems. Ciliate dysfunction can lead to a variety of ciliopathy disorders and symptoms, including but 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.

[0075] Polycystic kidney disease Polycystic kidney disease (PKD, also known as polycystic kidney syndrome) is a genetic disorder characterized by abnormal renal tubular structure, leading to the formation and growth of multiple cysts within the kidneys. These cysts consist of fluid-filled, non-functional renal tubules. The cysts vary in size, from tiny to enormous, and can compress adjacent normal renal tubules, eventually causing them to lose function. PKD is classified into two types, each with its own pathological and genetic causes: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The mutated gene is expressed in all cells of the body; therefore, cysts can also appear in the liver.

[0076] In various animal models of ciliasis, including polycystic kidney disease (PKD), tissue cAMP levels are elevated. Typically, tissue cAMP levels depend on the activity of membrane-bound and soluble adenylate cyclase (AC) and cAMP phosphodiesterase (PDE), the activities of which are influenced by complex regulatory mechanisms. For example, in some cases, AC may be positively or negatively regulated by G protein-coupled receptors (GPCRs) and extracellular ligands. For instance, somatostatin acts on five somatostatin receptors (SSTRs 1 through 5), thereby inhibiting AC and reducing intracellular cAMP levels.

[0077] Elevated cAMP levels disrupt renal tubular formation, stimulate chloride and fluid secretion within the cyst lumen, and activate pro-proliferative signaling pathways, including mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK / ERK), mTOR, and β-catenin signaling pathways. Activated mTOR transcription stimulates aerobic glycolysis, increasing ATP synthesis and decreasing AMP levels. This, along with β-Raf-dependent LKB1 activation, inhibits AMPK, further enhancing mTOR activity and CFTR-driven chloride and fluid secretion. Elevated cAMP levels lead to enhanced PKA signaling, which in turn activates multiple transcription factors, including STAT3 and cAMP response element-binding protein (CREB). Activated STAT3 induces the transcription of cytokines, chemokines, and growth factors, which in turn activate STAT3 on mesenchymal replacement activated (M2) macrophages, thereby forming a feedforward loop between cyst lining cells and M2 macrophages. Aberrant integrin-extracellular membrane interactions and cAMP signaling within the focal adhesion complex may also lead to enhanced adhesion of cyst-derived cells to laminin-322 and collagen. In ADPKD, overactive CREB mediates cAMP-dependent gene regulation, thereby regulating multiple cellular processes, including metabolism, cell survival and proliferation, differentiation, apoptosis, and immune responses. The central role of cAMP in the pathogenesis of PKD provides a strong theoretical basis for strategies to reduce cAMP levels in cystic tissue.

[0078] ADPKD is the most common inherited kidney disease, with an incidence of approximately one in a thousand (Clin. Med. (Lond) 2009 Jun; 9(3): 278-283). It is characterized by the slow, progressive development of bilateral renal cysts, typically leading to renal insufficiency, usually occurring around the age of fifty or sixty. The cysts that form in the kidneys of ADPKD patients originate from the renal tubules. Mutations in the PKD1 or PKD2 genes (encoding polycystin-1 or polycystin-2, 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, ultimately resulting in cyst formation (e.g., see...). FIG. 1 (Int. J. Mol. Sci. 2022 Mar 19; 23(6): 3317). Due to excessive chloride ion secretion within the cyst cavity, fluid transport increases, leading to cyst growth and expansion. Eventually, the cyst branches off from the main nephron, continuously exerting pressure on surrounding tissues, causing local damage. Although the process of normal kidney tissue being replaced by the cyst begins early in life, the reduction in total nephron mass is masked by compensatory changes in glomerular filtration rate (GFR), making the total GFR appear normal for many years until the compensatory mechanism fails. At this point, ADPKD patients often also experience symptoms such as back pain, hematuria, urinary tract infection, or renal colic. ADPKD often leads to chronic kidney disease and end-stage renal disease (ESRD), requiring dialysis or kidney transplantation for survival.

[0079] The biological functions of polycystin remain poorly understood. However, mounting evidence suggests that loss of the inhibitory role of polycystin in ciliary pathway activation may be the cause of cyst formation observed in ADPKD. In healthy individuals, polycystin-1 and polycystin-2 (PC1 / 2) bind directly to form a calcium channel that is localized on the primary cilia of renal epithelial cells (Nature Reviews Nephrology 2019; 15: 412-422). See also FIG. 2 (A)

[0080] Cilia are nonmotorized plasma membrane appendages that act as mechanoreceptors, detecting changes in fluid flow within the renal tubules and converting it into calcium. 2+Signal response. This makes cilia a special signaling hub with a much higher calcium concentration than the cytoplasm (Int. J. Mol. Sci. 2020 Sept 26; 21(19): 7109). High calcium levels directly inhibit ciliary adenylate cyclases 5 and 6 (AC5 / 6), which are responsible for converting ATP to cAMP and stimulating phosphodiesterase (PDE, an enzyme that catalyzes the hydrolysis of cAMP). Therefore, the functional polycystic protein complex maintains lower cAMP levels within the cilia. cAMP is a second messenger that plays a role in a variety of cellular processes, including cell growth and differentiation. See also FIG. 2 (A)

[0081] In ADPKD patients, mutations in polycystin-1 or 2 lead to the formation of dysfunctional or impaired channels, resulting in a significant decrease in intraciliary calcium levels (World J. Nephrol. 2016 Jan 6; 5(1): 76-83). Consequently, calcium-inhibitory AC5 / 6 activity is increased, while calcium-dependent PDE4 activity is decreased. Dysregulation of AC5 / 6 and PDE4 activity leads to a significant increase in intraciliary cAMP levels. See Figure 2(B).

[0082] High levels of cAMP trigger cyst formation by stimulating the expression of cAMP-dependent genes involved in proliferation and by activating the cystic fibrosis transmembrane transduction regulator (CFTR) stimulated by protein kinase A (PKA), driving chloride ion and fluid secretion within the cystic lumen. Therefore, in ADPKD, aberrant crosstalk between intraciliary calcium and the cAMP signaling pathway appears to play a crucial role in cyst formation. Consequently, the inventors hypothesize that selectively blocking adenylate cyclase activity within the cilia can inhibit / reduce cyst formation observed in ADPKD.

[0083] SSTR3 is a typical ciliary GPCR (Neuroscience 1999 Mar; 89(3): 909-26). The transport of SSTR3 to the cilia requires a series of highly regulated processes, including translocation of the receptor from the cytoplasm to the axonal filament via the transition region, primarily 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, activation of SSTR3 can inhibit adenylate cyclase activity (Murthy et al., J. Biol. Chem. 1996: 271(38): 23458-23463) and reduce ciliary-plasma cAMP levels, which is crucial for the development of ADPKD. See Figure 3.

[0084] Song et al. reported a public dataset (GSE7869) from a global genomic profiling study of renal cysts (Hum.Mol. Genet. 2009; 18: 2328-2343). This dataset contains microarray expression data from the kidneys of five PKD1 patients with cysts of varying sizes and three healthy subjects. The inventors reanalyzed the data using a transcriptome analysis console (Thermo Fisher). Detection of probes covering SSTRR3 (SSTR3) revealed that SSTRR3-mRNA expression levels were higher in both healthy and cystic tissues compared to somatostatin receptors 2 and 5 (SSTR2, SSTR5) or angiotensin receptor 2 (AVPR2) (see [link to original text]). FIG. 4 Therefore, the inventors determined that the cellular localization and signal transduction capabilities of SSTR3 make it an attractive target for the treatment of ADPKD.

[0085] Autosomal recessive polycystic kidney disease (ARPKD) is a major cause of end-stage renal disease (ESRD) and infant mortality, caused by mutations in the PKHD1 gene (encoding fibroblastin). Similar to ADPKD, cyst formation in ARPKD is due to dysregulation of cell differentiation mechanisms, leading to excessive cell proliferation and fluid secretion, as well as pathogenic interactions between mutant epithelial cells and abnormal extracellular matrix and alternatively activated mesenchymal macrophages. Dysregulation of crosstalk between ciliary calcium and cyclic adenosine monophosphate (cAMP) signaling pathways 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), thereby reducing cAMP levels and cAMP-dependent signaling.

[0086] In some embodiments, the somatostatin receptor modulators described herein are used to treat ciliary diseases in mammals. In some embodiments, the somatostatin receptor modulators described herein can reduce cAMP levels, which helps in the treatment of the ciliary diseases described herein. In some embodiments, the ciliary 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 ciliary 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 ciliary disease or condition is polycystic kidney disease (PKD). In some embodiments, the ciliary disease or condition is autosomal dominant polycystic kidney disease (ADPKD). In some embodiments, the ciliary disease or condition is autosomal recessive polycystic kidney disease (ARPKD).

[0087] This article also describes a method for treating mammalian diseases or conditions that benefits from modulating the activity of somatostatin receptor subtype 3 (SSTR3), including administering selective small molecule SSTR3 agonist compounds to mammals in need.

[0088] In some embodiments, the disease or condition is any one of the diseases or conditions described herein, or a combination thereof. In some embodiments, the disease or condition is associated with ciliary dysfunction. In some embodiments, the disease or condition is ciliopathy or a condition. In some embodiments, the selective small molecule SSTR3 agonist is a compound described herein.

[0089] compound Compounds of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (II), and formula (IIa) are provided, including their pharmaceutically acceptable salts, which are somatostatin subtype 3 receptor (SSTR3) agonists.

[0090] In some embodiments, the compound is a compound of formula (I): (I) in: R1 is unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted 6-membered heterocyclic alkyl, unsubstituted or substituted C 5-7 Bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl; If R1 is substituted, then R1 is substituted by 1-3 X, where each X is independently chosen from free halogens and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 3-6 The group consisting of cycloalkoxy groups, CN, and OH; L is a bond or CR2R3, where R2 is H or C. 1-6 Alkyl group, and R3 is H or C. 1-6 Alkyl, C 1-6 Alkoxy, CH2OCH3 or C 1-6 Fluoroalkyl groups; or R2 and R3 together with the carbon atoms to which they are attached to form C2+. 3-6 cycloalkyl; Z is or , R4 is H or a halogen; R5 is H or a halogen; and R6 is H, a halogen, CN, or C. 1-6 Alkyl or C1-6 Alkoxy; R7 is H, CN, or ; R8 represents H, D, OH, and C. 1-6 Alkyl, C 1-6 alkoxy group, NH2 or -NH(CH2)2OH; R A H, C(O)OC 1-6 Alkyl or C(O)C 1-6 alkyl; R B For H, D or C 1-6 alkyl; R C For H or D; R D It is H or halogen; m is an integer selected from 0 and 1; and n is an integer selected from 0, 1, and 2.

[0091] In some implementations, L is a key.

[0092] In some embodiments, L is CR2R3. In some embodiments, L is CR2R3 and R2 is H or methyl. In some embodiments, L is CR2R3 and R2 is H. In some embodiments, L is CR2R3 and R2 is methyl. In some embodiments, L is CR2R3 and R3 is H, methyl, ethyl, trifluoromethyl, or CH2OCH3. In some embodiments, L is CR2R3 and R3 is H. In some embodiments, L is CR2R3 and R3 is methyl. In some embodiments, L is CR2R3 and R3 is ethyl. In some embodiments, L is CR2R3 and R3 is trifluoromethyl. In some embodiments, L is CR2R3 and R3 is CH2OCH3. In some embodiments, L is CR2R3, R2 is H, and R3 is H. In some embodiments, L is CR2R3, R2 is H, and R3 is methyl.

[0093] In some embodiments, L is CR2R3, and R2 and R3 together with the carbon to which they are attached form C. 3-6 Cycloalkyl group. In some embodiments, L is CR2R3, and R2 and R3 together with the carbon atoms to which they are attached form a cyclopropyl moiety.

[0094] In some implementations, L is selected from: CH2、 , , , , , , , , as well as .

[0095] In some implementations, R1 is unsubstituted or substituted C 1-4 Alkyl group. In some embodiments, R1 is an unsubstituted C12. 1-4 Alkyl group. In some embodiments, R1 is a substituted C- group. 1-4 Alkyl group. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms. 1-4 Alkyl group, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a C substituted with X. 1-4 Alkyl group, wherein X is selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a C molecule substituted with two X atoms. 1-4 Alkyl groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0096] In some embodiments, R1 is an unsubstituted or substituted methyl group. In some embodiments, R1 is an unsubstituted methyl group. In some embodiments, R1 is a substituted methyl group. In some embodiments, R1 is a methyl group substituted with 1-2 X's, wherein each X is independently selected from trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a methyl group substituted with X's, wherein X's are selected from trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a methyl group substituted with 2 X's, wherein each X's are independently selected from trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0097] In some embodiments, R1 is an unsubstituted or substituted ethyl group. In some embodiments, R1 is an unsubstituted ethyl group. In some embodiments, R1 is a substituted ethyl group. In some embodiments, R1 is an ethyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is an ethyl group substituted with X groups, wherein X is selected from methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is an ethyl group substituted with 2 X groups, wherein each X is independently selected from methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0098] In some embodiments, R1 is an unsubstituted or substituted n-propyl group. In some embodiments, R1 is an unsubstituted n-propyl group. In some embodiments, R1 is a substituted n-propyl group. In some embodiments, R1 is a n-propyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a n-propyl group substituted with X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0099] In some embodiments, R1 is an unsubstituted or substituted isopropyl group. In some embodiments, R1 is an unsubstituted isopropyl group. In some embodiments, R1 is a substituted isopropyl group. In some embodiments, R1 is an isopropyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is an isopropyl group substituted with X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0100] In some embodiments, R1 is an unsubstituted or substituted n-butyl. In some embodiments, R1 is an unsubstituted n-butyl. In some embodiments, R1 is a substituted n-butyl. In some embodiments, R1 is a n-butyl substituted with 1-2 X's, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a n-butyl substituted with X's, wherein X's are selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a n-butyl substituted with 2 X's, wherein each X's are independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0101] In some embodiments, R1 is an unsubstituted or substituted isobutyl group. In some embodiments, R1 is an unsubstituted isobutyl group. In some embodiments, R1 is a substituted isobutyl group. In some embodiments, R1 is an isobutyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is an isobutyl group substituted with X groups, wherein X is selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is an isobutyl group substituted with 2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0102] In some embodiments, R1 is an unsubstituted or substituted sec-butyl group. In some embodiments, R1 is an unsubstituted sec-butyl group. In some embodiments, R1 is a substituted sec-butyl group. In some embodiments, R1 is a sec-butyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a sec-butyl group substituted with X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a sec-butyl group substituted with 2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0103] In some embodiments, R1 is an unsubstituted or substituted tert-butyl group. In some embodiments, R1 is an unsubstituted tert-butyl group. In some embodiments, R1 is a substituted tert-butyl group. In some embodiments, R1 is a tert-butyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a tert-butyl group substituted with X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH. In some embodiments, R1 is a tert-butyl group substituted with 2 X groups, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

[0104] In some implementations, R1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0105] In some implementations, R1 is unsubstituted or substituted C 3-6 Cycloalkyl. In some embodiments, R1 is an unsubstituted C12-hydroxyl group. 3-6 Cycloalkyl. In some embodiments, R1 is a substituted C 3-6 Cycloalkyl. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms. 3-6 Cycloalkyl, wherein each X is independently selected from the group consisting of fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a C substituted with X. 3-6Cycloalkyl, wherein X is selected from fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a C molecule substituted with two X atoms. 3-6 Cycloalkyl, wherein each X is independently selected from fluorine, methyl, difluoromethyl and trifluoromethyl.

[0106] In some embodiments, R1 is an unsubstituted or substituted cyclopropyl group. In some embodiments, R1 is an unsubstituted cyclopropyl group. In some embodiments, R1 is a substituted cyclopropyl group. In some embodiments, R1 is a cyclopropyl group substituted with 1-2 X groups, wherein each X is independently selected from the group consisting of fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclopropyl group substituted with X, wherein X is selected from fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclopropyl group substituted with 2 X groups, wherein each X is independently selected from fluorine, methyl, difluoromethyl, and trifluoromethyl.

[0107] In some embodiments, R1 is an unsubstituted or substituted cyclobutyl group. In some embodiments, R1 is an unsubstituted cyclobutyl group. In some embodiments, R1 is a substituted cyclobutyl group. In some embodiments, R1 is a cyclobutyl group substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclobutyl group substituted with X's, wherein X's are selected from fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclobutyl group substituted with 2 X's, wherein each X's are independently selected from fluorine, methyl, difluoromethyl, and trifluoromethyl.

[0108] In some embodiments, R1 is an unsubstituted or substituted cyclopentyl group. In some embodiments, R1 is an unsubstituted cyclopentyl group. In some embodiments, R1 is a substituted cyclopentyl group. In some embodiments, R1 is a cyclopentyl group substituted with 1-2 X groups, wherein each X is independently selected from the group consisting of fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclopentyl group substituted with X groups, wherein X is selected from fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclopentyl group substituted with 2 X groups, wherein each X is independently selected from fluorine, methyl, difluoromethyl, and trifluoromethyl.

[0109] In some embodiments, R1 is an unsubstituted or substituted cyclohexyl group. In some embodiments, R1 is an unsubstituted cyclohexyl group. In some embodiments, R1 is a substituted cyclohexyl group. In some embodiments, R1 is a cyclohexyl group substituted with 1-2 X groups, wherein each X is independently selected from the group consisting of fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclohexyl group substituted with X groups, wherein X is selected from fluorine, methyl, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a cyclohexyl group substituted with 2 X groups, wherein each X is independently selected from fluorine, methyl, difluoromethyl, and trifluoromethyl.

[0110] In some implementations, R1 is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0111] In some embodiments, R1 is an unsubstituted or substituted phenyl group. In some embodiments, R1 is an unsubstituted phenyl group. In some embodiments, R1 is a substituted phenyl group. In some embodiments, R1 is a phenyl group substituted with 1 to 3 X's, wherein each X is independently selected from fluorine, chlorine, methyl, methoxy, and CN. In some embodiments, R1 is a phenyl group substituted with X's, wherein each X is independently selected from fluorine, chlorine, methyl, methoxy, and CN. In some embodiments, R1 is a phenyl group substituted with 3 X's, wherein each X is independently selected from fluorine, chlorine, methyl, methoxy, and CN.

[0112] In some implementations, R1 is selected from: , , , , , , , , , , , , , as well as .

[0113] In some implementations, R1 is selected from: , , , , , , as well as .

[0114] In some implementations, R1 is selected from: , as well as .

[0115] In some embodiments, R1 is an unsubstituted or substituted pyridinyl group or an unsubstituted or substituted pyrimidinyl group.

[0116] In some embodiments, R1 is an unsubstituted or substituted pyridinyl group. In some embodiments, R1 is an unsubstituted pyridinyl group. In some embodiments, R1 is a pyridinyl group substituted with 1-2 X groups, wherein each X is independently selected from fluorine, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is a pyridinyl group substituted with X groups, wherein each X is independently selected from fluorine, methyl, trifluoromethyl, methoxy, and CN.

[0117] In some embodiments, R1 is an unsubstituted or substituted pyrimidinyl group. In some embodiments, R1 is an unsubstituted pyrimidinyl group. In some embodiments, R1 is a pyrimidinyl group substituted with X, wherein X is a methyl group.

[0118] In some implementations, R1 is selected from: , , , , , , , , , , , , , , , , , as well as .

[0119] In some implementations, R1 is selected from: , , , , , , , , , , , , , , , as well as .

[0120] In some implementations, R1 is selected from: , , , , , as well as .

[0121] In some implementations, R1 is selected from: , , , as well as .

[0122] In some implementations, R1 is selected from: and .

[0123] In some implementations, R1 is unsubstituted or substituted C 5-7 Bicycloalkyl. In some embodiments, R1 is an unsubstituted C1. 5-7 Bicycloalkyl. In some embodiments, R1 is a substituted C 5-7 Bicycloalkyl. In some embodiments, R1 is a C1 substituted with fluorine or trifluoromethyl. 5-7 Bicycloalkyl. In some embodiments, R1 is a fluorine-substituted C1.5-7 Bicycloalkyl. In some embodiments, R1 is a C1 substituted with a trifluoromethyl group. 5-7 Bicycloalkyl. In some embodiments, C 5-7 One or more carbon atoms in the bicycloalkyl group are bridging carbons. In some embodiments, C 5-7 One carbon atom of a bicycloalkyl group is a bridging carbon.

[0124] In some embodiments, R1 is an unsubstituted or substituted C5 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C5 bicycloalkyl group. In some embodiments, R1 is a substituted C5 bicycloalkyl group. In some embodiments, R1 is a C5 bicycloalkyl group substituted with fluorine or trifluoromethyl. In some embodiments, R1 is a C5 bicycloalkyl group substituted with fluorine. In some embodiments, R1 is a C5 bicycloalkyl group substituted with trifluoromethyl. In some embodiments, one or more carbon atoms of the C5 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C5 bicycloalkyl group is a bridging carbon.

[0125] In some embodiments, R1 is an unsubstituted or substituted C6 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C6 bicycloalkyl group. In some embodiments, R1 is a substituted C6 bicycloalkyl group. In some embodiments, R1 is a C6 bicycloalkyl group substituted with fluorine or trifluoromethyl. In some embodiments, R1 is a C6 bicycloalkyl group substituted with fluorine. In some embodiments, R1 is a C6 bicycloalkyl group substituted with trifluoromethyl. In some embodiments, one or more carbon atoms of the C6 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C6 bicycloalkyl group is a bridging carbon.

[0126] In some embodiments, R1 is an unsubstituted or substituted C7 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C7 bicycloalkyl group. In some embodiments, R1 is a substituted C7 bicycloalkyl group. In some embodiments, R1 is a C7 bicycloalkyl group substituted with fluorine or trifluoromethyl. In some embodiments, R1 is a C7 bicycloalkyl group substituted with fluorine. In some embodiments, R1 is a C7 bicycloalkyl group substituted with trifluoromethyl. In some embodiments, one or more carbon atoms of the C7 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C7 bicycloalkyl group is a bridging carbon.

[0127] In some implementations, R1 is selected from: , , , , as well as .

[0128] In some implementations, R1 is tetrahydropyran.

[0129] In some implementations, m is 1 and n is 1. In some implementations, m is 0 and n is 2.

[0130] In some implementations, R A It is hydrogen.

[0131] In some implementations, R B It is hydrogen; R C It is hydrogen; and R D It is hydrogen.

[0132] In some implementations, R A For hydrogen, R B For hydrogen, R C It is hydrogen, and R D It is hydrogen.

[0133] In some implementations, Z is .

[0134] In some implementations, Z is .

[0135] In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: (Ia) in: R1 is unsubstituted 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 six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from F, Cl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, OCH2CF3, CN and OH. L is a bond or CR2R3, where R2 is H or methyl, and R3 is H, methyl, ethyl, trifluoromethyl, or -CH2OCH3; or R2 and R3 together with the carbon attached to them form a cyclopropyl group; Z is or , Where R4 is H, F, or Cl; R5 is H or F; R6 is H, F, Cl, CN, methyl, or methoxy. R7 is H or ; R8 can be H, NH2, or methyl.

[0136] In some implementations, L is a key.

[0137] In some embodiments, L is CR2R3. In some embodiments, L is CR2R3 and R2 is H or methyl. In some embodiments, L is CR2R3 and R2 is H. In some embodiments, L is CR2R3 and R2 is methyl. In some embodiments, L is CR2R3 and R3 is H, methyl, ethyl, trifluoromethyl, or CH2OCH3. In some embodiments, L is CR2R3, R2 is H, and R3 is H. In some embodiments, L is CR2R3, R2 is H, and R3 is methyl. In some embodiments, L is CR2R3, and R2 and R3 together with the carbon atoms to which they are attached form a cyclopropyl moiety.

[0138] In some implementations, L is selected from: CH2、 , , , , , , , , as well as .

[0139] In some implementations, R1 is unsubstituted or substituted C 1-4 Alkyl group. In some embodiments, R1 is an unsubstituted C12. 1-4 Alkyl group. In some embodiments, R1 is a substituted C- group. 1-4 Alkyl group. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms. 1-4 Alkyl group, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In some embodiments, R1 is a C substituted with X. 1-4 Alkyl group, wherein X is selected from methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In some embodiments, R1 is a C molecule substituted with two X atoms. 1-4 Alkyl group, wherein each X is independently selected from methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy.

[0140] In some embodiments, R1 is an unsubstituted or substituted methyl group. In some embodiments, R1 is an unsubstituted methyl group. In some embodiments, R1 is a substituted methyl group. In some embodiments, R1 is a methyl-substituted trifluoromethoxy group.

[0141] In some embodiments, R1 is an unsubstituted or substituted ethyl group. In some embodiments, R1 is an unsubstituted ethyl group. In some embodiments, R1 is a substituted ethyl group. In some embodiments, R1 is an ethyl group substituted with 1-2 X's, wherein each X is independently selected from methyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In some embodiments, R1 is an ethyl group substituted with X's, wherein X's are selected from trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, and cyclopropoxy. In some embodiments, R1 is an ethyl group substituted with 2 X's, wherein each X's are independently selected from methyl and trifluoromethoxy.

[0142] In some embodiments, R1 is an unsubstituted or substituted n-propyl group. In some embodiments, R1 is an unsubstituted n-propyl group. In some embodiments, R1 is a substituted n-propyl group. In some embodiments, R1 is a n-propyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl and trifluoromethyl. In some embodiments, R1 is a n-propyl group substituted with X groups, wherein X is selected from methyl and trifluoromethyl. In some embodiments, R1 is a n-propyl group substituted with 2 X groups, wherein each X is methyl.

[0143] In some embodiments, R1 is an unsubstituted or substituted n-butyl. In some embodiments, R1 is an unsubstituted n-butyl. In some embodiments, R1 is a substituted n-butyl. In some embodiments, R1 is a n-butyl substituted with X, wherein X is selected from methyl and ethyl.

[0144] In some implementations, R1 is selected from: , , , , , , , , , , , , , , , as well as .

[0145] In some implementations, R1 is unsubstituted or substituted C 3-6 Cycloalkyl. In some embodiments, R1 is an unsubstituted C12-hydroxyl group. 3-6 Cycloalkyl. In some embodiments, R1 is a substituted C 3-6 Cycloalkyl. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms.3-6 Cycloalkyl, wherein each X is independently selected from the group consisting of fluorine, methyl, and trifluoromethyl. In some embodiments, R1 is a C substituted with X. 3-6 Cycloalkyl, wherein X is selected from the group consisting of fluorine, methyl, and trifluoromethyl. In some embodiments, R1 is a C molecule substituted with two X atoms. 3-6 Cycloalkyl, wherein each X is independently selected from the group consisting of fluorine, methyl and trifluoromethyl.

[0146] In some embodiments, R1 is an unsubstituted or substituted cyclopropyl group. In some embodiments, R1 is an unsubstituted cyclopropyl group. In some embodiments, R1 is a substituted cyclopropyl group. In some embodiments, R1 is a cyclopropyl group substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine, methyl, and trifluoromethyl. In some embodiments, R1 is a cyclopropyl group substituted with X's, wherein X's are selected from methyl and trifluoromethyl. In some embodiments, R1 is a cyclopropyl group substituted with 2 X's, wherein each X's is fluorine.

[0147] In some embodiments, R1 is an unsubstituted or substituted cyclobutyl group. In some embodiments, R1 is an unsubstituted cyclobutyl group. In some embodiments, R1 is a substituted cyclobutyl group. In some embodiments, R1 is a cyclobutyl group substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine, methyl, and trifluoromethyl. In some embodiments, R1 is a cyclobutyl group substituted with X's, wherein X's are selected from fluorine and trifluoromethyl. In some embodiments, R1 is a cyclobutyl group substituted with 2 X's, wherein each X's are independently selected from fluorine and methyl.

[0148] In some embodiments, R1 is an unsubstituted or substituted cyclopentyl group. In some embodiments, R1 is an unsubstituted cyclopentyl group. In some embodiments, R1 is a substituted cyclopentyl group. In some embodiments, R1 is a cyclopentyl group substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine and trifluoromethyl. In some embodiments, R1 is a cyclopentyl group substituted with X's, wherein X's are selected from fluorine and trifluoromethyl. In some embodiments, R1 is a cyclopentyl group substituted with 2 X's, wherein each X's is fluorine.

[0149] In some embodiments, R1 is an unsubstituted or substituted cyclohexyl group. In some embodiments, R1 is an unsubstituted cyclohexyl group. In some embodiments, R1 is a substituted cyclohexyl group. In some embodiments, R1 is a cyclohexyl group substituted with 1-2 X atoms, where X is fluorine. In some embodiments, R1 is a cyclohexyl group substituted with X atoms, where X is fluorine. In some embodiments, R1 is a cyclohexyl group substituted with 2 X atoms, where X is fluorine.

[0150] In some implementations, R1 is selected from: , , , , , , , , , , , , , , , , , , , as well as . In some embodiments, R1 is an unsubstituted or substituted phenyl group. In some embodiments, R1 is an unsubstituted phenyl group. In some embodiments, R1 is a substituted phenyl group. In some embodiments, R1 is a phenyl group substituted with 1-2 X's, wherein each X is independently selected from fluorine, chlorine, methyl, methoxy, and CN. In some embodiments, R1 is a phenyl group substituted with X's, wherein each X is independently selected from fluorine, chlorine, methyl, methoxy, and CN.

[0151] In some implementations, R1 is selected from: , , , , , , , , , , , as well as .

[0152] In some implementations, R1 is selected from: , , , , , as well as .

[0153] In some implementations, R1 is selected from: , as well as .

[0154] In some embodiments, R1 is an unsubstituted or substituted pyridinyl group. In some embodiments, R1 is an unsubstituted pyridinyl group. In some embodiments, R1 is a pyridinyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl, methoxy, and CN. In some embodiments, R1 is an X-substituted pyridinyl group, wherein X is selected from methyl, methoxy, and CN. In some embodiments, R1 is a pyridinyl group substituted with 2 X groups, wherein each X is methyl.

[0155] In some embodiments, R1 is an unsubstituted or substituted pyrimidinyl group. In some embodiments, R1 is an unsubstituted pyrimidinyl group. In some embodiments, R1 is a pyrimidinyl group substituted with X, wherein X is a methyl group.

[0156] In some implementations, R1 is selected from: , , , , , , , , , , , , , as well as .

[0157] In some implementations, R1 is selected from: , , , , , , , , , , , as well as .

[0158] In some implementations, R1 is selected from: , as well as .

[0159] In some implementations, R1 is selected from: and .

[0160] In some implementations, R1 is unsubstituted or substituted C 5-7 Bicycloalkyl. In some embodiments, R1 is an unsubstituted C1. 5-7 Bicycloalkyl. In some embodiments, R1 is a substituted C 5-7 Bicycloalkyl. In some embodiments, R1 is a fluorine-substituted C1. 5-7 Bicycloalkyl. In some embodiments, C 5-7 One or more carbon atoms in the bicycloalkyl group are bridging carbons. In some embodiments, C 5-7 One carbon atom in a bicycloalkyl group is a bridging carbon.

[0161] In some embodiments, R1 is an unsubstituted or substituted C5 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C5 bicycloalkyl group. In some embodiments, R1 is a substituted C5 bicycloalkyl group. In some embodiments, R1 is a C5 bicycloalkyl group substituted with X, where X is fluorine. In some embodiments, one or more carbon atoms of the C5 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C5 bicycloalkyl group is a bridging carbon.

[0162] In some embodiments, R1 is an unsubstituted or substituted C6 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C6 bicycloalkyl group. In some embodiments, one or more carbon atoms of the C6 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C6 bicycloalkyl group is a bridging carbon.

[0163] In some embodiments, R1 is an unsubstituted or substituted C7 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C7 bicycloalkyl group. In some embodiments, R1 is a substituted C7 bicycloalkyl group. In some embodiments, R1 is a C7 bicycloalkyl group substituted with X, where X is fluorine. In some embodiments, one or more carbon atoms of the C7 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C7 bicycloalkyl group is a bridging carbon.

[0164] In some implementations, R1 is selected from: , , , as well as .

[0165] In some implementations, R1 is tetrahydropyran.

[0166] In some implementations, R1 is .

[0167] In some implementations, Z is .

[0168] In some implementations, Z is .

[0169] In some embodiments, the compound of formula (Ia) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0170] In some embodiments, the compound of formula (Ia) is the compound presented in Table 1.

[0171] In some embodiments, the compound of formula (Ia) is compound 1.

[0172] In some embodiments, the compound of formula (Ia) is compound 2.

[0173] In some embodiments, the compound of formula (Ia) is compound 3.

[0174] In some embodiments, the compound of formula (Ia) is compound 4.

[0175] In some embodiments, the compound of formula (Ia) is compound 5.

[0176] In some embodiments, the compound of formula (Ia) is compound 6.

[0177] In some embodiments, the compound of formula (Ia) is compound 7.

[0178] In some embodiments, the compound of formula (Ia) is compound 8.

[0179] In some embodiments, the compound of formula (Ia) is compound 9.

[0180] In some embodiments, the compound of formula (Ia) is compound 10.

[0181] In some embodiments, the compound of formula (Ia) is compound 11.

[0182] In some embodiments, the compound of formula (Ia) is compound 12.

[0183] In some embodiments, the compound of formula (Ia) is compound 13.

[0184] In some embodiments, the compound of formula (Ia) is compound 14.

[0185] In some embodiments, the compound of formula (Ia) is compound 15.

[0186] In some embodiments, the compound of formula (Ia) is compound 16.

[0187] In some embodiments, the compound of formula (Ia) is compound 17.

[0188] In some embodiments, the compound of formula (Ia) is compound 18.

[0189] In some embodiments, the compound of formula (Ia) is compound 19.

[0190] In some embodiments, the compound of formula (Ia) is compound 20.

[0191] In some embodiments, the compound of formula (Ia) is compound 21.

[0192] In some embodiments, the compound of formula (Ia) is compound 22.

[0193] In some embodiments, the compound of formula (Ia) is compound 23.

[0194] In some embodiments, the compound of formula (Ia) is compound 24.

[0195] In some embodiments, the compound of formula (Ia) is compound 25.

[0196] In some embodiments, the compound of formula (Ia) is compound 26.

[0197] In some embodiments, the compound of formula (Ia) is compound 27.

[0198] In some embodiments, the compound of formula (Ia) is compound 28.

[0199] In some embodiments, the compound of formula (Ia) is compound 29.

[0200] In some embodiments, the compound of formula (Ia) is compound 30.

[0201] In some embodiments, the compound of formula (Ia) is compound 31.

[0202] In some embodiments, the compound of formula (Ia) is compound 32.

[0203] In some embodiments, the compound of formula (Ia) is compound 33.

[0204] In some embodiments, the compound of formula (Ia) is compound 34.

[0205] In some embodiments, the compound of formula (Ia) is compound 35.

[0206] In some embodiments, the compound of formula (Ia) is compound 36.

[0207] In some embodiments, the compound of formula (Ia) is compound 37.

[0208] In some embodiments, the compound of formula (Ia) is compound 38.

[0209] In some embodiments, the compound of formula (Ia) is compound 39.

[0210] In some embodiments, the compound of formula (Ia) is compound 40.

[0211] In some embodiments, the compound of formula (Ia) is compound 41.

[0212] In some embodiments, the compound of formula (Ia) is compound 42.

[0213] In some embodiments, the compound of formula (Ia) is compound 43.

[0214] In some embodiments, the compound of formula (Ia) is compound 44.

[0215] In some embodiments, the compound of formula (Ia) is compound 45.

[0216] In some embodiments, the compound of formula (Ia) is compound 46.

[0217] In some embodiments, the compound of formula (Ia) is compound 47.

[0218] In some embodiments, the compound of formula (Ia) is compound 48.

[0219] In some embodiments, the compound of formula (Ia) is compound 49.

[0220] In some embodiments, the compound of formula (Ia) is compound 50.

[0221] In some embodiments, the compound of formula (Ia) is compound 51.

[0222] In some embodiments, the compound of formula (Ia) is compound 52.

[0223] In some embodiments, the compound of formula (Ia) is compound 53.

[0224] In some embodiments, the compound of formula (Ia) is compound 54.

[0225] In some embodiments, the compound of formula (Ia) is compound 55.

[0226] In some embodiments, the compound of formula (Ia) is compound 56.

[0227] In some embodiments, the compound of formula (Ia) is compound 57.

[0228] In some embodiments, the compound of formula (Ia) is compound 58.

[0229] In some embodiments, the compound of formula (Ia) is compound 59.

[0230] In some embodiments, the compound of formula (Ia) is compound 60.

[0231] In some embodiments, the compound of formula (Ia) is compound 61.

[0232] In some embodiments, the compound of formula (Ia) is compound 62.

[0233] In some embodiments, the compound of formula (Ia) is compound 63.

[0234] In some embodiments, the compound of formula (Ia) is compound 64.

[0235] In some embodiments, the compound of formula (Ia) is compound 65.

[0236] In some embodiments, the compound of formula (Ia) is compound 66.

[0237] In some embodiments, the compound of formula (Ia) is compound 67.

[0238] In some embodiments, the compound of formula (Ia) is compound 68.

[0239] In some embodiments, the compound of formula (Ia) is compound 69.

[0240] In some embodiments, the compound of formula (Ia) is compound 70.

[0241] In some embodiments, the compound of formula (Ia) is compound 71.

[0242] In some embodiments, the compound of formula (Ia) is compound 72.

[0243] In some embodiments, the compound of formula (Ia) is compound 73.

[0244] In some embodiments, the compound of formula (Ia) is compound 74.

[0245] In some embodiments, the compound of formula (Ia) is compound 75.

[0246] In some embodiments, the compound of formula (Ia) is compound 76.

[0247] In some embodiments, the compound of formula (Ia) is compound 77.

[0248] In some embodiments, the compound of formula (Ia) is compound 78.

[0249] In some embodiments, the compound of formula (Ia) is compound 79.

[0250] In some embodiments, the compound of formula (Ia) is compound 80.

[0251] In some embodiments, the compound of formula (Ia) is compound 81.

[0252] In some embodiments, the compound of formula (Ia) is compound 82.

[0253] In some embodiments, the compound of formula (Ia) is compound 83.

[0254] In some embodiments, the compound of formula (Ia) is compound 84.

[0255] In some embodiments, the compound of formula (Ia) is compound 85.

[0256] In some embodiments, the compound of formula (Ia) is compound 86.

[0257] In some embodiments, the compound of formula (Ia) is compound 87.

[0258] In some embodiments, the compound of formula (Ia) is compound 88.

[0259] In some embodiments, the compound of formula (Ia) is compound 89.

[0260] In some embodiments, the compound of formula (Ia) is compound 90.

[0261] In some embodiments, the compound of formula (Ia) is compound 100.

[0262] In some embodiments, the compound of formula (Ia) is compound 101.

[0263] In some embodiments, the compound of formula (Ia) is compound 102.

[0264] In some embodiments, the compound of formula (Ia) is compound 103.

[0265] In some embodiments, the compound of formula (Ia) is compound 104.

[0266] In some embodiments, the compound of formula (Ia) is compound 105.

[0267] In some embodiments, the compound of formula (Ia) is compound 106.

[0268] In some embodiments, the compound of formula (Ia) is compound 107.

[0269] In some implementations, R4, R5, and R6 are halogens.

[0270] In some embodiments, R4 and R6 are halogens. In some embodiments, R4 and R6 are halogens, while R5 is hydrogen.

[0271] In some embodiments, R4 and R6 are fluorine. In some embodiments, R4 and R6 are fluorine, while R5 is hydrogen.

[0272] In some embodiments, the compound is a compound of formula (Ib) or formula (Ic), or a pharmaceutically acceptable salt thereof: (Ib) (Ic) in: R1 is unsubstituted or substituted C 1-3 Alkyl, unsubstituted or substituted C 3-4Cycloalkyl, unsubstituted or substituted C5 bicycloalkyl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from F, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, CN, and OH. L is a bond or CR2R3, where R2 is H and R3 is H, methyl, or -CH2OCH3; R5 is either H or F; R7 is H, D, or CN; and R8 can be H, D, OH, methoxy, or -NH(CH2)2OH.

[0273] In some embodiments, the compound is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: (Ib).

[0274] In some implementations, L is a key.

[0275] In some embodiments, L is CR2R3. In some embodiments, L is CR2R3 and R3 is H. In some embodiments, L is CR2R3 and R3 is methyl. In some embodiments, L is CR2R3 and R3 is CH2OCH3.

[0276] In some implementations, L is selected from: CH2、 and .

[0277] In some implementations, R1 is unsubstituted or substituted C 1-3 Alkyl group. In some embodiments, R1 is an unsubstituted C12. 1-3 Alkyl group. In some embodiments, R1 is a substituted C- group. 1-3 Alkyl group. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms. 1-3 Alkyl group, wherein each X is independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH. In some embodiments, R1 is a C substituted with X. 1-3 Alkyl group, wherein X is selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH. In some embodiments, R1 is a C molecule substituted with two X atoms. 1-3 Alkyl group, wherein each X is independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and OH.

[0278] In some embodiments, R1 is an unsubstituted or substituted ethyl group. In some embodiments, R1 is an unsubstituted ethyl group. In some embodiments, R1 is a substituted ethyl group. In some embodiments, R1 is an ethyl group substituted with 1-2 X's, wherein each X is independently selected from methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, and hydroxyl. In some embodiments, R1 is an ethyl group substituted with X's, wherein X's are selected from difluoromethoxy and trifluoromethoxy. In some embodiments, R1 is an ethyl group substituted with 2 X's, wherein each X's are independently selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, and hydroxyl.

[0279] In some embodiments, R1 is an unsubstituted or substituted n-propyl group. In some embodiments, R1 is an unsubstituted n-propyl group. In some embodiments, R1 is a substituted n-propyl group. In some embodiments, R1 is a n-propyl group substituted with 1-2 X groups, wherein each X is independently selected from methyl and trifluoromethyl. In some embodiments, R1 is a n-propyl group substituted with X groups, wherein X is trifluoromethyl. In some embodiments, R1 is a n-propyl group substituted with 2 X groups, wherein each X is independently selected from methyl and trifluoromethyl.

[0280] In some implementations, R1 is selected from: , , , , , , , , as well as .

[0281] In some implementations, R1 is unsubstituted or substituted C 3-4 Cycloalkyl. In some embodiments, R1 is an unsubstituted C12-hydroxyl group. 3-4 Cycloalkyl. In some embodiments, R1 is a substituted C 3-4 Cycloalkyl. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms. 3-4 Cycloalkyl, wherein each X is independently selected from the group consisting of fluorine, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a C substituted with X. 3-4 Cycloalkyl, wherein X is selected from fluorine, difluoromethyl, and trifluoromethyl. In some embodiments, R1 is a C molecule substituted with two X atoms. 3-4 Cycloalkyl, wherein each X is independently selected from fluorine, difluoromethyl and trifluoromethyl.

[0282] In some embodiments, R1 is an unsubstituted or substituted cyclopropyl group. In some embodiments, R1 is an unsubstituted cyclopropyl group. In some embodiments, R1 is a substituted cyclopropyl group. In some embodiments, R1 is a cyclopropyl group substituted with X, wherein X is selected from difluoromethyl or trifluoromethyl.

[0283] In some embodiments, R1 is an unsubstituted or substituted cyclobutyl group. In some embodiments, R1 is an unsubstituted cyclobutyl group. In some embodiments, R1 is a substituted cyclobutyl group. In some embodiments, R1 is a cyclobutyl group substituted with 1-2 X's, wherein each X is independently selected from the group consisting of fluorine and trifluoromethyl. In some embodiments, R1 is a cyclobutyl group substituted with X's, wherein X's are trifluoromethyl. In some embodiments, R1 is a cyclobutyl group substituted with 2 X's, wherein X's are fluorine.

[0284] In some implementations, R1 is selected from: , , , , , , , as well as .

[0285] In some embodiments, R1 is an unsubstituted or substituted pyridinyl group. In some embodiments, R1 is an unsubstituted pyridinyl group. In some embodiments, R1 is a pyridinyl group substituted with 1-2 X groups, wherein each X is independently selected from fluorine, methyl, trifluoromethyl, methoxy, and CN. In some embodiments, R1 is a pyridinyl group substituted with X groups, wherein each X is independently selected from fluorine, methyl, and CN.

[0286] In some implementations, R1 is selected from: , , , , , as well as .

[0287] In some implementations, R1 is selected from: , , as well as .

[0288] In some embodiments, R1 is an unsubstituted or substituted C5 bicycloalkyl group. In some embodiments, R1 is an unsubstituted C5 bicycloalkyl group. In some embodiments, R1 is a substituted C5 bicycloalkyl group. In some embodiments, R1 is a C5 bicycloalkyl group substituted with X, where X is trifluoromethyl. In some embodiments, one or more carbon atoms of the C5 bicycloalkyl group are bridging carbons. In some embodiments, one carbon atom of the C5 bicycloalkyl group is a bridging carbon.

[0289] In some implementations, R1 is selected from: .

[0290] In some embodiments, the compound of formula (Ib) or formula (Ic) is the compound presented in Table 2.

[0291] In some embodiments, the compound of formula (Ib) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0292] In some embodiments, the compound of formula (Ic) is selected from: and .

[0293] In some embodiments, the compound of formula (Ib) is compound 108.

[0294] In some embodiments, the compound of formula (Ic) is compound 109.

[0295] In some embodiments, the compound of formula (Ic) is compound 110.

[0296] In some embodiments, the compound of formula (Ib) is compound 111.

[0297] In some embodiments, the compound of formula (Ib) is compound 112.

[0298] In some embodiments, the compound of formula (Ib) is compound 113.

[0299] In some embodiments, the compound of formula (Ib) is compound 114.

[0300] In some embodiments, the compound of formula (Ib) is compound 115.

[0301] In some embodiments, the compound of formula (Ib) is compound 116.

[0302] In some embodiments, the compound of formula (Ib) is compound 117.

[0303] In some embodiments, the compound of formula (Ib) is compound 118.

[0304] In some embodiments, the compound of formula (Ib) is compound 119.

[0305] In some embodiments, the compound of formula (Ib) is compound 120.

[0306] In some embodiments, the compound of formula (Ib) is compound 121.

[0307] In some embodiments, the compound of formula (Ib) is compound 122.

[0308] In some embodiments, the compound of formula (Ib) is compound 123.

[0309] In some embodiments, the compound of formula (Ib) is compound 124.

[0310] In some embodiments, the compound of formula (Ib) is compound 125.

[0311] In some embodiments, the compound of formula (Ib) is compound 126.

[0312] In some embodiments, the compound of formula (Ib) is compound 127.

[0313] In some embodiments, the compound of formula (Ib) is compound 128.

[0314] In some embodiments, the compound of formula (Ib) is compound 129.

[0315] In some embodiments, the compound of formula (Ib) is compound 130.

[0316] In some embodiments, the compound of formula (Ib) is compound 131.

[0317] In some embodiments, the compound of formula (Ib) is compound 132.

[0318] In some embodiments, the compound of formula (Ib) is compound 133.

[0319] In some embodiments, the compound of formula (Ib) is compound 134.

[0320] In some embodiments, the compound of formula (Ib) is compound 135.

[0321] In some embodiments, the compound of formula (Ib) is compound 136.

[0322] In some embodiments, the compound of formula (Ib) is compound 137.

[0323] In some embodiments, the compound of formula (Ib) is compound 138.

[0324] In some embodiments, the compound of formula (Ib) is compound 139.

[0325] In some embodiments, the compound of formula (Ib) is compound 140.

[0326] In some embodiments, the compound of formula (Ib) is compound 141.

[0327] In some embodiments, the compound of formula (Ib) is compound 142.

[0328] In some embodiments, the compound of formula (Ib) is compound 143.

[0329] In some embodiments, the compound of formula (Ib) is compound 144.

[0330] In some embodiments, the compound of formula (Ib) is compound 145.

[0331] In some embodiments, the compound of formula (Ib) is compound 146.

[0332] In some embodiments, the compound of formula (Ib) is compound 147.

[0333] In some embodiments, the compound of formula (Ib) is compound 148.

[0334] In some embodiments, the compound of formula (Ib) is compound 149.

[0335] In some embodiments, the compound of formula (Ib) is compound 150.

[0336] In some embodiments, the compound of formula (Ib) is compound 151.

[0337] In some embodiments, the compound of formula (Ib) is compound 152.

[0338] In some implementations, R5 is hydrogen.

[0339] In some implementations, R7 is hydrogen and R8 is hydrogen.

[0340] In some implementations, R5 is hydrogen, R7 is hydrogen, and R8 is hydrogen.

[0341] In some embodiments, the compound is a compound of formula (Id) or a pharmaceutically acceptable salt thereof: (Id) in: R1 is unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is independently selected from F, Cl, methyl, ethyl, trifluoromethoxy and CN. L is a C2R2R3 bond, where R2 is H and R3 is H or a methyl group; R4 is H, F, or Cl; R5 is either H or F; R6 is H, F, or Cl; R A For H, C(O)OEt or C(O)Me; R B It can be H, D, or methyl; R C For H or D; R D For H or F; m is an integer selected from 0 or 1; and n is an integer selected from 0, 1, and 2.

[0342] In some implementations, L is a key.

[0343] In some embodiments, L is CR2R3. In some embodiments, L is CR2R3 and R is H. In some embodiments, L is CR2R3 and R is methyl.

[0344] In some implementations, L is selected from: CH2 and .

[0345] In some implementations, R1 is unsubstituted or substituted C 1-4 Alkyl group. In some embodiments, R1 is an unsubstituted C1-4 alkyl group. In some embodiments, R1 is a substituted C1-4 alkyl group. 1-4 Alkyl group. In some embodiments, R1 is a C substituted with X. 1-4 Alkyl, wherein X is methyl or trifluoromethoxy.

[0346] In some embodiments, R1 is an unsubstituted or substituted ethyl group. In some embodiments, R1 is an unsubstituted ethyl group. In some embodiments, R1 is a substituted ethyl group. In some embodiments, R1 is an ethyl group substituted with X, wherein X is a trifluoromethoxy group.

[0347] In some embodiments, R1 is an unsubstituted or substituted n-butyl. In some embodiments, R1 is an unsubstituted n-butyl. In some embodiments, R1 is a substituted n-butyl. In some embodiments, R1 is a n-butyl substituted with X, where X is a methyl group.

[0348] In some implementations, R1 is selected from: and .

[0349] In some implementations, R1 is unsubstituted or substituted C 3-5 Cycloalkyl. In some embodiments, R1 is an unsubstituted C12-hydroxyl group. 3-5 Cycloalkyl. In some embodiments, R1 is a substituted C 3-5 Cycloalkyl. In some embodiments, R1 is a C molecule substituted with 1-2 X atoms. 3-5 Cycloalkyl, wherein each X is independently selected from the group consisting of fluorine and trifluoromethyl. In some embodiments, R1 is a C substituted with X. 3-5 Cycloalkyl, wherein X is selected from fluorine and trifluoromethyl. In some embodiments, R1 is a C molecule substituted with two X atoms. 3-5 Cycloalkyl, wherein each X is independently selected from fluorine and trifluoromethyl.

[0350] In some embodiments, R1 is an unsubstituted or substituted cyclopropyl group. In some embodiments, R1 is an unsubstituted cyclopropyl group. In some embodiments, R1 is a substituted cyclopropyl group. In some embodiments, R1 is a cyclopropyl group substituted with X, where X is trifluoromethyl.

[0351] In some embodiments, R1 is an unsubstituted or substituted cyclobutyl group. In some embodiments, R1 is an unsubstituted cyclobutyl group. In some embodiments, R1 is a substituted cyclobutyl group. In some embodiments, R1 is a cyclobutyl group substituted with two X groups, where X is fluorine.

[0352] In some embodiments, R1 is an unsubstituted or substituted cyclopentyl group. In some embodiments, R1 is an unsubstituted cyclopentyl group. In some embodiments, R1 is a substituted cyclopentyl group. In some embodiments, R1 is a cyclopentyl group substituted with two X groups, where X is fluorine.

[0353] In some implementations, R1 is selected from: , as well as .

[0354] In some embodiments, R1 is an unsubstituted or substituted phenyl group. In some embodiments, R1 is an unsubstituted phenyl group. In some embodiments, R1 is a substituted phenyl group. In some embodiments, R1 is a phenyl group substituted with 1 to 3 X's, wherein each X is independently selected from fluorine, chlorine, and CN. In some embodiments, R1 is a phenyl group substituted with X's, wherein X's are selected from fluorine, chlorine, and CN. In some embodiments, R1 is a phenyl group substituted with 2 X's, wherein each X's are independently selected from fluorine and chlorine. In some embodiments, R1 is a phenyl group substituted with 3 X's, wherein each X's is fluorine.

[0355] In some implementations, R1 is selected from: , , , , as well as .

[0356] In some implementations, R1 is selected from: , , , as well as .

[0357] In some embodiments, R1 is an unsubstituted or substituted pyridyl group. In some embodiments, R1 is an unsubstituted pyridyl group. In some embodiments, R1 is a pyridyl group substituted with 1-2 X's, wherein each X is independently selected from methyl and CN. In some embodiments, R1 is a pyridyl group substituted with X's, wherein X is CN. In some embodiments, R1 is a pyridyl group substituted with 2 X's, wherein each X is independently selected from methyl and CN.

[0358] In some implementations, R1 is selected from: , as well as .

[0359] In some embodiments, the compound of formula (Id) is the compound presented in Table 3.

[0360] In some embodiments, the compound of formula (Id) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

[0361] In some embodiments, the compound of formula (Id) is compound 153.

[0362] In some embodiments, the compound of formula (Id) is compound 154.

[0363] In some embodiments, the compound of formula (Id) is compound 155.

[0364] In some embodiments, the compound of formula (Id) is compound 156.

[0365] In some embodiments, the compound of formula (Id) is compound 157.

[0366] In some embodiments, the compound of formula (Id) is compound 158.

[0367] In some embodiments, the compound of formula (Id) is compound 159.

[0368] In some embodiments, the compound of formula (Id) is compound 160.

[0369] In some embodiments, the compound of formula (Id) is compound 161.

[0370] In some embodiments, the compound of formula (Id) is compound 162.

[0371] In some embodiments, the compound of formula (Id) is compound 163.

[0372] In some embodiments, the compound of formula (Id) is compound 164.

[0373] In some embodiments, the compound of formula (Id) is compound 165.

[0374] In some embodiments, the compound of formula (Id) is compound 166.

[0375] In some embodiments, the compound of formula (Id) is compound 167.

[0376] In some embodiments, the compound of formula (Id) is compound 168.

[0377] In some embodiments, the compound of formula (Id) is compound 169.

[0378] In some embodiments, the compound of formula (Id) is compound 170.

[0379] In some embodiments, the compound of formula (Id) is compound 171.

[0380] In some embodiments, the compound of formula (Id) is compound 172.

[0381] In some embodiments, the compound of formula (Id) is compound 173.

[0382] In some embodiments, the compound of formula (Id) is compound 174.

[0383] In some embodiments, the compound of formula (Id) is compound 175.

[0384] In some embodiments, the compound of formula (Id) is compound 176.

[0385] In some embodiments, the compound of formula (Id) is compound 177.

[0386] In some embodiments, the compound of formula (Id) is compound 178.

[0387] In some embodiments, the compound of formula (Id) is compound 179.

[0388] In some embodiments, the compound of formula (Id) is compound 180.

[0389] In some embodiments, the compound of formula (Id) is compound 181.

[0390] In some embodiments, the compound of formula (Id) is compound 182.

[0391] In some embodiments, the compound of formula (Id) is compound 183.

[0392] In some embodiments, the compound of formula (Id) is compound 184.

[0393] In some embodiments, the compound of formula (Id) is compound 185.

[0394] In some embodiments, the compound of formula (Id) is compound 186.

[0395] In some embodiments, the compound of formula (Id) is compound 187.

[0396] In some embodiments, the compound of formula (Id) is compound 188.

[0397] In some embodiments, the compound of formula (Id) is compound 189.

[0398] In some embodiments, the compound of formula (Id) is compound 190.

[0399] In some embodiments, the compound of formula (Id) is compound 191.

[0400] In some embodiments, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof: (II) in: R1 is unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 fluoroalkyl, C 1-6 The group consisting of fluoroalkoxy groups and CN; and L is a bond or CR2R3, where R2 is H and R3 is H or a methyl group.

[0401] In some embodiments, the compound is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof: (IIa).

[0402] In some implementations, L is a key.

[0403] In some embodiments, L is CR2R3. In some embodiments, L is CR2R3 and R3 is H. In some embodiments, L is CR2R3 and R3 is methyl.

[0404] In some implementations, L is selected from: CH2 or .

[0405] In some embodiments, R1 is an unsubstituted or substituted ethyl group. In some embodiments, R1 is an unsubstituted ethyl group. In some embodiments, R1 is a substituted ethyl group. In some embodiments, R1 is an ethyl group substituted with 1-2 X's, wherein each X is independently selected from methoxy and trifluoromethoxy. In some embodiments, R1 is an ethyl group substituted with X's, wherein X's is trifluoromethoxy. In some embodiments, R1 is an ethyl group substituted with 2 X's, wherein each X's is independently selected from methoxy and trifluoromethoxy.

[0406] In some implementations, R1 is selected from: , as well as .

[0407] In some implementations, R1 is unsubstituted or substituted C 4-5 Cycloalkyl. In some embodiments, R1 is an unsubstituted C12-hydroxyl group. 4-5 Cycloalkyl. In some embodiments, R1 is a substituted C 4-5Cycloalkyl. In some embodiments, R1 is a fluorine-substituted C24. 4-5 Cycloalkyl.

[0408] In some embodiments, R1 is an unsubstituted or substituted cyclobutyl group. In some embodiments, R1 is an unsubstituted cyclobutyl group. In some embodiments, R1 is a substituted cyclobutyl group. In some embodiments, R1 is a cyclobutyl group substituted with two X groups, where X is fluorine.

[0409] In some embodiments, R1 is an unsubstituted or substituted cyclopentyl group. In some embodiments, R1 is an unsubstituted cyclopentyl group. In some embodiments, R1 is a substituted cyclopentyl group. In some embodiments, R1 is a cyclopentyl group substituted with two X groups, where X is fluorine.

[0410] In some implementations, R1 is selected from: and .

[0411] In some embodiments, R1 is an unsubstituted or substituted phenyl group. In some embodiments, R1 is an unsubstituted phenyl group. In some embodiments, R1 is a substituted phenyl group. In some embodiments, R1 is a phenyl group substituted with X, where X is CN.

[0412] In some implementations, R1 is: .

[0413] In some embodiments, R1 is an unsubstituted or substituted pyridinyl group.

[0414] In some embodiments, R1 is an unsubstituted or substituted pyridinyl group. In some embodiments, R1 is an unsubstituted pyridinyl group. In some embodiments, R1 is a pyridinyl group substituted with two X groups, wherein X is a methyl group.

[0415] In some implementations, R1 is: .

[0416] In some embodiments, the compound of formula (II) or formula (IIa) is the compound listed in Table 4.

[0417] In some embodiments, the compound of formula (II) is selected from: , , , as well as .

[0418] In some embodiments, the compound of formula (IIa) is selected from: , , , as well as .

[0419] In some embodiments, the compound of formula (II) is compound 192.

[0420] In some embodiments, the compound of formula (II) is compound 193.

[0421] In some embodiments, the compound of formula (II) is compound 194.

[0422] In some embodiments, the compound of formula (II) is compound 195.

[0423] In some embodiments, the compound of formula (IIa) is compound 196.

[0424] In some embodiments, the compound of formula (IIa) is compound 197.

[0425] In some embodiments, the compound of formula (IIa) is compound 198.

[0426] In some embodiments, the compound of formula (IIa) is compound 199.

[0427] In some embodiments, the compound of formula (IIa) is compound 200.

[0428] In some embodiments, the compound of formula (IIa) is compound 201.

[0429] The exemplary compounds described herein include those listed in the following table: Table 1: Compounds of Formula (Ia): (Ia)

[0430] The names of the compounds in Table 1 are shown below: 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: N-o-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]hex-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]pent-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-norbornel)-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]hex-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: N-o-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: N-o-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-Phenylocyclopropyl-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-benzimidazol-2-yl)nicotinamide.

[0431] In some embodiments, this document provides pharmaceutically acceptable salts of the compounds described in Table 1.

[0432] Table 2: Compounds of formulas (Ib) and (Ic) (Ib) (Ic)

[0433] *Single enantiomer, absolute stereochemistry undetermined. The names of the compounds in Table 2 are shown below: 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]pent-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)(2-²H)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.

[0434] 147: N-2-trifluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2-²H)nicotinamide; 148: N-[(1R,2R)-2-(trifluoromethyl)cyclopropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2-²H)nicotinamide; 149: N-2-Difluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2-²H)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)(2-²H)nicotinamide; and 152: N-2-Difluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)(2,6-²H2)nicotinamide.

[0435] In some embodiments, this document provides pharmaceutically acceptable salts of the compounds described in Table 2.

[0436] Table 3: Compounds of Formula (Id) (Id)

[0437] The names of the compounds in Table 3 are shown below: 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-{(2,2-²H2)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)nicotinamide; 176: N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(2,2-²H2)-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: 6-(5-{[(2,6-dimethyl-4-pyridyl)methyl]carbamoyl}-3-(3,4,5-trifluorophenyl)-4-pyridyl)-1,6-diaza-1-spiro[3,4]octanecarboxylic acid ethyl ester; 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.

[0438] In some embodiments, pharmaceutically acceptable salts of the compounds described in Table 3 are provided herein.

[0439] Table 4: Compounds of Formulas (II) and (IIa) (II) (IIa)

[0440] The names of the compounds in Table 4 are shown below: 192: N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 193: N-[(R)-3,3-difluorocyclopentyl]-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 194: N-2-trifluoromethoxyethyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 195: N-(m-cyanophenyl)methyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 196: N-[(2,6-dimethyl-4-pyridyl)methyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 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-pyridazine carboxamide; 198: N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 199: N-2-trifluoromethoxyethyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 200: N-[(R)-3,3,3-trifluoro-2-methoxypropyl]-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5-difluorophenyl)-3-pyridazine carboxamide; 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-pyridazine carboxamide.

[0441] In some embodiments, pharmaceutically acceptable salts of the compounds described in Table 4 are provided herein.

[0442] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, i.e., that the application of the material to an individual will not cause undesirable biological effects or adverse interactions with any component of a composition containing the material.

[0443] The term "pharmaceutically acceptable salt" refers to a therapeutic agent form consisting of a cationic therapeutic agent combined with a suitable anionic form, or, in an alternative embodiment, a therapeutic agent form consisting of an anionic therapeutic agent combined with a suitable cationic form.

[0444] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) with an acid. In some embodiments, the free basic form of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) is basic and reacts with an organic or inorganic acid.

[0445] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) with a base. In some embodiments, the compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) is acidic and reacts with a base.

[0446] In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) have one or more stereocenters, and each stereocenter exists independently in an R or S configuration. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) exist in an R configuration. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) exist in an S configuration. The compounds described herein include all diastereomers, single enantiomers, transisomers, epimeric forms, and tautomers, and suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, E (E), and Z (Z) isomers, and suitable mixtures thereof.

[0447] If desired, stereoisomers can be separated by stereoselective synthesis and / or chiral chromatography, diastereomers by achiral or chiral chromatography, or by crystallization and recrystallization in a suitable solvent or solvent mixture to obtain a single stereoisomer. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) are prepared by reacting a racemic mixture of the compound with an optically active resolving agent to generate a pair of diastereomer compounds / salts, followed by separation of the diastereomers and recovery of an optically pure single enantiomer. In some embodiments, the individual enantiomers are separated using covalent diastereomer derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by a separation / resolution technique based on solubility differences. In other embodiments, the separation of stereoisomers is carried out by chromatography or by forming a diastereomer salt and then recrystallizing or chromatography, or any combination thereof.

[0448] Compound Synthesis The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) described herein were synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0449] Unless otherwise specified, conventional mass spectrometry, nuclear magnetic resonance (NMR), and high-performance liquid chromatography (HPLC) methods are used.

[0450] The compounds were prepared using standard organic chemistry techniques. The synthetic transformation reactions described herein can be performed under different reaction conditions, such as varying the solvent, reaction temperature, reaction time, and using different chemical reagents and other reaction conditions.

[0451] 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.

[0452]

[0453] Option A a) i) iPrMgCl, THF, -40℃ to room temperature; ii) Dry ice, 6h; b) MeI, K2CO3, DMF, room temperature, 1h; c) IV, MeCN, DIEA, 100℃, 2h; d) VI, Pd(dtbpf)Cl2, K3PO4, toluene / H2O=10:1, 70℃, 1h; e) LiOH·H2O, MeOH / H2O=2:1, 60℃, 16h; f) IX, HATU, DIEA, DMF, room temperature, 30min; g) TFA, DCM, room temperature, 30min.

[0454] In some other embodiments, the compounds of formula (II) or formula (IIa) described herein are prepared as described in scheme B.

[0455]

[0456] Option B a) XIII, DIEA, MeCN, room temperature, 2h; b) XV, AcOH, DCM, room temperature, 30min; c) XVII, Pd(dppf)Cl2, K2CO3, toluene / water (5:1), 70℃, 3h; d) Pd / C, MeOH, room temperature, 2h; e) LiOH·H2O, MeOH / H2O = 2:1, 60℃, 1h; f) XXI, HATU, DIEA, NMP, room temperature, 1h; g) TFA, DCM, room temperature, 1h In some embodiments, the compound is prepared as described in the examples.

[0457] certain terms Unless otherwise stated, the following terms as used in this application have the following definitions. The use of the term "including" and other forms (such as "include," "includes," and "included") is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0458] As used in this article, C1-C x Including C1-C2, C1-C3... C1-C x For example, groups designated "C1-C6" indicate that the moiety contains one to six carbon atoms, i.e., groups containing 1, 2, 3, 4, 5, or 6 carbon atoms. Therefore, for example, "C1-C4 alkyl" indicates that the alkyl group contains one to four carbon atoms, meaning the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0459] “Alkyl” refers to an aliphatic hydrocarbon group. Alkyl groups are branched or straight-chain. In some embodiments, an “alkyl” has 1 to 6 carbon atoms, i.e., C1-C6 alkyl. Whenever it appears herein, numerical ranges such as “1 to 6” refer to each integer within a given range; for example, “1 to 6 carbon atoms” means that an alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms, but this definition also covers the occurrence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0460] "Alkoxy" refers to an (alkyl) O- group, where the alkyl group is as defined herein.

[0461] The term "aromatic" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine, pyrimidine). The term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) groups.

[0462] "Carbocyclic" or "carbocycle" refers to a ring or ring system in which all atoms constituting the ring skeleton are carbon atoms. Therefore, this term distinguishes a carbocyclic ring from a "heterocyclic" or "heterocyclic" ring, whose ring skeleton contains at least one non-carbon atom. In some embodiments, at least one of the two rings of a bicyclic carbocyclic ring is aromatic. In some embodiments, both rings of a bicyclic carbocyclic ring are aromatic. Carbocyclic rings include aryl and cycloalkyl groups.

[0463] As used herein, "aryl" refers to an aromatic ring in which each atom constituting the ring is a carbon atom. In some embodiments, the aryl group is phenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene).

[0464] "Cycloalkyl" refers to a monocyclic or polycyclic aliphatic nonaromatic radical in which each atom (i.e., skeleton atom) constituting the ring 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 simply "bicyclic alkyl". In one embodiment, the cycloalkyl group or bicyclic alkyl group is a spirocyclic or bridged ring compound.

[0465] “Cycloalkoxy” refers to a (cycloalkyl) O- group, the definition of which is given in this article.

[0466] The terms "halo," "halogen," or "halide" refer to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0467] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one respect, fluoroalkyl is a C1-C6 fluoroalkyl group.

[0468] "Fluoroalkoxy" refers to the (fluoroalkyl) O- group, the definition of which is given in this article.

[0469] "Heterocyclic" or "heterocyclic" refers to heteroaromatic rings (also called heteroaryl rings) and heterocyclic alkyl rings containing one to two heteroatoms, each heteroatom selected from O, S, and N, wherein the ring system of each heterocyclic group comprises three to six atoms, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also called heterocyclic alkyl groups) comprise three to six atoms, and aromatic heterocyclic groups comprise five to six atoms. Examples of non-aromatic heterocyclic groups include, but are not limited to, tetrahydropyranyl. Examples of aromatic heterocyclic groups include, but are not limited to, pyridyl and pyrimidinyl.

[0470] "Heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic heteroaryl groups, such as pyridyl and pyrimidinyl.

[0471] "Heterocyclic alkyl" refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary examples of heterocyclic alkyl groups include monocyclic heterocyclic alkyl groups, such as tetrahydropyranyl.

[0472] A “bond” is a chemical bond between two atoms or two parts when the atoms connected by a bond are considered part of a larger substructure. In one aspect, when the group described herein is a bond, the cited group is absent, thus allowing bonds to form between the remaining identified groups.

[0473] The term "part" refers to a specific segment or functional group within a molecule. A chemical part is typically a recognized chemical entity that is embedded in or attached to a molecule.

[0474] As used herein, the term “acceptable” in relation to formulations, compositions, or ingredients means that it has no lasting harmful effects on the overall health of the subject receiving the treatment.

[0475] As used herein, the term “modulation” refers to interacting with a target directly or indirectly to alter the target’s activity, including (by way of example only) enhancing, inhibiting, limiting, or prolonging the activity of a target.

[0476] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0477] As used herein, the terms “administer,” “administering,” “administration,” etc., refer to a method of delivering a compound or composition to a desired biological site of action.

[0478] As used herein, the terms "effective amount" and "therapeutic effective amount" refer to an adequate amount of a drug or compound administered that is capable of alleviating one or more symptoms of the disease or condition being treated to a certain degree. Results include reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use refers to an amount of a composition comprising the compounds disclosed herein that is capable of significantly reducing disease symptoms. In any specific case, an appropriate "effective" amount may be selectively determined using techniques such as dose escalation studies.

[0479] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, the mammal is the human being.

[0480] As used herein, the terms “treat,” “treating,” or “treatment” include relieving, reducing, or improving at least one symptom of a disease or condition, preventing other symptoms, inhibiting a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, relieving symptoms caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0481] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. These compositions are formulated using conventional methods, employing one or more pharmaceutically acceptable inactive ingredients to facilitate the processing of the active compounds into formulations suitable for therapeutic use. A suitable formulation depends on the route of administration. For an overview of the pharmaceutical compositions described herein, see, for example, Remington's *The Science and Practice of Pharmacy* (19th edition, Easton, PA: Mack Publishing, 1995); John E. Hoover's *Remington's Pharmaceutical Sciences* (Easton, PA: Mack Publishing, 1975); *Pharmaceutical Dosage Forms*, edited by H.A. Liberman and L. Lachman (New York, NY: Marcel Decker Publishing, 1980); and *Pharmaceutical Dosage Forms and Drug Delivery Systems* (7th edition, Lippincott Williams & Wilkins Publishing, 1999), all of which are incorporated herein by reference.

[0482] In some embodiments, the compounds described herein may be administered alone or in combination with one or more pharmaceutically acceptable carriers, excipients, and / or diluents as a pharmaceutical composition. The administration of the compounds and compositions described herein can be any method capable of delivering the compounds to the site of action.

[0483] In some embodiments, this document discloses a pharmaceutical composition comprising any one 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. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (Id) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, this document discloses a pharmaceutical composition comprising a compound of formula (IIa) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0484] Administration method and treatment regimen In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) or pharmaceutically acceptable salts thereof are used to prepare a medicament for treating diseases or conditions in mammals that will benefit from an SSTR3 agonist. The method of treating any disease or condition in a mammal requiring such treatment, as described herein, comprises administering to said mammal a therapeutically effective amount of a pharmaceutical composition containing at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) or a pharmaceutically acceptable salt thereof.

[0485] In some embodiments, compositions containing the compounds described herein are administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to at least partially relieve at least one symptom of the disease or condition. The effective amount for this purpose depends on the severity and course of the disease or condition, prior treatment, the patient's health status, weight, response to the drug, and the judgment of the attending physician. The therapeutically effective amount may be selectively determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0486] The dosage of a given compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa) or its pharmaceutically acceptable salt that meets the therapeutically effective amount varies depending on a variety of factors, such as the specific compound, the disease condition and its severity, and the characteristics of the subject or host requiring treatment (e.g., weight, sex), but ultimately must be determined on a case-by-case basis, including, for example, the specific agent being administered, the route of administration, the condition to be treated, and the subject or host being treated.

[0487] The toxicity and efficacy of such treatment regimens are determined using standard pharmaceutical procedures in cell culture or laboratory animals, including but not limited to determining LD50. 50 and ED 50 The dose ratio between toxic effects and therapeutic effects is the therapeutic index, expressed as LD50. 50 With ED 50 The ratio between. In some embodiments, data obtained from cell culture experiments and animal studies are used to determine therapeutically effective daily dose ranges and / or therapeutically effective unit doses applicable to mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within the range of ED. 50 And within the range of cyclic concentrations with the lowest toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form and route of administration.

[0488] As stated above, throughout the description of this invention, unless otherwise specified, the following abbreviations should be understood to have the following meanings: abbreviation: LCMS: Liquid Chromatography-Mass Spectrometry; HPLC: High Performance Liquid Chromatography; Prep-HPLC: Preparative high-performance liquid chromatography; Chiral-SFC: Chiral supercritical fluid chromatography; POCl3: Phosphorus oxychloride; DIEA: N,N-diisopropylethylamine or N-ethyl-N-isopropylpropyl-2-amine; DCM: Dichloromethane; PE: Petroleum ether; EtOAc or EA: Ethyl acetate; MeCN: Acetonitrile; Pd(dtbpf)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloro; 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(dibenzylacetone)dipalladium(O)-chloroform adduct; NMP: N-methylpyrrolidone; K2CO3: Potassium carbonate; NaOH: Sodium hydroxide; MeOH: Methanol; NaHSO4: Sodium bisulfate; FA: Formic acid; NH3·H2O: ammonia solution; Boc2O: ditert-butyl dicarbonate; AcOH: Acetic acid; NaHSO3: Sodium bisulfite; Na2SO4: Sodium sulfate; K3PO4: Potassium phosphate; Pd-C: Palladium on carbon catalyst; H2: Hydrogen gas; LiOH: Lithium hydroxide.

[0489] The following embodiments are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0490] 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)

[0491] Step 1-1, Preparation of 5-bromo-4-chloronicotinoyl chlorideA mixture of 5-bromo-4-chloronicotinic acid (2.50 g, 1 equivalent, 10.6 mmol; prepared according to step 2-1 of Example 2) and POCl3 (25 g, 15 mL, 15 equivalent, 0.16 mol) was added to 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 give 5-bromo-4-chloronicotinic acid chloride (2.85 g, 10 mmol, 95%, purity 90%).

[0492] Step 1-2, Preparation of 5-bromo-4-chloro-N-(2-methylbutyl)nicotinamide 2-Methylbut-1-amine (1.71 g, 2.00 equivalent, 19.6 mmol), DIEA (10.0 g, 13.5 mL, 7.88 equivalent, 77.4 mmol), and DCM (50 mL) were added to a 100 mL round-bottom flask. Then, 5-bromo-4-chloronicotinamide chloride (2.78 g, 90 wt%, 1 equivalent, 9.82 mmol) dissolved 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 chromatography (PE / EtOAc system, with EtOAc added increasing from 0% to 65% over 20 minutes). This yielded 5-bromo-4-chloro-N-(2-methylbutyl)nicotinamide (1.60 g, 5.24 mmol, 53.3%); LCMS (M+H). + = 305.0, 307.0.

[0493] Step 1-3, Preparation of 7-(3-bromo-5-((2-methylbutyl)carbamoyl)pyridin-4-yl)-1,7- diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester Step 1-4, Preparation of 7-(3-(3,5-difluorophenyl)-5-((2-methylbutyl)carbamoyl)pyridin-4- yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester Add 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-carboxylic acid (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) to a 50 mL round-bottom flask. Stir the resulting reaction mixture at 70°C for 2 hours. Cool the mixture to room temperature and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give 7-(3-bromo-5-((2-methylbutyl)carbamoyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (1.88 g, 3.79 mmol, 85.9%); LCMS (M+H) + = 495.2, 497.2.

[0494] Step 1-5, Preparation of N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5- difluorophenyl)nicotinamide dihydrochloride Step 1-6, Preparation of N-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5- difluorophenyl)nicotinamideTo a 50 mL round-bottom flask, add toluene (30 mL) and water (3 mL) containing tert-butyl 7-(3-bromo-5-((2-methylbutyl)carbamoyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid (1.88 g, 1 equivalent, 3.79 mmol), (3,5-difluorophenyl)boronic acid (3.00 g, 5.01 equivalent, 19.0 mmol), Pd(dtbpf)Cl2 (124 mg, 0.0501 equivalent, 190 μmol), and potassium phosphate (4.00 g, 4.97 equivalent, 18.8 mmol). The resulting mixture was stirred at 70°C for 5 hours under nitrogen protection. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1 to 1:5) to give 7-(3-(3,5-difluorophenyl)-5-((2-methylbutyl)carbamoyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (1.80 g, 3.40 mmol, 89.7%); LCMS (M+H) + = 529.3.

[0495] Step 2-1, Preparation of 5-bromo-4-chloronicotinic acid Step 2-2, Preparation of methyl 5-bromo-4-chloronicotinate To an 8 mL vial, add a mixture of 7-(3-(3,5-difluorophenyl)-5-((2-methylbutyl)carbamoyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (100 mg, 1 equivalent, 189 μmol) and HCl / diethyl ether (2.0 M diethyl ether with HCl; 2 mL). Stir the reaction mixture at 25°C for 2 hours. Concentrate the mixture under reduced pressure and then freeze-dry to give 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.

[0496] Step 2-3, Preparation of (S)-7-(3-bromo-5-(methoxycarbonyl)pyridin-4-yl)-1,7-diazaspiro[4.4] nonane-1-carboxylic acid tert-butyl ester Step 2-4, Preparation of (S)-7-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridin-4-yl)-1,7- diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl esterN-2-methylbutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)nicotinamide dihydrochloride (30 mg, 1 equivalent, 60 μmol) dissolved in water (5 mL) was added to an 8 mL vial, and the pH was adjusted to 9 with Na2CO3, followed by extraction 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-diaza-spiro[4.4]nonane-7-yl)nicotinamide (20 mg, 47 μmol, 78%); LCMS (M+H) + = 429.3.

[0497] The following compounds were prepared in a manner similar to that of Example 1, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0498]

[0499] 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)

[0500] Step 2-5, Preparation of (S)-4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonan-7-yl)-5- (3,5-difluorophenyl)nicotinic acid THF (150 mL) and 3,5-dibromo-4-chloropyridine (15.0 g, 1 equivalent, 55.3 mmol) were added to a 500 mL three-necked round-bottom flask purged with nitrogen and kept under an inert atmosphere. Isopropylmagnesium chloride (6.82 g, 30 mL, 2 M, 1.2 equivalent, 66.3 mmol) was then 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. Dry ice (300 g) was washed with 200 mL of THF, and then the THF was decanted. The reaction solution was immediately poured into dry ice and stirred for 3 hours. The reaction was then quenched with H₂O (150 mL). The resulting solution was extracted with ethyl acetate (2 × 100 mL). The pH of the aqueous phase was adjusted to 1–2 and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined and washed with 200 mL of saturated brine. The resulting mixture was concentrated under vacuum to obtain 5-bromo-4-chloronicotinic acid (9.6 g, 32 mmol, 59%, purity 80%).

[0501] Step 2-6, Preparation of (S)-7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin- 4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl esterAdd 5-bromo-4-chloronicotinic acid (1 g, 1 equivalent, 4 mmol) and DMF (10 mL) to a 40 mL vial. Then add potassium carbonate (2 g, 3 equivalent, 0.01 mol). Stir the resulting reaction mixture at 25°C for 3 hours to give methyl 5-bromo-4-chloronicotinic acid (800 mg, 3.19 mmol, 80%).

[0502] Step 2-7, Preparation of N-3,3-difluorocyclobutyl-4-{(S)-1,7-diaza-7-spiro[4.4]nonyl}-5-(3,5- difluorophenyl)nicotinamide Step 3-1, Preparation of tert-butyl ((2-cyanopyridin-4-yl)methyl)carbamate N-ethyl-N-isopropylprop-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 (S)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (500.1 mg, 1.1 equivalent, 2.210 mmol) in MeCN (5 mL). The mixture was heated at 100°C for 16 hours. The resulting product was concentrated to dryness under vacuum, and the residue was purified by silica gel column chromatography (eluting with 40% ethyl acetate in hexane). The purified fractions were combined, concentrated to dryness under vacuum, and dried under high vacuum to give (S)-7-(3-bromo-5-(methoxycarbonyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (866.0 mg, 1.967 mmol, 97.90%); LCMS (M+H) + = 440.1, 442.4.

[0503] Step 3-2, Preparation of 4-(aminomethyl)picolinonitrile hydrochloride Step 3-3, Preparation of 6-(3-bromo-5-(methoxycarbonyl)pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1- carboxylic acid tert-butyl esterToluene (10 mL) and water (1.0 mL) were added to a mixture of (S)-7-(3-bromo-5-(methoxycarbonyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (866.0 mg, 1 equivalent, 1.967 mmol), (3,5-difluorophenyl)boronic acid (465.8 mg, 1.5 equivalent, 2.950 mmol), Pd(dtbpf)Cl2 (256.4 mg, 0.2 equivalent, 393.3 μmol), and potassium phosphate (1.252 g, 3 equivalent, 5.900 mmol) in a sealed tube. N2 (g) was bubbled into the mixture 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 reversed-phase column chromatography. The purified fractions were combined, neutralized with saturated NaHCO3 (aqueous solution), and concentrated to remove MeCN. The aqueous residue was extracted twice with ethyl acetate, and the combined organic phases were dried over anhydrous MgSO4 and concentrated to dryness under vacuum to give (S)-7-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (706.5 mg, 1.492 mmol, 75.87%). LCMS (M+H) + = 474.1.

[0504] Step 3-4, Preparation of 6-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridin-4-yl)-1,6-diazaspiro[3.4] octane-1-carboxylic acid tert-butyl ester Step 3-5, Preparation of 4-(1-(tert-butoxycarbonyl)-1,6-diazaspiro[3.4]octan-6-yl)-5-(3,5- difluorophenyl)nicotinic acid Lithium hydroxide hydrate (575.1 mg, 10 equivalents, 13.71 mmol) was added to a solution of (S)-7-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (649.0 mg, 1 equivalent, 1.371 mmol) in a mixed solvent of methanol (10 mL) and water (5.0 mL). 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 the solution was neutralized to pH 6-7 with 1N HCl (aqueous solution). The solution was extracted with ethyl acetate (3 times) and then with 20% isopropanol / dichloromethane (1 time). The combined organic phases were dried over MgSO4 and concentrated to dryness under vacuum to give (S)-4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)nicotinic acid (564.2 mg, 1.228 mmol, 89.59%); LCMS (M+H) + = 460.2.

[0505] Step 3-6, Preparation of (R)-6-(3-(((2-cyanopyridin-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin- 4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester ​Add N-ethyl-N-isopropylpropyl-2-amine (793.5 mg, 1.07 mL, 5 equivalents, 6.139 mmol) to a solution of (S)-4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)nicotinic acid (564.2 mg, 1 equivalent, 1.228 mmol) and 3-((dimethylamino)(dimethyliminio))methyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-1-oxide hexafluorophosphate (V) (887.1 mg, 1.9 equivalent, 2.333 mmol) in DMF (1 mL). Stir the mixture at 25°C for 5 minutes. 3,3-Difluorocyclobut-1-amine hydrochloride (352.5 mg, 2 equivalents, 2.456 mmol) was added to the HATU-activated solution. The mixture was stirred at 25°C for 10 minutes. The crude product was purified directly by reversed-phase column chromatography. The purified fractions were combined, neutralized with saturated NaHCO3 (aqueous solution), and concentrated under vacuum to remove MeCN. The aqueous residue was extracted with ethyl acetate (twice). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under vacuum to dryness to give (S)-7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (487.5 mg, 888.7 μmol, 72.37%); LCMS (M+H) + = 549.6.

[0506] ​ ​ 2,2,2-trifluoroacetic acid (2.026 g, 1.360 mL, 20 equivalents, 17.77 mmol) was added to a solution of (S)-7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (487.5 mg, 1 equivalent, 888.7 μmol) in dichloromethane (1 mL). The mixture was stirred at 25°C for 30 min. The mixture was concentrated to dryness under vacuum, and the residue was purified by reversed-phase column chromatography. The purified fractions were combined, neutralized with saturated NaHCO3 (aqueous solution), and concentrated under vacuum to remove MeCN. The aqueous residue was extracted twice with ethyl acetate, and the combined organic phases were dried to dryness with anhydrous MgSO4 and then dried under high vacuum to give 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.

[0507] The following compounds were prepared in a manner similar to that of Example 2, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0508]

[0509] 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)

[0510] ​ To a 250 mL flask maintained under a nitrogen inert atmosphere, tert-butyl ((2-bromopyridin-4-yl)methyl)carbamate (5.0 g, 1 equivalent, 17 mmol), Zn(CN)₂ (5.0 g, 2.4 equivalent, 43 mmol), Pd₂(dba)₃·CH₃Cl (1.8 g, 0.10 equivalent, 1.7 mmol), and xanthan gum (2.0 g, 0.20 equivalent, 3.5 mmol) from NMP (100 mL) were added. The mixture was stirred at 120°C for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl ((2-cyanopyridin-4-yl)methyl)carbamate (3.0 g, 13 mmol, 74%); LCMS (M+H) + = 234.1.

[0511] ​ Add tert-butyl ((2-cyanopyridin-4-yl)methyl)carbamate (3.0 g, 1 equivalent, 13 mmol) and 4-(aminomethyl)pyridinecarboxynitrile hydrochloride (2.0 g, 12 mmol, 92%) to a 100 mL flask. Stir the mixture at 25°C for 1 hour. Concentrate the solution under reduced pressure. Add water and MeCN, and freeze-dry the mixture under vacuum to give 4-(aminomethyl)pyridinecarboxynitrile hydrochloride (2.0 g, 12 mmol, 92%).

[0512] ​ ​: Methyl 5-bromo-4-chloronicotinate (3.0 g, 1 equivalent, 12 mmol; prepared according to steps 2-1 to 2-2 of Example 2), tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylic acid oxalate (3.0 g, 0.83 equivalent, 9.9 mmol), and DIEA (6.0 g, 8.1 mL, 3.9 equivalent, 46 mmol) from MeCN (40 mL) were added to a 250 mL flask. The mixture was stirred at 60°C for 5 hours. The solution was concentrated under vacuum, and the residue was applied to a silica gel column and eluted with ethyl acetate / PE (1:3) to give tert-butyl 6-(3-bromo-5-(methoxycarbonyl)pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid (3.5 g, 8.2 mmol, 69%); LCMS (M+H) + = 426.1, 428.1.

[0513] ​ ​ To a 250 mL flask maintained under an inert nitrogen atmosphere, tert-butyl 1,4-dioxane (60 mL) and water (6 mL) were added, containing 6-(3-bromo-5-(methoxycarbonyl)pyridin-4-yl)-1,6-diazaspiro[3,4]octane-1-carboxylic acid (3.5 g, 1 equivalent, 8.2 mmol), Pd(dtbpf)Cl2 (500 mg, 0.093 equivalent, 767 μmol), (3,5-difluorophenyl)boronic acid (2.6 g, 2.0 equivalent, 16 mmol), and K2CO3 (3.5 g, 3.1 equivalent, 25 mmol). The mixture was stirred at 80°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was applied to a silica gel column and eluted with ethyl acetate / PE (2:1) to give 6-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridin-4-yl)-1,6-diazaspiro[3,4]octane-1-carboxylic acid tert-butyl ester (3.5 g, 7.6 mmol, 93%); LCMS (M+H). + = 461.1.

[0514] ​ ​Add 6-(3-(3,5-difluorophenyl)-5-(methoxycarbonyl)pyridin-4-yl)-1,6-diazaspiro[3,4]octane-1-carboxylic acid tert-butyl ester (3.5 g, 1 equivalent, 7.6 mmol) and NaOH (3.0 g, 9.8 equivalent, 75 mmol) to a 250 mL flask containing methanol (60 mL) and water (6 mL). Stir the mixture at 80°C for 1 hour. Concentrate the solution under vacuum and dilute with water. Adjust the pH of the solution to 5–6 with a saturated aqueous solution of NaHSO4. Extract the resulting solution with DCM (3 × 40 mL). The organic layers were combined, washed with brine, dried, and concentrated under vacuum to give 4-(1-(tert-butoxycarbonyl)-1,6-diazaspiro[3.4]oct-6-yl)-5-(3,5-difluorophenyl)nicotinic acid (3.0 g, 6.7 mmol, 88%); LCMS (M+H). + = 446.1.

[0515] ​ phenylpyridin-4-yl)-1,6-diazaspiro[3,4]octane-1-carboxylic acid tert-butyl ester Add 4-(1-(tert-butoxycarbonyl)-1,6-diazaspiro[3.4]octane-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 equivalent, 23 mmol), and HATU (2.5 g, 1.2 equivalent, 6.6 mmol) from DMF (40 mL) to a 100 mL flask. Stir the mixture at room temperature for 10 minutes, then add 4-(aminomethyl)pyridinecarboxynitrile hydrochloride (2.0 g, 2.1 equivalent, 12 mmol; from step 3-2). Stir the mixture at 25°C for 1 hour. The crude product was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions (2#-analyse-HPLC-SHIMADZU(HPLC-01)): column: SunFine prep OBD 19*150mm 5μm C-01; mobile phase: water (0.05% FA) and MeCN (increased from 27% MeCN to 47% within 7 minutes); detectors: 254 nm and 220 nm. Flow rate: 80 mL / min. The purified solution was concentrated under vacuum to obtain 1.8 g of product. The product was purified by chiral supercritical fluid chromatography (Chiral-SFC), yielding two diastereomers. The first peak (t = 2.69 min) was identified as (S)-6-(3-(((2-cyanopyridin-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (830 mg, 1.48 mmol, 26%); LCMS (M+H)+ = 561.4. The second peak (t=3.35 min) was identified as (R)-6-(3-(((2-cyanopyridin-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (740 mg, 1.32 mmol, 24%); LCMS (M+H) + = 561.3.

[0516] Steps 3-7, N-[(2-cyano-4-pyridyl)methyl]-4-{(S)-1,6-diaza-6-spiro[3.4]octyl}-5- Preparation of (3,5-difluorophenyl)nicotinamide Add (R)-6-(3-((((2-cyanopyridin-4-yl)methyl)carbamoyl)-5-(3,5-difluorophenyl)pyridin-4-yl)-1,6-diazaspiro[3,4]octane-1-carboxylic acid tert-butyl ester (740 mg, 1 equivalent, 1.32 mmol) to a 100 mL flask containing a mixture of TFA (2 mL) and DCM (10 mL). Stir the mixture at 25°C for 1 hour. Concentrate the solution under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions (2#-analyse-HPLC SHIMADZU(HPLC-01)): column, XBridge prep OBD 19*150mm 5μm C-01; mobile phase, water (0.05% NH3·H2O) and MeCN (increased from 26% MeCN to 48% within 7 min); detectors, 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.

[0517] The following compounds were prepared in a manner similar to that of Example 3, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0518]

[0519] Example A-4. Preparation of N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazine carboxamide (compound 192).

[0520] Step 4-1,7-(6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid Preparation of tert-butyl ester: Add methyl 4,6-dichloropyridazine-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 equivalent, 24 mmol) from MeCN (10 mL) to a 40 mL vial. The resulting solution was stirred at 25°C for 2 hours. Then, Boc2O (1.6 g, 1.7 mL, 1.8 equivalent, 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, eluting with PE / EtOAc (3:1) to give tert-butyl 7-(6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid (1.5 g, 3.8 mmol, 93%); LCMS (M+H) + = 397.2.

[0521] Step 4-2, Preparation of 7-(5-bromo-6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4] nonane-1-carboxylic acid tert-butyl ester Add tert-butyl 7-(6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid (1.5 g, 1 equivalent, 3.8 mmol), DCM (2.8 mL), and AcOH (14 mL) to a 40 mL vial. Then add 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (1.4 g, 1.0 equivalent, 3.8 mmol) at 0°C and stir the solution at 25°C for 30 min. Quench the resulting solution with NaHSO3 (10 mL) and adjust the pH to 7 with NaHCO3. Extract the reaction mixture with ethyl acetate (3 × 30 mL), combine the organic layers, wash with saturated brine (2 × 100 mL), and dry with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give 7-(5-bromo-6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (1.4 g, 2.9 mmol, 78%); LCMS (M+H). + = 475.1, 477.1.

[0522] Step 4-3, Preparation of 7-(6-chloro-5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazine-4-yl)-1,7-di Azaspiro[4.4]nonane-1-carboxylic acid tert-butyl esterTo a 40 mL vial, add 7-(5-bromo-6-chloro-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (750 mg, 1 equivalent, 1.58 mmol), (3,5-difluorophenyl)boronic acid (300 mg, 1.21 equivalent, 1.90 mmol), Pd(dtbpf)Cl2 (103 mg, 0.100 equivalent, 158 μmol), and K3PO4 (1.00 g, 2.99 equivalent, 4.71 mmol) to 1,4-dioxane (7 mL) and water (0.7 mL). Stir the resulting mixture at 70°C for 1 hour under a nitrogen atmosphere. Quench the mixture with water (20 mL) and extract with EtOAc (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, eluting with PE / EtOAc (1:3) to give 7-(6-chloro-5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (350 mg, 688 μmol, 43.6%); LCMS (M+H) + = 509.4, 511.4.

[0523] Step 4-4, Preparation of 7-(5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diaza Spiro[4.4]nonane-1-carboxylic acid tert-butyl ester 7-(6-chloro-5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (350 mg, 1 equivalent, 688 μmol) and Pd-C (35 mg, 0.48 equivalent, 0.33 mmol; 10 wt.%) were added to a 50 mL round-bottom flask containing 10 mL of MeOH. The reaction mixture was stirred at 25°C under H2 (3 bar) for 1 hour. The mixture was then filtered, and the filtrate was concentrated under vacuum to give 7-(5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (250 mg, 527 μmol, 76.6%); LCMS (M+H). + = 475.2.

[0524] Steps 4-5, preparing 4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5- Lithium difluorophenylpyridazine-3-carboxylateTo an 8 mL vial, add tert-butyl 7-(5-(3,5-difluorophenyl)-3-(methoxycarbonyl)pyrazin-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), followed by LiOH (4 mg, 2 equivalent, 0.2 mmol). Stir the mixture at 60°C for 1 hour. Concentrate the resulting mixture under vacuum to give lithium 4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)pyrazin-3-carboxylate (50 mg, 92 μmol, 87%, purity 86%).

[0525] Steps 4-6, preparation of 7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridazine-4- 1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester To an 8 mL vial, add lithium 4-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonane-7-yl)-5-(3,5-difluorophenyl)pyridazine-3-carboxylate (50 mg, 1 equivalent, 0.11 mmol), HATU (49 mg, 1.2 equivalent, 0.13 mmol), and DIEA (70 mg, 94 μL, 5.1 equivalent, 0.54 mmol) from DMF (1 mL). Stir the resulting reaction mixture at 25°C for 10 minutes. Then add 3,3-difluorocyclobutane-1-amine hydrochloride (23 mg, 1.5 equivalent, 0.16 mmol). Stir the resulting reaction mixture at 25°C for 1 hour. The mixture was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions: column, SunFire Prep C18 OBD column, 19 × 150 mm, 5 μm; mobile phase, water (0.1% TFA) and MeCN (proliferated from 30% MeCN to 75% within 7 min); total flow rate, 20 mL / min; detector, UV 220 nm. This yielded 7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester (30 mg, 55 μmol, 51%); LCMS (M+H). + = 550.4.

[0526] Steps 4-7, N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorobenzene) Preparation of 3-pyridazine carboxamideAdd 30 mg (1 equivalent, 55 μmol) 7-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyridazin-4-yl)-1,7-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester, DCM (3 mL), and TFA (1 mL) to a 50 mL round-bottom flask. Stir the mixture at room temperature for 1 hour. Concentrate the resulting mixture under reduced pressure, and purify the crude product by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions (2#-analyse-HPLC-SHIMADZU(HPLC-0013)): column, Kinetex EVO 21.2*150mm 5μm; mobile phase, water (0.1% TFA) and MeCN (increased from 25% MeCN to 55.0% within 15 min); detector, 220 nm. This yielded N-3,3-difluorocyclobutyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-5-(3,5-difluorophenyl)-3-pyridazine carboxamide bis(2,2,2-trifluoroacetate) (32.1 mg, 47.4 μmol, 87%); LCMS (M+H). + = 450.2.

[0527] The following compounds were prepared in a manner similar to that of Example 4, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0528]

[0529] Example B-1: SSTR Measurement Functional testing Overview: All five SSTR isoforms are Gi-coupled G protein-coupled receptors (GPCRs), and their activation by agonists leads to a decrease in intracellular cyclic AMP (cAMP) levels. Therefore, the measurement of intracellular cAMP levels can be used to assess whether a compound is an agonist of an SSTR isoform. A method for measuring intracellular cAMP is described below.

[0530] cAMP assay protocol for SSTR3 Two or four days prior to the assay, Chinese hamster ovary cells (CHO-K1, ATCC #CCL-61) stably expressing human somatostatin receptor subtype 3 were seeded at densities of 6,000 or 2,000 cells per well in 96-well tissue culture-treated plates. The culture medium was Ham's F12 growth medium (ThermoFisher #10-080-CM) supplemented with 10% donor bovine serum (Gemini Bio-Products #100-506); 100 U / mL penicillin; 100 μg / mL streptomycin; 2 mM L-glutamine (Gemini Bio-Products #400-110); and 0.25 mg / mL G418 (GoldBio #G-418-5). Cells were cultured at 37°C, 5% CO2, and 95% humidity. cAMP levels were determined using the HTRF dynamic cAMP assay kit (Cisbio, #62AM5PEJ) according to the manufacturer's instructions. On the day of assay, culture medium was aspirated, and cells were treated with 50 µL of stimulation buffer supplemented with 10.2 mM 3-isobutyl-1-methylxanthine (IBMX, Millipore Sigma #I5879) and 1.6 µM NKH477 (Tocris #1603), along with different dilutions of the compounds of this invention. Cells were incubated at 37°C for 20 min (the final concentration of the compounds of this invention is typically 0-10,000 nM). Cells were then treated with 50 µL of lysis buffer (HRTF cAMP kit, Cisbio) and incubated at room temperature with shaking at 600 rpm for 30 min, and finally diluted with 150 µL of stimulation buffer and shaken at 300 rpm for 5 min. The lysis buffer was transferred to 384-well plates and incubated at room temperature for 1-24 h. cAMP accumulation was detected using d2-labeled cAMP and anti-cAMP-Cryptate. Time-resolved fluorescence signals were read using an m1000 Pro (Tecan) or CLARIOStar (BMG Labtech) microplate reader. Samples were excited at 340 nm, and emission was measured at 620 nm and 665 nm. Data are expressed as fluorescence ratios (665 nm / 620 nm). Intracellular cAMP concentrations were calculated using a regression standard curve, and their relationship with the concentration of the compounds of this invention was plotted. The EC50 of the compounds was calculated using standard methods. 50 All data processing was performed on GraphPad Prism v9 (GraphPad, San Diego, California).

[0531] Table A reports the evaluation of the biological activity of compounds by inhibiting the cAMP activity of the human SSTR3 receptor.

[0532]

[0533] Example B-2: In vitro 3D cyst formation model Madin-Darby canine kidney (MDCK) cells were resuspended as single-cell suspensions in ice-cold type I collagen (Sigma-Aldrich) in complete culture medium and seeded at a density of 250 cells per well in 96-well plates (5 to 8 wells per condition). The plates were incubated at 37°C for 1 hour to allow collagen polymerization. To promote cyst growth, 100 μM of the pantothenic acid esterase inhibitor IBMX (3-isobutyl-1-methylxanthine) was added to the complete culture medium on the day of seeding. Simultaneously, different concentrations of compound 5 or compound 108 were added to the wells. The culture medium was changed every 48–72 hours over 9 days. On day 9, the effect of each treatment on the cysts was assessed. Fields of view were randomly selected, and multiple z-plane images were captured at 40x magnification using an inverted phase-contrast microscope (Olympus CK2) to cover all cysts within the field. The area of ​​all captured cysts was measured using ImageJ V.2.9.0, and the data were analyzed using GraphPad Prism software. Data (mean ± standard error) are expressed as cyst area (μm²) under each culture condition. The sample size for each experiment was n=2. Statistical analysis was performed using a two-tailed t-test: *P<0.05. See also Figure 5 .

[0534] Results. MDCK cells, derived from canine renal collecting ducts, are widely used in in vitro studies of cyst formation. When seeded in collagen gel, MDCK cells spontaneously form cysts and maintain polarity from the apex to the lateral base. Similar to what has been observed. In ADPKD patients, intracellular cAMP production drives cyst swelling in this system.

[0535] This system was used to develop a 3D culture system to test the potential therapeutic efficacy of the SSTR3 agonist disclosed herein. In this assay, cells were seeded in collagen in 96-well plates, and cyst growth was promoted by adding the pan-PDE inhibitor IBMX. IBMX was used to increase cAMP levels because this treatment was found to preferentially increase cAMP levels in cilia rather than in the cytoplasm. Figure 5 As shown, the addition of IBMX resulted in a significant increase in cyst volume. Importantly, this was achieved by using compound 5 (see...). Figure 5Treatment with (A) and compound 108 (see Figure 5(B)) attenuated IBMX-induced cyst swelling in a concentration-dependent manner.

[0536] These results support the hypothesis that SSTR3 receptor activation reduces ciliary cAMP levels and cyst expansion observed in ADPKD.

[0537] Example B-3: Evaluation of the effects of SSTR3 agonists on kidney weight and renal cyst index in an autosomal dominant polycystic kidney disease (ADPKD) mouse model The following experimental protocol was used to evaluate the efficacy of SSTR3 receptor agonists in reducing kidney size and kidney cyst index (KCI) in an autosomal dominant polycystic kidney disease (ADPKD) mouse model.

[0538] Construction of the ADPKD mouse model. The ADPKD mouse model is generated by selectively inactivating the Pkd1 gene in the kidneys of Pax8 Tet-O-Cre / Pkd1flox mice (Piontek et al., Clin J Am Soc Nephrol 2004, 15(12), 3035–3043; Piotek et al., Nat Med 2007, 13(12), 1490–1495; Traykova-Brauch et al., Nat Med 2008, 14(9), 979–984), thereby inducing renal cyst formation. Specifically, the Pkd1 gene deletion in the kidneys was induced by intraperitoneal injection of doxycycline hydrochloride (50 mg / kg) into Pax8 Tet-O-Cre / Pkd1flox mice on days 11 and 12 postnatal day (PND). By day 20 of PND, Pax8 Tet-O-Cre / Pkd1 flox mice (designated ADPKD mice) treated with doxycycline hydrochloride showed enlarged and cystic kidneys compared to untreated littermate control mice.

[0539] Application of SSTR3 agonists in an ADPKD mouse model. To evaluate the ability of SSTR3 agonists to reduce kidney weight and KCl in an ADPKD mouse model, male and female ADPKD mice at PND 12 were studied. From PND 12 to PND20, the solvent or SSTR3 agonist was administered once daily by gavage. Body weight and clinical symptoms were recorded daily. On day 20 after birth (PND20), mice were anesthetized 1–2 hours after treatment with the solvent or SSTR3 agonist. Left ventricular cardiac puncture was performed via thoracotomy using a needle coated with EDTA to collect blood. Blood was collected in EDTA tubes and stored on ice until plasma separation. Plasma samples were cryopreserved. The heart was removed and weighed to obtain the kidney-to-heart weight ratio. The left kidney was removed, weighed, longitudinally cut, and fixed overnight at 4°C in 4% paraformaldehyde solution. After fixation, the left kidney was processed and embedded in paraffin for histomorphometric analysis. Cross sections of the kidney, including the cortex, medulla, and renal papillae, were collected on glass slides and stained with hematoxylin and eosin. Images were taken at 1x and 4x magnification, and the total cystic area in the images was measured using ImageJ software. The renal cyst index (KCI) was calculated using the total cystic area.

[0540] Compound 108. From day 12 (PND 12) to day 20 (PND 20), ADPKD mice were orally administered either the solvent or compound 10, 30, or 100 mg / kg / day once daily. Mice were sacrificed on PND 20, and left kidney weight (A) and renal cyst index (%) were measured and calculated (B). Data are expressed as mean ± standard error (SEM) (solvent group n=17, 10 mg / kg / day group n=14, 30 mg / kg / day group n=15, 100 mg / kg / day group n=13). All data were analyzed using one-way ANOVA, and post-hoc tests (Dunnett's test) were performed to compare treatment groups with the solvent group. *p<0.5, ns: not significant. See also Figure 6 .

[0541] Results. Compound 108 was tested in an ADPKD mouse model 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:

[0542] Abbreviations: KCI = Kidney Cyst Index; SD = Standard Error Statistical significance was calculated using one-way ANOVA and post-hoc Dunnett's test to compare treatment groups with the solvent group. *p≤0.5, **p≤0.01.

[0543] In ADPKD model mice, oral administration of compound 108 at a dose of 100 mg / kg / day once daily from day 12 (PND 12) to day 20 (PND 20) significantly reduced the renal cyst index compared to the solvent group, with an inhibition rate of 13.3% (see [link to original text]). Figure 6 (B)), but the kidney weight did not change significantly (see Figure 6 (A)).

[0544] Based on these results, it is reasonable to expect that PKD, including ADPKD, can be successfully treated by administering the SSTR3 agonist disclosed herein to subjects.

[0545] The embodiments and implementation methods described herein are for illustrative purposes only. Various modifications or changes that can be made by those skilled in the art should be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) in: R1 is unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted 6-membered heterocyclic alkyl, unsubstituted or substituted C 5-7 Bicycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted 6-membered heteroaryl; wherein, if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, C 3-6 The group consisting of cycloalkoxy groups, CN, and OH; L is a bond or CR2R3, where R2 is H or C. 1-6 Alkyl group, and R3 is H or C. 1-6 Alkyl, C 1-6 Alkoxy, CH2OCH3 or C 1-6 Fluoroalkyl groups; or R2 and R3 together with the carbon atoms to which they are attached to form C2+. 3-6 cycloalkyl; Z is or , R4 is H or a halogen; R5 is H or a halogen; and R6 is H, a halogen, CN, or C. 1-6 Alkyl or C 1-6 Alkoxy; R7 is H, CN, or ; R8 represents H, D, OH, and C. 1-6 Alkyl, C 1-6 alkoxy group, NH2 or -NH(CH2)2OH; R A H, C(O)OC 1-6 Alkyl or C(O)C 1-6 alkyl; R B For H, D or C 1-6 alkyl; R C For H or D; R D It is H or halogen; m is an integer selected from 0 and 1; and n is an integer selected from 0, 1, and 2.

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

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is CR2R3.

4. The compound of any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, wherein R2 is H or methyl.

5. The compound of any one of claims 1, 3 and 4, or a pharmaceutically acceptable salt thereof, wherein R3 is H, methyl, ethyl, trifluoromethyl or CH2OCH3.

6. The compound of any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the carbon to which they are attached form C 3-6 Cycloalkyl.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: CH2、 , , , , , , , , as well as .

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 1-4 alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted with 1-2 X's, wherein each X' is independently selected from the group consisting of methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, cyclopropoxy, and OH.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , as well as .

11. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 3-6 Cycloalkyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, methyl, difluoromethyl and trifluoromethyl.

13. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

14. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted phenyl group.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is independently selected from the group consisting of fluorine, chlorine, methyl, methoxy and CN.

16. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , as well as .

17. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted pyridinyl group or an unsubstituted or substituted pyrimidinyl group.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, methyl, trifluoromethyl, methoxy, and CN.

19. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , as well as .

20. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 5-7 Bicycloalkyl.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted with fluorine or trifluoromethyl.

22. The compound of claim 20 or 21 or a pharmaceutically acceptable salt thereof, wherein C 5-7 One or more carbon atoms of a bicycloalkyl group are bridging carbons.

23. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , as well as .

24. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-23, wherein m is 1 and n is 1.

25. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein R A For H.

26. The compound of any one of claims 1-25 or a pharmaceutically acceptable salt thereof, wherein R B For H; R C For H; and R D For H.

27. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, wherein Z is .

28. The compound of any one of claims 1-7 and 11-13, or a pharmaceutically acceptable salt thereof, wherein Z is... .

29. The compound of claim 1, wherein the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: (him) in: R1 is unsubstituted 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 six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from F, Cl, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopropoxy, OCH2CF3, CN and OH. L is a bond or CR2R3, where R2 is H or methyl, and R3 is H, methyl, ethyl, trifluoromethyl, or -CH2OCH3; or R2 and R3 together with the carbon attached to them form a cyclopropyl group; Z is or , Where R4 is H, F, or Cl; R5 is H or F; R6 is H, F, Cl, CN, methyl, or methoxy. R7 is H or ; R8 is H, NH2, or methyl.

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

31. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein L is CR2R3.

32. The compound of any one of claims 29 and 31, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: CH2、 , , , , , , , , as well as .

33. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 1-4 alkyl.

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of methyl, ethyl, trifluoromethyl, ethoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy and cyclopropoxy.

35. The compound of any one of claims 29-34 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , as well as .

36. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 3-6 Cycloalkyl.

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, methyl and trifluoromethyl.

38. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , as well as .

39. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted phenyl group.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, chlorine, methyl, methoxy and CN.

41. The compound of any one of claims 29-32 and 39-40, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , as well as .

42. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted pyridinyl group or an unsubstituted or substituted pyrimidinyl group.

43. The compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, methyl, trifluoromethyl, methoxy and CN.

44. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , as well as .

45. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 5-7 Bicycloalkyl.

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein C 5-7 One or more carbon atoms in a bicycloalkyl group are bridging carbons.

47. The compound of any one of claims 45-46 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted with fluorine.

48. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , as well as .

49. The compound of any one of claims 29-32 or a pharmaceutically acceptable salt thereof, wherein R1 is tetrahydropyran.

50. The compound of any one of claims 29-32 and 49, or a pharmaceutically acceptable salt thereof, wherein R1 is... .

51. The compound of any one of claims 29-50 or a pharmaceutically acceptable salt thereof, wherein Z is .

52. The compound of any one of claims 29-32 and 36-37, or a pharmaceutically acceptable salt thereof, wherein Z is .

53. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

54. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-27 and 29-51, wherein R4 and R6 are fluorine.

55. The compound of claim 1, wherein the compound is a compound of formula (Ib) or (Ic) or a pharmaceutically acceptable salt thereof: (Ib) (Ic) in: R1 is unsubstituted or substituted C 1-3 Alkyl, unsubstituted or substituted C 3-4 Cycloalkyl, unsubstituted or substituted C5 bicycloalkyl, or unsubstituted or substituted 6-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from F, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, CN, and OH. L is a bond or CR2R3, where R2 is H and R3 is H, methyl, or -CH2OCH3; R5 is either H or F; R7 is either H or CN; and R8 can be H, D, OH, methoxy, or -NH(CH2)2OH.

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

57. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein L is CR2R3.

58. The compound of any one of claims 55 and 57, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: CH2、 as well as .

59. The compound of any one of claims 55-58 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C. 1-3 alkyl.

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy and OH.

61. The compound of any one of claims 55-60, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , , as well as .

62. The compound of any one of claims 55-59 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C 3-4 Cycloalkyl.

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, difluoromethyl and trifluoromethyl.

64. The compound of any one of claims 55-59 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , , , as well as .

65. The compound of any one of claims 55-59 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted pyridinyl group.

66. The compound of claim 65 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine, methyl, trifluoromethyl, methoxy, and CN.

67. The compound of any one of claims 55-59 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , , , , , as well as .

68. The compound of any one of claims 55-59 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C5 bicycloalkyl group.

69. The compound of claim 68 or a pharmaceutically acceptable salt thereof, wherein one or more carbon atoms of the C5 bicycloalkyl group are bridging carbons.

70. The compound of any one of claims 68-69 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted with trifluoromethyl.

71. The compound of any one of claims 55-59 or a pharmaceutically acceptable salt thereof, wherein R1 is... .

72. The compound of any one of claims 55-71, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof: (Ib).

73. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

74. The compound of claim 73 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ib): (Ib).

75. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-52, 54-72 and 74, wherein R7 is H and R8 is H.

76. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (1d) or a pharmaceutically acceptable salt thereof: in: R1 is unsubstituted or substituted C 1-4 Alkyl, unsubstituted or substituted C 3-5 Cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is 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 a methyl group; R4 is H, F, or Cl; R5 is either H or F; R6 is H, F, or Cl; R A For H, C(O)OEt or C(O)Me; R B It can be H, D, or methyl; R C For H or D; R D For H or F; m is an integer selected from 0 or 1; and n is an integer selected from 0, 1, and 2.

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

78. The compound of claim 76 or a pharmaceutically acceptable salt thereof, wherein L is CR2R3.

79. The compound of any one of claims 76 and 78, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: CH2 and .

80. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C. 1-4 alkyl.

81. The compound of claim 80 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted with methyl or trifluoromethoxy.

82. The compound of any one of claims 76-81 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: and .

83. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C. 3-5 Cycloalkyl.

84. The compound of claim 83 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of fluorine and trifluoromethyl.

85. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , as well as .

86. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted phenyl group.

87. The compound of claim 86 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-3 X, wherein each X is independently selected from the group consisting of fluorine, chlorine and CN.

88. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the following groups: , , , , as well as .

89. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted pyridinyl group.

90. The compound of claim 89 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from the group consisting of methyl and CN.

91. The compound of any one of claims 76-79 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: , as well as .

92. The compound of claim 76 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as .

93. Compounds of formula (II) or pharmaceutically acceptable salts thereof: (II) in: R1 is unsubstituted or substituted C 1-6 Alkyl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted six-membered heteroaryl, wherein if R1 is substituted, R1 is substituted by 1-2 X, wherein each X is independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 fluoroalkyl, C 1-6 The group consisting of fluoroalkoxy groups and CN; and L is a bond or CR2R3, where R2 is H and R3 is H or methyl.

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

95. The compound of claim 93 or a pharmaceutically acceptable salt thereof, wherein L is CH2 or .

96. The compound of any one of claims 93-95 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted ethyl group.

97. The compound of claim 96 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, R1 is substituted with 1-2 X's, wherein each X' is independently selected from methoxy and trifluoromethoxy.

98. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 93-97, wherein R1 is selected from the group consisting of: , as well as .

99. The compound according to any one of claims 93-95, or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted C. 4-5 Cycloalkyl.

100. The compound of claim 99 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, then R1 is substituted with fluorine.

101. The compound of any one of claims 93-95 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: and .

102. The compound of any one of claims 93-95 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted phenyl group.

103. The compound of claim 102 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, then R1 is substituted by CN.

104. The compound of any one of claims 93-95 or a pharmaceutically acceptable salt thereof, wherein R1 is... .

105. The compound of any one of claims 93-95 or a pharmaceutically acceptable salt thereof, wherein R1 is an unsubstituted or substituted pyridinyl group.

106. The compound of claim 105 or a pharmaceutically acceptable salt thereof, wherein if R1 is substituted, then R1 is substituted with a methyl group.

107. The compound of any one of claims 93-95 or a pharmaceutically acceptable salt thereof, wherein R1 is... .

108. The compound of claim 93 or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from the group consisting of: , , as well as .

109. The compound of any one of claims 93-107 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIa): (IIa)。 110. The compound of claim 109 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , ,、 as well as .

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

112. The method of claim 111, wherein the disease is polycystic kidney disease.

113. The method of any one of claims 111-112, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

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

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