Somatostatin subtype receptor 3 (SSTR3) agonists and uses thereof

Abstract

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

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 585,880, filed on September 27, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This article describes compounds that are somatostatin receptor subtype 3 (SSTR3) agonists, 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 regulation 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. In preclinical studies, somatostatin demonstrated (1) inhibition of cAMP production in MDCK cells and rat collecting ducts, (2) antagonism of vasopressin in toad bladders and canine collecting ducts, (3) inhibition of cAMP production, fluid secretion, and cell proliferation in bile duct epithelial cells, and (4) inhibition of the growth of connective tissue around the bile ducts and portal vein in rats with extrahepatic bile duct obstruction. Due to the approximately 3-minute half-life of somatostatin, more stable synthetic peptides (octreotide, lanreotide, and parreotide) have been developed for clinical use.

[0005] In preclinical studies, octreotide (binds to SSTR2 and SSTR5, but preferentially to SSTR2) and paretide (binds with high affinity to 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. Pkd2 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 SSTR5, 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 can lead to injection site reactions. Summary of the Invention

[0007] To the best of the inventors' knowledge, no SSTR3-selective small molecule modulators have been prepared or tested 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. These compounds are compounds of formula (I) having the general structure shown below, and their pharmaceutically acceptable salts: (I) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R6 is H or C 1-6 alkyl; J is or ; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R8 is H or C 1-6 alkyl; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C 1-6 Alkyl or C 1-6 Alkoxy; R 11 C 1-6 alkyl; A is , or ; R A C 1-6 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; R C For H or C 1-6 Halogenated alkyl groups; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups.

[0008] In one embodiment, the compound of formula (I) is selected from the following: Compound of formula (Ia): (Ia) in: R2 is H, halogen, or C. 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R4 represents H, halogen, and C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R6 is H or C 1-6 Alkyl; and R8 is H or C 1-6 alkyl; - Compounds of formula (Ib): (Ib) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C1-6 Alkyl or C 1-6 Alkoxy; R A C 1-6 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; and R C For H or C 1-6 Halogenated alkyl groups; - Compounds of formula (Ic): (Ic) in: Z is either CR3 or N; R2 is H, halogen, or C. 1-6 Alkoxy; R3 is H, halogen, or C. 1-6 Alkoxy; R4 is H, halogen, or C. 1-6 Alkoxy; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups; - Formula (Id) compounds: (Id) in: R2 is a halogen, C 1-6 Alkoxy or CN; R4 is a halogen or C 1-6 alkoxy groups; and R9 is C 1-6 Alkoxy or C 3-6 cycloalkyl; and Pharmaceutically acceptable salts of the above compounds.

[0009] In one embodiment, this document describes compounds of formula (Ia) or pharmaceutically acceptable salts thereof: (Ia) in: R2 is H, halogen, or C. 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R4 represents H, halogen, and C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R6 is H or C 1-6 Alkyl groups; and R8 is H or C 1-6 alkyl.

[0010] In one embodiment, R2 is H, halogen, or C. 1-3 alkoxy or CN; R3 is H, halogen, C 1-3 Alkoxy, C 1-3 Haloalkyl or CN; R4 is H, halogen, C 1-3 Alkoxy, C 1-3 Haloalkyl or CN; R6 is H or C 1-3 Alkyl; and R8 is H or C 1-3 alkyl.

[0011] In one embodiment, R3 is a halogen or C 1-3 Alkyl group.

[0012] In one implementation, R4 is C 1-3 Alkyl group.

[0013] In one implementation, R6 is H or Me.

[0014] In one implementation, R8 is H or Me.

[0015] In one embodiment, R2 is H; R3 is a halogen or C. 1-3 Alkyl group; R4 is C 1-3 Alkyl group; R6 is H or Me; and R8 is H or Me.

[0016] In one implementation, R2 is H, F, Cl, OMe, or CN.

[0017] In one implementation, R3 is H, F, Cl, OMe, CF3, or CN.

[0018] In one implementation, R4 is F, Cl, OMe, OEt, CF3, or CN.

[0019] In one embodiment, R2 is H, F, Cl, OMe, or CN; R3 is H, F, Cl, OMe, CN, or CF3; R4 is F, Cl, OMe, OEt, CF3, or CN; R6 is H or Me; and R8 is H or Me.

[0020] In one implementation, R2 is H.

[0021] In one implementation, R3 is F or OMe.

[0022] In one implementation, R4 is OMe or OEt.

[0023] In one implementation, R6 is H.

[0024] In one implementation, R8 is H.

[0025] In one implementation, R8 is Me.

[0026] In one embodiment, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

[0027] In another embodiment, this document describes compounds of formula (Ib), their N-oxides, or pharmaceutically acceptable salts thereof: (Ib) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C 1-6 Alkyl or C 1-6 Alkoxy; R A C 1-6 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; and R C For H or C 1-6 Halogenated alkyl groups.

[0028] In one embodiment, R1 is H, a halogen, or OH; R2 is H, a halogen, or C. 1-3 alkyl, C 1-3 alkoxy or CN; R3 is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C1-3 Alkoxy or CN; R4 is H, halogen, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, CN, OH or C(O)NH2; R5 is H, halogen or OH; R7 is H, C 1-3 Alkoxy, optionally C 1-3 alkyl, , or Substituted morpholino group; R9 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyclopropyl, or cyclopropoxy; R 10 C 1-3 Alkyl or C 1-3 Alkoxy; R A for C 1-3 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-4 cycloalkyl; and R C For H or C 1-3 Halogenated alkyl groups.

[0029] In one embodiment, R1 is H, F, or OH.

[0030] In one implementation, R2 is H, F, Cl, Me, OMe, or CN.

[0031] In one implementation, R3 is H, F, Cl, Me, CF3, OMe, or CN.

[0032] In one embodiment, R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2.

[0033] In one embodiment, R5 is H, F, or OH.

[0034] In one implementation, R7 is H, OMe, , , , , or .

[0035] In one embodiment, R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy.

[0036] In one implementation, R 10 For Me or OMe.

[0037] In one implementation, R A It is Me, CH2OH, or CH2OMe, and R B For H.

[0038] In one implementation, R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups.

[0039] In one implementation, R C It is H or CH2CH2F.

[0040] In one embodiment, R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is H, F, or OH; R7 is H, OMe, , , , , or R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R 10 For Me or OMe; R A For Me, CH2OH, or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups; and R C It can be H or CH2CH2F.

[0041] In one embodiment, R1 is H or OH.

[0042] In one implementation, R2 is H or F.

[0043] In one implementation, R3 is H, F, OMe, or CN.

[0044] In one implementation, R4 is Cl, OMe, or CN.

[0045] In one implementation, R5 is H.

[0046] In one implementation, R7 is H, OMe, or .

[0047] In one implementation, R8 is OMe or cyclopropyl.

[0048] In one implementation, R 10 For Me.

[0049] In one implementation, R A Let Me be the value of R. B For H.

[0050] In one implementation, R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups.

[0051] In one implementation, R C For H.

[0052] In one embodiment, R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H; R7 is H, OMe, or R9 is OMe or cyclopropyl; R 10 For Me; R A For Me; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups; and R C For H.

[0053] In one implementation, X is CR1; Y is CR2; and Z is CR3.

[0054] In one implementation, one of X, Y, or Z is N.

[0055] In one embodiment, the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

[0056] In another embodiment, this document describes compounds of formula (Ic) or pharmaceutically acceptable salts thereof: (Ic) in: Z is either CR3 or N; R2 is H, halogen, or C. 1-6 Alkoxy; R3 is H, halogen, or C. 1-6 Alkoxy; R4 is H, halogen, or C. 1-6 Alkoxy; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms attached to it, it forms a 3-6 membered heterocyclic alkyl group.

[0057] In one embodiment, R2 is H, halogen, or C. 1-3 alkoxy group; R3 is H, halogen, or C. 1-3 alkoxy group; R4 is H, halogen, or C. 1-3 Alkoxy; R D C 1-3 Alkyl groups; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms to which it is attached, it forms a 4-5 membered heterocyclic alkyl group.

[0058] In one implementation, R2 is H, F, or OMe.

[0059] In one implementation, R3 is H, F, or OMe.

[0060] In one implementation, R4 is F or OMe.

[0061] In one implementation, R D For Me or Et.

[0062] In one implementation, R D and R E Together with the nitrogen and carbon atoms to which it is attached, it forms a nitrogen heterocyclic butyl or pyrrolidinyl group.

[0063] In one embodiment, the compound is selected from: , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

[0064] In another embodiment, this document describes a compound of formula (Id) or a pharmaceutically acceptable salt thereof: (Id) in: R2 is a halogen, C 1-6 Alkoxy or CN; R4 is a halogen or C 1-6 alkoxy groups; and R9 is C 1-6 Alkoxy or C 3-6 Cycloalkyl.

[0065] In one embodiment, R2 is a halogen, C 1-3 Alkoxy or CN; R4 is halogen or C 1-3 Alkyl groups; and R9 is C 1-3 Alkoxy or cyclopropyl.

[0066] In one implementation, R2 is F, OMe, or CN.

[0067] In one implementation, R4 is F or OMe.

[0068] In one implementation, R9 is OMe or cyclopropyl.

[0069] In one embodiment, the compound is selected from: , , as well as Or its pharmaceutically acceptable salt.

[0070] In another embodiment disclosed herein, a method for treating a condition selected from polycystic kidney disease, polycystic liver disease, and ciliasis is provided, comprising administering to a subject in need a compound of formula (I), (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable salt thereof. In some embodiments, the condition is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

[0071] In another embodiment, this document provides compounds of formula (I), (Ia), (Ib), (Ic), or (Id), or pharmaceutically acceptable salts thereof, for treating diseases or conditions selected from polycystic kidney disease, polycystic liver disease, and cilia. In some embodiments, the condition is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

[0072] In another embodiment, this document provides the use of compounds of formula (I), (Ia), (Ib), (Ic), or (Id), or pharmaceutically acceptable salts thereof, for the preparation of medicaments for treating diseases or conditions selected from polycystic kidney disease, polycystic liver disease, and cilia. In some embodiments, the condition is polycystic kidney disease. In some embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD). Brief description of the attached diagram Figure 1 This study describes how abnormal primary ciliary function in autosomal dominant polycystic kidney disease (ADPKD) triggers cyst formation.

[0074] Figure 2 The interaction between calcium ions and cAMP ciliary signaling pathways in the kidney tissue of (A) healthy individuals and (B) individuals with ADPKD was depicted.

[0075] Figure 3 The mechanism by which SSTR3 activation inhibits adenylate cyclase activity and reduces cAMP levels in ciliated plasma was described.

[0076] Figure 4 illustrates the analysis of mRNA expression of SSTR2, SSTR3, SSTR5, and angiotensin receptor 2 (AVPR2) in healthy and cystic tissues. Detailed Implementation

[0077] 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.

[0078] 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.

[0079] 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.

[0080] In some embodiments, the SSTR3 agonists described herein are used to treat a variety of diseases or conditions, such as, but not limited to, ciliary disorders, including but not limited to polycystic kidney disease (PKD) and polycystic liver disease (PLD). In some embodiments, the SSTR3 agonists described herein are used to treat a variety of diseases or conditions associated with ciliary dysfunction, such as, but not limited to, PKD, autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and combinations thereof. In some embodiments, the SSTR3 agonists described herein are used to treat PKD. In some embodiments, the SSTR3 agonists described herein are used to treat ADPKD. In some embodiments, the somatostatin receptor modulators described herein are used to treat PKD in mammals.

[0081] 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), the organelle that forms 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 PLD, PKD, ADPKD, ARPKD, and combinations thereof.

[0082] 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.

[0083] In various animal models of ciliasis, including 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 (SSTR1 to 5), thereby inhibiting AC and reducing intracellular cAMP levels.

[0084] 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.

[0085] 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...). Figure 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.

[0086] 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 Figure 2 (A)

[0087] 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 Figure 2 (A)

[0088] 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).

[0089] 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.

[0090] 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.

[0091] 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 SSTR3 revealed that SSTR3-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]). Figure 4 Therefore, the inventors determined that the cellular localization and signal transduction capabilities of SSTR3 make it an attractive target for the treatment of ADPKD.

[0092] ARPKD is a major cause of end-stage renal disease (ESRD) and infant mortality, caused by mutations in PKD1 (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.

[0093] In some embodiments, the somatostatin receptor modulators described herein are used to treat ciliopathy in mammals. In some embodiments, the somatostatin receptor modulators described herein can reduce cAMP levels, which helps in the treatment of the ciliopathy described herein. In some embodiments, the ciliopathy or condition is selected from PKD, ADPKD, ARPKD, PLD, and combinations thereof. In some embodiments, the ciliopathy or condition is selected from PKD, ADPKD, and ARPKD. In some embodiments, the ciliopathy or condition is PKD. In some embodiments, the ciliopathy or condition is ADPKD. In some embodiments, the ciliopathy or condition is ARPKD.

[0094] 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.

[0095] 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.

[0096] compound Compounds of formula (I) are provided, including their pharmaceutically acceptable salts, which are somatostatin subtype 3 receptor (SSTR3) agonists.

[0097] Compound (I) has the structure shown below: (I) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R6 is H or C 1-6 alkyl; J is or ; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R8 is H or C 1-6 alkyl; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C 1-6 Alkyl or C 1-6 Alkoxy; R 11 C 1-6 alkyl; A is , or ; R A C 1-6 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; R C For H or C 1-6 Halogenated alkyl groups; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups.

[0098] In one embodiment, the compound of formula (I) is selected from the following: Compound of formula (Ia): (Ia) in: R2 is H, halogen, or C. 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R4 represents H, halogen, and C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R6 is H or C 1-6 Alkyl; and R8 is H or C 1-6 alkyl; - Compounds of formula (Ib): (Ib) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C 1-6 Alkyl or C 1-6 Alkoxy; R A C 1-6 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; and R C For H or C 1-6 Halogenated alkyl groups; - Compounds of formula (Ic): (Ic) in: Z is either CR3 or N; R2 is H, halogen, or C.1-6 Alkoxy; R3 is H, halogen, or C. 1-6 Alkoxy; R4 is H, halogen, or C. 1-6 Alkoxy; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups; - Formula (Id) compounds: (Id) in: R2 is a halogen, C 1-6 Alkoxy or CN; R4 is a halogen or C 1-6 alkoxy groups; and R9 is C 1-6 Alkoxy or C 3-6 cycloalkyl; and Pharmaceutically acceptable salts of the above compounds.

[0099] In some embodiments, in the compound of formula (I), X is CR1; Y is CR2; and Z is CR3; R1 is H; R5 is H; and J is... R9 is cyclopropyl; R 10 Methyl; R 11 A is methyl; A is ;R A For Me; R B For H; R C H is used. In this embodiment, the compound of formula (I) is the compound of formula (Ia).

[0100] In some embodiments, the compound is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof: (Ia) in: R2 is H, halogen, or C. 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R4 represents H, halogen, and C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R6 is H or C 1-6Alkyl groups; and R8 is H or C 1-6 alkyl.

[0101] In some embodiments, R2 is H, halogen, or C. 1-3 alkoxy or CN; R3 is H, halogen, C 1-3 Alkoxy, C 1-3 Haloalkyl or CN; R4 is H, halogen, C 1-3 Alkoxy, C 1-3 Haloalkyl or CN; R6 is H or C 1-3 Alkyl; and R8 is H or C 1-3 alkyl.

[0102] In some embodiments, R2 is H, F, Cl, Br, I, methoxy (OMe), ethoxy (OEt), n-propoxy (O-nPr), isopropoxy (O-iPr), or CN; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, or CN; R6 is H, methyl (Me), ethyl (Et), n-propyl (nPr), or isopropyl (iPr). R4 is H, F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, or CN; R6 is H, methyl (Me), ethyl (Et), n-propyl (nPr), or isopropyl (iPr); and R8 is H, methyl (Me), ethyl (Et), n-propyl (nPr), or isopropyl (iPr).

[0103] In some implementations, R2 is H or R4 is H.

[0104] In some embodiments, R2 is H; R3 is a halogen or C. 1-3 Alkyl group; R4 is C 1-3 Alkyl group; R6 is H or Me; and R8 is H or Me.

[0105] In some embodiments, R2 is H; R3 is a halogen or C. 1-3 Alkyl group; R4 is C 1-3 Alkyl group; R6 is H or Me; and R8 is H or Me.

[0106] In some implementations, R2 is H, F, Cl, OMe, or CN; R3 is H, F, Cl, OMe, CN, or CF3; R4 is F, Cl, OMe, OEt, CF3, or CN; R6 is H or Me; and R8 is H or Me.

[0107] In some implementations, R2 is H; R3 is F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R4 is OMe, OEt, O-nPr or O-iPr; R6 is H or Me; and R8 is H or Me.

[0108] In some implementations, R2 is H; R3 is F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R4 is OMe, OEt, O-nPr or O-iPr; R6 is H or Me; and R8 is H or Me.

[0109] In some implementations, R2 is H; R3 is F or OMe; R4 is OMe or OEt; R6 is H; and R8 is H or Me.

[0110] In some embodiments, R2 is H, halogen, or C. 1-3 Alkyl or CN. In some embodiments, R2 is H, F, Cl, or CN. In some embodiments, R2 is H. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is OMe. In some embodiments, R2 is CN.

[0111] In some embodiments, R3 is a halogen or C 1-3 Alkyl group. In some embodiments, R3 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr. In some embodiments, R3 is a halogen. In some embodiments, R3 is F, Cl, Br, or I. In some embodiments, R3 is C. 1-3 Alkoxy group. In some embodiments, R3 is OMe, OEt, O-nPr, or O-iPr.

[0112] In some embodiments, R3 is H, halogen, or C. 1-3 Alkoxy, C 1-3 Haloalkyl or CN. In some embodiments, R3 is H, F, Cl, OMe, CF3, or CN. In some embodiments, R3 is F or OMe. In some embodiments, R3 is H. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is OMe. In some embodiments, R3 is CF3. In some embodiments, R3 is CN.

[0113] In some implementations, R4 is C 1-3Alkoxy group. In some embodiments, R4 is OMe, OEt, O-nPr, or O-iPr. In some embodiments, R4 is OMe or OEt. In some embodiments, R4 is OMe. In some embodiments, R4 is OEt. In some embodiments, R4 is O-nPr. In some embodiments, R4 is O-iPr.

[0114] In some embodiments, R4 is H, halogen, C 1-3 Alkoxy, C 1-3 Haloalkyl or CN. In some embodiments, R4 is F, Cl, OMe, OEt, CF3, or CN. In some embodiments, R4 is OMe or OEt. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is OMe. In some embodiments, R4 is OEt. In some embodiments, R4 is CF3. In some embodiments, R4 is CN.

[0115] In some implementations, R6 is H or C. 1-3 Alkyl group. In some embodiments, R6 is H or Me. In some embodiments, R6 is H. In some embodiments, R6 is Me.

[0116] In some implementations, R8 is H or C. 1-3 Alkyl group. In some embodiments, R8 is H or Me. In some embodiments, R8 is H. In some embodiments, R8 is Me.

[0117] In some embodiments, the compound of formula (Ia) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

[0118] In some embodiments, the compound of formula (Ia) is the compound presented in Table 1.

[0119] In some embodiments, the compound of formula (Ia) is compound 1.

[0120] In some embodiments, the compound of formula (Ia) is compound 2.

[0121] In some embodiments, the compound of formula (Ia) is compound 3.

[0122] In some embodiments, the compound of formula (Ia) is compound 4.

[0123] In some embodiments, the compound of formula (Ia) is compound 5.

[0124] In some embodiments, the compound of formula (Ia) is compound 6.

[0125] In some embodiments, the compound of formula (Ia) is compound 7.

[0126] In some embodiments, the compound of formula (Ia) is compound 8.

[0127] In some embodiments, the compound of formula (Ia) is compound 9.

[0128] In some embodiments, the compound of formula (Ia) is compound 10.

[0129] In some embodiments, the compound of formula (Ia) is compound 11.

[0130] In some embodiments, the compound of formula (Ia) is compound 12.

[0131] In some embodiments, the compound of formula (Ia) is compound 13.

[0132] In some embodiments, the compound of formula (Ia) is compound 14.

[0133] In some embodiments, the compound of formula (Ia) is compound 15.

[0134] In some embodiments, the compound of formula (Ia) is compound 16.

[0135] In some embodiments, the compound of formula (Ia) is compound 17.

[0136] In some embodiments, the compound of formula (Ia) is compound 18.

[0137] In some embodiments, the compound of formula (Ia) is compound 19.

[0138] In some embodiments, the compound of formula (Ia) is compound 20.

[0139] In some embodiments, the compound of formula (Ia) is compound 21.

[0140] In some embodiments, the compound of formula (Ia) is compound 22.

[0141] In some embodiments, the compound of formula (Ia) is compound 23.

[0142] In some embodiments, the compound of formula (Ia) is compound 24.

[0143] In some embodiments, the compound of formula (Ia) is compound 25.

[0144] In some embodiments, the compound of formula (Ia) is compound 26.

[0145] In some embodiments, the compound of formula (Ia) is compound 27.

[0146] In some embodiments, the compound of formula (Ia) is compound 28.

[0147] In some embodiments, the compound of formula (Ia) is compound 29.

[0148] In some embodiments, the compound of formula (Ia) is compound 30.

[0149] In some embodiments, the compound of formula (Ia) is compound 31.

[0150] In some embodiments, the compound of formula (Ia) is compound 32.

[0151] In some embodiments, the compound of formula (Ia) is compound 33.

[0152] In some embodiments, the compound of formula (Ia) is compound 34.

[0153] In some embodiments, the compound of formula (Ia) is compound 35.

[0154] In some embodiments, the compound of formula (Ia) is compound 36.

[0155] In some embodiments, the compound of formula (Ia) is compound 168.

[0156] In some embodiments, in the compound of formula (I), R6 is H; R 11 Methyl; J is ; and A is In this embodiment, the compound of formula (I) is the compound of formula (Ib): In some embodiments, the compound is a compound of formula (Ib) or its N-oxide or a pharmaceutically acceptable salt thereof: (Ib) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C 1-6 Alkyl or C 1-6 Alkoxy; R A C 1-6Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; and R C For H or C 1-6 Halogenated alkyl groups; In some embodiments, X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein, when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, a halogen, or OH; R2 is H, a halogen, or C 1-3 Alkyl, C 1-3 alkoxy or CN; R3 is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or CN; R4 is H, halogen, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy group, CN, OH or C(O)NH2; R5 is H, halogen or OH; R7 is H, C 1-3 Alkoxy, optionally C 1-3 alkyl, , or Substituted morpholino group; R9 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyclopropyl, or cyclopropoxy; R 10 C 1-3 Alkyl or C 1-3 Alkoxy; R A C 1-3 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-4 cycloalkyl; and R C For H or C 1-3 Halogenated alkyl groups.

[0157] In some embodiments, X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; wherein, when X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, F, Cl, Br, I, or OH; R2 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr, O-iPr, or CN; and R3 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, or Cl halogen. R4 is H, F, Cl, Br, I, Me, Et, n-Pr, i-Pr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, OMe, OEt, O-nPr, O-iPr, C1 haloalkoxy, C2 haloalkoxy, C3 haloalkyl, CN, OH, or C(O)NH2; R5 is H, F, Cl, Br, I, or OH; R7 is H, OMe, OEt, O-nPr, O-iPr, optionally with Me, , or Substituted morpholinoyl group; R9 is Me, Et, n-Pr, i-Pr, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, OMe, OEt, O-nPr, O-iPr, cyclopropyl or cyclopropoxy; R 10 is Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr or O-iPr; R A For Me, Et, n-Pr, i-Pr, OMe, OEt, O-nPr, O-iPr, CH2OH, or CH2OMe; R B For H; or R A and R B Together with the carbon atoms attached to them, they form cyclopropyl or cyclobutyl groups; and R C It is an H or C1 haloalkyl, C2 haloalkyl or C3 haloalkyl.

[0158] In some embodiments, R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is H, F, or OH; R7 is H, OMe, , , , , or R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R 10 For Me or OMe; R A For Me, CH2OH, or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups; and R C It is H or CH2CH2F.

[0159] In some embodiments, X is CR1; Y is CR2; and Z is CR3; R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is H, F, or OH; R7 is H, OMe, , , , , or R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R 10 For Me or OMe; R A For Me, CH2OH, or CH2OMe; R B For H; or, R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups; R C It is H or CH2CH2F.

[0160] In some embodiments, one of X, Y, or Z is N; R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 is H, F, Cl, Me, CF3, OMe, or CN; R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2; R5 is H, F, or OH; R7 is H, OMe, , , , , or R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R 10 For Me or OMe; R A For Me, CH2OH, or CH2OMe; R B For H; or, R A and R BTogether with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups; and R C It is H or CH2CH2F.

[0161] In some embodiments, R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H; R7 is H, OMe, or R9 is OMe or cyclopropyl; R 10 For Me; R A For Me; R B For H; or, R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups; and R C For H.

[0162] In some embodiments, X is CR1; Y is CR2; and Z is CR3; R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H; and R7 is H, OMe, or... R9 is OMe or cyclopropyl; R 10 For Me; R A For Me; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups; and R C For H.

[0163] In some embodiments, one of X, Y, or Z is N; R1 is H or OH; R2 is H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H; R7 is H, OMe, or R9 is OMe or cyclopropyl; R 10 For Me; R A For Me; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups; and R C For H.

[0164] In some embodiments, R1 is H, a halogen, or OH. In some embodiments, R1 is H, F, or OH. In some embodiments, R1 is H or OH. In some embodiments, R1 is H. In some embodiments, R1 is F. In some embodiments, R1 is OH.

[0165] In some embodiments, R2 is H, halogen, or C. 1-3 Alkyl, C 1-3Alkyl or CN. In some embodiments, R2 is H, F, Cl, Me, OMe, or CN. In some embodiments, R2 is H or F. In some embodiments, R2 is H. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Me. In some embodiments, R2 is OMe. In some embodiments, R2 is CN.

[0166] In some embodiments, R3 is H, halogen, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl or CN. In some embodiments, R3 is H, F, Cl, Me, CF3, OMe, or CN. In some embodiments, R3 is H, F, OMe, or CN. In some embodiments, R3 is H. In some embodiments, R3 is F. In some embodiments, R3 is Cl. In some embodiments, R3 is Me. In some embodiments, R3 is CF3. In some embodiments, R3 is OMe. In some embodiments, R3 is CN.

[0167] In some embodiments, R4 is H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 The derivative is a haloalkoxy group, CN, OH, or C(O)NH2. In some embodiments, R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH, or C(O)NH2. In some embodiments, R4 is Cl, OMe, or CN. In some embodiments, R4 is H. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is Me. In some embodiments, R4 is CF3. In some embodiments, R4 is OMe. In some embodiments, R4 is OEt. In some embodiments, R4 is OCF3. In some embodiments, R4 is CN. In some embodiments, R4 is OH. In some embodiments, R4 is C(O)NH2.

[0168] In some embodiments, R5 is H, a halogen, or OH. In some embodiments, R5 is H, F, or OH. In some embodiments, R5 is H. In some embodiments, R5 is F. In some embodiments, R5 is OH.

[0169] In some implementations, R7 is H or C. 1-3 Alkoxy, optionally C 1-3 alkyl, , or Substituted morpholino group. In some embodiments, R7 is H, OMe, , , , , or In some implementations, R7 is H, OMe, or In some implementations, R7 is H. In some implementations, R7 is OMe. In some implementations, R7 is... In some implementations, R7 is... In some implementations, R7 is... In some implementations, R7 is... In some implementations, R7 is... In some implementations, R7 is... In some implementations, R7 is... .

[0170] In some implementations, R9 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyclopropyl, or cyclopropoxy. In some embodiments, R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy. In some embodiments, R9 is OMe or cyclopropyl. In some embodiments, R9 is ethyl. In some embodiments, R9 is CF3. In some embodiments, R9 is OMe. In some embodiments, R9 is OEt. In some embodiments, R9 is cyclopropyl. In some embodiments, R9 is cyclopropoxy.

[0171] In some implementations, R 10 C 1-3 Alkyl or C 1-3 Alkyl group. In some embodiments, R 10 For Me or OMe. In some implementations, R 10 For Me. In some implementations, R 10 For OMe.

[0172] In some implementations, R A C 1-3 Alkyl, CH2OH or CH2OMe; and R B For H. In some implementations, R A For Me, CH2OH or CH2OMe; and R B For H. In some implementations, R A For Me; and R B For H. In some implementations, R AIt is CH2OH; and R B For H. In some implementations, R A It is CH2OMe; and R B For H.

[0173] In some implementations, R A and R B Together with the carbon atoms they are attached to, they form C 3-4 Cycloalkyl. In some embodiments, R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups. In some embodiments, R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups. In some embodiments, R A and R B Together with the carbon atoms they are attached to, they form cyclobutyl groups.

[0174] In some implementations, R C For H or C 1-3 Halogenated alkyl groups. In some embodiments, R C It is H or CH2CH2F. In some embodiments, R C For H. In some implementations, R C It is CH2CH2F.

[0175] In some implementations, X is CR1; Y is CR2; and Z is CR3.

[0176] In some implementations, one of X, Y, or Z is N. In some implementations, X is N. In some implementations, Y is N. In some implementations, Z is N.

[0177] In some embodiments, the compound of formula (Ib) is its N-oxide.

[0178] In some embodiments, the compounds of formula (Ib) are selected from: , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

[0179] In some embodiments, the compound of formula (Ib) is the compound presented in Table 2.

[0180] In some embodiments, the compound of formula (Ib) is compound 37.

[0181] In some embodiments, the compound of formula (Ib) is compound 38.

[0182] In some embodiments, the compound of formula (Ib) is compound 39.

[0183] In some embodiments, the compound of formula (Ib) is compound 40.

[0184] In some embodiments, the compound of formula (Ib) is compound 41.

[0185] In some embodiments, the compound of formula (Ib) is compound 42.

[0186] In some embodiments, the compound of formula (Ib) is compound 43.

[0187] In some embodiments, the compound of formula (Ib) is compound 44.

[0188] In some embodiments, the compound of formula (Ib) is compound 45.

[0189] In some embodiments, compound (Ib) is compound 46.

[0190] In some embodiments, the compound of formula (Ib) is compound 47.

[0191] In some embodiments, the compound of formula (Ib) is compound 48.

[0192] In some embodiments, the compound of formula (Ib) is compound 49.

[0193] In some embodiments, the compound of formula (Ib) is compound 50.

[0194] In some embodiments, the compound of formula (Ib) is compound 51.

[0195] In some embodiments, the compound of formula (Ib) is compound 52.

[0196] In some embodiments, the compound of formula (Ib) is compound 53.

[0197] In some embodiments, the compound of formula (Ib) is compound 54.

[0198] In some embodiments, the compound of formula (Ib) is compound 55.

[0199] In some embodiments, the compound of formula (Ib) is compound 56.

[0200] In some embodiments, the compound of formula (Ib) is compound 57.

[0201] In some embodiments, the compound of formula (Ib) is compound 58.

[0202] In some embodiments, the compound of formula (Ib) is compound 59.

[0203] In some embodiments, the compound of formula (Ib) is compound 60.

[0204] In some embodiments, the compound of formula (Ib) is compound 61.

[0205] In some embodiments, the compound of formula (Ib) is compound 62.

[0206] In some embodiments, the compound of formula (Ib) is compound 63.

[0207] In some embodiments, the compound of formula (Ib) is compound 64.

[0208] In some embodiments, the compound of formula (Ib) is compound 65.

[0209] In some embodiments, the compound of formula (Ib) is compound 66.

[0210] In some embodiments, the compound of formula (Ib) is compound 67.

[0211] In some embodiments, the compound of formula (Ib) is compound 68.

[0212] In some embodiments, the compound of formula (Ib) is compound 69.

[0213] In some embodiments, the compound of formula (Ib) is compound 70.

[0214] In some embodiments, the compound of formula (Ib) is compound 71.

[0215] In some embodiments, the compound of formula (Ib) is compound 72.

[0216] In some embodiments, the compound of formula (Ib) is compound 73.

[0217] In some embodiments, the compound of formula (Ib) is compound 74.

[0218] In some embodiments, the compound of formula (Ib) is compound 75.

[0219] In some embodiments, the compound of formula (Ib) is compound 76.

[0220] In some embodiments, the compound of formula (Ib) is compound 77.

[0221] In some embodiments, the compound of formula (Ib) is compound 78.

[0222] In some embodiments, the compound of formula (Ib) is compound 79.

[0223] In some embodiments, the compound of formula (Ib) is compound 80.

[0224] In some embodiments, the compound of formula (Ib) is compound 81.

[0225] In some embodiments, the compound of formula (Ib) is compound 82.

[0226] In some embodiments, the compound of formula (Ib) is compound 83.

[0227] In some embodiments, the compound of formula (Ib) is compound 84.

[0228] In some embodiments, the compound of formula (Ib) is compound 85.

[0229] In some embodiments, the compound of formula (Ib) is compound 86.

[0230] In some embodiments, the compound of formula (Ib) is compound 87.

[0231] In some embodiments, the compound of formula (Ib) is compound 88.

[0232] In some embodiments, the compound of formula (Ib) is compound 89.

[0233] In some embodiments, the compound of formula (Ib) is compound 90.

[0234] In some embodiments, the compound of formula (Ib) is compound 100.

[0235] In some embodiments, the compound of formula (Ib) is compound 101.

[0236] In some embodiments, the compound of formula (Ib) is compound 102.

[0237] In some embodiments, the compound of formula (Ib) is compound 103.

[0238] In some embodiments, the compound of formula (Ib) is compound 104.

[0239] In some embodiments, the compound of formula (Ib) is compound 105.

[0240] In some embodiments, the compound of formula (Ib) is compound 106.

[0241] In some embodiments, the compound of formula (Ib) is compound 107.

[0242] In some embodiments, the compound of formula (Ib) is compound 108.

[0243] In some embodiments, the compound of formula (Ic) is compound 109.

[0244] In some embodiments, the compound of formula (Ic) is compound 110.

[0245] In some embodiments, the compound of formula (Ib) is compound 111.

[0246] In some embodiments, the compound of formula (Ib) is compound 112.

[0247] In some embodiments, the compound of formula (Ib) is compound 113.

[0248] In some embodiments, the compound of formula (Ib) is compound 114.

[0249] In some embodiments, the compound of formula (Ib) is compound 115.

[0250] In some embodiments, the compound of formula (Ib) is compound 116.

[0251] In some embodiments, the compound of formula (Ib) is compound 117.

[0252] In some embodiments, the compound of formula (Ib) is compound 118.

[0253] In some embodiments, the compound of formula (Ib) is compound 119.

[0254] In some embodiments, the compound of formula (Ib) is compound 120.

[0255] In some embodiments, the compound of formula (Ib) is compound 121.

[0256] In some embodiments, the compound of formula (Ib) is compound 122.

[0257] In some embodiments, the compound of formula (Ib) is compound 123.

[0258] In some embodiments, the compound of formula (Ib) is compound 124.

[0259] In some embodiments, the compound of formula (Ib) is compound 125.

[0260] In some embodiments, the compound of formula (Ib) is compound 126.

[0261] In some embodiments, the compound of formula (Ib) is compound 127.

[0262] In some embodiments, the compound of formula (Ib) is compound 128.

[0263] In some embodiments, the compound of formula (Ib) is compound 129.

[0264] In some embodiments, the compound of formula (Ib) is compound 130.

[0265] In some embodiments, the compound of formula (Ib) is compound 131.

[0266] In some embodiments, the compound of formula (Ib) is compound 132.

[0267] In some embodiments, the compound of formula (Ib) is compound 133.

[0268] In some embodiments, the compound of formula (Ib) is compound 134.

[0269] In some embodiments, the compound of formula (Ib) is compound 135.

[0270] In some embodiments, the compound of formula (Ib) is compound 136.

[0271] In some embodiments, the compound of formula (Ib) is compound 137.

[0272] In some embodiments, the compound of formula (Ib) is compound 138.

[0273] In some embodiments, the compound of formula (Ib) is compound 139.

[0274] In some embodiments, the compound of formula (Ib) is compound 140.

[0275] In some embodiments, the compound of formula (Ib) is compound 141.

[0276] In some embodiments, the compound of formula (Ib) is compound 142.

[0277] In some embodiments, the compound of formula (Ib) is compound 143.

[0278] In some embodiments, the compound of formula (Ib) is compound 144.

[0279] In some embodiments, the compound of formula (Ib) is compound 145.

[0280] In some embodiments, the compound of formula (Ib) is compound 146.

[0281] In some embodiments, the compound of formula (Ib) is compound 147.

[0282] In some embodiments, the compound of formula (Ib) is compound 148.

[0283] In some embodiments, the compound of formula (Ib) is compound 149.

[0284] In some embodiments, the compound of formula (Ib) is compound 150.

[0285] In some embodiments, the compound of formula (Ib) is compound 151.

[0286] In some embodiments, the compound of formula (Ib) is compound 152.

[0287] In some embodiments, in the compound of formula (I), X is CR1 and Y is CR2; R1 is H; R5 is H; R6 is H; R 11 Methyl; J is R7 is H; R9 is cyclopropyl; R 10 A is methyl; and A is In this embodiment, the compound of formula (I) is the compound of formula (Ic).

[0288] In this embodiment, the compound is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: (Ic) in: Z is either CR3 or N; R2 is H, halogen, or C. 1-6 Alkoxy; R3 is H, halogen, or C. 1-6 Alkoxy; R4 is H, halogen, or C. 1-6 Alkoxy; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 3-6 membered heterocyclic alkyl groups; In some embodiments, Z is CR3 or N; R2 is H, halogen, or C. 1-3 alkoxy group; R3 is H, halogen, or C. 1-3 alkoxy group; R4 is H, halogen, or C. 1-3 Alkoxy; R D C 1-3 Alkyl; R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms to which they are attached, they form 4-5 membered heterocyclic alkyl groups. In some embodiments, Z is CR3 or N; R2 is H, F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R4 is F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R D For Me, Et, n-Pr, or i-Pr; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 4-5 membered heterocyclic alkyl groups.

[0289] In some embodiments, Z is CR3; R2 is H, halogen, or C. 1-3 alkoxy group; R3 is H, halogen, or C.1-3 alkoxy group; R4 is H, halogen, or C. 1-3 Alkoxy; R D C 1-3 Alkyl; and RE is CH2OMe; or R D and R E Together with the nitrogen and carbon atoms to which they are attached, they form C4-5 heterocyclic alkyl groups. In some embodiments, Z is CR3 or N; R2 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R4 is F, Cl, Br, I, OMe, OEt, O-nPr, or O-iPr; R D For Me, Et, n-Pr, or i-Pr; R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 4-5 membered heterocyclic alkyl groups.

[0290] In some embodiments, Z is N; R3 is H, halogen, or C. 1-3 alkoxy group; R4 is H, halogen, or C. 1-3 Alkoxy; R D C 1-3 Alkyl; R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form C 4-5 Heterocyclic alkyl groups. In some embodiments, Z is CR3 or N; R2 is H, F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R3 is H, F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R4 is F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; R D For Me, Et, n-Pr, or i-Pr; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form 4-5 membered heterocyclic alkyl groups.

[0291] In some implementations, Z is CR3 or N; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; R D For Me or Et; R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form nitrogen-containing heterocyclic butyl or pyrrolidinyl groups.

[0292] In some implementations, Z is CR3; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; R D For Me or Et; R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form nitrogen heterocyclic butyl or pyrrolidinyl compounds.

[0293] In some implementations, Z is CR3; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; R D For Me or Et; R E It is CH2OMe.

[0294] In some implementations, Z is CR3; R2 is H, F, or OMe; R3 is H, F, or OMe; R4 is F or OMe; and R D and R E Together with the nitrogen and carbon atoms they are attached to, they form nitrogen-containing heterocyclic butyl or pyrrolidinyl groups.

[0295] In some implementations, Z is N; R2 is H, F, or OMe; R4 is F or OMe; R D For Me or Et; R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms they are attached to, they form nitrogen heterocyclic butyl or pyrrolidinyl compounds.

[0296] In some implementations, Z is N; R2 is H, F, or OMe; R4 is F or OMe; R D For Me or Et; and R E It is CH2OMe.

[0297] In some implementations, Z is N; R2 is H, F, or OMe; R4 is F or OMe; and R D and R E Together with the nitrogen and carbon atoms they are attached to, they form nitrogen-containing heterocyclic butyl or pyrrolidinyl groups.

[0298] In some embodiments, R2 is H, F, or OMe. In some embodiments, R2 is H. In some embodiments, R2 is F. In some embodiments, R2 is OMe.

[0299] In some implementations, R3 is H. In some implementations, R3 is F. In some implementations, R3 is OMe.

[0300] In some embodiments, R4 is H, F, or OMe. In some embodiments, R4 is H. In some embodiments, R4 is F. In some embodiments, R4 is OMe.

[0301] In some implementations, R D For Me or Et. In some implementations, R D For Me. In some implementations, R D For Et.

[0302] In some implementations, Z is CR3. In some implementations, Z is N.

[0303] In some implementations, R D and R E Together with the nitrogen and carbon atoms to which they are attached, they form nitrogen-containing heterocyclic butyl or pyrrolidinyl groups. In some embodiments, R D and R E Together with the nitrogen and carbon atoms to which they are attached, they form a nitrogen-containing heterocyclic butyl group. In some embodiments, R D and R E Together with the nitrogen and carbon atoms they are attached to, they form pyrrolidinyl groups.

[0304] In some embodiments, the compound of formula (Ic) is selected from: , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

[0305] In some embodiments, the compound of formula (Ic) is the compound presented in Table 3.

[0306] In some embodiments, the compound of formula (Ic) is compound 153.

[0307] In some embodiments, the compound of formula (Ic) is compound 154.

[0308] In some embodiments, the compound of formula (Ic) is compound 155.

[0309] In some embodiments, the compound of formula (Ic) is compound 156.

[0310] In some embodiments, the compound of formula (Ic) is compound 157.

[0311] In some embodiments, the compound of formula (Ic) is compound 158.

[0312] In some embodiments, the compound of formula (Ic) is compound 159.

[0313] In some embodiments, the compound of formula (Ic) is compound 160.

[0314] In some embodiments, the compound of formula (Ic) is compound 161.

[0315] In some embodiments, the compound of formula (Ic) is compound 162.

[0316] In some embodiments, the compound of formula (Ic) is compound 163.

[0317] In some embodiments, in the compound of formula (I), X is CR1, Y is CR2, and Z is CR3; R1 is H; R3 is H; R5 is H; R6 is H; R 11 Methyl; J is R7 is H; R 10 A is methyl; and A is In this embodiment, the compound of formula (I) is the compound of formula (Id).

[0318] In some embodiments, the compound is a compound of formula (Id) or a pharmaceutically acceptable salt thereof: (Id) in: R2 is a halogen, C 1-6 Alkoxy or CN; R4 is a halogen or C 1-6 alkoxy groups; and R9 is C 1-6 Alkoxy or C 3-6 Cycloalkyl.

[0319] In some embodiments, R2 is a halogen, C 1-3 Alkoxy or CN; R4 is halogen or C 1-3 Alkyl groups; and R9 is C 1-3 Alkyl or cyclopropyl. In some embodiments, R2 is F, Cl, Br, I, OMe, OEt, O-nPr, O-iPr or CN; R4 is F, Cl, Br, I, OMe, OEt, O-nPr or O-iPr; and R9 is OMe, OEt, O-nPr, O-iPr or cyclopropyl.

[0320] In some implementations, R2 is F, OMe, or CN; R4 is F or OMe; and R9 is OMe or cyclopropyl.

[0321] In some embodiments, R2 is a halogen, C 1-3 Alkyl or CN. In some embodiments, R2 is F, OMe, or CN. In some embodiments, R2 is F. In some embodiments, R2 is OMe. In some embodiments, R2 is CN.

[0322] In some embodiments, R4 is a halogen or C 1-3 Alkyl group. In some embodiments, R4 is F or OMe. In some embodiments, R4 is F. In some embodiments, R4 is OMe.

[0323] In some implementations, R9 is C 1-3 Alkoxy or cyclopropyl. In some embodiments, R9 is OMe or cyclopropyl. In some embodiments, R9 is OMe. In some embodiments, R9 is cyclopropyl.

[0324] In some embodiments, the compound of formula (Id) is selected from: , , as well as Or its pharmaceutically acceptable salt.

[0325] In some embodiments, the compound of formula (Id) is the compound presented in Table 4.

[0326] In some embodiments, the compound of formula (Id) is compound 164.

[0327] In some embodiments, the compound of formula (Id) is compound 165.

[0328] In some embodiments, the compound of formula (Id) is compound 166.

[0329] In some embodiments, the compound of formula (Id) is compound 167.

[0330] Exemplary compounds of formula (Ia) described herein include those described in Table 1: (Ia)

[0331] The names of the compounds in Table 1 are shown below: 1: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 2: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 3: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 4: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 5: N-[(S)-1-(3-chloro-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 6: N-[(S)-1-(3,4-dichlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 7: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 8: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 9: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-N-methyl-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 10: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 11: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 12: N-{(S)-1-[3-cyano-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 13: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 14: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 15: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 16: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 17: N-[(S)-1-(3,4-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 18: N-{(S)-1-[3-cyano-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 19: N-[(S)-1-(3,5-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 20: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 21: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 22: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 23: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 24: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 25: N-[(S)-1-(3-chloro-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 26: N-{(S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 27: N-[(S)-1-(3-chloro-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 28: N-{(S)-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 29: N-{(S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 30: N-[(S)-1-(3-chloro-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 31: N-{(S)-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 32: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 33: N-[(S)-1-(3,4-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 34: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 35: N-[(S)-1-(3,4-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; 36: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide; and 168: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide.

[0332] In some embodiments, this document provides pharmaceutically acceptable salts of compounds of formula (Ia) as described in Table 1.

[0333] Exemplary compounds of formula (Ib) described herein include those listed in Table 2:

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345] The names of the compounds in Table 2 are as follows: 37: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 38: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 39: N-[(S)-1-(m-chlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 40: N-[(S)-1-(p-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 41: N-[(S)-1-(m-cyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 42: N-[(S)-1-(m-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 43: N-[(S)-1-(3,4-difluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 44: N-[(S)-1-(2-methoxy-4-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 45: N-[(S)-1-(2,6-dimethyl-4-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 46: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 47: N-[(S)-1-(2-cyano-6-methyl-4-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 48: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 49: N-[(S)-1-(3-cyano-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 50: N-[(S)-1-(3,4-dichlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 51: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 52: N-{(S)-1-[m-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 53: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 54: N-[(S)-1-(3-fluoro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 55: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 56: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 57: N-[(S)-1-(m-Tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 58: N-[(S)-1-(m-trifluoromethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 59: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 60: N-[(S)-1-(3-chloro-5-cyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 61: N-[(S)-1-(3,5-dichlorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 62: N-[(S)-1-(3-chloro-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 63: N-[(R)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 64: N-[(S)-1-(3,5-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 65: N-[(S)-1-(5-chloro-3-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 66: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-6,8-dimethyl-1,7-diaza-3-naphthylcarboxamide; 67: N-[(S)-1-(4-chloro-3-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 68: N-[(S)-1-(5-cyano-3-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 69: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 70: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 71: N-[(S)-1-(3-fluoro-4-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 72: N-[(S)-1-(2,4-difluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 73: N-[(S)-1-(3-chloro-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 74: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[5-(hydroxymethyl)-1,4-diazacycloheptane-1-yl]-6-methyl-1,7-diaza-3-naphthylcarboxamide; 75: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methoxy-1,7-diaza-3-naphthylcarboxamide; 76: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 77: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 78: N-[(S)-1-(3-fluoro-5-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 79: N-[(S)-1-(3-chloro-5-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 80: N-[(S)-1-(3,4-difluoro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 81: N-[(S)-1-(3-cyano-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 82: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-6-methyl-8-(trifluoromethyl)-1,7-diaza-3-naphthylcarboxamide; 83: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 84: N-[(S)-1-(3-chloro-4-tolyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 85: N-[(S)-1-(3-fluoro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 86: N-[(S)-1-(2,4-difluoro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 87: N-[(S)-1-(4-cyano-3-hydroxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 88: N-[(S)-1-(4-cyano-2-pyridyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 89: N-[(S)-1-(3-carbamoyl-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 90: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-4-(2-fluoroethyl)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 91: N-{(S)-1-[3-cyano-5-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 92: N-{(S)-1-[2-(trifluoromethyl)-4-pyridyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 93: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-ethyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 94: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 95: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-ethoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 96: N-[(S)-1-(3,4-dicyanophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 97: N-{(S)-1-[3-cyano-4-(trifluoromethyl)phenyl]ethyl}-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 98: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-[5-(hydroxymethyl)-1,4-diazacycloheptane-1-yl]-6-methyl-1,7-diaza-3-naphthylcarboxamide; 99: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 100: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 101: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-6-methoxy-8-(trifluoromethyl)-1,7-diaza-3-naphthylcarboxamide; 102: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[5-(hydroxymethyl)-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 103: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 104: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 105: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 106: N-{(S)-1-[4-cyano-3-(trifluoromethyl)phenyl]ethyl}-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 107: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[5-(methoxymethyl)-1,4-diazacycloheptane-1-yl]-6-methyl-1,7-diaza-3-naphthylcarboxamide; 108: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 109: N-{(S)-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 110: N-[(S)-1-(3,5-dicyanophenyl)ethyl]-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 111: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 112: 3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-7-naphthon-7-ol salt; 113: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 114: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(R)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthoamide; 115: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 116: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 117: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 118: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 119: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 120: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 121: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 122: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 123: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 124: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 125: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 126: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 127: N-[(S)-1-(3-chloro-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 128: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 129: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 130: N-[(S)-1-(4-chloro-3-methoxyphenyl)ethyl]-4-(4,7-diaza-7-spiro[2.6]nonyl)-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 131: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-(5,8-diaza-8-spiro[3.6]decyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 132: N-[(S)-1-(3-cyano-5-fluoro-2-hydroxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 133: N-[(S)-1-(3-cyano-5-fluoro-2-hydroxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 134: N-[(S)-1-(3-cyano-2-hydroxy-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 135: N-[(S)-1-(3-cyano-2-hydroxy-5-methoxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 136: Ethyl 3-{3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylamino}propionate; 137: {3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthoxy}acetic acid; 138: 3-{3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylamino}propionic acid; 139: N-[(S)-1-(5-cyano-3-fluoro-2-hydroxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 140: N-[(S)-1-(5-cyano-3-fluoro-2-hydroxyphenyl)ethyl]-8-cyclopropyl-4-(4,7-diaza-7-spiro[2.6]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 141: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholinyl-1,7-diaza-3-naphthylcarboxamide; 142: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthylcarboxamide; 143: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-2-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide; 144: N-[(S)-1-(3-cyano-5-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthylcarboxamide; 145: N-[(S)-1-(3-chloro-4-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholinyl-1,7-diaza-3-naphthylcarboxamide; 146: N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthylcarboxamide; 147: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthylcarboxamide; 148: N-[(S)-1-(4-cyano-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthylcarboxamide; 149: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-2-morpholino-1,7-diaza-3-naphthylcarboxamide; 150: N-[(S)-1-(5-cyano-2-hydroxy-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 151: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-2-[(S)-3-methyl-4-morpholinyl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; and 152: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-2-[(R)-3-methyl-4-morpholinyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide.

[0346] In some embodiments, this document provides pharmaceutically acceptable salts of the compounds of formula (Ib) described in Table 2.

[0347] Exemplary compounds of formula (Ic) described herein include those listed in Table 3: (Ic)

[0348] The names of the compounds in Table 3 are as follows: 153: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthoamide; 154: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthoamide; 155: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 156: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 157: N-[(S)-1-(2-methoxy-4-pyridyl)ethyl]-8-cyclopropyl-4-(1,7-diaza-7-spiro[4.4]nonyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; 158: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(ethylamino)-3-(methoxymethyl)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthoamide; 159: N-[(S)-1-(3,5-difluorophenyl)ethyl]-8-cyclopropyl-4-[3-(ethylamino)-3-(methoxymethyl)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthylcarboxamide; 160: N-[(S)-1-(2-methoxy-4-pyridinyl)ethyl]-8-cyclopropyl-4-[3-(ethylamino)-3-(methoxymethyl)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthylcarboxamide; 161: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-{(R)-1,7-diaza-7-spiro[4.4]nonyl}-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 162: N-[(S)-1-(3,4-dimethoxyphenyl)ethyl]-8-cyclopropyl-4-(1,6-diaza-6-spiro[3,4]octyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide; and 163: N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-(1,6-diaza-6-spiro[3.4]octyl)-6-methyl-1,7-diaza-3-naphthylcarboxamide.

[0349] In some embodiments, this document provides pharmaceutically acceptable salts of compounds of formula (Ic) described in Table 3.

[0350] Exemplary compounds of formula (Id) described herein include those listed in Table 4: (Id)

[0351] The names of the compounds in Table 4 are as follows: 164: N-[(S)-1-(3-cyano-5-fluorophenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; 165: N-[(S)-1-(3,5-difluorophenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide 166: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-cyclopropyl-6-methyl-1,7-diaza-3-naphthylcarboxamide; and 167: N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide.

[0352] In some embodiments, pharmaceutically acceptable salts of the compounds of formula (Id) described in Table 4 are provided herein.

[0353] 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.

[0354] 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.

[0355] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), (Ia), (Ib), (Ic), or (Id) with an acid. In some embodiments, the free basic form of a compound of formula (I), (Ia), (Ib), (Ic), or (Id) is basic and reacts with an organic or inorganic acid.

[0356] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I), (Ia), (Ib), (Ic), or (Id) with a base. In some embodiments, the compound of formula (I), (Ia), (Ib), (Ic), or (Id) is acidic and reacts with a base.

[0357] In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), or (Id) 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), or (Id) exist in an R configuration. In some embodiments, compounds of formula (I), (Ia), (Ib), (Ic), or (Id) exist in an S configuration. The compounds described herein include all diastereomers, single enantiomers, trans-blocking isomers, epimeric forms, and tautomers, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, E (entgegen) (E), and Z (zusammen) (Z) isomers, tautomers, and suitable mixtures thereof.

[0358] 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 formulas (I), (Ia), (Ib), (Ic), and (Id) 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 the 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.

[0359] Compound Synthesis The compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) described herein were synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0360] Unless otherwise specified, conventional mass spectrometry, nuclear magnetic resonance (NMR), and high-performance liquid chromatography (HPLC) methods are used.

[0361] 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.

[0362] In some embodiments, the NH naphthidone compound of formula (Ia) described herein is prepared as described in scheme A.

[0363]

[0364] Option A (a) SOCl2, MeOH, 70℃, 16 h; (b) Pd(dppf)Cl2, K2CO3, dioxane, 100℃, 2 h; (c) NBS, DMF, 0℃ to room temperature, 1 h; (d) Pd(OAc)2, (C6H 11 (e) DIEA, DCM, 0℃, 1h; (f) NaOMe, MeOH, 80℃, 1h; (g) LiOH, MeOH, H2O, 60℃, 1h; (h) (COCl)2, DMF, DCM, room temperature, 16h; (i) X or Xa, DIEA, DCM, 0℃, 1h; (j) DIEA, MeCN, 80℃, 1h; (k) TFA, DCM, room temperature, 1h.

[0365] In some embodiments, the N-methylnaphthoidone compound of formula (Ia) described herein is prepared as described in scheme B.

[0366]

[0367] Option B (a) SOCl2, MeOH, 70℃, 16h; (b) Pd(dppf)Cl2, K2CO3, dioxane, 100℃, 2h; (c) MeB(OH)2, Pd(OAc)2, pyridine, dioxane, 100℃, 16h; (d) NBS, DMF, 0℃ to room temperature, 1h; (e) Pd(OAc)2, (C6H 11 (f) DIEA, DCM, 0℃, 1 h; (g) NaOMe, MeOH, 80℃, 1 h; (h) (COCl)2, DMF, DCM, room temperature, 6 h; (i) DIEA, MeCN, 80℃, 1 h; (j) LiOH, MeOH, H2O, 80℃, 1.5 h; (k) X or Xa, HATU, DIEA, DMF, room temperature, 1 h; (l) TFA, DCM, room temperature, 1 h.

[0368] In some embodiments, the naphthidine compounds of formula (Ib), (Ic), or (Id) described herein are prepared according to scheme C.

[0369]

[0370] Option C (a) XXVII, pure, 100 o C, 2 h; (b) PhOPh . PhPh, 258 o C, 10 min; (c) LiOH, MeOH / H2O (5:1), 65 o C, 1 h; (d) POCl3, 100 o C, 0.5-1 h; (e)XorXa,DIEA, DCM, 0 o C, 1 h;(f) HA-Boc, DIEA, dioxane, 110 o C, 16 h; (g) TFA, DCM, RT, 1 h.

[0371] In some embodiments, the compound of formula (Ib) described herein has an R7 moiety. The R7 moiety A non-restrictive example of the method of introduction is described in scheme D.

[0372]

[0373] Option D (a) Tf₂O, 2,6-dimethylpyridine, DCM, 0 o C, 1 h; (b) Cs2CO3, Pd(crotyl)(tBuBrettPhose)OTf, dioxane, 80 o C, 1 h; (c) TFA, DCM, room temperature, 1 h.

[0374] In some embodiments, the amine intermediate X is prepared as described in scheme E.

[0375]

[0376] Option E (a) i) Pd(PPh3)2Cl2, toluene, 100 o (i) C, 16 h; (ii) HCl, RT, 0.5 h; (b) Ti(OiPr)4, toluene, 80 h. o C, 16 h; (c) Lithium trisec-butylborohydride L-Selectride, THF, -78 oC, 1h; (d) HCl, ether, room temperature, 1h.

[0377] In some embodiments, the amine intermediate X is prepared as described in scheme F.

[0378]

[0379] Option F (a) Ti(OiPr)4, toluene, 80 o C, 4 h; (b) MeMgCl, DCM, -40 o C, 1h, then 0-5 o C, 8 h; (c) HCl, EtOAc, room temperature, 3 h.

[0380] In some embodiments, intermediate X is alkylated (e.g., using iodomethane) to prepare intermediate Xa as described in scheme G.

[0381]

[0382] Option G (a) Boc2O, Et3N, DCM, room temperature, 1h; (b) NaH, R6-I, DMF, room temperature, 1h; (c) HCl, dioxane, room temperature, 1h.

[0383] In some embodiments, the preparation of the compound is as described in the examples.

[0384] 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.

[0385] 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-C3 alkyl" indicates that the alkyl group contains one to three carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, propyl, and isopropyl.

[0386] “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.

[0387] "Alkoxy" refers to an (alkyl) O- group, where the alkyl group is as defined herein.

[0388] The terms "halo," "halogen," or "halide" refer to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

[0389] "Halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. In one respect, halogenated alkyl is a C1-C6 fluoroalkyl or a C1-C3 fluoroalkyl.

[0390] "Haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms. In one respect, haloalkoxy is a C1-C6 fluoroalkoxy or a C1-C3 fluoroalkoxy.

[0391] "Cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic free radical, wherein each atom constituting the ring (i.e., the skeleton atom) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged ring compound. In some embodiments, the cycloalkyl may be selectively fused with an aromatic ring, and the bonding point is located on a carbon atom of a non-aromatic ring. Cycloalkyl includes groups containing 3 to 10 ring atoms. In some embodiments, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bis[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl.

[0392] “Cycloalkoxy” refers to a (cycloalkyl) O- group, wherein the cycloalkyl group is as defined herein.

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] Pharmaceutical Composition In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) described herein, or pharmaceutically acceptable salts thereof, are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated using conventional methods, employing one or more pharmaceutically acceptable inactive ingredients to facilitate the processing of the active compound into a formulation 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, 1980); and *Pharmaceutical Dosage Forms and Drug Delivery Systems* (7th edition, Lippincott Williams & Wilkins, 1999), all of which are incorporated herein by reference.

[0401] 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.

[0402] Administration method and treatment regimen In some embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) described herein, or pharmaceutically acceptable salts thereof, are used to prepare medicaments 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 the mammal a therapeutically effective amount of a pharmaceutical composition containing at least one compound of formulas (I), (Ia), (Ib), (Ic), and (Id) or a pharmaceutically acceptable salt thereof.

[0403] 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.

[0404] The dosage of a given compound or its pharmaceutically acceptable salt that conforms to the therapeutically effective amount of formulas (I), (Ia), (Ib), (Ic), and (Id) 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.

[0405] 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.

[0406] As stated above, throughout the description of this invention, unless otherwise specified, the following abbreviations should be understood to have the following meanings: abbreviation: SOCl2: thionyl chloride MeOH: Methanol Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; K2CO3: Potassium carbonate; MeB(OH)2: Methylboric acid; Pd(OAc)2: Palladium acetate; NBS: N-bromosuccinimide; DMF: N,N-dimethylformamide; RT: Room temperature; (C6H 11 3P: Tricycloethylphosphide; K3PO4: Potassium phosphate; H2O: water; DIEA: N,N-diisopropylethylamine or N-ethyl-N-isopropyl-2-amine; DCM: Dichloromethane; NaOMe: Sodium methoxide (COCl)2: Oxygenyl chloride; LiOH: Lithium hydroxide; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; TFA: Trifluoroacetic acid or 2,2,2-trifluoroacetic acid; Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride; HCl: hydrochloric acid; Ti(OiPr)4: Titanium isopropoxide (IV); L-selectride: Lithium trisec-butylborohydride; THF: Tetrahydrofuran; h: hour; Min or mins: minutes; MeMgCl: Methyl magnesium chloride; EtOAc: Ethyl acetate; Boc2O: ditert-butyl dicarbonate; Et3N: Triethylamine; NaH: Sodium hydride; MeI: Iodomethane; NaHCO3 (sodium bicarbonate); Na2SO4: Sodium sulfate; ACN / MeCN: Acetonitrile; Prep-HPLC: Preparative high-performance liquid chromatography; NH3·H2O: ammonia solution; PE: Petroleum ether; Cs2CO3: Cesium carbonate; Pd(crotyl)(tBuBrettPhos)OTf:(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2-buten-1-yl)palladium(II)trifluoromethanesulfonate; Ruphos Pd 3G: (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate; NaHSO4: Sodium bisulfate; POCl3: phosphorus oxychloride; and Pd / C: Palladium on carbon catalyst.

[0407] Example The following embodiments are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0408] Example A: Synthesis of the compound Example A1. Preparation of N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide (compound 13)

[0409] Step A1-1, Preparation of methyl 5-amino-2-chloroisonicotinic acid: A mixture of 5-amino-2-chloroisonicotinic acid (11.4 g, 1 equivalent, 66.1 mmol) and methanol (114 mL) was placed in a 250 mL three-necked flask purged with nitrogen and kept under nitrogen inert atmosphere. SOCl2 (39.4 g, 24.2 mL, 5.01 equivalent, 331 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 70°C for 16 hours. After the reaction was complete, the reaction was concentrated under vacuum, and the residue was dissolved in dichloromethane (200 mL). The resulting solution was adjusted to pH 8 with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3 × 200 mL), the organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-amino-2-chloroisonicotinic acid (9.6 g, 51 mmol, 78%); (M+H). + =187.0.

[0410] Preparation of step A1-2,5-amino-2-methylisonicotinic acid methyl esterA mixture of methyl 5-amino-2-chloroisonicotinic acid (9.6 g, 1 equivalent, 51 mmol), 1,4-dioxane (96 mL), K₂CO₃ (21 g, 3.0 equivalent, 0.15 mol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (19 g, 2.9 equivalent, 0.15 mol), and PdCl₂(dppf) (1.9 g, 0.050 equivalent, 2.6 mmol) was added to a 250 mL round-bottom flask purged with nitrogen and maintained under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 2 hours. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (ethyl acetate increased from 0% to 50% over 30 minutes). The fraction was collected and concentrated under vacuum to give methyl 5-amino-2-methylisonicotinic acid (8.5 g, 51 mmol, 99%); (M+H) + =167.1.

[0411] Steps A1-3: Preparation of methyl 2-methyl-5-(methylamino)isonicotinic acid ester A mixture of methyl 5-amino-2-methylisonicotinic acid (8.5 g, 1 equivalent, 51 mmol), 1,4-dioxane (85 mL), pyridine (14 g, 14 mL, 3.5 equivalent, 0.18 mol), and copper diacetoxy (23 g, 2.5 equivalent, 0.13 mol) was added to a 250 mL round-bottom flask. The reaction mixture was stirred at 25°C for 30 min, then methylboric acid (15 g, 4.9 equivalent, 0.25 mol) was added, and the reaction mixture was stirred at 100°C for 16 h. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (ethyl acetate increased from 0% to 50% within 10 min). The collected fractions were combined and concentrated under vacuum to give methyl 2-methyl-5-(methylamino)isonicotinic acid (3.3 g, 18 mmol, 36%); (M+H) + =181.1.

[0412] Steps A1-4: Preparation of methyl 2-bromo-6-methyl-3-(methylamino)isonicotinic acidA mixture of methyl 2-methyl-5-(methylamino)isonicotinic acid (3.3 g, 1 equivalent, 18 mmol) and DMF (33 mL) was added to a 100 mL round-bottom flask. NBS (1.2 g, 1.2 equivalent, 21 mmol) was added to the mixture in portions at 0°C. The reaction mixture was stirred at 25°C for 1 hour, then poured into 50 mL of water at 0°C. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (3 × 20 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give methyl 2-bromo-6-methyl-3-(methylamino)isonicotinic acid (3.5 g, 14 mmol, 74%); (M+H) + =259.0.

[0413] Steps 1-5: Preparation of methyl 2-cyclopropyl-6-methyl-3-(methylamino)isonicotinic acid. 2-Bromo-6-methyl-3-(methylamino)isonicotinic acid methyl ester (3.5 g, 1 equivalent, 14 mmol), Pd(OAc)₂ (0.3 g, 0.1 equivalent, 1 mmol), cyclopropylboronic acid (3.5 g, 3.0 equivalent, 41 mmol), tripotassium phosphate (8.6 g, 3.4 mL, 3.0 equivalent, 41 mmol), tricyclohexylphosphine (0.76 g, 0.85 mL, 0.20 equivalent, 2.7 mmol), toluene (35 mL), and water (3.5 mL) were added to a 250 mL vial. The resulting solution was stirred at 80°C for 1 hour. The reaction mixture was concentrated under vacuum, the organic layer was separated, and the mixture was washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2 / 1) to give methyl 2-cyclopropyl-6-methyl-3-(methylamino)isonicotinic acid (2.3 g, 10 mmol, 77%); (M+H) + =221.1.

[0414] Steps A1-6: Preparation of 2-cyclopropyl-3-(3-methoxy-N-methyl-3-oxopropionylamino)-6-methylisonicotinic acid Methyl ester A mixture of methyl 2-cyclopropyl-6-methyl-3-(methylamino)isonicotinic acid (2.3 g, 1 equivalent, 10 mmol) and DCM (23 mL) was placed in a 250 mL vial, and methyl 3-chloro-3-oxopropionate (4.3 g, 3.0 equivalent, 31 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give methyl 2-cyclopropyl-3-(3-methoxy-N-methyl-3-oxopropionylamino)-6-methylisonicotinic acid (3.1 g, 9.7 mmol, 93%), which was used directly in the next step without purification.

[0415] Steps A1-7: Preparation of 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-methyl Methyl esterA mixture of methyl 2-cyclopropyl-3-(3-methoxy-N-methyl-3-oxopropionylamino)-6-methylisonicotinic acid (3.1 g, 1 equivalent, 9.7 mmol), sodium methoxide (2.1 g, 4.0 equivalent, 39 mmol), and MeOH (30 mL) was added to a 250 mL vial. The reaction mixture was stirred at 80°C for 1 hour. The crude product was concentrated under vacuum, and water (40 mL) was added to the residue. The pH of the mixture was adjusted to 3–4 with an aqueous solution of HCl (1 M). The resulting precipitate was collected by filtration and dried to give methyl 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (3.7 g, 9.0 mmol, 93%, purity 70%); (M+H) + =289.1.

[0416] Steps A1-8: Preparation of 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-carboxylic acid Methyl ester A mixture of methyl 8-cyclopropyl-4-hydroxy-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (3.7 g, 1 equivalent, 13 mmol), DCM (37 mL), DMF (0.94 g, 1.0 mL, 1.0 equivalent, 13 mmol), and oxaloyl chloride (4.9 g, 3.4 mL, 3.0 equivalent, 39 mmol) was added to a 250 mL round-bottom flask. The reaction mixture was stirred at 20°C for 6 hours. The reaction mixture was concentrated under vacuum, and ice water was added to the residue. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄, and filtered. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (3.7 g, 12 mmol, 94%); (M+H) + =307.1.

[0417] Steps A1-9, preparation of (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazacycloheptane-1-yl)-8- methyl cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylateA mixture of methyl 4-chloro-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (3.7 g, 1 equivalent, 12 mmol), DIEA (4.7 g, 6.3 mL, 3.0 equivalent, 36 mmol), (S)-7-methyl-1,4-diazacycloheptane-1-carboxylate tert-butyl ester (4.7 g, 1.8 equivalent, 22 mmol), and ACN (40 mL) was added to a 250 mL vial. The reaction mixture was stirred at 80°C for 1 hour. The resulting mixture was concentrated under vacuum and purified directly by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (EtOAc ratio increased from 0% to 100% over 12 minutes) to give (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazacycloheptane-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (4.707 g, 8.6 mmol, 97%, purity 89%); (M+H) + =485.3.

[0418] Step A1-10, (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazacycloheptane-1-yl)-8-cyclo Preparation of propyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acid A mixture of (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazacycloheptane-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (4.7 g, 1 equivalent, 9.7 mmol), MeOH (48 mL), water (24 mL), and LiOH (2.3 g, 9.9 equivalent, 96 mmol) was placed in a 250 mL round-bottom flask. The reaction mixture was stirred at 80°C for 1.5 hours. The reaction mixture was concentrated under vacuum and acidified to pH 5 with citric acid. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄, and filtered. After filtration, the filtrate was concentrated under reduced pressure to give (S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazacycloheptane-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acid (3.63 g, 7.71 mmol, 80%); (M+H) + =471.2.

[0419] Step A1-11, Preparation of (S)-4-(8-cyclopropyl-3-(((S)-1-(3-ethoxy-4-fluorophenyl)ethyl)amino (formyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthid-4-yl)-7-methyl-1,4-diazacycloheptane-1- tert-butyl formate(S)-4-(4-(tert-butoxycarbonyl)-5-methyl-1,4-diazacycloheptane-1-yl)-8-cyclopropyl-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acid (150 mg, 1 equivalent, 319 μmol), HATU (182 mg, 1.50 equivalent, 479 μmol), DIEA (247 mg, 333 μL, 6.00 equivalent, 1.91 mmol), and DMF (2 mL) were added to the reaction mixture. The resulting reaction mixture was stirred at 25°C for 10 min. Then, (S)-1-(3-ethoxy-4-fluorophenyl)ethyl-1-amine (175 mg, 3.00 equivalent, 955 μmol) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 1 h. The mixture was purified using preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions: column: SunFire Prep C18OBD column, 19 × 150 mm, 5 μm; mobile phase: water (0.1% NH3·H2O) and ACN (acetonitrile increased from 20% to 98% over 8 minutes); total flow rate: 70 mL / min; detector: UV detector, wavelength 220 nm. The result was (S)-4-(8-cyclopropyl-3-(((S)-1-(3-ethoxy-4-fluorophenyl)ethyl)carbamoyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthid-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (166 mg, 261 μmol, 81.9%); (M+H) + =636.4.

[0420] Steps A1-12, N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diaza] Preparation of cycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide PreparationA mixture of (S)-4-(8-cyclopropyl-3-(((S)-1-(3-ethoxy-4-fluorophenyl)ethyl)carbamoyl)-1,6-dimethyl-2-oxo-1,2-dihydro-1,7-naphthid-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (166 mg, 1 equivalent, 261 μmol) and DCM (5 mL) was added to a 50 mL vial, followed by the addition of TFA (1.5 mL). The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions: column: SunFire prep OBD 19*150mm, 5µm; mobile phase A: water (0.05% NH3·H2O); mobile phase B: ACN; gradient: increasing from 25% B to 65% B over 8 minutes; flow rate: 20 mL / min; wavelength: 220 nm. The collected fraction was freeze-dried to obtain N-[(S)-1-(3-ethoxy-4-fluorophenyl)ethyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-1-methyl-6-methyl-2-oxo-1,2-dihydro-1,7-diaza-3-naphthylcarboxamide (68.2 mg, 127 μmol, 48.8%); (M+H). + =536.3.

[0421] The following compounds were prepared in a manner similar to that of Example A1, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0422]

[0423] Example A2 Preparation of ethyl 3-{3-[N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylamino}propionate (compound 136).

[0424]

[0425] Step A2-1: Preparation of methyl 3-amino-2-bromo-6-methylisonicotinic acidA mixture of methyl 5-amino-2-methylisonicotinic acid (3.0 g, 1 equivalent, 18 mmol; prepared by steps 1-1 to 1-2 of Example A-1) and DMF (30 mL) was placed in a 250 mL vial, and NBS (3.9 g, 1.2 equivalent, 22 mmol) was added to it at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was then poured into 30 mL of water at 0°C, and the solid was filtered off to give methyl 3-amino-2-bromo-6-methylisonicotinic acid (3.4 g, 14 mmol, 77%); (M+H) + =244.9.

[0426] Step A2-2, Preparation of methyl 3-amino-2-cyclopropyl-6-methylisonicotinic acid 3-Amino-2-bromo-6-methylisonicotinic acid methyl ester (3.3 g, 1 equivalent, 13 mmol), Pd(OAc)₂ (0.3 g, 0.1 equivalent, 1 mmol), tripotassium phosphate (8.6 g, 3.4 mL, 3.0 equivalent, 41 mmol), cyclopropylboronic acid (3 g, 3 equivalent, 0.03 mol), tricyclohexylphosphine (0.76 g, 0.85 mL, 0.20 equivalent, 2.7 mmol), toluene (50 mL), and water (5 mL) were added to an 8 mL vial. The resulting solution was stirred at 80°C for 1 hour. The reaction mixture was extracted twice with EtOAc. The combined organic layers were washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with PE / EtOAc (2 / 1) to give methyl 3-amino-2-cyclopropyl-6-methylisonicotinic acid (2.8 g, 14 mmol, 100%); (M+H). + =207.1.

[0427] Step A2-3, Preparation of methyl 2-cyclopropyl-3-(3-ethoxy-3-oxopropionamido)-6-methylisonicotinic acid A mixture of methyl 3-amino-2-cyclopropyl-6-methylisonicotinic acid (1.6 g, 1 equivalent, 7.8 mmol), DIEA (3.0 g, 4.0 mL, 3.0 equivalent, 23 mmol), and DCM (50 mL) was placed in a 250 mL vial, and ethyl 3-chloro-3-oxopropionate (1.2 g, 1.0 equivalent, 8.0 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was purified directly by silica gel column chromatography, eluting with PE / EtOA (EtOAc ratio increased from 0% to 65% over 8 minutes) to give 2-cyclopropyl-3-(3-ethoxy-3-oxopropionyl) amine Methyl isonicotinic acid (1.75 g, 5.46 mmol, 70%); (M+H) + =321.2.

[0428] Steps A2-4, preparing ethyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acid. Ester / Methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acidA mixture of methyl 2-cyclopropyl-3-(3-ethoxy-3-oxopropamido)-6-methylisonicotinic acid (1.65 g, 1 equivalent, 5.15 mmol), sodium methoxide (1.11 g, 1.21 mL, 3.99 equivalent, 20.5 mmol), and MeOH (32 mL) was added to two 40 mL vials. The reaction mixture was stirred at 60°C for 2 hours. The crude product was concentrated under vacuum to give ethyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (528 mg, 1.83 mmol, 35.6%) and methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (432 mg, 1.58 mmol, 30.6%); (M+H) + =289.1, 275.1.

[0429] Preparation of step A2-5,8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acid Preparation Ethyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (528 mg, 1 equivalent, 1.83 mmol), methyl 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylate (432 mg, 0.860 equivalent, 1.58 mmol), MeOH (10 mL), and water (5 mL) were added to an 8 mL vial, followed by the addition of LiOH (439 mg, 10.0 equivalent, 18.3 mmol). The mixture was stirred at 60°C for 2 hours. The reaction was then cooled to room temperature, water (1 mL) was added, and the pH was adjusted to 5-6 with 1 M hydrochloric acid solution. The reaction mixture was then extracted with DCM (3 × 20 mL), the organic phases were combined, washed with brine (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxylic acid (800 mg, 3.07 mmol), which could be used directly in the next reaction without purification; (M+H) + =261.0.

[0430] Preparation of step A2-6,4-chloro-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-formyl chloride PreparationA mixture of 8-cyclopropyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-carboxylic acid (800 mg, 1 equivalent, 3.07 mmol) and oxalyl chloride (7 g, 5 mL, 20 equivalents, 0.06 mol) was placed in a 40 mL vial, and then DMF (22.5 mg, 23.8 μL, 0.100 equivalents, 308 μmol) was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give 4-chloro-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-carboxyl chloride (810 mg, 2.73 mmol), which was used directly in the next reaction without purification.

[0431] Steps A2-7, preparing methyl(S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl 2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxamide Add a mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-amine (923 mg, 2.00 equivalent, 5.46 mmol), DIEA (1.76 g, 2.37 mL, 5.00 equivalent, 13.6 mmol), and DCM (10 mL) to a 40 mL vial. Then, add a mixture of 4-chloro-8-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-carboxyl chloride (810 mg, 1 equivalent, 2.73 mmol), and DCM (5 mL) at 0°C. Stir the reaction mixture at 0°C for 1 hour. The mixture was purified directly by silica gel column chromatography, eluting with PE / EtOAc (the EtOAc ratio increased from 0% to 65% over 8 minutes), to give (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidine-3-carboxamide (1.04 g, 2.42 mmol, 88.7%); (M+H). + =432.1.

[0432] Step A2-8, (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl 4-( ... Preparation of estersA mixture of (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthyl-3-carboxamide (1.04 g, 1 equivalent, 2.42 mmol), DIEA (938 mg, 1.26 mL, 3.00 equivalent, 7.26 mmol), and (S)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (1.04 g, 2.01 equivalent, 4.85 mmol) and acetonitrile (10 mL) was added to a 40 mL vial. The reaction mixture was stirred at 80°C for 16 hours. The mixture was purified by rapid high-performance liquid chromatography (Flash-HPLC) under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (0.1% NH3·H2O) and acetonitrile (20.0% acetonitrile, linearly increasing to 98.0% within 7 min); total flow rate, 70 mL / min; detector, UV 220 nm. The collected fractions were combined and concentrated under vacuum to give (S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidin-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester (1.3 g, 2.1 mmol, 88%); (M+H) + =608.4.

[0433] Steps A2-9: Preparation of tert-butyl(S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl) (carbamoyl)-6-methyl-2-(((trifluoromethyl)sulfonyl)oxo)-1,7-naphthid-4-yl)-7-methyl-1,4-diazo Heterocyclic heptacarbon-1-carboxylic acid ester A mixture of tert-butyl(S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-oxo-1,2-dihydro-1,7-naphthidin-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylate (400 mg, 1 equivalent, 658 μmol), 2,6-dimethylpyridine (282 mg, 305 μL, 4.00 equivalent, 2.63 mmol), and DCM (8 mL) was placed in a 40 mL vial. A mixture of trifluoromethanesulfonic anhydride (613 mg, 365 μL, 3.30 equivalent, 2.17 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give tert-butyl(S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-(((trifluoromethyl)sulfonyl)oxo)-1,7-naphthid-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid ester (450 mg, 608 μmol, 92.4%), which could be used directly in the next reaction without purification.

[0434] Step A2-10, preparation of tert-butyl(S)-4-(8-cyclopropyl-2-((3-ethoxy-3-oxopropyl)amino)-3- (((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthid-4-yl)-7-methyl-1,4- diazacycloheptane-1-carboxylic acid ester Add tert-butyl(S)-4-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-2-(((trifluoromethyl)sulfonyl)oxo)-1,7-naphthid-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid ester (450 mg, 1 equivalent, 608 μmol), Cs₂CO₃ (595 mg, 3.00 equivalent, 1.83 mmol), ethyl 3-aminopropionate (143 mg, 2.01 equivalent, 1.22 mmol), Pd(crotonyl)(tBuBrettPhos)OTf (24.2 mg, 0.0500 equivalent, 30.4 μmol), and 1,4-dioxane (5 mL) to a 40 mL vial. Stir the resulting solution at 80°C for 1 hour. The reaction mixture was concentrated under vacuum, and the crude product was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions: column, C18 column; mobile phase, water (containing 0.1% ammonia) and acetonitrile (acetonitrile concentration increased linearly from 20% to 98% within 6 minutes); total flow rate, 70 mL / min; detector, UV 220 nm. This yielded tert-butyl(S)-4-(8-cyclopropyl-2-((3-ethoxy-3-oxopropyl)amino)-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthidium-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid ester (60 mg, 85 μmol, 14%); (M+H). + =707.6.

[0435] Step A2-11, preparing 3-{3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4- [(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylaminopropionic acid Ethyl acetate30 mg (1 equivalent, 42 μmol) of tert-butyl(S)-4-(8-cyclopropyl-2-((3-ethoxy-3-oxopropyl)amino)-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthid-4-yl)-7-methyl-1,4-diazacycloheptane-1-carboxylic acid ester, 1 equivalent, 42 μmol, DCM (3 mL), and TFA (1 mL) were added to a 50 mL round-bottom flask. The resulting solution was stirred at 20°C for 1 hour. The resulting mixture was concentrated under vacuum, and the crude product was purified by preparative high-performance liquid chromatography (Prep-HPLC) under the following conditions: column: SunFire prep OBD 19*150mm 5μm; mobile phase A: water (containing 0.05% TFA); mobile phase B: acetonitrile; gradient: linearly increased from 25% B to 65% B within 8 minutes; flow rate: 20 mL / min; wavelength: 220 nm. The collected fraction was freeze-dried to obtain ethyl 3-{3-[N-(S)-1-(4-fluoro-3-methoxyphenyl)ethylcarbamoyl]-4-[(S)-5-methyl-1,4-diazacycloheptane-1-yl]-8-cyclopropyl-6-methyl-1,7-diaza-2-naphthylamino}propionate (18.6 mg, 30.7 μmol, 72%); (M+H) + =607.4.

[0436] The following compounds were prepared in a manner similar to Example A2, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0437]

[0438] Example A3 Preparation of N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthoamide (compound 153)

[0439] Step A3-1: Preparation of diethyl malonate, 2-(((2-bromo-6-methylpyridin-3-yl)amino)methylene)malonateA mixture of 2-bromo-6-methylpyridin-3-amine (5.00 g, 1 equivalent, 26.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.94 g, 1.20 equivalent, 32.1 mmol) was added to a 40 mL vial. The reaction mixture was stirred at 100°C for 2 hours. The mixture was cooled to room temperature, diluted with PE (200 mL), filtered to collect the precipitate, and dried to give diethyl 2-(((2-bromo-6-methylpyridin-3-yl)amino)methylene)malonate (7.63 g, 21.4 mmol, 79.9%); (M+H) + =357.1.

[0440] Step A3-2, preparation of diethyl 2-(((2-cyclopropyl-6-methylpyridin-3-yl)amino)methylene)malonate A mixture of diethyl 2-(((2-bromo-6-methylpyridin-3-yl)amino)methylene)malonate (8.00 g, 1 equivalent, 22.4 mmol), cyclopropylboronic acid (10.0 g, 5.20 equivalent, 116 mmol), Ruphos Pd 3G (200 mg, 0.0107 equivalent, 239 μmol), potassium carbonate (21.7 g, 7.01 equivalent, 157 mmol), toluene (150 mL), and water (30 mL) was placed in a 500 mL round-bottom flask purged with nitrogen and kept under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. The resulting mixture was purified directly by rapid column chromatography, eluted with PE / EtOA (3 / 1), to give diethyl 2-(((2-cyclopropyl-6-methylpyridin-3-yl)amino)methylene)malonate (5.25 g, 16.5 mmol, 73.6%); (M+H)+=319.1.

[0441] Step A3-3: Preparation of ethyl 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyl-3-carboxylate A phenyl ether-biphenyleutetic eutectic (50 g, 9.3 equivalents, 0.15 mol) was placed in a 100 mL three-necked round-bottom flask. The mixture was heated to 258°C, and 2-(((2-cyclopropyl-6-methylpyridin-3-yl)amino)methylene)diethyl malonate (5.25 g, 1 equivalent, 16.5 mmol) was added in a single batch at 258°C. The reaction mixture was stirred at 258°C for 20 minutes, cooled to room temperature, diluted with petroleum ether (200 mL), filtered to collect the precipitate, and dried to give ethyl 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyl-3-carboxylate (2.85 g, 10.5 mmol, 63.5%); (M+H) + =273.1.

[0442] Preparation of steps A3-4, 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthidine-3-carboxylic acidA mixture of ethyl 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyl-3-carboxylic acid (1.00 g, 1 equivalent, 3.67 mmol), LiOH (1.00 g, 11.4 equivalent, 41.8 mmol), and MeOH (20 mL) was added to a 40 mL vial. Water (4 mL) was then added, and the reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (30 mL) and the pH was adjusted to 6.0 with saturated NaHSO4 solution. The resulting precipitate was collected by filtration and dried to give 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthyl-3-carboxylic acid (850 mg, 3.48 mmol, 94.8%); (M+H). + =245.1.

[0443] Preparation of steps A3-5,4-chloro-8-cyclopropyl-6-methyl-1,7-naphthidine-3-formyl chloride A mixture of 8-cyclopropyl-4-hydroxy-6-methyl-1,7-naphthidine-3-carboxylic acid (600 mg, 1 equivalent, 2.46 mmol) and POCl3 (5.0 g, 3.0 mL, 13 equivalents, 33 mmol) was placed in an 8 mL vial. The reaction mixture was stirred at 100°C for 30 minutes. The reaction mixture was then concentrated under reduced pressure to give 4-chloro-8-cyclopropyl-6-methyl-1,7-naphthidine-3-carboxyl chloride (660 mg, 2.35 mmol, 95.6%), which was used directly for the next reaction without purification.

[0444] Steps A3-6, (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-1,7- Preparation of naphthidine-3-carboxamide A mixture of (S)-1-(4-fluoro-3-methoxyphenyl)ethyl-1-amine (100 mg, 2.1 equivalents, 591 μmol), diisopropylethylamine (DIEA) (370 mg, 499 μL, 10 equivalents, 2.86 mmol), and dichloromethane (DCM) (1 mL) was placed in an 8 mL vial. Then, a mixture of 4-chloro-8-cyclopropyl-6-methyl-1,7-naphthidine-3-carboxyl chloride (80 mg, 1 equivalent, 0.28 mmol) and dichloromethane (DCM) (1 mL) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was purified directly by silica gel column chromatography, eluting with PE / EtOA (the EtOA ratio increased from 0% to 75% over 7 minutes) to give (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-1,7-naphthidine-3-carboxamide (60 mg, 0.14 mmol, 51%); (M+H). + =414.2.

[0445] Steps A3-7, Preparation of 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidine-3-amineTo an 8 mL vial, add a mixture of tert-butyl (1-benzyl-3-(methoxymethyl)pyrrolidine-3-yl)carbamate (800 mg, 1 equivalent, 2.50 mmol) and lithium aluminum hydride (III) (300 mg, 3.17 equivalent, 7.91 mmol) in tetrahydrofuran (2 mL). Stir the reaction mixture at 70°C for 1 hour. Then quench the reaction with 5 mL of water and extract the resulting solution with ethyl acetate (3 × 10 mL). Dry the organic layer with anhydrous sodium sulfate and concentrate under vacuum to give 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidine-3-amine (700 mg, 2.99 mmol), which was used directly for the next reaction without purification; (M+H) + =235.2.

[0446] Steps A3-8: Preparation of tert-butyl(1-benzyl-3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamic acid ester A mixture of 1-benzyl-3-(methoxymethyl)-N-methylpyrrolidine-3-amine (700 mg, 1 equivalent, 2.99 mmol), di-tert-butyl dicarbonate (900 mg, 1.38 equivalent, 4.12 mmol), and triethylamine (1000 mg, 1.38 mL, 3.31 equivalent, 9.882 mmol) in DCM (10 mL) was stirred at 25°C for 16 hours. Water (20 mL) was then added, and the reaction mixture was extracted with EtOAc (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give tert-butyl(1-benzyl-3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamate (530 mg, 1.58 mmol, 53.0%); (M+H). + =335.2.

[0447] Steps A3-9: Preparation of tert-butyl(3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamate Under a hydrogen (H2) atmosphere, tert-butyl(1-benzyl-3-(methoxymethyl)pyrrolidone-3-yl)(methyl)carbamate (530 mg, 1 equivalent, 1.58 mmol), methanol (10 mL), and Pd-C (200 mg, 1.19 equivalent, 1.88 mmol) were added to a 50 mL round-bottom flask. The resulting solution was stirred at 25°C for 1 hour, then filtered to remove Pd-C, and the solution was concentrated under vacuum to give tert-butyl(3-(methoxymethyl)pyrrolidone-3-yl)(methyl)carbamate (240 mg, 982 μmol, 62.0%); (M+H) + =245.2.

[0448] Step A3-10: Preparation of tert-butyl(1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino) (methylcarbamoyl)-6-methyl-1,7-naphthid-4-yl)-3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamate:A mixture of (S)-4-chloro-8-cyclopropyl-N-(1-(4-fluoro-3-methoxyphenyl)ethyl)-6-methyl-1,7-naphthidine-3-carboxamide (60 mg, 1 equivalent, 0.14 mmol), tert-butyl(3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamate (100 mg, 2.8 equivalent, 409 μmol), DIEA (60 mg, 81 μL, 3.2 equivalent, 0.46 mmol), and dioxane (1 mL) was placed in an 8 mL vial. The reaction mixture was stirred at 110°C for 16 hours. 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 (containing 0.1% formic acid) and acetonitrile (acetonitrile concentration increased from 30% to 98% within 7 minutes); total flow rate: 20 mL / min; detector: UV 220 nm. The product was tert-butyl(1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthidin-4-yl)-3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamate (60 mg, 97 μmol, 67%). (M+H) + =622.4.

[0449] Step A3-11, N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl) Preparation of 3-(methylamino)-1-pyrrolidinyl]-6-methyl-1,7-diaza-3-naphthylcarboxamide tert-butyl(1-(8-cyclopropyl-3-(((S)-1-(4-fluoro-3-methoxyphenyl)ethyl)carbamoyl)-6-methyl-1,7-naphthid-4-yl)-3-(methoxymethyl)pyrrolidine-3-yl)(methyl)carbamate (50 mg, 1 equivalent, 80 μmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added to an 8 mL vial. The resulting reaction mixture was stirred at 25°C for 1 hour. The mixture was purified by preparative high-performance liquid chromatography (Prep-HPLC-013) under the following conditions: column: SunFire Prep C18 OBD column, 19*150 mm, 5 µm; mobile phase: water (0.05% NH3·H2O) and acetonitrile (30.0% ACN, linearly increased to 50.0% within 7 min); total flow rate: 20 mL / min; detector: UV 220 nm. The fractions were collected and combined, concentrated under vacuum, and then lyophilized to give N-[(S)-1-(4-fluoro-3-methoxyphenyl)ethyl]-8-cyclopropyl-4-[3-(methoxymethyl)-3-(methylamino)-1-pyrrolyl]-6-methyl-1,7-diaza-3-naphthylcarboxamide (32.4 mg, 62.1 μmol, 77%); (M+H) + =522.3.

[0450] The following compounds were prepared in a manner similar to that of Example A3, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0451]

[0452] Example A4 Preparation of N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide (compound 167)

[0453] Step A4-Preparation of diethyl 1,2-(((2-methoxy-6-methylpyridin-3-yl)amino)methylene)malonate Preparation 2-Methoxy-6-methylpyridin-3-amine (5 g, 1 equivalent, 0.04 mol) and diethyl 2-(ethoxymethylene)malonate (15.6 g, 2 equivalents, 72.1 mmol) were added to a 100 mL flask. The resulting solution was stirred at 100°C for 1 hour. The resulting solution was diluted with PE (50 mL) and stirred for 1 hour. The precipitate was collected to give diethyl 2-(((2-methoxy-6-methylpyridin-3-yl)amino)methylene)malonate (8.9 g, 29 mmol, 80%); (M+H) + =309.1 Step A4-2: Preparation of ethyl 4-hydroxy-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylate At 252°C, diethyl 2-(((2-methoxy-6-methylpyridin-3-yl)amino)methylene)malonate (10.5 g, 1 equivalent, 34.1 mmol) was added in portions to boiling phenyl ether-biphenyl eutectic (220.0 g, 207.7 mL, 19.9 equivalents, 678.1 mmol), and the mixture was stirred at 252°C for 30 min. After cooling to room temperature, the reaction mixture was filtered, and the solid was washed with petroleum ether (200 mL) to give ethyl 4-hydroxy-8-methoxy-6-methyl-1,7-naphthyl-3-carboxylic acid (4.2 g, 16 mmol, 47%); (M+H) + =263.1.

[0454] Step A4-3: Preparation of ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylateA mixture of ethyl 4-hydroxy-8-methoxy-6-methyl-1,7-naphthyl-3-carboxylate (8 g, 1 equivalent, 0.03 mol), DMF (0.09 g, 0.1 mL, 0.04 equivalent, 1 mmol), and DCM (400 mL) was added to a 1000 mL three-necked round-bottom flask purged with nitrogen and kept under an inert atmosphere. Oxaloyl chloride (5 g, 3 mL, 1.3 equivalent, 0.04 mol) was added dropwise over 10 minutes at 0°C. The reaction mixture was then stirred at 25°C for 1 hour. The mixture was quenched with an aqueous solution of NaHCO3 (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC) under the following conditions: silica gel column (120 g), PE / EtOAc system, EtOAc ratio increased from 0% to 50% within 15 minutes, flow rate: 70 mL / min; wavelength: 254 nm. The fraction was collected and concentrated to give ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylate (7.56 g, 26.9 mmol, 90%); (M+H). + =281.0.

[0455] Step A4-4, to prepare 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy Ethyl 6-methyl-1,7-naphthyl-3-carboxylate Add a solution of ethyl 4-chloro-8-methoxy-6-methyl-1,7-naphthyl-3-carboxylate (150 mg, 1 equivalent, 534 μmol) and DIEA (138 mg, 186 μL, 2.0 equivalent, 1.07 mmol) in 1.5 mL of ACN to a 250 mL vial. Add tert-butyl(2S,6R)-2,6-dimethylpiperazine-1-carboxylate (344 mg, 3.0 equivalent, 1.60 mmol). Stir the resulting mixture at 80°C for 16 hours. The crude product was purified by Flash-Prep-HPLC under the following conditions (IntelFlash-1): column, C18 silica gel; mobile phase, water (containing 0.1% ammonia) and acetonitrile (acetonitrile concentration increased from 30% to 98% within 4 minutes); detector, UV 254 and 220 nm. The fraction was collected and concentrated to give ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylic acid (240 mg, 523 μmol, 97.9%); (M+H). + =459.5.

[0456] Step A4-5,4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6- Preparation of methyl-1,7-naphthidine-3-carboxylic acidA mixture of ethyl 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylic acid (240 mg, 1 equivalent, 523 μmol), lithium hydroxide (127 mg, 10.1 equivalent, 5.29 mmol), methanol (5 mL), and water (2.5 mL) was added to a 40 mL vial. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was diluted with water (50 mL), the pH was adjusted to 5.0 with saturated NaHSO4 solution, the precipitate was collected by filtration, and dried to give 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylic acid (200 mg, 465 μmol, 88.8%); (M+H) + =431.5.

[0457] Steps A4-6: Preparation of tert-butyl(2S,6R)-4-(3-(((S)-1-(3,5-dimethoxyphenyl)ethyl)aminomethyl Acyl)-8-methoxy-6-methyl-1,7-naphthid-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid ester A solution of 4-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)-8-methoxy-6-methyl-1,7-naphthidine-3-carboxylic acid (100 mg, 1.0 equivalent, 232 μmol), DIEA (150 mg, 202 μL, 5.0 equivalent, 1.16 mmol), and HATU (132 mg, 1.5 equivalent, 348 mmol) in DMF (2 mL) was added to an 8 mL vial. The reaction mixture was stirred at 25°C for 15 minutes. Then, (S)-1-(3,5-dimethoxyphenyl)ethyl-1-amine hydrochloride (152 mg, 3.0 equivalent, 697 μmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 1 hour. The resulting solution was purified using preparative HPLC (Prep-HPLC) under the following conditions (2#-analyse-HPLC-SHIMADZU(HPLC-0013)). Column: Kinetex EVO 21.2*150mm 5µm; Mobile phase: water (containing 0.1% ammonia) and acetonitrile (acetonitrile concentration increased from 20% to 60.0% within 7 minutes); Detector: UV 220 nm. This yielded tert-butyl(2S,6R)-4-(3-(((S)-1-(3,5-dimethoxyphenyl)ethyl)carbamoyl)-8-methoxy-6-methyl-1,7-naphthidium-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid ester (80 mg, 0.13 mmol, 58%); (M+H) + =594.7.

[0458] Steps A4-7, N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperidine] Preparation of [azinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide80 mg (1 equivalent, 0.13 mmol) of tert-butyl(2S,6R)-4-(3-(((S)-1-(3,5-dimethoxyphenyl)ethyl)carbamoyl)-8-methoxy-6-methyl-1,7-naphthid-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid ester, 2 mL of trifluoroacetic acid, and 0.4 mL of dichloromethane were added to an 8 mL vial. The resulting reaction mixture was stirred at 25°C for 1.5 hours. The resulting solution was concentrated under vacuum, and the crude product was purified by preparative high-performance liquid chromatography (Prep-HPLC-013) under the following conditions: column: SunFire Prep C18 OBD column, 19 × 150 mm, 5 µm, 10 nm; mobile phase: water (0.1% ammonia) and acetonitrile (acetonitrile was increased from 15% to 50% over 10 minutes). Total flow rate: 20 mL / min. Detector: UV 220 nm. N-[(S)-1-(3,5-dimethoxyphenyl)ethyl]-4-[(3R,5S)-3,5-dimethyl-1-piperazinyl]-8-methoxy-6-methyl-1,7-diaza-3-naphthylcarboxamide (41.8 mg, 84.7 μmol, 63%) was obtained; (M+H) + =494.6.

[0459] The following compounds were prepared in a manner similar to that of Example A4, and were prepared by means of well-known chemistry and appropriate substitution of reagents and / or substrates and / or modification of functional groups.

[0460]

[0461] 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.

[0462] SSTR3 cAMP assay protocol Two or four days prior to the assay, Chinese hamster ovary cells (CHO-K1, ATCC#CCL-61) stably expressing human somatostatin receptor subtype 3 were seeded at densities of 6,000 or 2,000 cells per well in 96-well tissue culture plates. The culture medium was Ham's F12 growth medium (ThermoFisher#10-080-CM) supplemented with 10% donor bovine serum (GeminiBio-Products#100-506); 100 U / mL penicillin; 100 μg / mL streptomycin; 2 mL M glutamine (GeminiBio-Products#400-110); and 0.25 mg / mL LG418 (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, the culture medium was aspirated, and cells were treated with 50 µL of stimulation buffer supplemented with 10.2 mM 3-isobutyl-1-methylxanthine (IBMX, MilliporeSigma #15879) 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 hours. cAMP accumulation was detected using d2-labeled cAMP and anti-cAMP-Cryptate. Time-resolved fluorescence signals were read using an m1000Pro (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 compound of the present invention was plotted. The EC50 of the compound was calculated using standard methods. 50 All data processing was performed on GraphPadPrismv9 (GraphPad, San Diego, California).

[0463] Table A reports the evaluation of the biological activity of compounds by inhibiting the cAMP activity of the human SSTR3 receptor.

[0464]

[0465] 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 (Ia) or a pharmaceutically acceptable salt thereof: (him) in: R2 is H, halogen, or C. 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R4 represents H, halogen, and C. 1-6 Alkoxy, C 1-6 Halogenated alkyl or CN; R6 is H or C 1-6 Alkyl; and R8 is H or C 1-6 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R2 is H, halogen, or C. 1-3 Alkoxy or CN; R3 represents H, halogen, or C. 1-3 Alkoxy, C 1-3 Halogenated alkyl or CN; R4 represents H, halogen, and C. 1-3 Alkoxy, C 1-3 Halogenated alkyl or CN; R6 is H or C 1-3 Alkyl groups; and R8 is H or C 1-3 alkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is a halogen or C 1-3 Alkyl group.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R4 is C 1-3 Alkyl group.

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R6 is H or Me.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R8 is H or Me.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: R2 is H; R3 is a halogen or C 1-3 Alkoxy; R4 is C 1-3 Alkoxy; R6 is either H or Me; and R8 is either H or Me.

8. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, Cl, OMe or CN.

9. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-2, 4-6 or 8, wherein R3 is H, F, Cl, OMe, CF3 or CN.

10. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, 5-6 or 8-9, wherein R4 is F, Cl, OMe, OEt, CF3 or CN.

11. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-2 or 8-10, wherein: R2 is H, F, Cl, OMe, or CN; R3 is H, F, Cl, OMe, CN, or CF3; R4 is F, Cl, OMe, OEt, CF3, or CN; R6 is either H or Me; and R8 is either H or Me.

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R2 is H.

13. The compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R3 is F or OMe.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R4 is OMe or OEt.

15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R6 is H.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein R8 is H.

17. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein R8 is Me.

18. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

19. A compound of formula (Ib), its N-oxide, or a pharmaceutically acceptable salt thereof: (One) in: X is CR1 or N; Y is CR2 or N; and Z is CR3 or N; Where X is N, Y is CR2 and Z is CR3; when Y is N, X is CR1 and Z is CR3; and when Z is N, X is CR1 and Y is CR2; R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy or CN; R3 represents H, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or CN; R4 represents H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R7 represents H and C. 1-6 Alkoxy, optionally C 1-6 alkyl, , or Substituted morpholino group; R9 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 Cycloalkoxy; R 10 C 1-6 Alkyl or C 1-6 Alkoxy; R A C 1-6 Alkyl, CH2OH or CH2OMe; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; and R C For H or C 1-6 Halogenated alkyl groups.

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein: R1 is H, halogen, or OH; R2 is H, halogen, or C. 1-3 Alkyl, C 1-3 Alkoxy or CN; R3 represents H, halogen, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or CN; R4 represents H, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, CN, OH, or C(O)NH2; R5 can be H, halogen, or OH; R7 represents H and C. 1-3 Alkoxy, optionally C 1-3 alkyl, , or Substituted morpholino group; R9 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, cyclopropyl, or cyclopropoxy; R 10 C 1-3 Alkyl or C 1-3 Alkoxy; R A C 1-3 Alkyl, CH2OH or CH2OMe; R B For H; Or R A and R B Together with the carbon atoms they are attached to, they form C 3-4 cycloalkyl; and R C For H or C 1-3 Halogenated alkyl groups.

21. The compound of claim 19 or 20 or a pharmaceutically acceptable salt thereof, wherein R1 is H, F or OH.

22. The compound of any one of claims 19-21 or a pharmaceutically acceptable salt thereof, wherein R2 is H, F, Cl, Me, OMe or CN.

23. The compound of any one of claims 19-22 or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, Cl, Me, CF3, OMe or CN.

24. The compound of any one of claims 19-23 or a pharmaceutically acceptable salt thereof, wherein R4 is H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH or C(O)NH2.

25. The compound of any one of claims 19-24 or a pharmaceutically acceptable salt thereof, wherein R5 is H, F or OH.

26. The compound of any one of claims 19-25 or a pharmaceutically acceptable salt thereof, wherein R7 is H, OMe, , , , , or .

27. The compound of any one of claims 19-26 or a pharmaceutically acceptable salt thereof, wherein R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy.

28. The compound of any one of claims 19-27 or a pharmaceutically acceptable salt thereof, wherein R 10 For Me or OMe.

29. The compound of any one of claims 19-28 or a pharmaceutically acceptable salt thereof, wherein R A It is Me, CH2OH, or CH2OMe, and R B For H.

30. The compound of any one of claims 19-28 or a pharmaceutically acceptable salt thereof, wherein R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups.

31. The compound of any one of claims 19-30 or a pharmaceutically acceptable salt thereof, wherein R C It is H or CH2CH2F.

32. The compound of any one of claims 19-31 or a pharmaceutically acceptable salt thereof, wherein: R1 is H, F, or OH; R2 is H, F, Cl, Me, OMe, or CN; R3 can be H, F, Cl, Me, CF3, OMe, or CN; R4 can be H, F, Cl, Me, CF3, OMe, OEt, OCF3, CN, OH or C(O)NH2; R5 is H, F, or OH; R7 is for H, OMe, , , , , or ; R9 is ethyl, CF3, OMe, OEt, cyclopropyl, or cyclopropoxy; R 10 For Me or OMe; R A It can be Me, CH2OH, or CH2OMe; R B For H; Or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups; and R C It can be H or CH2CH2F.

33. The compound of any one of claims 19-32 or a pharmaceutically acceptable salt thereof, wherein R1 is H or OH.

34. The compound of any one of claims 19-33 or a pharmaceutically acceptable salt thereof, wherein R2 is H or F.

35. The compound of any one of claims 19-34 or a pharmaceutically acceptable salt thereof, wherein R3 is H, F, OMe or CN.

36. The compound of any one of claims 19-35 or a pharmaceutically acceptable salt thereof, wherein R4 is Cl, OMe or CN.

37. The compound of any one of claims 19-36 or a pharmaceutically acceptable salt thereof, wherein R5 is H.

38. The compound of any one of claims 19-37 or a pharmaceutically acceptable salt thereof, wherein R7 is H, OMe, or .

39. The compound of any one of claims 19-38 or a pharmaceutically acceptable salt thereof, wherein R8 is OMe or cyclopropyl.

40. The compound of any one of claims 19-39 or a pharmaceutically acceptable salt thereof, wherein R 10 For Me.

41. The compound of any one of claims 19-40, or a pharmaceutically acceptable salt thereof, wherein R A Let Me be the value of R. B For H.

42. The compound of any one of claims 19-40, or a pharmaceutically acceptable salt thereof, wherein R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups.

43. The compound of any one of claims 19-42 or a pharmaceutically acceptable salt thereof, wherein R C For H.

44. The compound of any one of claims 19-43 or a pharmaceutically acceptable salt thereof, wherein: R1 is H or OH; R2 is either H or F; R3 is H, F, OMe, or CN; R4 is Cl, OMe, or CN; R5 is H; R7 is H, OMe, or ; R9 is OMe or cyclopropyl; R 10 For Me; R A For Me; R B For H; or R A and R B Together with the carbon atoms they are attached to, they form cyclopropyl groups; and R C For H.

45. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 19-44, wherein X is CR1; Y is CR2; and Z is CR3.

46. ​​The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 19-44, wherein one of X, Y or Z is N.

47. The compound of claim 19 or claim 20, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

48. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof: (Ic) in: Z is either CR3 or N; R2 is H, halogen, or C. 1-6 Alkoxy; R3 is H, halogen, or C. 1-6 Alkoxy; R4 is H, halogen, or C. 1-6 Alkoxy; R D C 1-6 Alkyl; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms attached to it, it forms a 3-6 membered heterocyclic alkyl group.

49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein: R2 is H, halogen, or C. 1-3 Alkoxy; R3 is H, halogen, or C. 1-3 Alkoxy; R4 is H, halogen, or C. 1-3 Alkoxy; R D C 1-3 Alkyl groups; and R E For CH2OMe; or R D and R E Together with the nitrogen and carbon atoms to which it is attached, it forms a 4-5 membered heterocyclic alkyl group.

50. The compound of claim 48 or claim 49 or a pharmaceutically acceptable salt thereof, wherein R2 is H, F or OMe.

51. The compound of any one of claims 48-50 or a pharmaceutically acceptable salt thereof, wherein R3 is H, F or OMe.

52. The compound of any one of claims 48-51 or a pharmaceutically acceptable salt thereof, wherein R4 is F or OMe.

53. The compound of any one of claims 48-52 or a pharmaceutically acceptable salt thereof, wherein R D For Me or Et.

54. The compound of any one of claims 48-52 or a pharmaceutically acceptable salt thereof, wherein R D and R E Together with the nitrogen and carbon atoms to which it is attached, it forms a nitrogen heterocyclic butyl or pyrrolidinyl group.

55. The compound of claim 48 or claim 49, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , , , , , , , , as well as Or its pharmaceutically acceptable salt.

56. A compound of formula (Id) or a pharmaceutically acceptable salt thereof: (Id) in: R2 is a halogen, C 1-6 Alkoxy or CN; R4 is a halogen or C 1-6 alkoxy groups; and R9 is C 1-6 Alkoxy or C 3-6 Cycloalkyl.

57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein: R2 is a halogen, C 1-3 Alkoxy or CN; R4 is a halogen or C 1-3 alkoxy groups; and R9 is C 1-3 Alkoxy or cyclopropyl.

58. The compound of claim 56 or claim 57 or a pharmaceutically acceptable salt thereof, wherein R2 is F, OMe or CN.

59. The compound of any one of claims 56-58 or a pharmaceutically acceptable salt thereof, wherein R4 is F or OMe.

60. The compound of any one of claims 56-59 or a pharmaceutically acceptable salt thereof, wherein R9 is OMe or cyclopropyl.

61. The compound of claim 56 or claim 57, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , as well as Or its pharmaceutically acceptable salt.

62. A method of treating a condition selected from polycystic kidney disease, polycystic liver disease, and cilia, comprising administering to a subject in need a compound of any one of claims 1-61 or a pharmaceutically acceptable salt thereof.

63. The method of claim 62, wherein the condition is polycystic kidney disease.

64. The method of claim 63, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease (ADPKD).

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