Enhancers of particulate guanylyl cyclase receptor b

Abstract

In some embodiments, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein the groups shown in Formula (I) are as disclosed herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising any of the compounds as disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a method of modulating particulate guanylyl cyclase receptor B (GC-B) in a cell, the method comprising contacting the cell with an effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof.

Description

[0001] ENHANCERS OF PARTICULATE GUANYLYL CYCLASE RECEPTOR B CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Application Serial No. 63 / 547,294, filed November 3, 2023. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application. STATEMENT AS TO FEDERALLY SPONSORED RESEARCH This invention was made with government support under AG056315 and HL158548 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD This invention relates to organic compounds, and more particularly to halobenzo[d]thiazole compounds that can be used to, for example treat conditions such as fibrosis. BACKGROUND Myocardial fibrosis is a classic pathological characteristic of the heart due to cardiovascular disease (CVD), and excessive fibrosis can lead to new onset heart failure (HF) and increased mortality. Current pharmacological therapies for myocardial fibrosis are limited. The discovery of novel drugs that target aberrant myocardial fibrosis would represent a breakthrough in cardiovascular therapeutics. The particulate guanylyl cyclase B receptor (GC-B), via activation by its endogenous ligand, C-type natriuretic peptide (CNP), possesses anti-fibrotic properties such as the ability to inhibit fibroblast proliferation and collagen synthesis through generation of its second messenger, cGMP (Chen et al., J Mol Cell Cardiol, 130:140-150, 2019; Michel et al., JCI Insight, 5, 2020; and Sangaralingham et al., Cardiovasc Res, 118:3416-3433, 2023). GC-B is highly expressed on fibroblasts and thus represents a molecular therapeutic target for CVD. SUMMARY This document is based, at least in part, on the identification of a small moleculethat directly engages the GC-B receptor to potentiate cGMP production. As demonstratedherein, cell-based high throughput screening (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) was conducted, resulting in the identification of small molecule GC-B positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship (SAR) studies resulted in the development of a GC-B PAM, referred herein to as Compound 24, that enhances CNP-mediated cGMPgeneration in human cardiac fibroblasts and inhibited cardiac fibroblast proliferation invitro. Binding analysis confirmed that Compound 24 binds to GC-B and selectively enhances the binding of CNP to GC-B. Thus, the work described herein resulted in the discovery and development of a small molecule GC-B PAM that can be orally delivered and can serve as a therapeutic for CVD and cardiac fibrosis. Compound 24 reiterated important allosteric binding sites on guanylyl cyclase receptors that have the ability to bind PAMs and enhance the effects of GC ligands that bind to the orthosteric site of the receptor. PAMs have unique advantages over orthosteric interacting molecules, including not competing for the same binding site as the ligand, potentially being safer since they require ligand binding to be effective and thus avoid overstimulation of the receptor, and the fact that allosteric sites are generally less conserved, which allows for the opportunityto selectively target specific subfamily of receptors (Wenthur et al., Annu Rev PharmacolToxicol., 54:165-184, 2014; Abdel-Magid, ACS Med Chem Lett., 6:104-107, 2015;Christopoulos, Nat Rev Drug Discov., 1:198-210, 2002; and Andresen et al., Br JPharmacol., 10.1111 / bph.16203, 2023). The present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein the groups shown in Formula (I) are as disclosed herein. The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In addition, the present disclosure provides a method of modulating particulate guanylyl cyclase receptor B (GC-B) in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Further, the present disclosure provides a method of modulating particulate guanylyl cyclase receptor B (GC-B) in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof., or a pharmaceutical composition comprising same. The present disclosure also provides a method of treating or preventing a disease or condition responsive to modulation of a particulate guanylyl cyclase receptor B (GC- B) in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of the compounds as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. In some embodiments, the disease or condition is cardiac fibrosis. In a first aspect, this document features a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1is halo or C1-C6haloalkyl; n = 0, 1 or 2; Y is O or S; X is CR3or NR2; R3is H, C1-C6alkyl or cyano-C1-C6alkyl; R2is H, cyano-C1-C6alkyl, phenyl, benzyl, COC1-C6alkyl, (C1-C6alkoxy)C1- C6alkyl, C1-C6haloalkyl, (C1-C6alkoxycarbonyl)C1-C6alkyl, (5- or 6- membered)heteroaryl-C1-C6alkyl, or cyano-C1-C6acyl; and Z is 5-membered heteroaryl. In some cases, n can be 1. In some cases, n can be 1 and R1can be halo, Cl, F, 2-F, 2-Cl, 3-F, 3-Cl, 4-F, C1-C6haloalkyl, CF3, 2-CF3, or 3-CF3. In some cases, n can be 2.In some cases, n can be 2 and each R1can be halo, each R1can be Cl, or one R1can be 2- Cl and one R1can be 5-Cl. Y can be O. Y can be S. X can be CR3. In such cases, R3can be H, R3is C1-C6alkyl, or cyano-C1-C6alkyl. In some cases, X can be NR2. In such cases, R2can be H, cyano-C1-C6alkyl, CH2CH2CN, CH2CN, phenyl, benzyl, COC1-C6alkyl, COCH3, (C1-C6alkoxy)C1-C6alkyl, CH3OCH2CH2, C1-C6haloalkyl, FCH2CH2, (C1-C6alkoxycarbonyl)C1-C6alkyl, CH2CH2CO2C2H5, (5- or 6-membered)heteroaryl-C1- C6alkyl, pyridinyl-C2H5, 2-pyridinyl-C2H5, 3-pyridinyl-C2H5, cyano-C1-C6acyl, orCOCH2CN. In some cases, Z can be furanyl, isoxazolyl, pyrazolyl, oxazolyl, In another aspect, this document provides a pharmaceutical composition containing a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, this document features a method of modulating GC-B in a cell. The method can include, or consist essentially of, contacting the cell with an effective amount of a compound provided herein, or with a pharmaceutical composition containing a compound provided herein. In another aspect, this document features a method for modulating GC-B in a mammal. The method can include, or consist essentially of, administering to the mammal an effective amount of a compound provided herein, or a pharmaceutical composition containing a compound provided herein. In still another aspect, this document features a method for treating or preventing a disease or condition responsive to modulation of GC-B in a mammal in need thereof. The method can include, or consist essentially of, administering to the mammal a therapeutically effective amount of a compound provided herein, or a pharmaceutical composition containing a compound provided herein. This document also features a method for treating fibrosis in a mammal in need thereof. The method can include, or consist essentially of, administering to the mammal a therapeutically effective amount of a compound provided herein, or a pharmaceutical composition containing a compound provided herein. The mammal can be a human. The method can include administering, to the mammal, a therapeutically effective amount of Compound 24. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is a scatter plot of the percent activity for GC-B potentiators in the NIH Molecular Libraries Small Molecule Repository (MLSMR). The largest cluster represents test compounds at 10 mM in the presence of 3 nM CNP, combined with negative control in the presence of 3 nM CNP (0% potentiation, CNP). The top cluster represents positive control in the presence of 300 nM CNP (100% potentiation). Compounds with >35%activity were considered hits in the screen. The Z for the assay was ~ 0.87 with a signalto background of ~4.2 determined from the positive and negative control wells containing 300 nM and 3 nM CNP in 0.3% DMSO, respectively. The screening plates were normalized by GeneData pattern correction software. FIG.2 is a graph plotting percent cGMP response curves for Compound 1 in HEK293 cells overexpressing GC-B (referred to as HEK293 GC-B cells) in the presence or absence of CNP (3 nM), or in HEK293 cells overexpressing the particulate guanylyl cyclase A receptor (GC-A; cells referred to as HEK293 GC-A cells) in the presence of ANP (9 pM), as indicated. Data are the average of three independent experiments, and are expressed as mean ± SD. FIG. 3 shows a representative procedure for synthesis of Compound 24 andanalogs. 5-(2,5-dichlorophenyl)furan-2-carbaldehyde (0.05 g, 0.207 mmol), 3-(piperidin-4-yl)propanenitrile hydrochloride (0.047 g, 0.270 mmol), elemental sulfur (0.08 g, 0.311 mmol) were weighed into a 2-5 mL microwave tube with a magnetic stir bar. Anhydrous acetonitrile (3.0 mL) was added, and the mixture was heated under microwave irradiation at 130°C and constant pressure for 45 minutes. The dark mixture was then partitioned between dichloromethane (12.0 mL) and water (6.0 mL). Insoluble material was filtered off and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash silica-gel column chromatography (0-20% ethyl acetate / hexanes) to obtain Compound 24, 3-(1-((5-(2,5-dichlorophenyl)furan-2-yl)(l3- sulfaneylidene)methyl)piperidin-4-yl)propanenitrile as a yellow solid (0.04 g, 49%).1H NMR (600 MHz, CDCl3) 7.77 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.5 Hz, 1H), 7.20 (d, J = 3.7 Hz, 1H), 7.17 (d, J = 3.6 Hz,1H), 5.50 (s, 1H), 4.51 (s, 1H), 3.47 – 3.12 (m, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.02 – 1.86 (m, 3H), 1.72 (q, J = 7.0 Hz, 2H), 1.56 – 1.40 (m, 2H). ESI-MS, calculated for C19H18Cl2N2OS, [M+H] = 393.06, observed [M+H] = 393.01. FIG.4 shows a1H Nuclear Magnetic Resonance of Compound 24. FIG.5 shows a Liquid Chromatography Mass Spectrometry Trace (214 nm) of Compound 24. FIG.6 shows a Mass Spectrum (ESI+ve) of Compound 24. FIGS. 7A-7E show the activity of Compound 24 in HEK293 cells. FIG.7A is a graph plotting the percent cGMP concentration-response curves for cGMP response of CNP alone, Compound 24 alone, and Compound 24 in the presence of 3 nM CNP in HEK293 GC-B cells. FIG.7B is a graph plotting cGMP generation in HEK293 GC-B cells treated with CNP alone (Veh) and CNP in the presence of Compound 24 at the indicated concentrations. *P < 0.05 compared to vehicle group (Veh) using one-way ANOVA followed by multiple comparisons with Tukey method. FIG.7C is a graph plotting cGMP generation in HEK293 GC-B cells treated with of vehicle alone (Veh) or Compound 24 alone at the indicated concentrations. FIG.7D is a graph plotting percent cGMP concentration-response curves in HEK293 GC-B cells for CNP titrated alone and CNP titrated together with increasing concentrations of Compound 24 at the indicated concentrations. FIG.7E is a graph plotting change in cGMP concentration-response for the EC30 concentration of CNP determined in FIG.7D in the presence of increasing concentrations of Compound 24.The line fits are non-linear regression analysis of the data. In FIGS.7A, 7D, and 7E, data are presented as mean ± SD. In FIGS.7B and 7C, data are presented as mean ± SEM. FIG.8 is a graph plotting cGMP generation in HEK293 GC-A cells in response to treatment with ANP alone (Veh) and ANP in the presence of Compound 24 at the indicated concentrations. FIG.9 is a graph plotting percent cGMP response curves in HEK293 GC-B cells treated with CNP titrated alone and CNP titrated together with increasing concentrations of Compound 22. The data indicate that there was no shift in CNP potency in the presence of Compound 22, as compared to the data shown in FIG. 7D for Compound 24. FIG.10 is a graph plotting plasma concentrations of Compound 24 after administration IV (solid squares) or orally (open squares) to mice over 8 hours, as an indication of the in vivo bioavailability of Compound 24. FIGS. 11A-11C show biological actions of Compound 24 on CNP in human cardiac fibroblasts (HCFs). FIG.11A is a graph plotting generation of cGMP in HCFs stimulated by 10-10M CNP alone or in the presence of 1 µM, 5 µM, or 10 µM Compound 24. *P < 0.05 compared to CNP alone group using one-way ANOVA followed by multiple comparisons with Tukey method. FIG. 11B is a graph plotting inhibition of TGF 1-induced HCF proliferation by CNP (10-10M) alone or CNP in the presence of 1 µM, 5 µM, and 10 µM Compound 24. *P < 0.05 compared to TGF 1+CNP (10-10 M)using two-way ANOVA followed by multiple comparisons with Tukey method for the main group effect. FIG.11C is a graph plotting HCF proliferation induced by TGF 1 alone or by TGF 1 in the presence of 1 µM, 5 µM, and 10 µM Compound 24. Data are presented as mean ± SEM. DETAILED DESCRIPTION This document provides methods and materials that can be used, for example, to treat mammals having cardiovascular disorders. For example, this document provides small molecule agonists of GC-B that can be used to treat mammals having cardiac fibrosis. Without being bound by a particular theory, it is believed that the heart is a vital endocrine organ that fine-tunes the body’s metabolic homeostasis. In the human heart, CNP is expressed in endothelial cells, cardiomyocytes and fibroblasts (Chaffin et al., Nature, 608:174-180, 2022). CNP levels are significantly elevated in advanced atherosclerotic lesions (Casco et al., J Histochem Cytochem, 50:799-809, 2002; and Naruko et al., Circulation, 94:3103-3108, 1996), and in HF, a compensatory rise in circulating CNP can occur (Ma et al., JACC Heart Fail, 9:613-623, 2021; and Lok et al., Eur J Heart Fail, 16:958-966, 2014). However, this rise in CNP is suboptimal from an organ protection standpoint and therefore HF is a relative CNP deficiency state. The molecular target of CNP is the particulate guanylyl cyclase receptor B (GC-B) which functions via the second messenger cGMP. Among various physiological functions of GC-B are cardiac growth, skeletal bone growth, female fertility, fat metabolism, and gastrointestinal function. The GC-B / cGMP signaling pathway also has been demonstrated to be an inhibitor of organ fibrosis in various experimental models of CVD, as well as in kidney and lung injury or disease (Kimura et al., Respir Res., 17:19, 2016; Soeki et al., J Am Coll Cardiol., 45:608-616, 2005; and Murakami et al., Am J Physiol Lung Cell Mol Physiol., 287:L1172-1177, 2004). Without being bound by a theory, it is believed that the compounds described herein increase GC-B responsiveness to the endogenous ligand (CNP), even at reduced levels, by enhancing the GC-B function in a positive allosteric manner. Certain embodiments of the GC-B activator compounds, pharmaceutical compositions containing the same, and methods of their use to treat GC-B associated conditions (alone or in combination with other agents) are described herein. Therapeutic compounds The compound of this disclosure may be described by reference to any of the following Formulae, or a pharmaceutically acceptable salt thereof. Compounds of Formula (I) In some embodiments, the present disclosure provides a compound of Formula (I): A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R1is halo or C1-C6haloalkyl; n = 0, 1 or 2; Y is O or S; X is CR3or NR2; R3is H, C1-C6alkyl or cyano-C1-C6alkyl; R2is H, cyano-C1-C6alkyl, phenyl, benzyl, COC1-C6alkyl, (C1-C6alkoxy)C1- C6alkyl, C1-C6haloalkyl, (C1-C6alkoxycarbonyl)C1-C6alkyl, (5- or 6- membered)heteroaryl-C1-C6alkyl, or cyano-C1-C6acyl; and Z is 5-membered heteroaryl. In some embodiments, n = 1. In some embodiments, n = 1 and R1is halo. In some embodiments, n = 1 and R1is Cl. In some embodiments, n = 1 and R1is F. In some embodiments, n = 1 and R1is 2-F. In some embodiments, n = 1 and R1is 2-Cl. In some embodiments, n = 1 and R1is 3-F. In some embodiments, n = 1 and R1is 3-Cl. In some embodiments, n = 1 and R1is 4-F. In some embodiments, n = 1 and R1is 4-F. In some embodiments, n = 1 and R1is C1-C6haloalkyl. In some embodiments, n = 1 and R1is CF3.In some embodiments, n = 1 and R1is 2-CF3. In some embodiments, n = 1 and R1is 3-CF3. In some embodiments, n = 2. In some embodiments, n = 2 and each R1is halo. In some embodiments, n = 2 and each R1is Cl. In some embodiments, n = 2, one R1is 2-Cl and one R1is 5-Cl. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, X is CR3. In some embodiments, X is NR2. In some embodiments, R3is H. In some embodiments, R3is C1-C6alkyl.In some embodiments, R3 is cyano-C1-C6alkyl.In some embodiments, R2is H. In some embodiments, R2is cyano-C1-C6alkyl. In some embodiments, R2is CH2CH2CN. In some embodiments, R2is CH2CN. In some embodiments, R2is phenyl. In some embodiments, R2is benzyl. In some embodiments, R2is COC1-C6alkyl. In some embodiments, R2is COCH3. In some embodiments, R2is (C1-C6alkoxy)C1-C6alkyl. In some embodiments, R2is CH3OCH2CH2. In some embodiments, R2is C1-C6haloalkyl. In some embodiments, R2is FCH2CH2. In some embodiments, R2is (C1-C6alkoxycarbonyl)C1-C6alkyl. In some embodiments, R2is CH2CH2CO2C2H5. In some embodiments, R2is (5- or 6-membered)heteroaryl-C1-C6alkyl. In some embodiments, R2is pyridinyl-C2H5. In some embodiments, R2is 2-pyridinyl-C2H5. In some embodiments, R2is 3-pyridinyl-C2H5. In some embodiments, R2is cyano-C1-C6acyl. In some embodiments, R2is COCH2CN. In some embodiments, Z is furanyl. In some embodiments, Z is isoxazolyl. In some embodiments, Z is pyrazolyl. In some embodiments, Z is oxazolyl.In some embodiments, Z isIn some embodiments, Z isIn some embodiments, Z is In some embodiments, the compound of Formula (I) is a compound of Formula (A): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (B): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (C): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound selected from the group consisting of the compounds of TABLES 1A, 1B, and 1C below, or a pharmaceutically acceptable salt thereof:

[0002] TABLE 1A

[0003] TABLE 1B TABLE 1C Pharmaceutically acceptable salts In some embodiments, a salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of the present disclosure include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of the present disclosure include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine), such as N,N-dimethyl-N- (2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some embodiments, the compounds of this disclosure, or pharmaceutically acceptable salts thereof, are substantially isolated. The compounds disclosed herein may have asymmetric centers. Compounds containing an asymmetrically substituted atom may be in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials, for example by chiral chromatography. All forms, including enantiomers, diastereomers, racemic mixtures, scalemic mixtures, as well as mixtures of diastereomers, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specified. Methods of making therapeutic compounds Compounds of this disclosure, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. A person skilled in the art knows how to select and implement appropriate synthetic protocols, and appreciates that the processes described are not the exclusive means by which compounds provided herein may be synthesized, and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds provided herein. Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols.1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2ndEdition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991). The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, Inc., New York (2006). An example of a synthesis of compounds disclosed herein is shown in Scheme I hereinbelow. Methods of using therapeutic compounds The present disclosure provides, at least in part, that the GC-B / cGMP pathway is a valuable molecular target for cardiovascular (CV) therapeutics. Accordingly, in a general aspect, this document provides methods for modulating GC-B in a cell, where the methods include contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cell can be contacted in vitro, in vivo, or ex vivo.This document also provides methods for modulating GC-B in a subject, where the methods include administering to a subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. In some embodiments of the methods of the present disclosure, modulating of GC-B includes positive allosteric enhancement of activity of GC-B (e.g., where the modulating includes increased production of cGMP in a cell, such as a cell in a mammal). In some embodiments, the cell is a cardiac cell, a renal cell, or a fat cell. The present disclosure also provides methods for treating or preventing a disease or condition responsive to modulation of GC-B in a subject. The methods can include administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. This document also provides a compound as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, for use in a manufacture of a medicament for the treatment or prevention of a disease or condition responsive to modulation of GC-B in a subject. The present disclosure also provides a compound as described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, for use the treatment or prevention of a disease or condition responsive to modulation of GC-B in a subject. In some embodiments, the disease or condition responsive to modulation of GC-B can be, without limitation, cardiac fibrosis, renal fibrosis, lung fibrosis, liver fibrosis, organ fibrosis, or bone-related disorders such as skeletal dysplasias (e.g., achondroplasia). For example, the disease or condition responsive to modulation of GC-B is a metabolic disease or disorder. In some embodiments, the metabolic disorder is acquired. Suitable examples of such disorders include diabetes (e.g., type 1 diabetes, diabetes insipidus, or type II diabetes mellitus), obesity, metabolic syndrome, non-alcoholic steatohepatitis, dyslipidemia, hipolipidemia (hyperlipoproteinemia), hyperthyroidism, hypoparathyroidism, hypothyroidism, Cushing’s syndrome, hyperuricemia, hemochromatosis, and hyperparathyroidism. Other examples of metabolic disorders include glucose intolerance, insulin resistance, fibrinolysis disorder, endothelial dysfunction, atherosclerosis, impaired fasting glycemia, hyperinsulinemia, galactosemia, mucopolysaccaridose, tyrosinemia, methylmalonic aciduria, acidemia (e.g., propionic acidemia, isovaleric acidemia), and hyperammonemia. In some embodiments, the metabolic disease is selected from obesity, hypertriglyceridemia, metabolic syndrome, insulin resistance, hyperinsulinemia, diabetes, and acidemia. In some embodiments, the disease or condition responsive to modulation of a particulate guanylyl cyclase receptor B (GC-B) is a cardiovascular disease. Suitable examples of cardiovascular disorders include high blood pressure, myocardial infarction, abnormal heart rhythms (e.g., arrhythmia), aorta disease, Marfan syndrome, congenital heart disease, coronary artery disease (e.g., narrowing of the arteries), deep vein thrombosis, pulmonary embolism, heart attack, heart failure, heart muscle disease (e.g., cardiomyopathy), heart valve disease, pericardial disease, peripheral vascular disease, rheumatic heart disease, stroke, vascular disease (e.g., blood vessel disease or atherosclerosis), cardiomyopathies, hypertension, aortic stenosis, mitral valve insufficiency, mitral valve prolapse, pericarditis, rheumatic heart disease, and cardiorenal syndrome. In some embodiments, the cardiovascular disease is selected from heart failure, cardiomyopathy, hypertension, high blood pressure, and myocardial infarction. In some embodiments, the disease or condition responsive to modulation of a particulate guanylyl cyclase receptor B (GC-B) is kidney disease. Suitable examples of renal diseases include nephropathy, acute kidney injury, kidney failure, acute renal failure, glomerulonephritis, polycystic kidney disease, kidney infection (pyelonephritis), simple kidney cysts, diabetic kidney disease, nephropathy, lupus nephritis, Henoch- Schönlein purpura, goodpasture syndrome, ectopic kidney, amyloidosis, acquired cystic kidney disease, glomerular disease, kidney dysplasia, medullary sponge kidney, nephrotic syndrome, kidney damage, renal artery stenosis, renal tubular acidosis, and solitary kidney. In some embodiments, the kidney disease is selected from nephropathy, acute renal failure, chronic kidney disease, cardiorenal syndrome and diabetic kidney disease. In some embodiments, the disease or condition responsive to modulation of a particulate guanylyl cyclase receptor B (GC-B) can be cancer. Suitable example of cancer include bladder cancer, brain cancer, breast cancer, colorectal cancer (e.g., colon cancer), rectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer (e.g., pancreatic neuroendocrine tumor), prostate cancer, endometrial cancer, renal cancer (kidney cancer) (e.g., advanced kidney cancer), skin cancer, liver cancer, thyroid cancer, leukemia, and testicular cancer. Pharmaceutical compositions and formulations The present application also provides pharmaceutical compositions comprising an effective amount of a compound of as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The carrier(s) and excipient(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%-100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients. Routes of administration and dosage forms The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed.2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product. In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia. Compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g., 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant. The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols. The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, J Pharm Pharmacol., 56:3- 17, 2004 and Ilium, Eur J Pharm Sci., 11:1-18, 2000. The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave-on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin-identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners. The compounds and therapeutic agents of the present application may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in U.S. Patent Nos.6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant, or vehicle, as those terms are used herein. According to another embodiment, the present application provides an implantable drug release device impregnated with or containing a compound or a therapeutic agent, or a composition comprising a compound of the present application or a therapeutic agent, such that said compound or therapeutic agent is released from said device and is therapeutically active. Dosages and regimens In the pharmaceutical compositions of the present application, a compound as described herein is present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. In some embodiments, an effective amount of a compound as described herein can range, for example, from about 0.001 mg / kg to about 1000 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 2 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 10 mg / kg to about 100 mg / kg, from about 100 mg / kg to about 200 mg / kg, or from about 200 mg / kg to about 1000 mg / kg). In some embodiments, an effective amount of a compound as described herein is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg. The foregoing dosages can be administered at any appropriate frequency and for any appropriate duration. In some cases, an effective frequency of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can be a frequency that reduces one or more symptoms associated with a disorder (e.g., cardiac fibrosis) in the mammal, without producing significant toxicity to the mammal. In some cases, an effective frequency of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can be a frequency that reduces one or more symptoms associated with a disorder (e.g., cardiac fibrosis) in a mammal as compared to a control mammal having a comparable disorder and not treated with the composition. For example, an effective frequency of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can be from about three times a day about once a month (e.g., three times a day, twice a day, once a day, twice a week, once a week, once every 14 days, once every 21 days, or once every 28 days). The frequency of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can remain constant or can be variable during the duration of treatment. Various factors can influence the actual effective frequency used for a particular application. For example, the effective amount, the severity of the disorder when treating a mammal, the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments, and the judgment of the treating physician may require an increase or decrease in the actual effective frequency of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein. In some cases, an effective duration of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can be a duration that reduces one or more symptoms associated with a disorder (e.g., cardiac fibrosis) in a mammal, without producing significant toxicity to the mammal. In some cases, an effective duration of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can be a duration that reduces one or more symptoms associated with a disorder (e.g., cardiac fibrosis) in a mammal as compared to a control mammal having a comparable disorder and not treated with the composition. For example, an effective duration of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein can vary from a single time point of administration to administration over the course of several weeks to several years (e.g., 2 to 4 weeks, 4 to 8 weeks, 8 to 12 weeks, 12 to 16 weeks, 16 to 26 weeks, 26 to 52 weeks, or more than 52 weeks). Multiple factors can influence the actual effective duration used for a particular application. For example, the severity of the disorder, the effective frequency, the effective amount, the route of administration, the age and general health condition of the mammal, excipient usage, the possibility of co-usage with other therapeutic or prophylactic treatments, and the judgment of the treating physician may require an increase or decrease in the actual effective duration of administration of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or the pharmaceutically acceptable salt as described herein. Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent in a suitable amount or dosage. Definitions At various places in the present specification, substituents of compounds of the present application are disclosed in groups or in ranges. It is specifically intended that various embodiments of the present application include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5 alkyl, and C6 alkyl. As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value). As used herein, the term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures named or depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. As used herein, the term “tautomer” refers to compounds which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting two atoms or groups and the position of these atoms or groups in the compound. As used herein, the term “isomer” refers to structural, geometric, and stereo isomers. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbon atoms. Examples include C1-4, C1-6, and the like. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. As used herein, the term “Cn-malkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n- hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, the term “Cn-m haloalkyl”, which may be used interchangeably with “Cn-Cmhaloalkyl”, such as C1-C6haloalkyl, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, “Cn-m alkynyl” refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “Cn-m alkylene,” employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,1-diyl, ethan-1,2-diyl, propan- 1,1,-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms. As used herein, the term “Cn-m alkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m haloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “amino” refers to a group of formula –NH2. As used herein, the term “Cn-malkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(n- butyl)amino and N-(tert-butyl)amino), and the like. As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-m alkoxycarbonyl” refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. “Cn-m alkoxycarbonyl” may be used interchangeably with “(Cn-Cmalkoxycarbonyl),” such as (C1-C6alkoxycarbonyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl), and the like. As used herein, the term “Cn-m alkylcarbonyl” refers to a group of formula -C(O)- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n- propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert- butylcarbonyl), and the like. As used herein, the term “Cn-malkylcarbonylamino” refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonylamino” refers to a group of formula -NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonyl” refers to a group of formula -S(O)2NH2. As used herein, the term “Cn-malkylaminosulfonyl” refers to a group of formula -S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminosulfonyl” refers to a group of formula -S(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonylamino” refers to a group of formula - NHS(O)2NH2. As used herein, the term “Cn-malkylaminosulfonylamino” refers to a group of formula -NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-m alkyl)aminosulfonylamino” refers to a group of formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminocarbonylamino,” employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2. As used herein, the term “Cn-m alkylaminocarbonylamino” refers to a group of formula -NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-m alkyl)aminocarbonylamino” refers to a group of formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “carbamyl” to a group of formula –C(O)NH2. As used herein, the term “Cn-malkylcarbamyl” refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-m-alkyl)carbamyl” refers to a group of formula – C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “thio” refers to a group of formula -SH. As used herein, the term “Cn-malkylthio” refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfinyl” refers to a group of formula -S(O)- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonyl” refers to a group of formula -S(O)2- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “carbonyl,” employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O). As used herein, the term “carboxy” refers to a -C(O)OH group. As used herein, the term “cyano-Cn-m alkyl,” which may be used interchangeably with “cyano-Cn-Cmalkyl,” such as cyano-C1-C6alkyl and cyano-C1-6alkyl, refers to a group of formula -(Cn-m alkylene)-CN. As used herein, the term “HO-C1-3 alkyl” refers to a group of formula -(C1-3 alkylene)-OH. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings). The term “Cn-m aryl” refers to an aryl group havingfrom n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl. As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six- membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin- 3-yl ring is attached at the 3-position. As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system. For example, “contacting” the particulate guanylyl cyclase receptor B with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having particulate guanylyl cyclase receptor B, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the particulate guanylyl cyclase receptor B. As used herein, the term “individual,” “patient,” or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology). As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition, or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition, or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition, or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition, or disorder from occurring. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. EXAMPLES Synthesis of compounds of Formula (I): Exemplary syntheses are shown below. Compounds disclosed herein may be made in analogous fashion. Scheme 1 5-(2,5-dichlorophenyl)furan-2-carbaldehyde (0.05 g, 0.207 mmol), 3-(piperidin-4- yl)propanenitrile hydrochloride (0.047 g, 0.270 mmol), elemental sulfur (0.08 g, 0.311 mmol) were weighed into a 2-5 mL microwave tube with a magnetic stir bar. Anhydrous acetonitrile (3.0 mL) was added, and the mixture was heated under microwave irradiation at 130 °C and constant pressure for 45 min. The dark mixture was then partitioned between dichloromethane (12.0 mL) and water (6.0 mL). Insoluble material was filtered off and the organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash silica-gel column chromatography (0-20% ethyl acetate / hexanes) to obtain the product 24, 3-(1-((5-(2,5-dichlorophenyl)furan-2-yl)(l3- sulfaneylidene)methyl)piperidin-4-yl)propanenitrile as a yellow solid (0.04 g, 49%). 1H NMR (600 MHz, CDCl3) 7.77 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.5 Hz, 1H), 7.20 (d, J = 3.7 Hz, 1H), 7.17 (d, J = 3.6 Hz,1H), 5.50 (s, 1H), 4.51 (s, 1H), 3.47 – 3.12 (m, 2H), 2.46 (t, J = 7.2 Hz, 2H), 2.02 – 1.86 (m, 3H), 1.72 (q, J = 7.0 Hz, 2H), 1.56 – 1.40 (m, 2H). ESI-MS, calculated for C19H18Cl2N2OS, [M+H] = 393.06, observed [M+H] = 393.01 Biological data: MATERIALS AND METHODS Peptides and Compounds: Human C-type natriuretic peptide (CNP) (Phoenix Pharmaceutical, Burlingame, CA) was dissolved in water at 500 mM stock and aliquoted and stored at -20°C. Compound 1 (CAS# 332862-27-8) was purchased from LifeChem (F1813-1161 Woodbridge, CT). Compound 1 was resynthesized, and analogs were prepared at the University of Florida according to the representative procedure (FIG.3) or at BioDuro-Sundia, China. Compound 24 was scaled up for PK studies at Jubilant Biosys Limited (Bengaluru, India). All other chemicals and reagents were from Sigma- Aldrich (St. Louis, MO). The identity and purity of Compound 24 was confirmed using H1nuclear magnetic resonance (NMR), liquid chromatography-mass spectrometry (LC- MS) trace, and mass spectrometry (MS) spectra (FIGS. 4-6). Cell Culture for HTS: HEK293 cells overexpressing human GC-B (Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN) and the parental cell line (ATCC®CRL-1573) devoid of either GC-B or GC-A were cultured in growth media consisting of Dulbecco’s modified Eagle medium (DMEM) (Corning; Cat. No.10013CM) containing 1% L-glutamine and sodium pyruvate and supplemented with 10% fetal bovine serum (HyClone; SH30396.03), 500 g / mL G418 (Thermo Fisher; Cat. No. 10131035). Cell cultures were maintained in a cell culture incubator at 37°C in 5% CO2, and were routinely subcultured twice weekly by trypsin-ethylenediaminetetraacetic acid (EDTA) treatment (0.25% trypsin-EDTA). On the day of the assay, cells were thawed, counted, and resuspended in assay media (OPTI-MEM™ containing 2% heat-activated fetal bovine serum and 1% L-glutamine) and used as described below in high throughput screening (HTS) cGMP production assays. High Throughput Screening cGMP Production: To identify GC-B PAMs from the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MSMLR), a procedure was used similar to that described elsewhere for targeting the GC- A receptor (Sangaralingham et al., Proc Natl Acad Sci USA 118(52):e2109386118, 2021). In brief, production of cGMP (the second messenger generated by GC-B activation) was monitored by homogenous time-resolved florescence (HTRF) competition assay using labeled-cGMP in HEK293 cells overexpressing the human GC-B receptor. Compound EC50 values were determined in the primary cell-based screening assay in the presence or absence of CNP to determine mode of action as positive modulators. Compounds were tested for selectivity in the same assay platform but in HEK293 cells overexpressing human GC-A, for which ANP rather than CNP is the endogenous ligand. For HTS, GC-B suspension cells were plated in 1536 well and stimulated in the presence of 10 µM compound concentration and a submaximal concentration of CNP. The quantity of cGMP was detected by HTRF and normalized to the maximal amount produced by CNP. Specifically, 20 nL of 10 mM test compounds in DMSO from the NIH MLSMR (370,620 test compounds) were added to columns 5-48 of 1536 well white high base screening plates (Corning, New York, NY) using a 550 ECHO acoustic dispenser (Labcyte, San Jose, CA). CNP was prepared as working stock aliquots at 500 µM in PBS with 0.1% BSA. An approximate EC30 concentration of CNP (3 nM) in assay buffer (HBSS containing 5 mM HEPES and 0.05% BSA) was added to columns 3-48 at a volume of 1 µL. Assay buffer only was added to column 1 , and assay buffer containing a saturating concentration of CNP (300 nM) was added to column 2. HEK293 cells overexpressing human GC-B in assay media were stirred continuously for 2 hours at RT at a density of 6 x 105cells / mL, and 2 µL were plated in screening plates (1200 cells / well) using a BioRaptr 2. Plates were spun at 1000 rpm for 1 minute and incubated for 30 minutes at RT. d2-labled cGMP (1.5 µL) followed by 1.5 µL Eu3+cryptate- labeled anti-cGMP cGMP detection kit (CiBio; Cat No.62GM2PEC) prepared according to the manufacturer’s protocol were added to all wells using a BioRaptr 2, and TR-FRET signal was detected on an ENVISION™ detector (PerkinElmer). Wells treated with 0.3% DMSO served only as blank controls (column 1), wells treated with 0.3% DMSO and 300 nM CNP (column 2) served as positive controls, and wells treated with 0.3% DMSO and 3 nM CNP (columns 3-4) served as negative controls. DMSO did not exceed 0.3% in all wells. EC50 cGMP Determination: Compound EC50 values were determined in the primary cell-based screening assay in the presence or absence of CNP to determine mode of action as positive modulators. Test compounds at 10 mM DMSO stock concentration were added to 384 well assay plates using Tecan dispensing, starting at a concentration of 8 M and diluted 2-fold for 10-point concentration response curves. Wells were backfilled with DMSO so that the final concentration of DMSO in all wells was maintained at 0.3% DMSO. Wells with compounds were stimulated with an EC30 concentration of CNP. The quantity of cGMP was detected by HTRF and normalized to the maximal amount produced by CNP. An approximate EC30 concentration of CNP (1 nM) in assay buffer (Hanks’ Balanced Salt Solution [HBSS] containing 5 mM HEPES and 0.05% BSA) was added to columns 3 to 48 at a volume of 10 L. Assay buffer only was added to column 1, and assay buffer containing a saturating concentration of CNP (100 nM) was added to column 2. HEK293 cells overexpressing human GC-B in assay media were stirred continuously at room temperature at a density of 2 × 106cells / mL, and 10 L were plated in screening plates (5,000 cells / well) using a viaflo-multichannel pipettor. Plates were spun at 1,000 rpm for 1 minute and incubated for 30 minutes at room temperature, and then 5 L d2-labled cGMP followed by 5 L Eu3+ cryptate- labeled anti-cGMP cGMP detection kit (CiBio; #62GM2PEC) prepared according to manufacturer’s protocol were added to all wells using a viaflo-multichannel pipettor. TR- FRET signal was detected on a Clariostar-plus plate reader (BMG-Labtech). Wells treated with 0.3% DMSO served only as blank controls (column 1), wells treated with 0.3% DMSO and 50 nM CNP (columns 2) served as positive controls, and wells treated with 0.3% DMSO and 1 nM CNP (columns 3 to 4) served as negative controls. DMSO did not exceed 0.3% in all wells. A 100% response was determined from wells in the absence of compound and the presence of a saturating concentration of CNP (100 nM), and 0% response was determined from wells containing an EC20 concentration of CNP. cGMP Levels in HEK293 Cells Overexpressing Human GC-B or GC-A Receptor: HEK293 GC-B or GC-A were seeded at 105cells / well in 48-well plates and cultured overnight to reach 80%-90% confluency. In all experiments, a treatment buffer consisting of HBSS, 0.5 mM 3-isobutyl-1-methylzanthine (IBMX, a nonspecific inhibitor of phosphodiesterase), 2 mM Hepes, and 0.1% BSA was used. On the day of the experiment, HEK293 GC-B or GC-A cells were pretreated with Compound 24 at doses of 0.5, 1, 2.5, 5, and 10 M for 5 minutes at 37°C. The culture medium was then replaced by the treatment buffer containing 10-10M CNP (for HEK293 GC-B cells) or 10-10M ANP (for HEK293 GC-A cells) and incubated at 37°C for an additional 10 minutes. After the treatment, cells were washed once with PBS and lysed with 0.1 M HCl. Intracellular cGMP was measured in the lysate using a cGMP ELISA Kit (Enzo Life Sciences) following the manufacturer’s instructions. cGMP Levels in Human Primary Cardiac Fibroblasts: Human cardiac fibroblasts (HCFs) (PromoCell, Heidelberg, Germany; Cat. No.12375) were maintained and sub- cultured according to the manufacturer’s protocols. Cells at passages 4-8 were used in the studies described herein. Briefly, HCFs were cultured in 6-well plates to 80% confluency before being treated with treatment buffer (same as in the HEK293 cell experiments) alone, with 10-10M CNP alone, or with 10-10M CNP and different concentrations (1, 5, and 10 M) of Compound 24 for 10 minutes. After treatment, the cells were washed once with PBS and lysed with 0.1 M HCl. Intracellular cGMP was measured in the lysate using a cGMP ELISA Kit (Enzo Life Sciences) following the manufacturer’s instructions. Live Cell, Real Time Human Cardiac Fibroblast Proliferation Imaging and Analysis: A HCF (same as above) proliferation assay was performed using the automated live cell, real time imaging and analysis INCUCYTE®Zoom system (Essen BioScience, Ann Arbor, MI). HCF proliferation was monitored by time-lapse imaging and analyzed with the INCUCYTE®Zoom system software, enabling determination of cell density (percent confluence) over time. Briefly, HCFs were seeded at 1.5×104cells / well in a 96- well plate and cultured for 24 hours without starvation. The cells were then treated with PBS (vehicle) alone, 5 ng / mL of the profibrotic cytokine TGF 1 (R&D Systems, Minneapolis, MN) alone, TGF 1 (5 ng / mL) together with CNP (10-10M), TGF 1 (5 ng / mL) together with CNP (10-10M) and different concentrations (1, 5, and 10 M) of Compound 24, or TGF 1 (5 ng / mL) together with 1, 5, or 10 M of Compound 24. Phase contrast images were taken continuously for 4 days as instructed by the manufacturer and data images were analyzed using the corresponding software. The effect of Compound 24 (on top of CNP) on HCF proliferation was compared to the CNP alone group. The effect of Compound 24 (on top of TGF 1) on HCF proliferation was compared to the TGF 1 alone group. GC-B Binding Studies: Surface plasmon resonance (SPR) measurements were performed at 25°C on a BI-4500 SPR instrument (Biosensing Instrument Inc.). As per the instructions by the Biosensing instrument manual, 400 mM nickel sulfate in deionized water was linked to the Ni-NTA sensor chip (Biosensing Instrument Inc.). The extracellular domain of human GC-B recombinant protein (MyBioSource Inc.) at a concentration of 40 g / mL was then immobilized onto the nickel sulfate on the Ni-NTA sensor chip. The chip was then washed with buffer (150 mM NaCl, 50 M EDTA pH 7.4, 0.1% DMSO), followed by the injection of 100 L of sequentially diluted Compound 24 (0.31, 0.625, 1.25, 2.5, or 5 M) alone at a rate of 60 L / min and allowed to dissociate for 60 seconds. For GC-B binding studies with CNP, 100 L of sequentially diluted CNP (0.0625, 0.125, 0.25, 0.5, and 1 nM) alone or CNP (0.0625, 0.125, 0.25, 0.5, and 1 nM) together with Compound 24 (5 M) were injected at the rate of 60 L / min and allowed to dissociate for 200 seconds. Similar experiments were performed with Compound 22. All data were collected as sensorgrams, and the binding kinetics were derived from sensorgrams using the BI-Data Analysis Program (Biosensing Instrument Inc.). Affinity analysis of GC-B with CNP and / or Compound 24 interactions were performed using a 1:1 Langmuir binding model. Two series of experiment were performed for all studies. Pharmacokinetics (PK) Studies: All procedures used for the PK studies were performed at Jubilant Biosys Limited (Bengaluru, India). The PK of Compound 24 was investigated in male Balb / C mice (Vivo Biotech, Hyderabad, India; 6-8 weeks old, 23-26 grams) using sparse sampling design. A total of 24 mice were divided into two groups to receive one of the following treatments: a single dose of 5 mg / kg intravenously (IV), or 10 mg / kg doses orally (PO; per os) by gavage. The mice in the IV group were fed food and water ad libitum throughout the study, while for mice in the PO group were kept for 4 hours fasting before dosing and food was provided 2 hours post dose with water ad libitum. The vehicle used was TWEEN®-80 and 0.5% methyl cellulose (0.5:99.5; v / v) in Milli-Q water for PO dosing, or DMSO, Solutol:Ethanol (1:1) and normal saline (10:10:80 v / v) for IV dosing. Two aliquots of each (IV and PO) formulation were dose- validated by high performance liquid chromatography (HPLC). All blood samples were transferred to micro-centrifuge tubes containing 5 L of 10% K2EDTA (0.5 mL) as an anticoagulant agent, and were placed on ice until they were processed for plasma. Blood samples were processed for plasma by centrifugation at 10000 rpm for 5 minutes at 4°C, quickly frozen, and stored at -80°C until quantification by LC-MS / MS. Statistical Analysis and Regression Curve Fitting: All concentration-response curves were analyzed to determine EC50 and Emax. All Emax values were calculated using the equation Emax = 100 / [1+10(LogEC50-X)*Hill-slope], where X is the log of the tested compound concentration and the Hill slope is set to be 1. For concentration-response data, nonlinear regression curve fitting and statistical analyses were performed using Prism 9 (GraphPad Software Inc.), and a P value < 0.05 was considered as statistically significant. All presented experimental data related to cells and mouse studies were acquired in at least three biological replicates (n 3). Unless specified otherwise, all numeric data are expressed as mean SEM or SD. Unpaired t test assuming unequal variance was performed for the comparison between each pair of two groups in HEK293 cells and HCFs. For the PK studies, plasma concentration data were analyzed with standard non-compartmental analysis with the Phoenix WinNonlin software (version 8.1, © 2023; Certara, Princeton, NJ). Mean plasma concentration–time profiles were constructed for PK analysis in the mouse. The systemic clearance (CL) and the steady state volume of distribution (Vss) and half-life were calculated after IV administration and the Cmax, Tmax, and area under the curve (AUC) values were calculated using a combination of linear trapezoidal and linear interpolation summations. The absolute oral bioavailability (%F) was estimated by taking the ratio of dose-normalized AUC values. RESULTS Discovery of Small Molecule GC-B PAM Scaffolds: The NIH MLSMR of 370,620 compounds (FIG. 1) was screened in the presence of a sub-concentration (3 nM in a 1536 well screening assay) of CNP to sensitize the HTS toward detection of PAMs, and the screening identified 399 hits with >35% activity in the HEK 293 cells expressing the GC- B receptor. Compound concentration-responses in the primary cell-based screening assay and a counter screen assay performed in parental HEK 293 cells devoid of expressed GC- B receptor confirmed 199 of the compounds as having GC-B activity. Of these, 106 compounds had activity >28% in HEK 293 cells expressing the GC-A receptor. Finally, 86 potential selective modulators of GC-B were identified that had >28% activity at the target receptor and <28% activity at the GC-A receptor. The hits were confirmed to be devoid of agonist activity in the absence of added CNP when tested in the HEK293 GC-B overexpressing cells, thereby, supporting their mode of action as PAMs. These compounds were graded according to activity, structure, and liability as potential pan- assay interference compounds (PAINS), resulting in 25 compounds that met the internal criteria and were available as commercial powders (Baell and Holloway, J Med Chem 53:2719-2740, 2010). Hit Confirmation Studies: The active hits from the primary screening were binned into 12 scaffolds, and commercially available analogs around these scaffolds were procured and assayed for potency as PAMs against GC-B / cGMP signaling assay in the presence of 3 nM CNP and selectivity vs GC-A / cGMP signaling assay in the presence of 3 pM ANP, resulting in five chemical scaffolds. Chemical stability, synthetic tractability, solubility, and complete dose response and potency criteria led to prioritization of the 5- aryl furan-2-thiocarboxamide and 5-aryl furan-2-carboxamide cores, respectively, represented by Compound 1 (TABLE 1A). As illustrated in FIG.2, Compound 1 was specific in stimulating GC-B in the presence of an EC20 concentration of CNP and exhibited sub micromolar potency and efficacy (0.74 µM and Emax of 112%; pEC50 of - 6.6 0.3, n=3) compared to saturating concentrations of CNP. Further, Compound 1 wasdevoid of activity in HEK293 GC-B cells tested in the absence of CNP, and also devoid of activity in HEK293 GC-A cells in the presence of ANP up to 67 µM, indicating its GC-B specificity and potentiation. Hit to Lead SAR Studies: Compound 1, the primary hit representing scaffold 1, was resynthesized and recapitulated the activity of the commercial compound from the screening library (TABLE 1A, Compound 1). Its synthesis was modified from a procedure described elsewhere based on the Wilgerodt Kindler reaction (Fedorovich et al., Russ J Org Chem, 43:1190-1195, 2007) to access the key thioamide from thecorresponding amine, furan-2-carboxaldehyde and elemental sulfur. The synthesis was conducted under microwave irradiation (acetonitrile, 130°C for 2 hours) instead of thermal conditions. Replacement of thioamide with an amide resulted in complete loss of activity, demonstrating that the thioamide is critical (Compound 2). Syntheses were then focused on aryl substitution at the R1 position, based on synthesis of analogs from commercially available building blocks. The presence of an unsubstituted phenyl group (Compound 3) resulted in about an 8-fold loss of activity, which was dialed back with halogenated substituents and 2-F, 3-Cl and 4-Cl substituents that resulted in equipotent analogs within 0.5-2.0 x EC50 of Compound 1. Attention then shifted to R2 substituents at the 1-position of the piperazine moiety. Having no substituent (R2 = H) or having aryl and benzyl substituents at R2 led to inactive analogs (TABLE 1B, Compounds 11-13). Surprisingly, an N-acetyl piperazine analog was tolerated (Compound 14). Replacement of the nitrile group from the propionitrile substituent in Compound 1 with an electron rich methyl ether led to inactive Compound 15. However, other electron withdrawing substituents capable of forming H-bonds (donor) such as -F and -CO2Et were tolerated (Compound 17). Replacement of the nitrile group in Compound 1 with a 3-pyridinyl group led to an inactive compound, whereas a 2-pyridinyl substituent retained moderate activity (Compounds 19 and 18, respectively). Compounds 16-19 highlighted the requirement of a specifically located linker of the small electron withdrawing and H- bonding group at this position as a key driver of activity. Shortening the linker or having an acyl link between the nitrile and piperazine moieties led to 2.5- to 3-fold loss of activity (Compounds 20 and 21). Some core replacements also were examined, demonstrating that replacement of the furan ring with other heterocycles such as isoxazole and pyrazole led to complete loss of activity (TABLE 1C, Compounds 22 and 23). However, it was found that piperidine analog 24 (TABLE 1C, Compound 24) retained the potency of the piperazine-containing Compound 1. Alkyl or acyl piperazines can have metabolic and potential toxic liabilities. Thus, Compound 24 represented a significant change in the structure from Compound 1 while retaining equipotency. The biological and pharmacokinetic properties of Compound 24 were then evaluated as described below. The structure, procedure for synthesis and characterization of Compound 24 and analogs thereof are shown in FIGS. 3-6. Biological Profile of Compound 24: Compound 24 was identified as a selective GC-B PAM, as it was able to dose-dependently potentiate CNP-mediated cGMP with a potency of EC50 = 0.80 µM and Emax = 86% in HEK293 GC-B cells (FIG.7A). Compound 24 specifically increased cGMP levels by 4-fold in the presence of CNP (FIG. 7B). In the absence of CNP, Compound 24 had no cGMP generating activity in HEK293 GC-B cells (FIGS. 7A and 7C). This absence of an agonist response further indicated that Compound 24 was modulating only the CNP target engagement with the GC-B receptor. Further, confirming that the chemical series represented by Compound 1 retained selectivity to the GC-B receptor (FIG.2), it was observed that Compound 24 was devoid of cGMP generating activity in HEK293 GC-A cells in the presence of ANP (FIG. 8). To further characterize its mode of action as a GC-B PAM, CNP was titrated in the absence or presence of Compound 24 (FIG. 7D). Increasing concentrations of Compound 24 shifted the CNP-mediated cGMP dose-response curve to the left, indicating increasing potency, with no additional enhancing effect on the maximal cGMP response. This confirmed that Compound 24 is a PAM without agonistic activity. The EC50 value of CNP alone was 3.0 nM (in the 384 well dose-response assay), and the EC50 values of CNP in the presence of increasing concentrations (0.157, 0.313, 0.625, 1.25, 2.5, and 5.0 µM) of Compound 24 decreased to CNP’s EC50 to 1.4, 0.81, 0.70, 0.53, 0.37, and 0.31 nM, respectively, resulting in an overall 6.4-fold increase in affinity of CNP for GC-B when in the presence of 5.0 µM Compound 24 compared to CNP alone. From the data in FIG.7D, the change in the percent cGMP response of the EC30 concentration of the CNP (0.9 nM) curve in the absence of Compound 24 (logEC30 = -8.7 ± 0.1) to the CNP curves in the presence of increasing concentrations of Compound 24 was determined. The percent cGMP response change of the EC30 concentration was plotted versus the corresponding concentration of Compound 24 (FIG.7E, which is referred to as the EC30 sensitivity assay). Nonlinear regression analysis of these data resulted in pEC50= -6.4 ± 0.2 (EC50= 0.36 µM), which provides a quantitative assessment of intrinsic PAM affinity. By contrast, a less potent compound from the SAR studies, Compound 22 (EC50 > 10 µM), showed no potentiation effects on cGMP activity in the presence of CNP in HEK293 GC-B cells (FIG.9). Altogether, these studies demonstrated that Compound 24 was selective for the GC-B receptor and stimulated cGMP generation only in PAM mode. Surface plasmon resonance (SPR) analysis was further conducted for the binding of Compound 24 alone, CNP alone, or Compound 24 in the presence of increasing concentrations of CNP to the extracellular domain of human GC-B (TABLE 2). Binding of Compound 24 to human GC-B was confirmed to have a KD of 710 nM. Strong binding of CNP to human GC-B was validated with a KDof 0.17 nM. Moreover, the binding of CNP to GC-B was enhanced in the presence of Compound 24, which resulted in a 2.6- fold increase in the association rate of the complex, thereby shifting the KD (kd / ka) lower to 0.062 nM in the presence of Compound 24 (5 µM). To further support Compound 24 as a GC-B PAM, the binding of Compound 22 – which did not show potentiation effects on cGMP in the cell-based assay – was evaluated (FIG. 9). These SPR studies demonstrated that the binding of Compound 22 to the GC-B domain had a KD of 558 nM, but Compound 22 did not alter the binding of CNP to GC-B since the KDof CNP in the presence of Compound 22 (KD = 0.16 nM) remained similar to that of the binding of CNP alone to GC-B (KD= 0.14). Together, these results indicated that Compound 24 bound to the GC-B receptor and enhanced the affinity of CNP for the GC-B receptor by increasing the association rate, thus reducing the equilibrium dissociation rate. TABLE 2: SPR binding kinetics for Compound 24 and CNP to the human GC-B receptor *ka, association rate; kd, dissociation rate; KD, equilibrium dissociation rate. In Vivo PK and Bioavailability in Mice: In vivo PK studies in mice showed that Compound 24 (5 mg / kg) was bioavailable for 8 hours when administered IV (FIG. 10). When given orally, Compound 24 (10 mg / kg) exhibited limited absorption, but the compound was detectable for up to 2 hours (FIG.10). In addition, Compound 24 had an oral bioavailability of 0.26 (TABLE 3). TABLE 3: Pharmacokinetics (PK) of Compound 24 *Tmax= time to reach peak plasma concentration; C0= plasma concentration at time zero; Cmax = peak plasma concentration; Vss = steady-state volume of distribution; AUC0-t= area under curve from time zero to time of last measurable concentration; AUC0-= area under the curve from time zero to infinite time; CL = clearance; T1 / 2= half-life. In Vitro cGMP Generation of Compound 24 in Human Cardiac Fibroblasts: Theability of Compound 24 to enhance the cGMP generation of CNP in HCFs was further evaluated. Consistent with the potency observed in HEK293 GC-B cells, these studies demonstrated that the addition of increasing concentrations (1 µM, 5 µM, and 10 µM) of Compound 24 on top of 10-10M CNP significantly enhanced cGMP generation in HCFs (FIG.11A). In Vitro Inhibition of Human Cardiac Fibroblasts Proliferation with Compound24: A key property of the GC-B / cGMP signaling pathway is its anti-fibrotic actionswithin the heart under pathophysiological stress. To further define the therapeutic potential of Compound 24, live-cell, time-lapsed imaging studies were conducted to evaluate the ability of Compound 24 to enhance anti-fibrotic actions of GC-B’s natural ligand, CNP, in HCFs stimulated by the potent fibrotic cytokine, TGF 1, using inhibition of fibroblast proliferation as the primary endpoint. These studies demonstrated that the presence of Compound 24 at concentrations of 5 µM and 10 µM together with CNP (10- 10M) significantly inhibited TGF 1-stimulated HCF proliferation, as compared to CNP alone (FIG.11B). In the absence of CNP, there was no suppression of TGF 1-stimulated HCF proliferation with Compound 24 (FIG.11C). OTHER EMBODIMENTS It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is halo or C1-C6haloalkyl; n = 0, 1 or 2; Y is O or S; X is CR3or NR2; R3is H, C1-C6alkyl or cyano-C1-C6alkyl; R2is H, cyano-C1-C6alkyl, phenyl, benzyl, COC1-C6alkyl, (C1-C6alkoxy)C1- C6alkyl, C1-C6haloalkyl, (C1-C6alkoxycarbonyl)C1-C6alkyl, (5- or 6- membered)heteroaryl-C1-C6alkyl, or cyano-C1-C6acyl; and Z is 5-membered heteroaryl.

2. The compound of claim 1, wherein n = 1.

3. The compound of claim 2, wherein R1is halo.

4. The compound of claim 3, wherein R1is Cl.

5. The compound of claim 3, wherein R1is F.

6. The compound of claim 3, wherein R1is 2-F.

7. The compound of claim 3, wherein R1is 2-Cl.

8. The compound of claim 3, wherein R1is 3-F.

9. The compound of claim 3, wherein R1is 3-Cl.

10. The compound of claim 3, wherein R1is 4-F.

11. The compound of claim 2, wherein R1is C1-C6haloalkyl.

12. The compound of claim 11, wherein R1is CF3.

13. The compound of claim 11, wherein R1is 2-CF3.

14. The compound of claim 11, wherein R1is 3-CF3.

15. The compound of claim 1, wherein n = 2.

16. The compound of claim 15, wherein each R1is halo.

17. The compound of claim 15, wherein each R1is Cl.

18. The compound of claim 15, wherein one R1is 2-Cl and one R1is 5-Cl.

19. The compound of any one of claims 1-18, wherein Y is O.

20. The compound of any one of claims 1-18, wherein Y is S.

21. The compound of any one of claims 1-20, wherein X is CR3.

22. The compound of any one of claims 1-20, wherein X is NR2.

23. The compound of claim 21, wherein R3 is H.

24. The compound of claim 21, wherein R3 is C1-C6alkyl.

25. The compound of claim 21, wherein R3 is cyano-C1-C6alkyl.

26. The compound of claim 22, wherein R2is H.

27. The compound of claim 22, wherein R2is cyano-C1-C6alkyl.

28. The compound of claim 27, wherein R2is CH2CH2CN.

29. The compound of claim 27, wherein R2is CH2CN.

30. The compound of claim 22, wherein R2is phenyl.

31. The compound of claim 22, wherein R2is benzyl.

32. The compound of claim 22, wherein R2is COC1-C6alkyl.

33. The compound of claim 32, wherein R2is COCH3.

34. The compound of claim 22, wherein R2is (C1-C6alkoxy)C1-C6alkyl.

35. The compound of claim 34, wherein R2isCH3OCH2CH2.

36. The compound of claim 22, wherein R2is C1-C6haloalkyl.

37. The compound of claim 36, wherein R2is FCH2CH2.

38. The compound of claim 22, wherein R2is (C1-C6alkoxycarbonyl)C1-C6alkyl.

39. The compound of claim 38, wherein R2is CH2CH2CO2C2H5.

40. The compound of claim 22, wherein R2is (5- or 6-membered)heteroaryl-C1- C6alkyl.

41. The compound of claim 40, wherein R2is pyridinyl-C2H5.

42. The compound of claim 40, wherein R2is 2-pyridinyl-C2H5.

43. The compound of claim 40, wherein R2is 3-pyridinyl-C2H5.

44. The compound of claim 22, wherein R2is cyano-C1-C6acyl.

45. The compound of claim 44, wherein R2is COCH2CN.

46. The compound of any one of the preceding claims, wherein Z is furanyl.

47. The compound of any one of claims 1-46, wherein Z is isoxazolyl.

48. The compound of any one of claims 1-46, wherein Z is pyrazolyl.

49. The compound of any one of claims 1-46, wherein Z is oxazolyl.

50. The compound of any one of claims 1-46, wherein Z is.

51. The compound of any one of claims 1-46, wherein Z is52. The compound of any one of claims 1-46, wherein Z is53. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

54. A method of modulating particulate guanylyl cyclase receptor B (GC-B) in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of the claims 1-52, or the pharmaceutical composition of claim 53.

55. A method of modulating particulate guanylyl cyclase receptor B (GC-B) in a mammal, the method comprising administering to the mammal an effective amount of the compound of any one of the claims 1-52, or the pharmaceutical composition of claim 53.

56. A method of treating or preventing a disease or condition responsive to modulation of a particulate guanylyl cyclase receptor B (GC-B) in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the compound of any one of the claims 1-52, or the pharmaceutical composition of claim 53.

57. A method of treating fibrosis in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of the compound of any one of the claims 1-52, or the pharmaceutical composition of claim 53.

58. The method of any one of claims 54-57, wherein the mammal is a human.

59. The method of any one of claims 54-58, wherein the method comprises administering, to the mammal, a therapeutically effective amount of Compound 24.

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