Methods and materials for treating renal stores

Abstract

This document provides methods and materials for reducing formation and / or slowing progression of renal stones. For example, methods and materials for using soluble guanylate cyclase (sGC) agonists of Formula I, Group I, and / or Group II to reduce renal stone formation within a mammal and / or to slow renal stone progression within a mammal are provided. sGC agonists of Formula I, Group I, and / or Group II and compositions containing sGC agonists of Formula I, Group I, and / or Group II also are provided.

Description

[0001] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0002] METHODS AND MATERIALS FOR TREATING RENAL STONES TECHNICAL FIELD

[0003] This document relates to methods and materials involved in treating renal stones. For example, this document provides methods and materials for using soluble guanylate cyclase (sGC) agonists (e.g., oxidized or non-oxidized sGC agonists) of Formula I, Group I, and / or Group II to prevent or reduce formation and / or to slow progression of renal stones.

[0004] BACKGROUND

[0005] Kidney stones are small, hard deposits that can form in one or both kidneys. To be cleared from the body, the stones travel from the kidney, through the ureters, to the bladder, then through the urethra to be excreted. Patients with relatively small renal stones (e.g., less than 4 mm) typically undergo watchful waiting until the stone dislodges and is passed through the urinary system. Larger kidney stones (e.g., greater than 6 mm) can become lodged in the urinary tract, thereby causing substantial complications and patient discomfort. There is currently few, if any, effective treatments to prevent or hinder renal stone formation or progression.

[0006] SUMMARY

[0007] This document provides methods and materials for reducing formation and / or slowing progression of renal stones. For example, this document provides soluble guanylate cyclase (sGC) agonists of Formula I, Group I, and / or Group II, compositions containing one or more sGC agonists of Formula I, Group I, and / or Group II, and methods for using sGC agonists of Formula I, Group I, and / or Group II and / or compositions containing one or more sGC agonists of Formula I, Group I, and / or Group II to treat mammals having, or likely to develop, one or more renal stones.

[0008] As demonstrated herein, loss of sGC signaling (e.g., through genetic inactivation of enzymes in pathways that regulate nitric oxide signaling) resulted in significant increases in renal stone formation. These results demonstrate that sGC agonists of Formula I, Group I, and / or Group II can be used to treat renal stones and / or to slow progression of renal stone formation. Having the ability to reduce formation and / or slow growth of renal stones as described herein can allow patientsAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0009] and clinicians to treat patients who have renal stones and are otherwise undergoing watchful waiting.

[0010] In general, one aspect of this document features a method for reducing renal stone formation. The method can include (or consist essentially of, or consist of) administering a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II to a mammal having one or more renal stones or likely to develop one or more renal stones, wherein formation of a renal stone within the mammal is reduced. The mammal can be a human. Formation of a renal stone within the mammal can be delayed. Formation of a renal stone within the mammal can be delayed for at least 6 months. The mammal can be a mammal having one or more renal stones. The mammal can be a mammal likely to develop one or more renal stones.

[0011] In another aspect, this document features a method for slowing renal stone progression or enlargement. The method can include (or consist essentially of, or consist of) administering a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II to a mammal having one or more renal stones, wherein progression or enlargement of at least one of the one or more renal stones within the mammal is reduced. The mammal can be a human. Progression of at least one of the one or more renal stones within the mammal can be slowed by at least 10 percent. Progression of at least one of the one or more renal stones within the mammal can be slowed by at least 25 percent. Progression of at least one of the one or more renal stones within the mammal can be slowed by at least 50 percent.

[0012] In another aspect, this document features a compound of Formula I:

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] R1is selected from NH2, morpholinyl, piperidinyl, pyrrolidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, each of which is optionally substituted with 1 or 2 substituentsAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0016] independently selected from C1-3 alkyl, OH, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, COOH, and CH2COOH;

[0017] X1is a 5-membereed heteroaryl, optionally substituted with halo, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0018] R2is selected from H, C(=O)C1-3 alkyl, C(=O)C1-3 haloalkyl, and S(=O)2R4; R4is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, CN, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0019] n is 1, 2, or 3; and

[0020] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy. X1can be a 5-membereed heteroaryl. X1can be selected from 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, and 1,3,4-thiadiazolyl. The compound of Formula I can have formula:

[0021]

[0022] or a pharmaceutically acceptable salt thereof. The compound of Formula I can have formula:

[0023]

[0024] or a pharmaceutically acceptable salt thereof. R2can be H. R2can be selected from C(=O)C1-3 alkyl and C(=O)C1-3 haloalkyl. The compound can have formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0025]

[0026] or a pharmaceutically acceptable salt thereof. R4can be selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and C1-3 alkoxy. The compound can have formula:

[0027]

[0028] or a pharmaceutically acceptable salt thereof. N can be 1 or 2. R3can be selected from halo, C1-3 alkyl, and C1-3 alkoxy. The compound can have formula:

[0029]

[0030] or a pharmaceutically acceptable salt thereof. The compound can have formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0031]

[0032] or a pharmaceutically acceptable salt thereof. The compound can have formula selected from:

[0033]

[0034] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0035]

[0036] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0037]

[0038]

[0039] p, ndAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0040]

[0041] (Compound A6), or a pharmaceutically acceptable salt thereof.

[0042] In another aspect, this document features a compound selected from:

[0043]

[0044] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0045]

[0046] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0047]

[0048] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0049]

[0050] p,Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0051]

[0052] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0053]

[0054] or a pharmaceutically acceptable salt thereof.

[0055] In another aspect, this document features a pharmaceutical composition containing (or consisting essentially of, or consisting of) a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0056] 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.

[0057] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, andAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0058] advantages of the invention will be apparent from the description and drawings, and from the claims.

[0059] DESCRIPTION OF DRAWINGS

[0060] Figure 1 is a graph plotting expression of DDAH1, DDAH2, PRMT1, and SLC7A2 in renal tissue from patients undergoing surgical procedures for removal of advanced renal stones compared to patients undergoing a clinically-indicated renal biopsy unrelated to renal stone formation. Expression of molecules associated with asymmetric dimethylarginine (ADMA) metabolism and transport are altered in humans with advanced renal stone formation such that: 1) DDAH1 and DDAH2, the enzymes that degrade the endogenous inhibitor of nitric oxide synthase ADMA, are both upregulated in diseased tissue.

[0061] Figure 2 contains results showing changes in renal stone formation in LA-D+ / +and LA-D+ / -mice following 6 months of Western diet feeding detected by postmortem high resolution CT scanning of the entire kidney. Loss of sGC signaling, through genetic inactivation of enzymes in pathways that regulate nitric oxide signaling, resulted in significant increases in renal stone formation (evidenced by the intense white signal in the kidney).

[0062] Figure 3 is a graph plotting changes in blood urea nitrogen levels (BUN; mg / dL) and electrolytes (Na+, K+, and Cl-; mmol / L) from LA-D+ / +and LA-D ' mice. Despite increased blood pressure and renal calcifications, there was no observed evidence of overt end organ / kidney dysfunction in LA-D+ / -mice, suggesting that the focal renal calcifications were not secondary to overt / global end organ damage.

[0063] Figures 4A-4C are graphs plotting results demonstrating changes in canonical BMP signaling (pSMADl / 5 / 8; Figure 4A), Osterix protein (Figure 4B), and SMAD target genes (Figure 4C) in kidney from LA-D+ / +and LA-D+ / -mice. While calcified renal foci in LA-D+ / -mice were not associated with increases in canonical BMP signaling, Osterix was nearly doubled in these regions, again suggesting a highly localized process that does not stem from global end organ damage secondary to high blood pressure (i.e., an insult that is not related specifically to local nitric oxide signaling).

[0064] Figures 5A-5B are graphs plotting results demonstrating changes in USF-1 protein levels (Figure 5A) and the USF-1 target genes osteopontin and alkalineAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0065] phosphatase (Figure 5B) in kidney from LA-D+ / +and LA-D+ / -mice. A marked increase in USF-1 near calcified foci in LA-D+ / -mice was accompanied by significantly upregulated alkaline phosphatase, but not SPP1, expression. Figures 5C-5D are graphs plotting the correlations between calcification and pSMAD 1 / 5 / 8 (Figure 5C) or USF1 (Figure 5D) in kidney tissue.

[0066] Figures 6A-6C are graphs plotting results demonstrating changes in levels of SPP1 protein (Figure 6A) and protein (Figure 6B) and mRNA (Figure 6C) levels of tartrate-resistant alkaline phosphatase in kidney from LA-D+ / +and LA-D+ / -mice.

[0067] DETAILED DESCRIPTION

[0068] This document provides methods and materials for reducing formation and / or slowing progression of renal stones. For example, this document provides soluble guanylate cyclase (sGC) agonists of Formula I, Group I, and / or Group II, compositions containing one or more sGC agonists of Formula I, Group I, and / or Group II, and methods for using sGC agonists of Formula I, Group I, and / or Group II and / or compositions containing one or more sGC agonists of Formula I, Group I, and / or Group II to treat mammals having, or likely to develop, one or more renal stones.

[0069] As described herein, one or more sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) to reduce renal stone formation and / or to slow renal stone progression within the mammal. For example, one or more sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) having one or more renal stones (or likely to develop one or more renal stones) to reduce renal stone formation and / or to slow renal stone progression.

[0070] Any type of mammal having or likely to develop one or more renal stones can be treated as described herein. Examples of mammals that can have or be likely to develop one or more renal stones and can be treated as described herein include, without limitation, humans, non-human primates such as monkeys, dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats. In some cases, a human having one or more renal stones can be treated as described herein. In some cases, a human likely to develop one or more renal stones can be treated as described herein.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0071] Any appropriate method can be used to identify a mammal (e.g., a human) as being a mammal having one or more renal stones. For example, urinalysis, blood tests, x-ray, or computed tomography scanning can be used to identify a mammal (e.g., a human) as being a mammal having one or more renal stones. Any appropriate method can be used to identify a mammal (e.g., a human) as being a mammal likely to develop one or more renal stones. For example, confirmation of one or more prior renal stones via patient questioning or review of a patient’s medical history, family history of renal stone formation, genetic testing for gene variants that increase risk for stone formation, and / or dietary and / or fluid intake habits (e.g., high sodium intake, low fluid volume intake) can be used to identify a mammal (e.g., a human) as being a mammal likely to develop one or more renal stones.

[0072] In some cases, one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal having one or more renal stones (or likely to develop one or more renal stones) to reduce renal stone formation by delaying or preventing the formation of a new renal stone within the mammal. For example, one or more sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having or likely to develop a renal stone) to reduce the formation of a new renal stone within the mammal. In some cases, the methods and materials described herein can be effective to delay the formation of a renal stone within a mammal by, for example, at least 6 months (e.g., at least about 7 months, at least about 8 months, at least about 10 months, at least about 1 year, at least about 1.5 years, at least about 2 years, at least about 2.5 years, at least about 3 years, at least about 4 years, or at least about 5 years). In some cases, the formation of a new renal stone within a mammal being treated as described herein (e.g., by administration of one or more sGC agonists of Formula I, Group I, and / or Group II) can be delayed for as long as the mammal is administered one or more sGC agonists of Formula I, Group I, and / or Group II.

[0073] In some cases, one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal having one or more renal stones to slow progression of the one or more renal stones. For example, one or more sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having a renal stone) to slow progression (e.g., to slow further growth) of that renal stoneAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0074] within the mammal. In some cases, the methods and materials described herein can be effective to slow progression of one or more renal stones within a mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the progression of an existing renal stone within a mammal being treated as described herein (e.g., by administration of one or more sGC agonists of Formula I, Group I, and / or Group II) can be reduced to no observable growth for as long as the mammal is administered one or more sGC agonists of Formula I, Group I, and / or Group II.

[0075] Any appropriate sGC agonist of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) having (or likely to develop) one or more renal stones to reduce renal stone formation and / or slow renal stone progression as described herein.

[0076] In some cases, a mammal (e.g., a human) having (or likely to develop) one or more renal stones can be administered or instructed to self-administer one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II. For example, a mammal (e.g., a human) having (or likely to develop) one or more renal stones can be administered a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II to reduce renal stone formation and / or slow renal stone progression as described herein. In some cases, a mammal (e.g., a human) having (or likely to develop) one or more renal stones can be instructed to self-administer a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II to reduce renal stone formation and / or slow renal stone progression as described herein.

[0077] In some cases, when a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II is administered to a mammal (e.g., a human) having or likely to develop one or more renal stones, the composition can be designed for oral or parenteral (including, without limitation, subcutaneous, intramuscular, intravenous, intradermal, intracerebral, intrathecal, intraabdominal, and intraperitoneal injections) administration to the mammal. Compositions suitable for oral administration include, without limitation, liquids, tablets, capsules, pills, powders, gels, and granules. Compositions suitable for parenteral administration include, without limitation, aqueous and nonaqueous sterile injection solutions that can contain anti-oxidants, buffers,Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0078] bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient. In some cases, a pharmaceutically acceptable composition including one or more sGC agonists of Formula I, Group I, and / or Group II can be administered locally or systemically. For example, a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II can be administered systemically by injection to a mammal (e.g., a human). In some cases, each sGC agonist of Formula I, Group I, and / or Group II to be administered when two or more sGC agonists of Formula I, Group I, and / or Group II are to be administered can be administered by the same or different routes. For example, one sGC agonist of Formula I, Group I, and / or Group II can be administered orally, and a second sGC agonist of Formula I, Group I, and / or Group II can be administered by injection.

[0079] In some cases, a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II can be in the form of a sterile injectable suspension (e.g., a sterile injectable aqueous or oleaginous suspension). This suspension may be formulated using, for example, suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can 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. Examples of acceptable vehicles and solvents that can be used include, without limitation, saline, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In some cases, sterile, fixed oils can be used as a solvent or suspending medium. In some cases, a bland fixed oil can be used such as synthetic mono- or di-glycerides.

[0080] When one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II are formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal (e.g., a human) having or likely to develop one or more renal stones to reduce renal stone formation and / or slow renal stone progression as described herein, the composition can deliver the sGC agonist(s) of Formula I, Group I, and / or Group II in any manner. In some cases, a composition including one or more sGC agonists of Formula I, Group I, and / or Group II can be an immediate release composition (e.g., an immediate release oral dosage form). In some cases, a composition including one or more sGC agonists of Formula I, Group I, and / or Group II can be a controlled (e.g., delayedAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0081] and / or sustained) release compositions (e.g., a controlled release oral dosage form). For example, a controlled release composition including one or more sGC agonists of Formula I, Group I, and / or Group II can be designed to release the one or more sGC agonists of Formula I, Group I, and / or Group II over 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0082] When designing a composition (e.g., a pharmaceutically acceptable composition) containing one or more sGC agonists of Formula I, Group I, and / or Group II for administration to a mammal (e.g., a human) having or likely to develop one or more renal stones to reduce renal stone formation and / or slow renal stone progression as described herein, the composition (e.g., pharmaceutically acceptable composition) can include any appropriate effective amount of the one or more sGC agonists of Formula I, Group I, and / or Group II. For example, a therapeutically effective amount of one or more sGC agonists of Formula I, Group I, and / or Group II can be formulated together with one or more pharmaceutically acceptable carriers (additives), excipients, and / or diluents. Examples of pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein include, without limitation, cyclodextrins (e.g., beta-cyclodextrins such as KLEPTOSE®), dimethylsulfoxide (DMSO), sucrose, lactose, starch (e.g., starch glycolate), cellulose, cellulose derivatives (e.g., modified celluloses such as microcrystalline cellulose, and cellulose ethers like hydroxypropyl cellulose (HPC) and cellulose ether hydroxypropyl methylcellulose (HPMC)), xylitol, sorbitol, mannitol, gelatin, polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), crosslinked polyvinylpyrrolidone (crospovidone), carboxymethyl cellulose, polyethylene-polyoxypropylene-block polymers, and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium)), titanium oxide, azo dyes, silica gel, fumed silica, talc, magnesium carbonate, vegetable stearin, magnesium stearate, aluminum stearate, stearic acid, antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), citric acid, sodium citrate, parabens (e.g., methyl paraben and propyl paraben), petrolatum, dimethyl sulfoxide, mineral oil, serum proteins (e.g., human serum albumin), glycine, sorbic acid, potassium sorbate, water, salts or electrolytes (e.g., saline such as phosphate buffered saline, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyacrylates, waxes, wool fat,Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0083] lecithin, and corn oil. If required, the solubility and bioavailability of the one or more sGC agonists of Formula I, Group I, and / or Group II in a pharmaceutically acceptable composition can be enhanced using lipid excipients and / or block copolymers of ethylene oxide and propylene oxide. See, e.g., U. S. Patent No. 7,014,866 and U. S. Patent Application Publication Nos. 2006 / 0094744 and 2006 / 0079502.

[0084] In some cases, a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II can be designed to be in unit-dose or multi-dose containers, for example, sealed ampules and vials, and can be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.

[0085] One or more sGC agonists of Formula I, Group I, and / or Group II (e.g., a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II) can be administered to a mammal in any amount, at any frequency, and for any duration effective to achieve a desired outcome (e.g., to reduce formation and / or to slow progression of one or more renal stones).

[0086] An effective amount of a sGC agonist of Formula I, Group I, and / or Group II that can be administered to a mammal as described herein can be any amount that reduces formation of one or more renal stones within the mammal and / or slows progression of one or more renal stones within the mammal without producing significant toxicity to the mammal. For example, an effective amount of a sGC agonist of Formula I, Group I, and / or Group II can be from about 0.0001 mg of sGC agonist / kg of body weight to about 8000 mg of sGC agonist / kg of body weight (e.g., from about 0.0001 mg / kg to about 5000 mg / kg, from about 0.0001 mg / kg to about 1000 mg / kg, from about 0.0001 mg / kg to about 500 mg / kg, from about 0.0001 mg / kg to about 100 mg / kg, from about 0.0001 mg / kg to about 50 mg / kg, from about 0.0001 mg / kg to about 20 mg / kg, from about 0.0001 mg / kg to about 10 mg / kg, from about 0.0001 mg / kg to about 1 mg / kg, from about 0.0001 mg / kg to about 0.1 mg / kg, from about 0.0001 mg / kg to about 0.01 mg / kg, from about 0.0001 mg / kg to about 0.001 mg / kg, from about 0.001 mg / kg to about 8000 mg / kg, from about 0.01 mg / kg to about 8000 mg / kg, from about 0.1 mg / kg to about 8000 mg / kg, from about 1 mg / kg to about 8000 mg / kg, from about 10 mg / kg to about 8000 mg / kg, from about 20 mg / kg to about 8000 mg / kg, from about 50 mg / kg to about 8000 mg / kg, from about 100 mg / kg to about 8000 mg / kg, from about 500 mg / kg to about 8000 mg / kg, from about 1000Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0087] mg / kg to about 8000 mg / kg, from about 5000 mg / kg to about 8000 mg / kg, from about 0.001 mg / kg to about 5000 mg / kg, from about 0.01 mg / kg to about 1000 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 50 mg / kg, from about 0.0001 mg / kg to about 0.01 mg / kg, from about 0.001 mg / kg to about 0.1 mg / kg, from about 0.01 mg / kg to about 1 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 20 mg / kg, from about 10 mg / kg to about 50 mg / kg, from about 20 mg / kg to about 100 mg / kg, from about 50 mg / kg to about 500 mg / kg, from about 100 mg / kg to about 1000 mg / kg, from about 500 mg / kg to about 5000 mg / kg, or from about 1000 mg / kg to about 8000 mg / kg). In some cases, between about 0.1 mg and 200 mg (e.g., between about 0.1 mg and 150 mg, between about 0.1 mg and 100 mg, between about 0.1 mg and 50 mg, between about 0.1 mg and 20 mg, between about 0.1 mg and 10 mg, between about 0.1 mg and 5 mg, between about 0.1 mg and 1 mg, between about 1 mg and 200 mg, between about 5 mg and 200 mg, between about 10 mg and 200 mg, between about 20 mg and 200 mg, between about 50 mg and 200 mg, between about 100 mg and 200 mg, between about 150 mg and 200 mg, between about 1 mg and 150 mg, between about 5 mg and 100 mg, between about 10 mg and 50 mg, between about 0.1 mg and 5 mg, between about 1 mg and 10 mg, between about 5 mg and 20 mg, between about 10 mg and 50 mg, between about 20 mg and 100 mg, between about 50 mg and 150 mg, or between about 100 mg and 200 mg) of a sGC agonist of Formula I, Group I, and / or Group II can be administered to an average sized human (e.g., about 70 kg human) daily for about 20 weeks. If a particular mammal fails to respond to a particular amount, then the amount of sGC agonist of Formula I, Group I, and / or Group II can be increased by, for example, two-fold. After receiving this higher amount, the mammal can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly. Reciprocally, if a mammal experiences side effects at an initial dose (e.g., blood pressure lowering), the amount of sGC agonist of Formula I, Group I, and / or Group II can be decreased while still monitoring for efficacy with regards to renal stone formation. The effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route ofAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0088] administration, and severity of the condition (e.g., renal stone formation and / or progression) can require an increase or decrease in the actual effective amount administered.

[0089] A composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) having or likely to develop one or more renal stones in any appropriate frequency. The frequency of administration can be any frequency that reduces formation of one or more renal stones within the mammal and / or slows progression of one or more renal stones within the mammal without producing significant toxicity to the mammal. For example, the frequency of administration can be from about once a week to about three times a day, or from about twice a month to about six times a day, or from about twice a week to about once a day. The frequency of administration can remain constant or can be variable during the duration of treatment. A course of treatment with a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II can include rest periods. For example, a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II can be administered daily over a two week period followed by a two week rest period, and such a regimen can be repeated multiple times. As with the effective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition (e.g., renal stone formation and / or progression) can require an increase or decrease in administration frequency.

[0090] A composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II can be administered to a mammal (e.g., a human) having or likely to develop one or more renal stones for any appropriate duration. An effective duration for administering a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II can be any duration that reduces formation of one or more renal stones within the mammal and / or slows progression of one or more renal stones within the mammal without producing significant toxicity to the mammal. In some cases, the effective duration can vary from several days to several weeks, months, or years. In general, the effective duration for the treatment of renal stones as described herein can range inAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0091] duration from several months to several years. In some cases, an effective duration can be for as long as an individual mammal is alive. Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, route of administration, and severity of the condition (e.g., renal stone formation and / or progression) being treated.

[0092] In some cases, methods for treating a mammal (e.g., a human) having or likely to develop one or more renal stones as described herein (e.g., by administering one or more sGC agonists of Formula I, Group I, and / or Group II) can include administering to the mammal the one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II as the sole active ingredient(s) to treat renal stone formation and / or progression within the mammal. For example, a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II can include the one or more sGC agonists of Formula I, Group I, and / or Group II as the sole active ingredient in the composition that is effective to reduce formation of one or more renal stones within the mammal and / or to slow progression of one or more renal stones within the mammal.

[0093] In some cases, methods for treating a mammal (e.g., a human) having or likely to develop one or more renal stones as described herein (e.g., by administering one or more sGC agonists of Formula I, Group I, and / or Group II) can include administering to the mammal the one or more (e.g., one, two, three, four, or more) sGC agonists of Formula I, Group I, and / or Group II in combination with one or more cGMP-specific phosphodiesterase 5 A (PDE5 A) inhibitors. In some cases, the one or more sGC agonists of Formula I, Group I, and / or Group II can be administered together as a single composition with the one or more PDE5A inhibitors. In some cases, the one or more sGC agonists of Formula I, Group I, and / or Group II and the one more PDE5A inhibitors can be administered to the mammal being treated at the same time as separate compositions. In some cases, the one or more sGC agonists of Formula I, Group I, and / or Group II can be administered to the mammal first followed by the one more PDE5 A inhibitors. In some cases, the one more PDE5 A inhibitors can be administered to the mammal first followed by the one or more sGC agonists of Formula I, Group I, and / or Group II. Examples of PDE5A inhibitors include, without limitation, sildenafil, vardenafil, tadalafil, EMD 360527, DA 8159, UK-343-664Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0094] (Walker et al., Xenobiotica, 31:651-664 (2001)), UK-427-387, UK-357903 ([1-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2-methoxyethoxy)-5-pyridylsulphonyl}piperazine]) (Gardiner et al., J.

[0095] Pharmacol. Exp. Ther., 312:265-271 (2005)), UK-371800 (Pfizer), UK-313794 (Pfizer), UK-343664 (Abel et al., Xenobiotica, 31:665-76 (2001)), TA-1790 (Tanabe Seiyaku), CP-248 (Osi Pharmaceuticals), CP-461 (Osi Pharmaceuticals), exisulind (Deguchi et al., Mol. Ther., 803-809 (2002); (Osi Pharmaceuticals)), pyrazolinone, EMD82639 (Merck KgaA, Darmstadt, DE; (4-(4-[2-ethyl-phenylamino)-methylene]-3-methyl-5-oxo-4,5-di-hydro-pyrazol-l-yl)-benzoic acid; Senzaki et al., FASEB J., 15:1718-1726 (2001), and Scutt et al., BMC Pharmacol., 4:10 (2004)), EMD360527 (Merck KgaA, Darmstadt, DE; [7-(3-Chloro-4-methoxy-benzylamino)-l-methyl-3-propyl-lH-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]-acetic acid; Scutt et al., BMC Pharmacol., 4:10 (2004)), EMD221829 (Merck KgaA, Darmstadt, DE; 4-[4-(3-Chloro-4-methoxy-benzylamino)-benzo[4,5]thieno[2,3-d]-pyrimidin-2-yl]-cyclohexanecarboxylic acid, ethanolamin salt; Scutt et al., BMC Pharmacol., 4:10 (2004)), EMDl 71827 (Merck KgaA, Darmstadt, DE; 5 -[4-(3 -Chi oro-4-m ethoxy -benzylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-pentanoic acid; Scutt et al., BMC Pharmacol., 4:10 (2004)), DA-8259 (3-(l-Methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide), E-4021 (Dukarm et al., Am. J. Respir. Crit. Care Med., 160:858-865 (1999)), pentoxifylline, and FR22934 (Fujisawa). Additional examples of PDE5A inhibitors can be set forth in U. S. Patent Nos: 6,916,927, 6,911,542, 6,903,099, 6,878,711, 6,872,721, 6,858,620, 6,825,197, 6,774,128, 6,723,719, 6,699,870, 6,670,366, 5,859,006, and 5,250,534 and International Patent Application Publication No. WO 03 / 063875, WO 03 / 1012761, WO 2004 / 037183, and WO 98 / 38168.

[0096] In some cases, a course of treatment and the severity of renal stone formation and / or progression can be monitored. Any appropriate method can be used to determine whether or not treatment with one or more sGC agonists of Formula I, Group I, and / or Group II as described herein is effective to reduce renal stone formation and / or to slow renal stone progression within the mammal being treated. For example, renal stone progression during a course of treatment described herein can be assessed using imaging techniques at different time points.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0097] This document also provides sGC agonists of Formula I, Group I, and / or Group II and compositions containing one or more sGC agonists of Formula I, Group I, and / or Group II. The sGC agonists of Group I are GPHR312770, GPHR312771, GPHR312772, GPHR312773, GPHR312853, GPHR312854, GPHR312855, GPHR312856, GPHR312858, Compound Al, Compound A2, Compound A3, Compound A4, Compound A5, and Compound A6. The sGC agonists of Group II are GPHR312768, GPHR312769, GPHR312844, GPHR312845, GPHR312846, GPHR312847, GPHR312848, GPHR312849, GPHR312850, GPHR312857, GPHR312859, Compound Bl, Compound B2, Compound B3, Compound B4, Compound B5, and Compound B6. In some cases, a composition containing one or more sGC agonists of Formula I, Group I, and / or Group II can include one or more PDE5A inhibitors.

[0098] Compounds of Formula (I)

[0099] This document also provides compounds of Formula (I).

[0100]

[0101] or a pharmaceutically acceptable salt thereof, wherein:

[0102] R1is selected from NH2, morpholinyl, piperidinyl, pyrrolidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, COOH, and CH2COOH;

[0103] X1is a 5-membereed heteroaryl, optionally substituted with halo, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0104] R2is selected from H, C(=O)C1-3 alkyl, C(=O)C1-3 haloalkyl, and S(=O)2R4; R4is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, CN, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0105] n is 1, 2, or 3; and

[0106] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy.

[0107] In some embodiments, R1is NH2.

[0108] In some embodiments, R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, COOH, and CH2COOH.

[0109] In some embodiments, R1is morpholinyl. In some embodiments, R1is piperidinyl, optionally substituted with COOH or CH2COOH. In some embodiments, R1is pyrrolidinyl, optionally substituted with OH. In some embodiments, R1is 2-oxa-6-azaspiro[3.3]heptanyl.

[0110] In some embodiments, the compound of Formula I has formula:

[0111]

[0112] or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, X1is a 5-membereed heteroaryl. In some embodiments, X1is selected from 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, and 1,3,4-thiadiazolyl,

[0114] In some embodiments, the compound of Formula I has formula:

[0115]

[0116] or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0117] In some embodiments, the compound of Formula I has formula:

[0118]

[0119] or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, R2is H. In some embodiments, R2is selected from C(=O)Ci-3 alkyl and C(=O)Ci-3 haloalkyl. In some embodiments, R2is C(=O)Ci-3 alkyl. In some embodiments, R2is C(=O)Ci-3 haloalkyl.

[0121] In some embodiments, R2is S(=O)2R4.

[0122] In some embodiments, the compound of Formula I has formula:

[0123]

[0124] or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, R4is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and C1-3 alkoxy. In some embodiments, R4is selected from thiophenyl and phenyl, each of which is optionally substituted with halo, CN, or C1-3 alkoxy.

[0126] In some embodiments, R4is thiophenyl, optionally substituted with halo. In some embodiments, R4is phenyl, optionally substituted with halo, CN, or C1-3 alkoxy.

[0127] In some embodiments, the compound of Formula I has formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0128]

[0129] or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, n is 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3.

[0131] In some embodiments, R3is selected from halo, C1-3 alkyl, and C1-3 alkoxy. In some embodiments, R3is selected from halo and C1-3 alkoxy.

[0132] In some embodiments, R3is halo. In some embodiments, R3is C1-3 alkoxy. In some embodiments, n is 1 and R3is halo. In some embodiments, n is 2 and each R3is halo. In some embodiments, n is 2, one R3is halo, and the other R3is C1-3 alkoxy. In some embodiments, n is 2 and each R3is C1-3 alkoxy.

[0133] In some embodiments, the compound of Formula I has formula:

[0134]

[0135] or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the compound of Formula I has formula:

[0137]

[0138] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0139] or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the compound of Formula I is selected from any one of the following compounds:

[0141]

[0142] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0143]

[0144] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0145]

[0146] p,

[0147]

[0148] p,Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0149] or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, this document provides a compound of formula:

[0151]

[0152] or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, this document provides a compound of formula:

[0154]

[0155] or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, this document provides a compound of formula:

[0157]

[0158] or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0159] In some embodiments, this document provides a compound of formula:

[0160]

[0161] or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, this document provides a compound of formula:

[0163]

[0164] or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, this document provides a compound of formula:

[0166]

[0167] or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, this document provides a compound of formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0169]

[0170] or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, this document provides a compound of formula:

[0172]

[0173] (GPHR312849), or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, this document provides a compound of formula:

[0175]

[0176] or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, this document provides a compound of formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0178]

[0179] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, this document provides a compound of formula:

[0181]

[0182] or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, this document provides a compound of formula:

[0184]

[0185] (Compound Bl), or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0186] In some embodiments, this document provides a compound of formula:

[0187]

[0188] (Compound B2), or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, this document provides a compound of formula:

[0190]

[0191] (Compound B3), or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, this document provides a compound of formula:

[0193]

[0194] or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0195] In some embodiments, this document provides a compound of formula:

[0196]

[0197] (Compound B5),

[0198] or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments, this document provides a compound of formula:

[0200]

[0201] (Compound B6),

[0202] or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, a salt of a compound of Formula I, Group I, and / or Group II can be 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, for use as described herein. In some cases, a sGC agonist of Formula I, Group I, and / or Group II can be a pharmaceutically acceptable acid addition salt of a sGC agonist of Formula I, Group I, and / or Group II.

[0204] In some cases, acids commonly used to form pharmaceutically acceptable salts of a sGC agonist of Formula I, Group I, and / or Group II can 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 paratoluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamicAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0205] 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, P-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In some cases, 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.

[0206] In some cases, bases commonly used to form pharmaceutically acceptable salts of a sGC agonist of Formula I, Group I, and / or Group II can 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 hydroxylsubstituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Cl-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 cases, a compound of Formula I, Group I, and / or Group II, or a pharmaceutically acceptable salt thereof, can be substantially isolated.

[0207] A sGC agonist of Formula I, Group I, and / or Group II, including salts thereof, can be prepared using organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. For example, appropriate synthetic protocols can be selected and implemented to synthesize the sGC agonists of Formula I, Group I, and / or Group II described herein.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0208] Suitable synthetic methods of starting materials, intermediates and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vol. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vol. 1-49 (J. Heterocyclic Chem.. 1964-2012); Carreira et al. (Ed.) Science of Synthesis, Vol. 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, 2nd Edition, 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); and Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0209] The reactions for preparing the compounds of Formula I, Group I, and / or Group II provided herein can be carried out in suitable solvents that 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.

[0210] Preparation of the compounds of Formula I, Group I, and / or Group II 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).

[0211] Selected definitions

[0212] As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0213] At various places in this document, substituents of compounds of Formula I, Group I, and / or Group II are disclosed in groups or in ranges. It is specifically intended that the subject matter include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, Cs alkyl, and Ce alkyl.

[0214] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0215] 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 carbons.

[0216] Examples include Ci-4, C1-6, and the like.

[0217] As used herein, the term “Cn-m alkyl”, 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, / / -propyl, isopropyl, / / -butyl, tert-butyl, isobutyl, ec-butyl; higher homologs such as 2-methyl-l -butyl, / / -pentyl, 3-pentyl, / / -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.

[0218] As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l 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.

[0219] 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., / / -propoxy and isopropoxy), butoxy (e.g., / / -butoxy and tert-Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0220] butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0221] 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.

[0222] 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 “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.

[0223] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0224] The compounds of Formula I, Group I, and / or Group II described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of Formula I, Group I, and / or Group II that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds of Formula I, Group I, and / or Group II described herein, and all such stable isomers are contemplated. Cis and trans geometric isomers of the compounds of Formula I, Group I, and / or Group II provided herein are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound of Formula I, Group I, and / or Group II has the (R) -configuration. In some embodiments, the compound of Formula I, Group I, and / or Group II has the (S)-configuration.

[0225] Compounds of Formula I, Group I, and / or Group II provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomericAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0226] protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.

[0227] Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0228] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0229] EXAMPLES

[0230] Example 1 - DDAH1 expression is increased in high plaque renal stone patients and protects against renal damage in hypertension Human Tissue Samples

[0231] Papillary biopsies were obtained from calcium oxalate stone patients undergoing percutaneous stone removal procedures as described elsewhere (Wang et al., Clin. J. Am. Soc. Nephrol., 9:1757-1763 (2014)). Control biopsies were obtained from individuals undergoing urologic procedures that did not have a history of kidney stone disease.

[0232] Alizarin Red Staining

[0233] Frozen cross-sections (10 micron thickness) were fixed in cold normal buffered formalin for 10 minutes and subsequently washed in PBS for 5 minutes. Sections were then incubated for approximately 5 minutes in Alizarin Red (Sigma Aldrich) stain. Following Alizarin Red incubation, slides were dehydrated in acetone for 10-20 seconds, then incubated for 10-20 seconds in an acetone-xlyenes mixture, and then submersed in xylenes for 10-20 seconds. Lastly, slides were mounted in a xylene mounting medium (Protocol) and imaged using brightfield microscopy (Olympus). Adobe Photoshop was utilized to semi-quantitate and analyze calcium positive stained regions, as described elsewhere (Roos et al., Am. J. Physiol. Heart Circ. Physiol., 305: H1428-1439 (2013)).Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0234] Quantitative Real-Time RT-PCR

[0235] Quantitative real-time PCR was performed on a StepOne Plus RT-PCR machine (Applied Biosystems). Gene expression for DDAH isoforms, ADMA transporters (SLC7A2), osteogenic pathways, and USF-1 related genes were measured using TaqMan Gene Expression Assay primers (Life Technologies). Gene expression levels were normalized by GADPH and hypoxanthine phosphoribosyltransferase 1 (HPRT1), both commonly used housekeeper genes and expressed using the AACt method.

[0236] Statistical analyses

[0237] Between-group differences were detected using unpaired, Bonferroni-corrected t-tests in GraphPad Prism Software. All data are expressed as mean ± SE.

[0238] Results

[0239] In order to understand differences in ADMA in synthesizing or degrading enzymes in renal tissue, papillary biopsy tissue was acquired from patients undergoing clinically-indicated renal stone removal surgery. Papillary tissue from all subjects with renal stones was characterized clinically as having large (>5% papillary surface area) amounts of Randall’s plaque. While DDAH1 expression was increased in high plaque renal stone patients, paralleling observations in calcified aortic valves, unlike the calcified valves, expression of DDAH2 and PRMT1 were increased in the high plaque stone patients (Figure 1). Similar to observations in human aorta, expression of SLC7A2 was not increased in high plaque renal stone patients (Figure 1). Altogether, these results demonstrate that the coordinated upregulation of both DDAH1 and DDAH2 represents an adaptive response to increases in circulating ADMA (and potential augmented local ADMA synthesis by PRMT1).

[0240] Example 2 - Loss of sGC signaling results in significant increases in renal stone formation

[0241] This Example identifies nitric oxide signaling as a modulator of ectopic calcification in kidney tissues. Genetic inactivation of enzymes in pathways that regulate nitric oxide signaling led to loss of sGC signaling, resulting in significantAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0242] increases in renal stone formation in mice, a phenomenon that is typically extremely rare.

[0243] Animals

[0244] To experimentally alter DDAH1 levels, low density lipoprotein receptordeficient, apolipoprotein B100-only (LA) mice that were either wild-type (D+ / +) or heterozygous (D+ / -) for DDAH1 were used. Mice were studied following six months of Western diet feeding (TD88137, Harlan Teklad). This model faithfully recaptures multiple phenotypic and molecular changes observed in tissues from aged humans with end-stage disease (Miller et al., Arterioscler Thromb Vase Biol 33:459-465 (2013); Weiss et al., Circulation 114:2065-2069 (2006)). Littermate-matched pairs were studied at each time point whenever possible. Animals were euthanized using intraperitoneal injection of pentobarbital sodium (>100 mg / kg).

[0245] Circulating glucose and ADMA levels

[0246] Mice were fasted for 12 hours prior to euthanasia. Whole blood glucose was measured at the time of sacrifice using a point-of-care device (AccuChek). Plasma samples were collected at the time of sacrifice and stored at -80°C. Plasma ADMA concentration was measured using ELISA / EIA kits (Immundiagnostik AG).

[0247] Renal function

[0248] Plasma samples were collected from centrifugation of whole blood. The BUN was measured by pHOx Ultra (Nova Biomedical, Waltham, MA).

[0249] Blood pressure (in vivo)

[0250] Systolic blood pressure was measured non-invasively at six month time point using a tail-cuff method (CODA system, Kent Scientific). More specifically, blood pressure was measured for 5 consecutive days, with the first 3 days considered to be “acclimatization” to the stress of gentle restraint, and the mean of systolic blood pressure measurements during the last two days being used for data analysis.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0251] Micro-computed tomography (ex vivo)

[0252] Changes in renal calcification / stone formation were evaluated using formalin-fixed, intact kidneys ex vivo using SCANCO viva CT 40 (SCANCO Medical AG, Switzerland). In brief, whole kidneys were placed in a saline-filled tube and were imaged in entirety in 10 μm sections with 45 kVp and 177mA. This allowed for subsequent reconstruction of the entire kidney in 3 dimensions, at which point the number of calcified nodules were manually counted by individuals blinded to each treatment group.

[0253] Quantitative Real-Time RT-PCR

[0254] Quantitative real-time PCR was performed on a StepOne Plus RT-PCR machine (Applied Biosystems). Gene expression for DDAH isoforms, ADMA transporters (SLC7A2), osteogenic pathways, and USF-1 related genes were measured using TaqMan Gene Expression Assay primers (Life Technologies). Gene expression levels were normalized by GADPH and hypoxanthine phosphoribosyltransferase 1 (HPRT1), both commonly used housekeeper genes, and expressed using the AACt method (Table 1).

[0255] Table 1. Primer sets used for gene expression assays. All primer sets were purchased from Life Technologies.

[0256]

[0257] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0258] Immunohistochemistry

[0259] Murine descending thoracic aorta (1-2 mm length), aortic valve, and kidney were embedded in tissue freezing medium (Triangle Biomedical Sciences). Cross-sections of the frozen embedded tissue were subsequently cryosectioned (10 μm thickness), and used for histological and immunohistochemical analyses. Osterix (1:500 dilution, AbCam), USF-1 (1:200 dilution, AbCam), and pSMADl / 5 / 8 (1:100 dilution, Cell Signaling Technology) primary antibodies were used on individual slides and co-stained with species matched Alexa Fluor 647 secondary antibodies as noted in Table 2. Primary antibody incubation duration was 24 hours for USF-1 and pSMADl / 5 / 8 experiments (4° C) and one hour incubation for osterix (room temperature), and secondary antibody incubation duration was 1 hour (room temperature). Sections were mounted in ProLong Gold DAPI solution and then imaged on a Zeiss 780 LSM confocal microscope at 20x magnification. Subsequently, images were quantified and analyzed using the software Image J (NIH).

[0260] Table 2. Antibodies used for immunohistochemistry / immunofluorescence experiments. All antibody sets were purchased from Life Technologies.

[0261]

[0262] *CST, Cell Signaling Technology; LT, Life Technologies

[0263] Statistical analyses

[0264] Between-group differences were detected using unpaired, Bonferroni-corrected t-tests in GraphPad Prism Software. All data are expressed as mean ± SE.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0265] Results

[0266] To determine whether reducing DDAH1 increases propensity for mice to develop renal stones, kidney tissue from LA-D+ / +and LA-D+ / -mice were examined. In line with previous reports suggesting that rodents are resistant to development of renal stones (Billbault & Haymann, World J Nephrol 5:189-194 (2016); Kahn & Glenton, J Urol 184: 1189-1196 (2010)), LA-D+ / +mice did not develop evidence of ectopic calcified foci in any kidneys imaged. In contrast, all LA-D+ / _mice developed evidence of multiple, small ectopic calcified foci (Figure 2). Despite the increased blood pressure and microscopic calcifications observed in LA-D+ / -mice, evidence of overt end organ / kidney dysfunction was not observed in this model as blood urea nitrogen and plasma electrolytes were normal (Figure 3).

[0267] Interestingly, while the calcified renal foci in LA-D+ / -mice were not associated with increases in canonical BMP signaling (e.g., p-SMADl / 5 / 8 levels in Figure 4A), immunofluorescence of Osterix was nearly doubled in these regions (Figure 4B), which was consistent with previous reports of osteogenic signaling near renal calcification induced in rodents following oral administration of the oxalate precursor hydroxy-L- proline (Kahn et al., Kidney Int 70:914-923 (2006)). After confirming lack of SMAD1 / 5 / 8 target gene upregulation in these tissues (Figure 4C), USF-1 immunofluorescence was subsequently evaluated, and marked increases near calcified foci were found (Figure 5 A). While expression of SPP1 was not increased (Figure 5B), the USF-1 target gene alkaline phosphatase was significantly upregulated (Figure 5B). Compared with pSMADl / 5 / 8 (Figure 5C), USF1 expression (Figure 5D) showed a higher correlation with levels of tissue calcification. Furthermore, while protein levels of SPP1 were not significantly increased in kidney tissue (Figure 6A), expression of TRAP was significantly elevated in LA-D+ / -compared to LA-D+ / +littermates independent of changes in mRNA levels (Figures 6B-6C). When combined with prior observations that SPP1 is involved in the prevention of renal stone formation in mice (Mo et al., Am. J. Physiol. Renal Physiol., 293: F1935-1943 (2007); Wesson et al., J. Am. Soc. Nephrol., 14:139-147 (2003)), these results demonstrate that reductions in DDAH1 and / or increases in ADMA may contribute to an SPP1 / TRAP imbalance that actively contributes to ectopic calcium accumulation in renal tissues.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0268] Collectively, these data demonstrate that upregulation of DDAH1 levels in LA-D+ / - mouse kidney tissue is an adaptive response that protects against renal stone formation, and can be used to prevent non-osteogenic renal stone formation through suppression of USF-1 and subsequent reductions in expression of alkaline phosphatase. These results also demonstrate that sGC agonists of Formula I, Group I, and / or Group II can be used to reduce formation of one or more renal stones within mammals and / or to slow progression of one or more renal stones within mammals, in some cases, by restoring impaired nitric oxide signaling.

[0269] Example 3 - Compound Synthesis

[0270] Compounds 1 and 2 were prepared by methylation of 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)-7V-(4-(piperidin-l-ylsulfonyl)phenyl)benzamide (see, e.g., International Patent Application Publication No. W02000 / 002851). See, Scheme 1.

[0271] Scheme 1:

[0272]

[0273] Compound 3 was prepared from previously reported carboxylic acid (International Patent Application Publication No. W02000 / 002851) and commercially available N-methyl-4-(morpholinosulfonyl)aniline by using HATU as an amide coupling agent. See, Scheme 2.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0274]

[0275] 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)- / V-methyl-7V-(4- (morpholinosulfonyl)phenyl)benzamide (GPHR312768)

[0276] Results: m / z: ESI / APCI [M+H]+: 590.1

[0277]

[0278] 5-chloro-2-((5-chloro-N-methylthiophene)-2-sulfonamido)-N-methyl-N-(4- (morpholinosulfonyl)phenyl)benzamide (GPHR312845)

[0279] Results: m / z: ESI / APCI [M+H]+: 604.3

[0280]

[0281] 5-chloro-2-((5-chloro-N-methylthiophene)-2-sulfonamido)-N-(4-(morpholinosulfonyl)phenyl)benzamide (GPHR312844)

[0282] Results: m / z: ESI / APCI [M+H]+: 590.1

[0283]

[0284] Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0285] Compounds 4-9 were prepared by following the standard procedures (International Patent Application Publication No. W02000 / 002851) by employing commercially available reagents.

[0286] 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)-N-(4-sulfamoylphenyl)benzamide (GPHR312850)

[0287] Results: m / z: ESI / APCI [M+H]+: 505.9

[0288]

[0289] (R)-5-chloro-2-((5-chlorothiophene)-2-sulfonamido)-N-(4-((3-hydroxypyrrolidin-l-yl)sulfonyl)phenyl)benzamide (5, GPHR312847)

[0290] Results: m / z: ESI / APCI [M+H]+: 576.1

[0291]

[0292] (S)-5-chloro-2-((5-chlorothiophene)-2-sulfonamido)-N-(4-((3-hydroxypyrrolidin-l-yl)sulfonyl)phenyl)benzamide (6)

[0293] Results: m / z: ESI / APCI [M+H]+: 576.0

[0294]

[0295] 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)-N-(4-(pyrrolidin-l-ylsulfonyl)phenyl)benzamide (7, GPHR312849)Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0296] Results: m / z: ESI / APCI [M+H]+: 561.0

[0297]

[0298] 5-chloro-2-((4-fluorophenyl)sulfonamido)-N-(4- (morpholinosulfonyl)phenyl)benzamide (8, GPHR312859)

[0299] Results: m / z: ESI / APCI [M+H]+: 554.1

[0300]

[0301] Compounds 10 was prepared by the cycloaddition reaction of commercially available acetylene derivative and azide obtained according to a previously reported procedure (Sanphanya et al., Bioorg. Med. Chem. Lett., 23(10):2962-7 (2013)).

[0302] Compound 11 was derived from compound 10 by reacting with 5-chloro-2-methylsulfonyl chloride (Scheme 3). Acylation of compound 10 in pyridine / DMF

[0303] provided compound 12.

[0304] Scheme 3:

[0305]

[0306] 4-chloro-2-(1-(4-(morpholinosulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)aniline (10, GPHR312854)

[0307] Results: m / z: ESI / APCI [M+H]+: 420.3Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0308]

[0309] 5-chloro-N-(4-chloro-2-(1-(4-(morpholinosulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)thiophene-2-sulfonamide (11, GPHR312770)

[0310] Results: m / z: ESI / APCI [M+H]+: 600.1

[0311]

[0312] 11

[0313] Compound 12 was prepared by the cycloaddition reaction of commercially

[0314] available acetylene derivative and 2-azido-4-chloroaniline (obtained by Cu-catalyzed coupling of azide with commercially available 2-iodo-4-chloroaniline). Compound 14

[0315] was derived from compound 13 by reacting with 5-chloro-2-methylsulfonyl chloride (Scheme 4).

[0316] Scheme 4:

[0317]

[0318] 4-chloro-2-(4-(4-(morpholinosulfonyl)phenyl)-1H-1,2,3-triazol-1-yl)aniline (12, GPHR312855)

[0319] Results: m / z: ESI / APCI [M+H]+: 420.1Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0320]

[0321] 5-chloro-N-(4-chloro-2-(4-(4-(morpholinosulfonyl)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)thiophene-2-sulfonamide (13, GPHR312771)

[0322] Results: m / z: ESI / APCI [M+H]+: 600.2

[0323]

[0324] N-(4-chloro-2-(4-(4-(morpholinosulfonyl)phenyl)-1H-1,2,3-triazol-1-yl)phenyl)acetamide (GPHR312858)

[0325] Results: m / z: ESI / APCI [M+H]+: 462.1

[0326]

[0327] 4-(morpholinosulfonyl)benzonitrile was treated with hydroxylamine hydrochloride and sodium carbonate in EtOH to obtain N-hydroxy-4-(morpholinosulfonyl)benzimidamide that upon reacting with the activated 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)benzoic acid under microwave conditions provided compound 15 (Scheme 5).Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0328] Scheme 5:

[0329]

[0330] 5-chloro-N-(4-chloro-2-(3-(4-(morpholinosulfonyl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)thiophene-2-sulfonamide (15, GPHR312853)

[0331] Results: m / z: ESI / APCI [M+H]+: 601.0

[0332]

[0333] Compound 16, a hydrazide, was obtained from 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)benzoic acid and 4-(4-morpholinylsulfonyl)benzoyl chloride using a previously known procedure. Compound 17 was obtained by treatment of compound 16 with POCl₃ under reflux in toluene. Treatment of compound 16 with Lawesson’s reagent under reflux resulted in compound 18, a 1,3,4-thiadiazole. Scheme 6.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0334] Scheme 6:

[0335]

[0336] 5-chloro-N-(4-chloro-2-(2-(4-((tetrahydro-2H-pyran-4-yl)sulfonyl)benzoyl)hydrazine-l-carbonyl)phenyl)thiophene-2-sulfonamide (16, GPHR312857)

[0337] Results: m / z: ESI / APCI [M+H]+: 619.1

[0338]

[0339] 5-chloro-N-(4-chloro-2-(5-(4-(morpholinosulfonyl)phenyl)-l,3,4-oxadiazol-2-yl)phenyl)thiophene-2-sulfonamide (17, GPHR312772)

[0340] Results: m / z: ESI / APCI [M+H]+: 601.3

[0341]

[0342] 5-chloro-N-(4-chloro-2-(5-(4-(morpholinosulfonyl)phenyl)-l,3,4-thiadiazol-2-yl)phenyl)thiophene-2-sulfonamide (18, GPHR312856)

[0343] Results: m / z: ESI / APCI [M+H]+: 616.9Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0344]

[0345] 5-chloro-2-((5-chlorothiophene)-2-sulfonamido)benzoic acid was treated with oxalyl chloride followed by hydrazine to obtain hydrazinamide intermediate that upon heating with 4-(4-morpholinylsulfonyl)benzonitrile in nBuOH at 150°C provided compound 19. Scheme 7.

[0346] Scheme 7:

[0347]

[0348] 5-chloro-N-(4-chloro-2-(5-(4-(morpholinosulfonyl)phenyl)-4H-l,2,4-triazol-3-yl)phenyl)thiophene-2-sulfonamide (GPHR312773)

[0349] Results: m / z: ESI / APCI [M+H]+: 600.2

[0350]

[0351] Example 4 - Treating Renal Stones

[0352] A human identified as having a renal stone is administered a composition containing 0.01 mg to 400 mg (e.g., 10 mg to 250 mg) of an sGC agonist of Formula I, Group I, and / or Group II daily. After administering the sGC agonist of Formula I, Group I, and / or Group II daily for 30 days, the renal stone within the human is reduced in size.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355

[0353] Example 5 - Preventing Development of Renal Stones A human identified as having had prior renal stones is administered a composition containing 0.01 mg to 400 mg (e.g., 10 mg to 250 mg) of an sGC agonist of Formula I, Group I, and / or Group II daily. While receiving daily administration of the sGC agonist of Formula I, Group I, and / or Group II daily, the human does not develop any new renal stones.

[0354] OTHER EMBODIMENTS

[0355] 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

Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355WHAT IS CLAIMED IS:

1. A method for reducing renal stone formation, wherein said method comprises administering a composition comprising one or more sGC agonists of Formula I, Group I, and / or Group II to a mammal having one or more renal stones or likely to develop one or more renal stones, wherein formation of a renal stone within said mammal is reduced.

2. The method of claim 1, wherein said mammal is a human.

3. The method of any one of claims 1-2, wherein formation of a renal stone within said mammal is delayed.

4. The method of any one of claims 1-2, wherein formation of a renal stone within said mammal is delayed for at least 6 months.

5. The method of any one of claims 1-4, wherein said mammal is a mammal having one or more renal stones.

6. The method of any one of claims 1-5, wherein said mammal is a mammal likely to develop one or more renal stones.

7. A method for slowing renal stone progression or enlargement, wherein said method comprises administering a composition comprising one or more sGC agonists of Formula I, Group I, and / or Group II to a mammal having one or more renal stones, wherein progression or enlargement of at least one of said one or more renal stones within said mammal is reduced.

8. The method of claim 7, wherein said mammal is a human.

9. The method of any one of claims 7-8, wherein progression of at least one of said one or more renal stones within said mammal is slowed by at least 10 percent.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-35510. The method of any one of claims 7-8, wherein progression of at least one of said one or more renal stones within said mammal is slowed by at least 25 percent.

11. The method of any one of claims 7-8, wherein progression of at least one of said one or more renal stones within said mammal is slowed by at least 50 percent.

12. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is selected from NH2, morpholinyl, piperidinyl, pyrrolidinyl, and 2-oxa-6-azaspiro[3.3]heptanyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, COOH, and CH2COOH;X1is a 5-membereed heteroaryl, optionally substituted with halo, OH, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;R2is selected from H, C(=O)C1-3 alkyl, C(=O)C1-3 haloalkyl, and S(=O)2R4; R4is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, CN, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;n is 1, 2, or 3; andeach R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy.

13. The compound of claim 12, wherein X1is a 5-membereed heteroaryl.

14. The compound of claim 12, wherein X1is selected from 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, and 1,3,4-thiadiazolyl.Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-35515. The compound of claim 12, the compound of Formula I has formula:or a pharmaceutically acceptable salt thereof.

16. The compound of claim 12, the compound of Formula I has formula:or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 12-16, wherein R2is H.

18. The compound of any one of claims 12-16, wherein R2is selected from C(=O)Ci-3 alkyl and C(=O)Ci-3 haloalkyl.

19. The compound of any one of claims 12-16, wherein the compound has formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 12-19, wherein R4is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, CN, and C1-3 alkoxy.

21. The compound of claim 20, wherein the compound has formula:or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 12-21, wherein n is 1 or 2.

23. The compound of any one of claims 12-22, wherein R3is selected from halo, C1-3 alkyl, and C1-3 alkoxy.

24. The compound of any one of claims 12-19, wherein the compound has formula:or a pharmaceutically acceptable salt thereof.

25. The compound of claim 24, wherein the compound has formula:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355or a pharmaceutically acceptable salt thereof.

26. The compound of claim 12, wherein the compound has formula selected from:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355p, ndAttorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355(Compound A6), or a pharmaceutically acceptable salt thereof.

27. A compound selected from:Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355p,Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355Attorney Docket No.: 07039-2392WO1 / 2021-421 / 2019-355or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound of any one of claims 12-27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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