# US 2019/0167679 A1 · sGC STIMULATORS

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- Number: US 2019/0167679 A1
- Document ID: US20190167679A1
- Status: Published application
- Kind: A1
- Application number: 16/178,771
- Filed: 2018-11-02
- Published: 2019-06-06
- Earliest claimed: 2013-03-15
- Assignees: Ironwood Pharmaceuticals, Inc.
- Applicants: Ironwood Pharmaceuticals, Inc.
- Inventors: Takashi Nakai; Joel Moore; Nicholas Robert Perl; Rajesh R. Iyengar; Ara Mermerian; G-Yoon Jamie Im; Thomas Wai-Ho Lee; Colleen Hudson; Glen Robert Rennie; James Jia; Paul Allan Renhowe; Timothy Claude Barden; Xiang Y. Yu; James Edward Sheppeck; Karthik Iyer; Joon Jung; George Todd Milne; Kimberly Kafadar Long; Mark G. Currie
- Web page: https://patentgrep.com/patent/US20190167679A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 451/02: containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D 471/04: Ortho-condensed systems
- C07D 471/08: Bridged systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 495/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Compounds of Formulae I′ and I are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

## Claims

### Claim at position 1

-169. (canceled)

### Claim 170

A method of treating diabetic nephropathy in a subject in need of treatment, comprising administering a therapeutically effective amount of compound I-324
or a pharmaceutically acceptable salt thereof, to the subject in need of treatment.

### Claim 171 (depends on 170)

The method of claim 170, further comprising administering an effective amount of one or more additional therapeutic agents to the subject.

### Claim 172 (depends on 171)

The method of claim 171, wherein the one or more additional therapeutic agents are selected from anti-diabetic agents, SGLT-2 inhibitors, neprilysin inhibitors, angiotensin receptor blockers (ARB), angiotensin converting enzyme (ACE) inhibitors, mineralocorticoid receptor (MR) antagonists, and endothelin receptor antagonists (ERAs).

### Claim 173 (depends on 172)

The method of claim 172, wherein the one or more additional therapeutic agents are anti-diabetic agents selected from insulin and insulin mimetics, sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinone compounds, insulin sensitizers, insulin secretagogues, GLP-1 receptor agonists, incretin mimetics, amylin analogues, glucose lowering agents, dipeptidyl peptidase IV (DPP4) inhibitors, AVE-0277, Alum-GAD, BHT-3021, IBC-VS01, and other drugs in development for the treatment of diabetes.

### Claim 174 (depends on 173)

The method of claim 173, wherein the sulfonylureas are selected from glyburide, glybenclamide, glipizide, gliclazide, gliquidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, and tolazimide; the α-glucosidase inhibitors are selected from acarbose, epalrestat, voglibose, and miglitol; the thiazolidinone compounds are selected from rosiglitazone, troglitazone, ciglitazone, pioglitazone, and englitazone; the insulin sensitizers are selected from pioglitazone and rosiglitazone; the insulin secretagogues are selected from repaglinide, nateglinide, and mitiglinide; the GLP-1 receptor agonists are selected from lixisenatide, albiglutide, dulaglutide, ZYD-1, ZYOG-1; the incretin mimetics are selected from exanatide and liraglutide; the amylin analogue is pramlintide; the dipeptidyl peptidase IV inhibitors are selected from sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alogliptin benzoate/metformin hydrochloride, anagliptin, teneligliptin, atorvastatin calcium/glimepiride, empagliflozin/linagliptin, gemigliptin, sitagliptin phosphate monohydrate/pioglitazone hydrochloride, sitagliptin/atorvastatin calcium, PSN-491, irbesartan/atorvastatin, and atorvastatin calcium/losartan potassium; and other drugs in development for the treatment of diabetes are selected from dapagliflozin, alogliptin benzoate/metformin hydrochloride, anagliptin, insulin degludec, insulin degludec/insulin aspart, insulin human (rDNA origin) inhalation powder, recombinant human insulin, teneligliptin, albiglutide, aleglitazar, atorvastatin calcium/glimerpiride, BYK-324677, balaglitazone, CSG-452, canagliflozin, canagliflozin/metformin hydrochloride, dapagliflozin/metformin hydrochloride, empagliflozin, empaglifozin/Linagliptin, gemigliptin, hepatic-directed vesicle insulin, human isophane insulin, IN-105, insulin degludec/liraglutide, insulin glargine, ipragliflozin L-proline, LY-2605541, LY-2963016, lixisenatide/insulin glargine, lobeglitazone sulfate, luseogliflozin, otelixizumab, tanolazine, sitagliptin phosphate monohydrate/pioglitazone hydrochloride, sitagliptin/atorvastatin calcium, TAK-875, TT-401, ZYH-2, ZYO-1, 701645, 701499, 743300, 448661, AD-1, colesevelam hydrochloride, DBPR-108, nodlin, PSN-491, and tolimidone.

### Claim 175 (depends on 173)

The method of claim 173, wherein the one or more additional therapeutic agents is a metformin.

### Claim 176 (depends on 173)

The method of claim 173, wherein the one or more additional therapeutic agents is a GLP-1 receptor agonist.

### Claim 177 (depends on 172)

The method of claim 172, wherein the one or more additional therapeutic agents are SGLT-2 inhibitors selected from dapagliflozin, CSG-452, canagliflozin, canagliflozin/metformin hydrochloride, dapagliflozin/metformin hydrochloride, empagliflozin, empaglifozin/linagliptin, Ipragliflozin L-proline, and luseogliflozin.

### Claim 178 (depends on 172)

The method of claim 172, wherein the one or more additional therapeutic agents are selected from neprilysin inhibitors and angiotensin receptor blockers (ARB), wherein the neprilysin inhibitors are selected from enkephalinase inhibitors, and neutral endopeptidase (NEP) inhibitors; and wherein the angiotensin receptor blockers (ARB) are selected from losartan, valsartan, candesartan cilexetil, eprosaran, irbesartan, telmisartan, olmesartan medoxomil, azilsartan medoxomil, azilsartan, amlodipine besylate/irbesartan, azilsartan/amlodipine besilate, cilnidipine/valsartan, fimasartan, irbesartan/atorvastatin, irbesartan/trichlormethiazide, losartan potassium/hydrochlorothiazide/amlodipine besylate, pratosartan, LFF-269, atorvastatin calcium/losartan potassium, nifedipine/candesartan cilexetil, CYT006-AngQb, LCZ-696, and TAK-591, and olmesartan medoxomil.

### Claim 179 (depends on 172)

The method of claim 172, wherein the one or more additional therapeutic agents are angiotensin converting enzyme (ACE) inhibitors selected from sulfhydryl-containing agents, dicarboxylate-containing agents, phosphonate-containing agents, naturally occurring ACE inhibitors, alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril, and spirapril.

### Claim 180 (depends on 178)

The method of claim 178, wherein the sulfhydryl-containing agents are selected from captopril and zofenopril; the dicarboxylate-containing agents are selected from enalapril, ramipril, qunapril, perindopril, lisinopril, and benazepril; the phosphonate-containing agent is fosinopril; and the naturally occurring ACE inhibitors are selected from casokinins, lactokinins, lactotripeptides Val-Pro-Pro and Re-Pro-Pro produced by Lactobacillu helveticus or derived from casein.

### Claim 181 (depends on 172)

The method of claim 172, wherein the one or more additional therapeutic agents are mineralocorticoid receptor (MR) antagonists.

### Claim 182 (depends on 181)

The method of claim 181, wherein the one or more additional therapeutic agents are mineralocorticoid receptor (MR) antagonists selected from amiloride hydrochloride/spironolactone, MT-3995, and BAY-94-8862.

### Claim 183 (depends on 172)

The method of claim 172, wherein the one or more additional therapeutic agents are endothelin receptor antagonists selected from bosentan, sitaxentan, ambrisentan, acetelion-1, TBC-3711, macitentan, BQ-123, and tezosentan disodium.