EA038096B1 - USE OF sGC STIMULATORS FOR THE TREATMENT OF NONALCOHOLIC STEATOHEPATITIS (NASH) - Google Patents

Abstract

The invention relates to methods, uses, pharmaceutical compositions and kits comprising an sGC stimulator represented by formula IC or formula XY or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents, for the treatment of Nonalcoholic Steatohepatitis (NASH). The invention offers considerable advantages over other current alternative therapies targeted at delivering NO to the liver or at increasing its synthesis.

Description

Cross-reference to related claims

This application claims priority to Provisional Applications US 62/289463, filed February 1, 2016, and US 62/398872, filed September 23, 2016, the full disclosure of which is incorporated herein by reference.

Technology area

The present invention relates to methods of using soluble guanylate cyclase (sGC) stimulants and pharmaceutically acceptable salts thereof, alone or in combination with one or more additional therapeutic agents, for the treatment of non-alcoholic steatohepatitis (NASH).

Background of the invention

NASH.

Non-alcoholic steatohepatitis (NASH) is a common, often silent liver disease. It is similar to alcoholic liver disease, but occurs in people who drink little or no alcohol. Three main features characterize NASH and distinguish it from other metabolic liver diseases: abnormal accumulation or deposition of fat in the liver (liver steatosis), liver inflammation, liver damage, or damage to liver tissue (fibrosis).

Most people with NASH feel good and are unaware that they have a liver problem. However, NASH can be serious and can lead to cirrhosis, in which the liver is irreversibly damaged and traumatized and can no longer function properly. Cirrhosis can progress even further and become hepatocellular carcinoma. Approximately 10-15% of patients with histologically confirmed NASH progress to cirrhosis and its complications such as liver failure and hepatocellular carcinoma (HCC).

NASH affects 2 to 5% of Americans. Another 10 to 20% of Americans have liver fat but not liver inflammation or damage, a condition called fatty liver (or steatosis). While it is not normal to have fat in the liver, it is likely to cause little or little permanent damage on its own. If a person who drinks little or no alcohol is suspected of obesity based on blood tests or liver scans, the problem is called non-alcoholic fatty liver disease (NAFLD). If a liver biopsy is taken in this case, it will show that some people have NASH, while others have simple fatty liver (FL).

Both NASH and NAFLD are becoming more prevalent, possibly due to more obese Americans. Over the past 10 years, obesity rates have doubled in adults and tripled in children. Obesity also contributes to diabetes and high blood cholesterol, which can further worsen the health of someone with NASH.

Usually, the presence of NASH is assumed in a person who has elevated levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and triglycerides (TG) in liver function tests that are included in routine clinical blood tests. When further evaluation shows no clear cause for liver disease (such as drug use, viral hepatitis, or excessive alcohol consumption), and when liver x-rays or imaging studies show fat, NASH is suspected. The only means of confirming the diagnosis of NASH and separating it from the diagnosis of simple fatty liver is a liver biopsy. In a liver biopsy, a needle is inserted through the skin to remove a small piece of the liver. NASH is diagnosed when tissue examination with a microscope reveals fat along with inflammation and liver cell damage or fibrosis. If the tissue shows fat without inflammation or damage, simple fatty liver or NAFLD is diagnosed. An important piece of biopsy information is whether scar tissue (fibrous tissue) has developed in the liver. No blood tests or scans can reliably provide this information at this time.

NASH is usually a quiet illness with little or no symptoms. Patients generally do well in the early stages, and symptoms such as fatigue, weight loss, and weakness do not begin to be experienced until the disease progresses or cirrhosis develops. The progression of NASH can take years, even decades. The process can stop and, in some cases, reverse on its own without specific therapy. Alternatively, NASH can slowly deteriorate, causing further scarring (fibrosis) and accumulation in the liver. As the fibrosis worsens, cirrhosis develops; the liver becomes severely scarred, hardened, and cannot function normally. Not every person with NASH develops cirrhosis, but once severe scarring or cirrhosis is present, a little treatment can stop the progression. A person with cirrhosis has fluid retention, muscle wasting, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for progressive cirrhosis with liver failure, and transplantation is increasingly being performed in people with NASH. NASH is considered one of the main

- 1 038096 causes of cirrhosis in America after hepatitis C and alcoholic liver disease.

Although NASH has become more common, its root cause is still unclear. It is most common in middle-aged and overweight or obese people. Many NASH patients have elevated blood lipid levels such as cholesterol and triglycerides, and many have diabetes or pre-diabetes, but not every obese patient or not every patient with diabetes or pre-diabetes has NASH. In addition, some NASH patients are not obese, have no diabetes or prediabetes, and have normal cholesterol and lipid levels. NASH can occur without any obvious risk factor and can even occur in children. Thus, NASH is not just obesity that affects the liver.

Although the underlying mechanisms of liver injury causing NASH are unknown, several factors are possible candidates. These include insulin resistance, the secretion of toxic inflammatory proteins by fat cells (cytokines), and oxidative stress.

There are currently no specific treatments for NASH. The most important advice given to people with the condition is to reduce their weight (if obese or overweight), eat a balanced and healthy diet, increase physical activity, avoid alcohol, avoid unnecessary medications, and control blood sugar, usually through medication. for the treatment of diabetes.

Experimental approaches to be evaluated for patients with NASH include antioxidants such as vitamin E, selenium, and betaine. These drugs work by reducing oxidative stress, which appears to be increased in the liver in NASH patients. Although these substances are not known to actually help in the treatment of the disease, the results of clinical trials should become available in the next few years. Another experimental approach to treating NASH is the use of new antidiabetic drugs - even in people without diabetes or prediabetes. Most NASH patients are insulin resistant, which means that insulin normally present in the bloodstream is less effective for them at controlling blood glucose and blood fatty acid levels than for people who do not have NASH. Newer antidiabetic drugs make the body more sensitive to insulin and may help reduce liver damage in NASH patients. Research is currently underway on these drugs, including metformin, rosiglitazone and pioglitazone, obeticholic acid, or INT-767 (a dual farnesoid X receptor (FXR) and a TGR5 agonist).

NASH and the NO / cGMP pathway.

In the body, nitric oxide (NO) is synthesized from arginine and oxygen by various enzymes, nitrogen synthases (NOS) and through the sequential reduction of inorganic nitrates. Three different NOS isoforms have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; neural NOS (nNOS or NOS I) involved in neurotransmission and long-term potentiation; and constitutive endothelial NOS (eNOS or NOS III), which regulate smooth muscle relaxation and blood pressure.

Soluble guanylate cyclase (sGC) is the major NO receptor in vivo. In response to NO activation, sGC converts guanosine triphosphate (GTP) into a secondary messenger, cyclic guanosine monophosphate (cGMP). Elevated cGMP levels, in turn, modulate the activity of downstream effectors, including protein kinases such as protein kinase G (PKG), phosphodiesterase (PDE), and ion channels.

Experimental evidence from both cell and animal studies suggests that dysregulation of the NO / cGMP / PKG pathway in the liver may play a vital role in the inflammation, steatosis, and fibrosis that are characteristic of NASH (see, for example: Nitric oxide plays a crucial role in the development / progression of nonalcoholic steatohepatitis in the choline-deficient, L-amino acid-defined dietfed rat model, Fujita K. et al., Alcohol Clin Exp Res., 2010; 34 Suppl 1: S18-24 or Nitric Oxide in liver diseases, Yasuko Iwakiri et al., Trends in Pharmacol. Sci., 36 (8), 524 (2015)).

Substances targeting different steps in the NO pathway have been evaluated for the treatment of NASH primarily in animal models. For example, arginine supplementation was evaluated in the rat model of NASH induced by intralipid (IL) administration (Marwa M. Abu-Serie et al., Lipids in Health and Disease, 14 (128), 1, (2015)). NO donors such as S-nitrosothiols (e.g. S-hutpo3O-Nacetylcysteine, SNAP) have been proposed to prevent and reverse NASH in OB / OB mice (de Oliverira CP et al., J. Am. Coll. Nutri., 27 (2), 299-305 (2008)). In an animal model in rats, SNAP has also been shown to prevent the onset of NASH (de Oliverira CP et al., World J. Gastroenterol, 12 (12), 1905-1911 (2006). However, NO donors have not been approved for Human Use in NASH The NO donors nitroprusside, isosorbide dinitrate and nitroglycerin, which are used to treat certain cardiovascular diseases, are known to have limitations that prevent their long-term use, such as tolerance development and other side effects.

It has been shown that a liver-selective NO donor NCX-1000 (a derivative of ursodeoxycholic acid with NO donor properties) reverses experimental NASH in rats (Haddad Y. et al., Int. J. Hepatol. 2011; 2011: 136816 .doi: 10.4061 / 2011 / 136816.Epub 2011 Oct 16). To

- 2 038096 The same compound, when tested in humans, did not lower portal pressure in cirrhotic patients (Berzigotti A. et al., Am. J. Gastroenterol. 2010 May; 105 (5): 1094-101. Doi: 10.1038 /ajg.2009.661. Epub 2009 Nov 17). Another liver-selective NO donor, VPYRRO / NO, has been shown to protect against hepatic steatosis and improve postprandial glucose tolerance in mice fed a high fat diet (Edyta Maslak et al., Biochem Pharmacol, 93, 389-400 (2015) The use of PDE5 inhibitors (eg, sildenafil) for the treatment of hepatic steatosis in some animal models has also been reported (see, eg, Tateya et al., Diabetes, 62, 19131922 (2013)).

NO and its derivatives play an important role in both physiology and pathophysiology of the liver. Certain patterns of NO influence on the pathogenesis and progression of liver diseases were observed. Mainly, NO derived from endothelial NO synthase (eNOS) in liver sinusoidal endothelial cells (LSEC) appears to protect against disease progression, while NO derivatives of inducible NOS (iNOS) appear to promote pathological processes. It has been suggested that, under pathological conditions, iNOS produces large amounts of NO and that this is the main source of reactive nitrogen species and thus oxidative stress. It has also been suggested that the NO generated by the elevated NOS seen in liver disease may inhibit eNOS activity (which helps maintain liver homeostasis), contributing to the reduction of NO generated by eNOS and downregulating the NO-cGMP-PKG pathway.

Summary of the invention

Thus, it may be successful to activate sGC under conditions in which activation of the NO signaling pathway is impaired. SGC stimulants are compounds capable of stimulating sGC synergistically with NO as well as in an NO-independent manner. As a result, they can provide significant advantages over other existing alternative treatments aimed at delivering NO to the liver or increasing synthesis. There is a need to develop methods of treating NASH by administering sGC stimulants, especially when these sGC stimulants are able to spread predominantly in the liver.

There remains a need for new treatments for NASH. Targeting the aberrant NO-cGMP-PKG pathway using the sGC stimulator of the invention represents a novel and useful therapeutic approach for the treatment of NASH.

In one aspect, the invention provides a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an sGC stimulant or a pharmaceutically acceptable salt thereof, wherein the sGC stimulant is a compound of formula IC or a pharmaceutically acceptable salt thereof:

Formula IC where J ^B is halogen;

R ¹ represents hydrogen or C | _-6 αalkyl;

R ² represents a C _1-6 alkyl group optionally and independently having up to three substituents selected from R ^5a ;

each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, —OR ^6a , —SR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , —C (O) N ( R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) C (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a and C3 8 cycloalkyl ring, where each of said C1-6 alkyl group optionally and independently has up to 3 substituents selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -COO (C _1-4 alkyl) , —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; and each R ^{6a is} independently selected from hydrogen and C _1-6 alkyl.

In this formula, each R ^{5a is} independently selected from halogen, -CN, C1-6 alkyl, -OR ^6a , -COR ^6a , -OC (O) R ^6a , -C (O) OR ^6a , -C (O) N (R ^6a ) 2, -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) 2, - (C = O) NHOR ^6a and C3-8 cycloalkyl ring, where each of said C1-6 alkyl group is optionally and independently has up to 3 substituents selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, —OH, —NH2, —NH (C _1-4 alkyl) or —CN.

More preferably, each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, —OR ^6a , —C (O) N (R ^6a ) 2, —N (R ^6a ) C (O) R ^6a , —N (R ^6a ) 2, - (C = O) NHOR ^6a and C3 _-8 cycloalkyl ring, where each of said C _1-6 alkyl group optionally and independently has up to 3 substituents selected from halogen,

- 3 038096

C ₁ . ₄ α-alkyl, C ₁ . ₄ halogenaalkyl, —OH, —NH ₂ , —NH (C _{1. 4} alkyl) or —CN.

In one embodiment, each R ^{5a is} independently selected from CF3, —C (O) NH _2, and —OH.

In particular, the sGC stimulant can be

or a pharmaceutically acceptable salt thereof.

In another embodiment, the sGC stimulant is

or a pharmaceutically acceptable salt thereof.

According to a further embodiment of the invention, the sGC stimulant is

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an sGC stimulant or a pharmaceutically acceptable salt thereof, wherein the sGC stimulant is a compound of Formula XY

where n denotes 0 or an integer selected from 1 to 3;

each J ^{B is} independently selected from halogen, —CN, C1-6α aliphatic, —OR ^B, or C3-8 cycloaliphatic; where each of said C _1-6 α aliphatic group and each of said C _3-8 cycloaliphatic ring optionally has up to 3 substituents selected from halogen;

each R ^{B is} independently selected from hydrogen, a C1-6α aliphatic group, or a C3-8 cycloaliphatic ring; where each of said R ^B , which is a C1-6α aliphatic group, and each of said R ^B , which is a C _3-8 cycloαliphatic ring, optionally has up to 3 substituents selected from halogen;

each J ^C , if present, is independently selected from halogen;

R ¹ is hydrogen or C _1-6 αalkyl; and

R ² is C _1-6 alkyl.

Preferably n is 1;

J ^B is fluorine;

- 4 038096

J ^C is fluorine;

R ¹ is hydrogen or methyl; and

R ² is methyl or ethyl.

In one embodiment, the sGC stimulant is riociguat or vericiguat

-OMe (riotsiguat), or ° 'Me (veritsiguat).

In this case, the patient in need of the specified treatment can be an adult or a child.

According to the invention, a patient in need of said treatment is clinically obese and has been diagnosed with diabetes, or prediabetes, or metabolic syndrome.

Preferably, administration of the stimulant sGC or a pharmaceutically acceptable salt thereof results in (i) an observable or measurable decrease in the level of steatosis or abnormal accumulation of fat in the liver, (ii) an observable or measurable decrease in the degree of liver inflammation or hepatitis, (iii) an observable or measurable decrease in the degree of fibrosis, cirrhosis or sclerosis of the liver, (iv) an observable or measurable reduction in the levels of steatosis, inflammation and fibrosis of the liver, (v) an observable or measurable reduction in feelings of fatigue, (vi) an observable or measurable reduction in feelings of fatigue, an observable or measurable decrease in an increase in liver enzymes, (vii) an observable or measurable decrease in the increase in the level of inflammatory cytokines, (viii) an observable or measurable inhibition of weight loss.

In yet another aspect of the invention, the sGC stimulant is selected from one of the following or a pharmaceutically acceptable salt thereof

- 5 038096

- 6 038096

Brief description of graphic materials

FIG. 1 illustrates fibrosis that was detected using Picrosirius Red staining in animals treated in accordance with embodiments of the invention.

FIG. 2 shows mRNA expression levels for liver fibrosis markers evaluated in this study using embodiments of the invention.

FIG. 3 illustrates mRNA expression levels for markers of liver inflammation evaluated in this study using embodiments of the invention.

FIG. 4 shows the results of trichrome staining and a-SMA deposition in the liver of MCD / HFD mice treated in accordance with embodiments of the invention.

FIG. 5 compares the ratio of liver tissue mass to total body weight (graph on the left) and the decrease in the percentage of white adipose tissue in the liver (graph on the right) in animals of the control group compared to animals treated in accordance with embodiments of the invention.

FIG. 6 shows a comparison of the inflammatory infiltrate determined by immunohistochemistry F4 / 80 in the liver of control animals compared to animals treated in accordance with embodiments of the invention.

FIG. 7 illustrates a comparison of the overall NAS (steatosis + inflammation + ballooning) score in the liver of control animals versus animals treated in accordance with embodiments of the invention.

FIG. 8 shows slides stained with Sirius red showing the accumulation of collagen in the liver of control animals compared to animals treated in accordance with embodiments of the invention.

FIG. 9 shows the percentage of collagen accumulation in control animals and animals treated in accordance with embodiments of the invention.

Detailed description

In the following, reference is made to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and claims. While the invention has been described in conjunction with the embodiments listed, it should be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein, but includes any methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. In the event that one or more references to literature, patents or similar materials differ or contradict this application, including, but not limited to, the specified terms, the use of the term, the described methods or the like,

- 7 038096 this application takes precedence. The compounds described herein can be defined by their chemical structures and / or chemical names. When a compound is characterized by both chemical structure and chemical name, the chemical structure is critical for establishing the identity of the compound.

Therapeutic methods.

The terms disease, disorder, and condition may be used interchangeably herein when referring to a medical or pathological condition mediated by sGC, cGMP and / or NO.

As used herein, the terms subject and patient are used interchangeably to refer to an animal (e.g., a bird, such as a chicken, quail, or turkey, or a mammal), preferably a mammal, including non-primates (e.g., a cow, pig, horse, sheep, rabbit , guinea pig, rat, cat, dog and mouse) and primates (eg, monkey, chimpanzee, and humans), and more preferably humans. In one embodiment, the subject is a non-human animal, such as a farm animal (eg, horse, cow, pig, or sheep) or a companion animal (eg, dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject or patient is a human.

As used herein, the term patient in need is used to refer to a patient suffering from NASH. In some embodiments, the patient in need is a patient with NASH, or who has been diagnosed with NASH, or who is genetically predisposed to developing NASH, or who may be predisposed to developing NASH because he or she has metabolic syndrome, obesity, diabetes, or prediabetes. In other embodiments, the patient in need is a person who has been tested and found to display clinical findings consistent with NASH (abnormal liver fat accumulation, liver inflammation and liver fibrosis), even if he has or she may not show any of the physical symptoms of NASH. In some cases, a patient in need will show symptoms of NASH, although the diagnosis has not yet been established. In some embodiments, the patient in need thereof is a patient suffering from metabolic syndrome, obesity, diabetes, or prediabetes.

As used herein, the term treat, treat, or cure in relation to a disorder or disease refers to amelioration or elimination of the cause and / or consequences or symptoms or clinical manifestations of the disorder or disease. More specifically, as used herein, the terms treat, treat, and cure refer to reducing or improving or slowing the progression, severity and / or duration of NASH. In some embodiments, the terms treat, treat, and cure refer to reducing, improving, or slowing the progression, severity, and / or duration of one or more physical symptoms or clinical manifestations (preferably one or more measurable physical symptoms or clinical manifestations) of a condition as a result of one or more multiple therapies (eg, the sGC stimulant or a pharmaceutically acceptable salt thereof, either alone or in combination therapy). In some embodiments, treatment may result in complete or partial relief of the disease (i.e., as determined by normalizing clinical parameters, outcomes, or manifestations associated with the disease). In other embodiments, treatment can slow or arrest the progression of NASH in cirrhosis.

In some embodiments, the terms treat, treat, and cure refer to delaying the onset of NASH in a patient in need thereof. In some embodiments, the terms treat, treat, and cure refer to delaying the onset of a physical symptom or set of physical symptoms or clinical manifestations or outcomes associated with NASH. In other embodiments, the terms treat, treat, and cure refer to delaying the onset of a physical symptom or set of physical symptoms or clinical manifestations or outcomes associated with cirrhosis. In some embodiments, the clinical manifestation of cirrhosis is determined by histology.

In some embodiments, treatment results in an improvement in at least one measurable physical symptom of NASH, such as, for example, weight loss, weakness, or fatigue. In other embodiments, treatment results in an improvement in at least one clinical parameter or detection of NASH, such as abnormal liver fat accumulation, liver fibrosis as determined by biopsy, liver inflammation, abnormal liver enzyme levels, abnormal inflammatory cytokine levels, or NAS.

In other embodiments, treatment reduces, inhibits, or slows the progression of NASH, either physically, for example, by stabilizing a measurable symptom or set of symptoms (such as fatigue, weight loss, or weakness), or clinically / physiologically, for example, stabilizing a measurable parameter such as abnormal accumulation of fat in the liver, abnormal levels of liver enzymes, abnormal levels of inflammatory mark

- 8 038096 liver moat, abnormal liver biopsy results, NAS score, or both. In another embodiment, the treatment can also result in preventing the cause and / or consequences of the clinical manifestation of NASH or one of the symptoms resulting from NASH before the disease or disorder is fully manifested.

In some embodiments, treatment results in increased survival or survival time in the NASH patient. In some embodiments, the treatment results in a reduction in the possible need for liver transplantation for a patient with NASH. In other embodiments, the treatment eliminates the need for the NASH patient to undergo liver transplantation. In other embodiments, this results in a reduced chance that the NASH patient will develop cirrhosis. In other embodiments, this results in prevention of progression of cirrhosis as determined by histology.

Treatment can include administering a compound, composition, or kit described herein to a patient diagnosed with NASH, and can include administering the compound to a patient who is asymptomatic. In contrast, treatment may include administering a compound, composition, or kit to a patient at risk of developing NASH or to a patient who has reported one or more physiological symptoms of a disease, although a diagnosis of the disease may not have been established.

The term therapeutically effective amount, as used herein, means that amount of an active compound or pharmaceutical agent that elicits a biological or drug response in a tissue, system, animal, or human, initiated by an investigator, veterinarian, physician, or other clinician. The therapeutically effective amount of the compound administered will be determined by such considerations, and is the minimum amount necessary to improve, cure, or treat a disease or disorder or one or more of its symptoms.

The term prophylactically effective amount refers to an amount effectively reducing the chances of developing a disorder or decreasing the severity of the disorder or one or more of its symptoms before they are diagnosed or before symptoms develop fully.

In one aspect, the invention provides a method of treating NASH comprising administering a therapeutically or prophylactically effective amount of an sGC stimulant, or a pharmaceutically acceptable salt thereof, alone or in combination with a therapeutically or prophylactically effective amount of one or more additional therapeutic agents, to a patient in need thereof.

In another aspect, the invention relates to a pharmaceutical composition comprising an sGC stimulant, or a pharmaceutically acceptable salt thereof, for use in treating NASH in a patient in need thereof. In another aspect, the invention relates to a pharmaceutical composition comprising an sGC stimulant, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, for use in treating NASH in a patient in need thereof.

In another aspect, the invention relates to a kit containing at least two separate unit dosage forms (A) and (B), where (A) is a therapeutic agent, a combination of more than one therapeutic agent, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof , and (B) is an sGC stimulant, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an sGC stimulant or a pharmaceutically acceptable salt thereof, for use in treating NASH in a patient in need thereof.

In some embodiments of the above methods, uses, compositions, and kits, the patient in need thereof is an adult. In other embodiments, the patient is a child. In some embodiments of the above methods, uses, compositions, and kits, the patient is clinically obese. In other embodiments, the patient has been diagnosed with diabetes or prediabetes. In other embodiments, the patient has been diagnosed with metabolic syndrome. In other embodiments, the patient is of normal weight. In yet other embodiments, the patient is clinically overweight.

In some embodiments of the above methods, uses, compositions, and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable reduction in hepatic steatosis or abnormal fat accumulation. In some embodiments, this results in an observable or measurable reduction in the degree of inflammation or hepatitis. In some embodiments, this results in an observable or measurable decrease in the degree of liver fibrosis, cirrhosis, or sclerosis. In other embodiments, this results in an observable or measurable concurrent decrease in levels of hepatic steatosis, inflammation, and fibrosis.

In some embodiments of the above methods, uses, compositions, and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable decrease in sensation.

- 9 038096 fatigue. In some embodiments, this results in an observable or measurable decrease in the feeling of weakness. In other embodiments, the implementation of this leads to an observable or measurable decrease in the increase in the level of liver enzymes. In other embodiments, the implementation of this leads to an observable or measurable decrease in the increase in the level of inflammatory cytokines.

In some embodiments of the above methods, uses, compositions and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in observable or measurable inhibition of sudden or uncontrolled weight loss. In other embodiments, this results in observable or measurable weight loss in a person who is clinically overweight or obese.

In some embodiments of the above methods, uses, compositions and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable improvement in one or more levels of inflammation, steatosis, and liver fibrosis.

In some embodiments of the above methods, uses, compositions and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable improvement in NAS score (NAFDL Activity Scale). The total NAS score is the sum of the scores for steatosis, lobular inflammation and ballooning, and ranges from 0 to 8. NASH must be diagnosed first (or alternatively fatty liver is not a NASH diagnosis), then NAS is used to assess activity. In the reference study, NAS scores 0-2 are generally considered non-diagnostic for NASH, with scores 3-4 evenly distributed among those not considered diagnostic, borderline, or positive for NASH. Scores 5-8 occur in cases that are largely considered a NASH diagnosis.

In some embodiments of the above methods, uses, compositions and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in a measurable reduction in the degree of steatosis or abnormal fat accumulation in the liver as determined by tissue biopsy.

In some embodiments of the above methods, uses, compositions and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in a measurable reduction in liver inflammation or hepatitis as determined by tissue biopsy.

In some embodiments of the above methods, uses, compositions, and kits, administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in a measurable reduction in liver fibrosis, sclerosis, or cirrhosis as determined by liver biopsy or magnetic resonance elastography. or histology.

In some embodiments of the above methods, uses, compositions, and kits, the administration of an sGC stimulant or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising an sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent in need thereof, is targeted to or results in to reduce the patient's chances of developing NAFLD. In other embodiments, this reduces the chances that a patient with diabetes, prediabetes, or metabolic syndrome will develop necrotic inflammatory liver damage, fibrosis, liver damage, liver sclerosis, or cirrhosis. In other embodiments, this reduces the chances that a patient who is clinically overweight or obese will develop NASH.

In some embodiments of the above methods, uses, compositions, and kits, administration of an sGC stimulant or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, to a patient in need thereof, is intended to either leads to complete or partial relief of NASH, which is determined by partial or complete normalization of one or more clinical pictures.

In some embodiments of the above methods, uses, compositions, and kits, administration of an sGC stimulant or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, to a patient in need thereof, is intended to either leads to slowing or stopping the progression of NASH in cirrhosis, which is determined by histology.

In some embodiments of the above methods, uses, compositions, and kits, administration of an sGC stimulant or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, to a patient in need thereof, is intended to either leads to an increase in the survival time of the patient diagnosed with NASH.

In some embodiments of the above methods, uses, compositions and kit

- 10 038096 mov the administration of an sGC stimulant or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing an sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent in need thereof, to a patient in need, aims at or results in a reduction or complete elimination of the need subject the patient to a liver transplant.

SGC stimulants.

Definitions and general terminology.

For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, and the 75th Edition of Chemistry and Physics Handbook, 1994. In addition, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books. Sausalito: 1999, and March's Advanced Organic Chemistry, 5 ^{th Ed, Smith, MB and March} , J., eds.. John Wiley & Sons, New York: 2001, which are incorporated herein by reference in their entirety.

The compounds described herein may optionally be substituted with one or more substituents, such as those illustrated generally below, or as shown in specific classes, subclasses, and forms of the invention. The phrase optionally substituted is used interchangeably with the phrase substituted or unsubstituted. Typically, the term substituted refers to the replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be replaced by more than one substituent selected from the specified group, the substituents can be either the same or different at each position, unless otherwise indicated. As will be obvious to the person skilled in the art, groups such as —H, halogen, —NO ₂ , —CN, —OH, —NH2, or —OCF3 are not substitutable groups.

The phrase before, as used herein, refers to zero or any integer that is equal to or less than the number following the phrase. For example, up to 3 means any of 0, 1, 2, or 3. As described herein, a certain numerical range of atoms includes any integer. For example, a group having 1-4 atoms can have 1, 2, 3, or 4 atoms. When any variable occurs more than once in any position, its definition in each case is independent of every other case.

The choice of substituents and combinations provided by the present invention are only those that result in the formation of stable or chemically acceptable compounds. Such choices and combinations will be obvious to those skilled in the art and can be determined without undue experimentation. The term stable, as used herein, refers to compounds that are not significantly altered by processing under the conditions of their preparation, detection and, in some embodiments, their isolation, purification, and use for one or more of the purposes described herein. In some embodiments, the stable compound is a compound that does not change significantly when stored at 25 ° C or lower in the absence of moisture or other reactive conditions for at least a week. A chemically feasible compound is a compound that can be obtained by a person skilled in the art based on the materials described herein, if necessary, appropriate knowledge in this field.

A compound such as described herein can be in its free form (eg, amorphous form, or crystalline form, or polymorph). Compounds can also form co-forms under certain conditions. As used herein, the term co-form is synonymous with the term multicomponent crystalline form. When one of the components in the co-form clearly transfers a proton to the other component, the resulting co-form is called a salt. Salt formation is determined by how large the difference in pKa is between the partners that form the mixture. For the purposes of this specification, compounds include pharmaceutically acceptable salts, even if the term “pharmaceutically acceptable salts” is not explicitly mentioned.

If only one of the isomers is depicted or specifically named, the structures depicted herein should also include all stereoisomeric (eg, enantiomeric, diastereomeric, atroisomeric and cis-trans isomeric) types of structures; for example, R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) configurations for a double bond, and cis and trans conformational isomers. Therefore, the individual stereochemical isomers as well as racemates and mixtures of enantiomers, diastereomers and cis-trans isomers (double bond or conformational) of the compounds of the present invention are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are also included within the scope of the invention. As an example, the substitute below is:

- 11 038096

where R can be hydrogen will include both compounds shown below:

One embodiment of the invention includes isotopically labeled compounds that are identical to those of the present invention, but with one or more atoms replaced by an atom having an atomic mass or mass number other than the atomic mass or mass number normally found in nature. All isotopes of any particular atom or element as defined herein are contemplated within the scope of the compounds of the present invention. Examples of isotopes that can be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I, respectively. Certain isotopically labeled compounds of the present invention (eg, those labeled with ³ H and ¹⁴ C) can be used in compound and / or substrate tissue distribution assays. Tritiated (i.e. ³ H) and carbon-14 (i.e. ¹⁴ C) isotopes can be used due to their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H) may provide certain therapeutic benefits associated with greater metabolic stability (e.g., increased in vivo half-life or reduced doses) and, therefore, may be preferred in some cases. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and 18 F can be used in positron emission tomography (PET) studies to study substrate receptor activity.

The term aliphatic or aliphatic group as used herein means a linear (ie, unbranched) or branched substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturation units. Unless otherwise indicated, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl, acetylene, and the like. For complete clarity, the term aliphatic chain may be used interchangeably with the term aliphatic or aliphatic group.

The term alkyl, as used herein, refers to a straight or branched chain saturated monovalent hydrocarbon radical. Unless otherwise indicated, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 atoms carbon). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, and the like.

The term alkenyl refers to a straight or branched chain monovalent hydrocarbon radical containing at least one site of unsaturation, i. E. sp2 a carbon-carbon double bond, where the alkenyl radical includes radicals having the cis and trans orientations, or alternatively the E and Z orientations.Unless otherwise indicated, the alkenyl group contains 2-20 carbon atoms (for example, 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms, or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl, and the like.

The term alkynyl refers to a linear or branched monovalent hydrocarbon radical containing at least one site of unsaturation, i. E. triple bond carbon

- 12 038096 carbon. Unless otherwise indicated, an alkynyl group contains 2-20 carbon atoms (for example, 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms, or 23 carbon atoms) ... Examples include, but are not limited to, ethynyl, propynyl, and the like.

The term carbocyclic refers to a ring system formed only by carbon and hydrogen atoms. Unless otherwise indicated, in the present description, the term carbocycle is used synonymously with the terms non-aromatic carbocycle or cycloaliphatic. In some cases, this term can be used in the phrase aromatic carbocycle, in which case it refers to an aryl group as defined below.

The term cycloaliphatic (or non-aromatic carbocycle, non-aromatic carbocyclyl, non-aromatic carbocyclic) refers to a cyclic hydrocarbon that is completely saturated or contains one or more unsaturation units, but which is not aromatic, and which has one point of attachment to the rest of the molecule. Unless otherwise indicated, the cycloaliphatic group can be monocyclic, bicyclic, tricyclic, fused, spiro, or bridged. In one embodiment, the term cycloaliphatic refers to a monocyclic C ₃ -C ₁₂ hydrocarbon or a bicyclic C ₇ -C ₁₂ hydrocarbon. In some embodiments, any single ring in a bicyclic or tricyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.

The term cycloaliphatic also includes polycyclic ring systems in which a non-aromatic carbocyclic ring may be fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or combinations thereof, provided the radical or point of attachment is on a non-aromatic carbocyclic ring.

Cycloalkyl, as used herein, refers to a ring system that is fully saturated and that has one point of attachment to the rest of the molecule. Unless otherwise indicated, the cycloaliphatic group can be monocyclic, bicyclic, tricyclic, fused, spiro, or bridged. In one embodiment, the term cycloalkyl refers to a monocyclic C ₃ -C ₁₂ saturated hydrocarbon or a bicyclic C 7 -C 12 saturated hydrocarbon. In some embodiments, any single ring in a bicyclic or tricyclic ring system has 3-7 members. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

Heterocycle (or heterocyclyl or heterocyclic), as used herein, refers to a ring system in which one or more ring members are an independently selected heteroatom that is fully saturated or contains one or more unsaturation units, but which is not aromatic and has one point of attachment to the rest of the molecule. Unless otherwise indicated, in this description, the term heterocycle is used synonymously with a non-aromatic heterocycle. In some cases, this term can be used in the phrase aromatic carbocycle, in which case it refers to an aryl group as defined below. The term heterocycle also includes fused, spiro or bridged heterocyclic ring systems. Unless otherwise indicated, the heterocycle can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heterocycle has 3-18 ring members, of which one or more ring members is a heteroatom independently selected from oxygen, sulfur, or nitrogen, and each ring in the system contains 3 to 7 ring members. In other embodiments, the heterocycle may be a monocycle containing 3-7 ring members (2-6 carbon atoms and 1-4 heteroatoms) or a bicycle containing 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms) ... Examples of bicyclic heterocyclic ring systems include, but are not limited to, adamantanyl, 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl.

As used herein, the term heterocycle also includes polycyclic ring systems in which the heterocyclic ring is fused to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or combinations thereof, provided the radical or point of attachment is on the heterocyclic ring.

Examples of heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, , 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3

- 13 038096 pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 4-imidazolidinyl, 2-imidazolidinyl, 2-imidazolidinyl , 5-imidazolidinyl; and the following bicycles: 3-1H-benzimidazol-2-one, 3- (1-alkyl) benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane and 1,3-dihydroimidazol-2-one.

As used herein, the term aryl (as in an aryl ring or in an aryl group), used alone or as part of a larger moiety, as in aralkyl, aralkoxy, aryloxyalkyl, refers to a carbocyclic system in which at least one ring in the system is aromatic and has one point of attachment to the rest of the molecule. Unless otherwise indicated, the aryl group can be monocyclic, bicyclic or tricyclic and contain 6-18 ring members. The term also includes polycyclic ring systems in which an aryl ring is fused to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or combinations thereof, when the radical or point of attachment is on the aryl ring. Examples of aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl.

The term aralkyl refers to a radical having an aryl ring substituted with an alkylene group, where the open end of the alkylene group allows the aralkyl radical to bond to another portion of the compound. An alkylene group is a bivalent linear or branched saturated hydrocarbon group. As used herein, the term C _7-12 aralkyl means an aralkyl radical where the total number of carbon atoms in the aryl ring and the attached alkylene group is from 7 to 12. Examples of aralkyl include, but are not limited to, a phenyl ring substituted with C _{1- 6} alkylene group, for example benzyl and phenylethyl, and a naphthyl group substituted with a C _1-2 alkylene group.

The term heteroaryl (or heteroaromatic, or heteroaryl group, or aromatic heterocycle), used alone or as part of a larger moiety, as in heteroaralkyl or heteroarylalkoxy, refers to a ring system in which at least one ring in the system is aromatic and contains one or multiple heteroatoms, with each ring in the system containing from 3 to 7 ring members and which has one point of attachment to the rest of the molecule. Unless otherwise indicated, the heteroaryl ring system can be monocyclic, bicyclic, or tricyclic and has a total of five to fourteen ring members. In one embodiment, all rings in the heteroaryl system are aromatic. Also included in this definition are heteroaryl radicals where the heteroaryl ring is fused to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or a combination thereof, when the radical or point of attachment is on the heteroaryl ring. A bicyclic 6, 5 heteroaromatic system, as used herein, for example, is a six-membered heteroaromatic ring fused to a second five-membered ring where the radical or point of attachment is on the six-membered ring.

Heteroaryl rings include, but are not limited to, the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (for example, 3 pyridazinyl), 2 -thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (for example, 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g. 2-indolyl), purinyl, quinolinyl (e.g. 2-quinolinyl , 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (for example, 1isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

As used herein, the term cyclo (or cyclic or cyclic moiety) encompasses mono-, bi- and tricyclic ring systems, including cycloaliphatic, heterocyclic, aryl, or heteroaryl, each of which was previously defined.

Fused bicyclic ring systems contain two rings that share two common ring atoms.

Bridged bicyclic ring systems contain two rings that have three or four common ring atoms. As used herein, the term bridge refers to an atom or chain of atoms connecting two different parts of a molecule. The two atoms that are linked across a bridge (usually, but not always, two tertiary carbon atoms) are called bridge heads. In addition to the bridge, the two bridge heads are linked by at least two separate atoms or chains of atoms. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2- oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo

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[3.2.1] octyl and 2,6-dioxatricyclo [3.3.1.03,7] nonyl. Spiro-bicyclic ring systems share only one ring atom (usually a quaternary carbon atom) between the two rings.

The term “ring atom” refers to an atom such as C, N, O, or S that is part of an aromatic ring, cycloaliphatic ring, heterocyclic, or heteroaryl ring. The substituted ring atom is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can optionally be replaced with a suitable substituent group. Thus, the term substitutable ring atom does not include ring nitrogen or carbon atoms that are common when two rings are fused. In addition, a substitutable ring atom does not include ring carbon or nitrogen atoms when the structure shows that they are already attached to one or more moieties other than hydrogen, and they do not have replaceable hydrogen atoms.

A heteroatom refers to one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, a quaternized form of any basic nitrogen, or a displaceable nitrogen of a heterocyclic or heteroaryl ring such as N (as in 3.4 -dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in the case of N-substituted pyrrolidinyl).

In some embodiments, when specifically indicated, two independent variables may be taken together with the atom (s) with which each variable is associated to form a 5-8 membered heterocyclyl, aryl, or heteroaryl ring or a 3-8 membered cycloaliphatic ring ... Examples of rings that are formed when two independent substituent variants are taken together with the atom (s) to which each variable is associated include, but are not limited to, the following: a) two independent substituent variants that are bonded to the same atom, and taken together with this atom to form a ring, where both variants of the substituent are taken together with the atom to which they are attached to form a heterocyclyl, heteroaryl, cycloaliphatic or aryl ring, where the group is attached to the rest of the molecule by one point of attachment; and b) two independent substituent variants that are bonded to different atoms and taken together with both of these atoms to form a heterocyclyl, heteroaryl, cycloaliphatic or aryl ring, where the resulting ring has two points of attachment with the rest of the molecule. For example, when a phenyl group is substituted with two -OR ° substituents as in formula D _1, the two -OR ° substituents, taken together with the carbon atoms to which they are attached, form a fused 6-membered oxygen-containing ring, as in formula D ₂

It will be understood that various other rings can be formed when two independent substituents are taken together with the atom (s) to which each substituent is bonded, and that the above examples are not intended to be limiting. They will be indicated in each case, if necessary.

In some embodiments, the alkyl or aliphatic chain may optionally be interrupted by another atom or group. If so, it will be clearly indicated in the definition of a particular alkyl or aliphatic chain (eg, a particular variable will be described as a C _1-6 alkyl group, wherein said alkyl group is optionally interrupted by a specific group). Unless otherwise indicated, alkyl and aliphatic chains will be considered formed by carbon atoms only, without interruption. This means that the methylene unit of the alkyl or aliphatic chain may optionally be replaced by another atom or group. Unless otherwise indicated, optional substitutions form a chemically stable compound. Possible interrupts, if specified, can occur both within the chain and / or at both ends of the chain; those. both at the point (s) of attachment to the rest of the molecule and / or at the end. The two optional substitutions can also be adjacent to each other within the chain, in the event that this leads to a chemically stable connection. Unless otherwise indicated, if substitution or interruption occurs at the end of the chain, the substituent atom at the end is bonded to H. For example, if —CH ₂ CH ₂ CH _{3 is} optionally interrupted by —O—, the resulting compound could be —OCH2CH3, —CH2OCH3, or -CH2CH2OH. In another, when

- 15 038096 if the bivalent linker —CH2CH2CH2— is optionally interrupted by —O—, the resulting compound could be —OCH2CH2—, —CH2OCH2— or —CH2CH2O—. Optional substitutions, when specifically indicated, can also completely replace all carbon atoms in the chain. For example, a C ₃ aliphatic group can optionally be replaced by -N (R ') -, -C (O) - and -N (R') - to form -N (R ') C (O) N (R') - (urea).

Typically, the term vicinal refers to the placement of substituents on a group that includes two or more carbon atoms, where the substituents are attached to adjacent carbon atoms.

As described herein, the bond depicted from a substituent to the center of one ring in a multi-ring system (as shown below) represents substitution with a substituent at any substitutable position on any of the rings in the multi-ring system. For example, Formula D3 depicts a possible substitution at any of the positions shown in Formula D4

This also applies to various ring systems condensed with possible ring systems (which will be represented by dashed lines). For example, in Formula D5, X is an optional substituent on both Ring A and Ring B.

If, however, two rings in a multi-ring system have different substituents depicted from the center of each ring, then, unless otherwise indicated, each substituent is a substitution on the ring to which it is attached. For example, in Formula D _6, Y is an optional substituent for ring A only, and X is an optional substituent for ring B only.

As used herein, the terms alkoxy or alkylthio refer to an alkyl group as defined above attached to a molecule or to another chain or ring through an oxygen atom (alkoxy, i.e. -O-alkyl-) or a sulfur atom (alkylthio, i.e. e. -S-alkyl).

As used herein, the terms halogen or halo means F, Cl, Br, or I.

The terms haloalkyl, haloalkenyl, haloaliphatic and haloalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. For example, C _1-3 haloalkyl may be —CFHCH2CHF2 and C1-2 haloalkoxy may be —OC (Br) HCHF ₂ . This term includes perforated alkyl groups such as —CF3 and —CF2CF3.

As used herein, the term cyano refers to -CN or -C ^ N.

The terms cyanoalkyl, cyanoalkenyl, cyanoaliphatic and cyanoalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. For example, C _1-3 cyanoalkyl can be —C (CN) ₂ CH ₂ CH ₃ and C _1-2 cyanoalkenyl can be ═CHC (CN) H ₂ .

As used herein, the term amino group refers to —NH ₂ .

The term hydroxyl or hydroxy refers to —OH.

As used herein, the term carbonyl, alone or in connection with another group, refers to —C (O) - or —C (O) H. For example, as used herein, the term alkoxycarbonyl refers to a group such as —C (O) O (alkyl).

As used herein, the term oxo refers to = O, where the oxo group is usually, but not always, attached to a carbon atom (for example, it can also be attached to a sulfur atom). The aliphatic chain may optionally be interrupted by a carbonyl group, or may optionally be substituted with an oxo group, and both expressions refer to the same, for example

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-CH2-C (O) -CH3.

In all other situations, a linker, as used herein, refers to a bivalent group in which the two free valences are on different atoms (e.g., carbon or heteroatom) or are on the same atom, but may be substituted with two different substituents. For example, a methylene group may be a C ₁ alkyl linker (-CH2-), which may be substituted by two different groups, one on each free valency (e.g., as in Ph-CH ₂ -Ph, which acts as a methylene linker between the two phenyl rings). Ethylene can be a C ₂ alkyl linker (—CH 2 CH 2—) where the two free valences are on different atoms. An amide group, for example, can act as a linker when in an internal chain position (eg —CONH—). The linker can result from the interruption of the aliphatic chain with certain functional groups or the replacement of methylene units with the specified chain by the indicated functional groups. For example, the linker can be a C1 _-6 aliphatic chain in which up to two methylene units are replaced by -C (O) - or -NH- (as in -CH2-NH-CH2-C (O) -CH ₂ - or - CH ₂ -NH-C (O) -CH ₂ -).

An alternative way of describing the same —CH ₂ —NH — CH ₂ —C (O) —CH ₂ - and —CH ₂ —NH — C (O) —CH ₂ - groups is a C ₃ alkyl chain optionally interrupted to two —C (O) - or -NH-fragments. Cyclic groups can also form linkers, for example 1,6-cyclohexanediyl can be a linker

R— (X — R between two groups R, as in \ '

The linker can additionally be optionally substituted at any part or position.

Divalent groups of the R-CH = or R ₂ C = type are also possible, where both free valences are on the same atom and are attached to the same substituent. In this case, they will be indicated by IUPAC names. For example, an alkylidene (such as, for example, methylidene (= CH ₂ ) or ethylidene (= CH — CH ₃ )) will not be encompassed by the definition of a linker in this specification.

The compounds of the invention are described herein by their chemical structures and / or chemical names. When a compound is indicated by both, by both chemical structure and chemical name, the chemical structure is decisive for the identity of the compound.

In some embodiments of the above methods, uses, pharmaceutical compositions, and kits, the sGC stimulant is selected from compounds described in patent applications WO 2013101830 (for example, any of compounds 1 to 122), WO 2012064559 (for example, any of compounds I-1 to I-68), WO 2012003405 (for example, any of the compounds I-1 to I-312), WO 2011115804 (for example, any of the compounds I-1 to I-63), WO 2014047111 (for example, any of the compounds I-1 to I-5), WO 2014047325 (for example, any of the compounds I-1 to I-10); WO 2014144100 (for example, any of compounds I-1 to I-634); WO 2015089182 (for example, any of the compounds I-1 to I-72), WO 2016044447 (for example, any of the compounds 1 to 217), WO 2016044446 (for example, any of the compounds I-1 to I-94), WO 2016044445 (for example, any of compounds I-1 to I-39), WO 2016044441 (for example, any of compounds I-1 to I-20) or pharmaceutically acceptable salts thereof.

In other embodiments of the above methods, uses, pharmaceutical compositions and kits, the sGC stimulant is a compound described in one or more of the following publications: US 20140088080 (WO 2012165399), WO 2014084312, US 6414009, US 6462068, US 6387940, US 6410740 ( WO 9816507), US 6451805 (WO 9823619), US 6180656 (WO 9816223), US 20040235863 (WO 2003004503), US 20060052397, US 7173037 (WO 2003095451), US 20060167016, US 7091198 (WO 200600109589), US 740014959 (WO 2004009590), US 20100004235 (WO 2007124854, for example examples 1, 2, 3, 6, 7, 18 or 19), US 20100029653 (WO 2008031513, for example examples 1, 2, 3, 4 or 7), US 20100113507 ( WO 2007128454, for example examples 1, 4 or 7), US 20110038857, US 8114400 (WO 2008061657), US 20110218202 (WO 2010065275, for example examples 1, 3, 59, 60 or 111), US 20110245273 (WO 2010078900, for example examples 1 or 5), US 2012029002 (WO 2010079120), US 20120022084, US 20130237551, US 8420656 (WO 2011147809, W O 2011147810), US 20130210824 (WO 2013104598), US 20130172372 (WO 2012004259, for example examples 2, 3 or 4), US 20130267548 (WO 2012059549, for example examples 1, 2, 7, 8 or 13), WO 2012143510 (for example, examples 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), WO 2012004258 (for example, examples 1, 18, 19 or 27), WO 2012152629 (for example, examples 11 or 12), WO 2012152630 (for example, examples 1, 5, 8, 11, 15 or 19), WO 2012010577 (for example, examples 3-1, 4, 5 or 6), WO 2012028647 (for example, examples 1, 2 or 3), WO 2013104597 ( e.g. examples 16, 18, 22 or 23), WO 2013131923 (e.g. examples 1, 2, 7, 8 or 9), WO 2013104703, WO 2013004785 (e.g. examples 1, 3 or 6), WO 2013030288, US 20090209556 , US 8455638, US 20110118282 (WO 2009032249), US 20100292192, US 20110201621, US 7947664, US 8053455 (WO 2009094242), US 20100216764, US 8507512, (WO 2010099054), US 20110218205 (WO 2013 201186527 ), US 20130072492 (WO 2011149921, for example example # 160, example # 164 and example # 181), U S 20130210798 (WO 2012058132), US 8796305 (WO 2014068095), US 20140128372 and US 20140179672 (WO 2014068099),

- 17 038096

US 8778964 (US 20140128386, US 20140128424, WO 2014068104), WO 2014131741, US 20140249168 (WO 2014131760), WO 2011064156, WO 2011073118, WO 1998023619, WO 2000006567, WO 2000006569 200204, 2000021900 WO 2002042300, WO 2002042301,

WO 2002042302, WO 2002092596, WO 2003097063, WO 2004031186, WO 2004031187, WO 2014195333,

WO 2015018814, WO 2015082411, WO 2015124544, US 6833364 (DE 19834047), WO 2001017998 (DE 19942809), WO 2001047494 (DE 19962926), WO 2002036120 (DE 10054278), WO 2011064171,

WO 2013086935, WO 2014128109, WO 2012010578, WO 2013076168, WO 2000006568, WO 2015124544,

WO 2015150366, WO 2015150364, WO 2015150363, WO 2015150362, WO 2015140199, WO 2015150350,

WO 2015140254, WO 2015088885 and WO 2015088886.

In some additional embodiments of the above methods, uses, pharmaceutical compositions, and kits, the sGC stimulant is a compound described in one or more of the following publications: WO 2000006568, WO 2001017998, WO 2001047494, and WO 2002036120.

In some additional embodiments of the above methods, uses, pharmaceutical compositions and kits, the sGC stimulant is a compound described in one or more of the following publications: US 20110131411, WO 2011064156 and WO 2011073118.

In some additional embodiments of the above methods, uses, pharmaceutical compositions and kits, the sGC stimulant is a compound described in one or more of the following publications: US 20140315926, WO 2003095451, WO 2011064171, WO 2013086935 and WO 2014128109.

In some additional embodiments of the above methods, uses, pharmaceutical compositions, and kits, the sGC stimulant is a compound described in one or more of the following publications: WO 2011147809, WO 2012010578, WO 2012059549, and WO 2013076168.

In some embodiments of the above methods, uses, pharmaceutical compositions, and kits, the sGC stimulant is a compound shown below:

riociguat (BAY 63-2521, Adempas®, FDA approved drug described in DE 19834044)

unliciguat (BAY 60-4552 described in WO 2003095451)

veriziguat (BAY 1021189)

- 18 038096

° ~ Me

BAY 41-2272 (described in DE 19834047 and DE 19942809)

one of the compounds shown below and described in US 20130072492 (WO 2011149921)

- 19 038096

In another aspect, the invention relates to a compound according to formula I 'or a pharmaceutically acceptable salt thereof

J

Formula I ';

where ring A is a 5-membered heteroaryl ring;

each substituent X is independently selected from C or N, and the bond between each two substituents X is either single or double bond, thus making ring A an aromatic heterocycle;

where at least 2 substituents X and at most 3 substituents X in ring A can simultaneously represent N;

W or

i) is absent and J ^B is bonded directly to a carbon atom bearing two J groups; where each J group is independently selected from hydrogen or methyl, n is 1, and J ^B is a C _2-7 alkyl chain independently substituted with 2 to 9 fluoro substituents; where, optionally, one unit of -CH ₂ -specified C _2-7 alkyl chain may be replaced by -O- or -S-;

ii) Ring B is selected from phenyl, a 5- or 6-membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from N, O or S, a C _3-7 cycloalkyl ring and a 4-7 membered heterocyclic ring containing up to 3 heteroatoms independently selected from O, N or S;

where when W is ring B, each J is hydrogen;

n is 0 or an integer selected from 1, 2 or 3;

each J ^{B is} independently selected from halogen, —CN, C1-6 aliphatic, —OR ^B, or C3-8 cycloaliphatic; where each specified C _1-6 α aliphatic group and each specified C _3-8 cycloaliphatic ring is optionally and independently substituted with up to 3 substituents R ³ ;

each R ^{B is} independently selected from hydrogen, a C1-6 aliphatic group, or a C3-8 cycloaliphatic ring; where each of said R ^B , which is a C1-6 aliphatic group, and each of said R ^B , which is a C _3-8 cycloaliphatic ring, is optionally and independently substituted with up to 3 substituents R ^3a ;

each R ^{3 is} independently selected from halogen, —CN, C _1-4 alkyl, C _1-4 haloalkyl, —O (C _1-4 alkyl), or —O (C _1-4 halogenaalkyl);

each R ^{3a is} independently selected from halogen, —CN, C _1-4 alkyl, C _1-4 haloalkyl, —O (C _1-4 alkyl), or —O (C _1-4 gαlogenaalkyl);

Z ¹ in ring D is selected from CH, CF, or N; Z is selected from C or N; where if Z ¹ represents CH or CF, then Z must represent C; and if Z ¹ is N, then Z can be C or N;

each JD is independently selected from J ^A , -CN, -NO2, -ORD, -SRD, -C (O) RD, -C (O) OR ^d , -OC (O) R ^d , -C (O) N ( RD) 2, -N (RD) 2, -N (R ^d ) C (O) RD, -N (R ^d ) C (O) ORD, -N (R ^d ) C (O) N (RD) 2 , -OC (O) N (RD) ₂ , -SO2RD,

- 20 038096

-SO2N (R ^d ) 2, -N (R ^d ) SO2R ^D , -N (R ^d ) SO2NHR ^D , -N (R ^d ) SO2NHC (O) OR ^D , -N (R ^d ) SO2NHC (O) R ^D , C1-6 aliphatic group, - (C1-6 aliphatic group) -R ^D , C3-8 cycloaliphatic ring, 6-10 membered aryl ring, 4-8 membered heterocyclic ring or 5-10 membered heteroaryl ring; where each said 4-8 membered heterocyclic ring and each said 5-10 membered heteroaryl ring contains between 1 and 3 heteroatoms independently selected from O, N or S; and where each said C _1-6 aliphatic group, each said C _1-6 aliphatic moiety - (C _1-6 aliphatic group) -R ^D fragment, each said C _3-8 cycloaliphatic ring, each said 6-10 membered aryl ring, each said 4-8 membered heterocyclic ring and each said 5-10 membered heteroaryl ring are optionally and independently substituted with up to 5 R ^5d substituents;

J ^{A is} selected from a pair of electrons on a nitrogen, hydrogen, halogen, oxo, methyl, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, or —NR ^a R ^b ; where R ^a and R ^b are each independently selected from hydrogen, Cl _-6 alkyl or 3-6-cycloalkyl ring; or where R ^a and R ^b together with the nitrogen atom to which they are both attached form a 4-8 membered heterocyclic ring or a 5-membered heteroaryl ring optionally containing up to two additional heteroatoms selected from N, O and S; where each of said 4 to 8 membered heterocyclic ring and 5 membered heteroaryl ring is optionally and independently substituted with up to 6 fluoro substituents;

each R ^{d is} independently selected from hydrogen, C1-6 aliphatic, - (C1-6 aliphatic α group) -R ^f , C3-8 cycloaliphatic ring, 4-10 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each said 4-10 membered heterocyclic ring and each said 5-6 membered heteroaryl ring contain from 1 to 3 heteroatoms independently selected from O, N or S; and where each said Cl _-6 aliphatic alpha group, each said Cl _-6 aliphatic moiety - (C _1-6 aliphatic group) -R ^f fragment, each said C3-8 cycloaliphatic ring, each said 4-10 membered heterocyclic ring, each said phenyl and each of said 5-6 membered heteroaryl ring is optionally and independently substituted with up to 5 R ^5a ; where when any R ^D _{is one of C1-6} aliphatic or - (C 1-6 aliphatic α group) -R ^f group, one or two -CH2- units that form said C _1-6 aliphatic chains, optionally, may be replaced by a group independently selected from —N (R ^d ) -, —CO—, or —O—;

each R ^{d is} independently selected from hydrogen, a C1-6 aliphatic group, - (C1-6 aliphatic α group) -R ^f , a C3-8 cycloaliphatic ring, a 4-8 membered heterocyclic ring, phenyl, or a 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring and each specified 5- or 6-membered heteroaryl ring contain from 1 to 3 heteroatoms independently selected from O, N or S; and where each said C _1-6 aliphatic α group, each said C _1-6 aliphatic moiety - (C _1-6 aliphatic α group) -R ^{f of a} fragment, each said C3-8 cycloaliphatic ring, each said 4-8 membered heterocyclic ring, each said phenyl and each said 5-6 membered heteroaryl ring are optionally and independently substituted with up to 5 R ^5b substituents; where when any R ^d is one of a C1-6 aliphatic group or - (C _1-6 aliphatic α group) -R ^f group, one or two -CH2- units that form said Cl _-6 aliphatic chains may optionally be replaced by a group independently selected from —N (R ^dd ) -, —CO—, or —O—;

each R ^{dd is} independently selected from hydrogen, C1-6 aliphatic, - (C1-6 aliphatic) -R ^f , C3-8 cycloaliphatic ring, 4-8 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring and each specified 5- or 6-membered heteroaryl ring contains from 1 to 3 heteroatoms independently selected from O, N or S; and where each said C _1-6 aliphatic α group, each said C ₁ . ₆ aliphatic moiety - (C _1-6 aliphatic group) -R ^f fragment, each specified C _3-8 cycloaliphatic ring, each specified 4-8 membered heterocyclic ring, each specified phenyl and each specified 5-6 membered heteroaryl ring optionally and independently substituted with up to 5 substituents R ^5b ;

each R ^{f is} independently selected from C _1-3 alkyl, C _3-8 cycloaliphatic ring, 4-10 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each specified 4-10 membered heterocyclic ring and each specified 5-6 membered heteroaryl ring contains from 1 to 4 heteroatoms independently selected from O, N or S; and where each said C _3-8 cycloaliphatic ring, each said 4-10 membered heterocyclic ring, each said phenyl and each said 5-6 membered heteroaryl ring is optionally and independently substituted with up to 5 R ^5c substituents;

when J ^D is -C (O) N (R ^D ) 2, -N (R ^D ) 2, -N (R ^d ) C (O) N (R ^D ) 2, -OC (O) N (R ^D ) 2 or —SO2N (R ^D ) 2, two R ^D groups, together with a nitrogen atom attached to two R ^D groups, can form a 4-8 membered heterocyclic ring or a 5 membered heteroaryl ring; where each said 4-8 membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contain up to 3 additional heteroatoms independently selected from N, O or S, in addition to the nitrogen atom to which the two R ^D groups are attached; and where each said 4-8 membered heterocyclic ring and each said 5 membered heteroaryl ring are optionally and independently substituted with up to 5 R ⁵ substituents;

21 038096 when J ^D is -N (R ^d ) C (O) R ^D , the R ^D group together with the carbon atom attached to the R ^d group, together with the nitrogen atom attached to the R ^D group and the R group ^D can form a 4-8 membered heterocyclic ring or a 5 membered heteroaryl ring; where each specified 4-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S, in addition to the nitrogen atom to which the group R ^D is attached; and where each said 4-8 membered heterocyclic ring and each said 5 membered heteroaryl ring are optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D represents -N (R ^d ) C (O) OR ^D , the group R ^D together with the oxygen atom attached to the group R ^d , together with the carbon atom -C (O) - part of the group -N (R ^d ) C (O) OR ^D , together with the nitrogen atom attached to the R ^d group and with said R ^d group, can form a 4-8 membered heterocyclic ring; wherein said 4-8 membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O, or S, and is optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D is —N (R ^d ) C (O) N (R ^D ) ₂ , one of the R ^d groups attached to the nitrogen atom together with said nitrogen atom and with the N atom attached to the R ^d group, and with the specified group R ^d can form a 4-8 membered heterocyclic ring; wherein said 4-8 membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O, or S, and is optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D is —N (R ^d ) SO ₂ R ^D , the R ^D group together with the sulfur atom attached to the R ^d group together with the nitrogen atom attached to the R ^d group and with the specified R ^d group can be combined to form a 4-8 membered heterocyclic ring; wherein said 4-8 membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O, or S, and is optionally and independently substituted with up to 5 R ⁵ substituents;

each R ^{5 is} independently selected from halogen, —CN, C1-6 alkyl, - (C1-6 alkyl) —R ⁶ , —OR ⁶ , —SR ⁶ , —COR ⁶ , —OC (O) R ⁶ , —C (O) OR ⁶ , -C (O) N (R ⁶ ) 2, -C (O) N (R ⁶ ) SO2R ⁶ , -N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) C (O ) OR ⁶ , -N (R ⁶ ) C (O) N (R ⁶ ) 2, -N (R ⁶ ) 2, -SO2R ⁶ , -SO2OH, -SO2NHOH, -SO2N (R ⁶ ) 2, -SO2N ( R ⁶ ) COOR ⁶ , -SO2N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) SO2R ⁶ , - (C = O) NHOR ⁶ , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, A 5- or 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each specified C _1-6 alkyl, C _1-6 alkyl part of the group - (C _1-6 alkyl) -R ⁶ moiety, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6- member heteroaryl ring, benzyl or phenyl group optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is phenyl a ring or 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH ₂ , —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN , —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two R ⁵ substituents attached to the same or different J ^d atoms, together with the indicated atom or atoms to which they are attached, can optionally form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring resulting in a bicyclic system, where the two rings of the bicyclic system are spiro-fused, fused or bridged, wherein said 4-6-membered heterocycle or said 5- or 6-membered heteroaryl ring contain up to four ring heteroatoms independently selected from N, O, or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkoxy, C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -NR (CO) O (C _1-4 alkyl), -CONH2, - OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, - (C1-6 alkyl) R ^6a , —OR ^6a , —SR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , -C (O) N (R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) C (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2OH, -SO2NHOH, -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 - or a 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, where each of said C _1-6 alkyl, C _1-6 alkyl moiety of the moiety - (C _1-6 alkyl) R ^6a , C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, benzyl or pe

- 22 038096 nyl groups are optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl ) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is phenyl a ring or 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH ₂ , —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN , —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

each R ^{5b is} independently selected from halogen, —CN, C1-6 alkyl, - (C1-6 alkyl) R ^6a , —OR ^6a , —SR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , -C (O) N (R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) С (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2OH, -SO2NHOH, -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 - or a 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, where each of said C _1-6 alkyl, C _1-6 alkyl moiety of the moiety - (C _1-6 alkyl) R ^6a , C 3 _-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, benzyl or phenyl group optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl , C _1-4 haloalkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -CONH2, -COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is phenyl a ring or 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two substituents R ^5a or two substituents R ^5b attached to the same or different atoms RD or Rd, respectively, together with the indicated atom or atoms to which they are attached, can optionally form a C _3-8 cycloalkyl ring, 4- 6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system, where the two rings of the bicyclic system are spiro connected, fused or bridged to each other; wherein said 4-6 membered heterocycle or said 5 or 6 membered heteroaryl ring contains up to four ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkoxy, C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -C (O) NH ₂ , -NR (CO) O (C _{1- 4} alkyl), -OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{5c is} independently selected from halogen, -CN, C1-6alkyl, - (C1-6alkyl) -R ^6b , -OR ^6b , -SR ^6b , -COR6b, -OC (O) R ^6b , -C (O) OR6b , -C (O) N (R ^6b ) 2, -C (O) N (R ^6b ) SO2R ^6b , -N (R ^6b ) C (O) R ^6b , -N (R ^6b ) C (O) OR ^6b , -N (R ^6b ) C (O) N (R ^6b ) 2, -N (R ^6b ) 2, -SO2R ^6b , -SO2OH, -SO2NHOH, -SO2N (R ^6b ) 2, -SO2N (R ^6b ) COOR ^6b , -SO2N (R ^6b ) C (O) R ^6b , -N (R ^6b ) SO2R ^6b , - (C = O) NHOR ^6b , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or a 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each of said 5- or 6-membered heteroaryl ring and each of said 4-7-membered heterocyclic ring contain up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, C _1-6 alkyl portion of said fragment - (C _1-6 alkyl) -R ^bb , each of said C _3-8 cycloalkyl ring, each of said 4-7 membered heterocyclic ring , each of said 5- or 6-membered heteroaryl ring, each of said benzyl and each of said phenyl group is optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _{1- 4} alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -CONH2, -COO (C _1-4 alkyl), -O (C _1-4 alkyl), -O (C _{1- 4} haloalkyl) or oxo; wherein said bicyclic group contains a first ring and a second ring fused or bridged, said first ring is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said second ring is a phenyl ring or a 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two R ^5c substituents attached to the same or different Rf atoms, together with

- 23 038096 linked atom or atoms to which they are attached can optionally form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system, where the two rings of the bicyclic system are spiro connected, fused or bridged to each other; wherein said 4-6 membered heterocycle or said 5 or 6 membered heteroaryl ring contains up to four ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -CONH2, -NR (CO) O (C _1-4 alkyl), -OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{5d is} independently selected from halogen, —CN, C1-6 alkyl, - (C1-6 alkyl) -R ⁶ , —OR ⁶ , —SR ⁶ , —COR ⁶ , —OC (O) R ⁶ , —C (O) OR ⁶ , -C (O) N (R ⁶ ) 2, -N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) C (O) OR ⁶ , -N (R ⁶ ) C (O ) N (R ⁶ ) 2, -N (R ⁶ ) 2, -SO2R ⁶ , -SO2OH, -SO2NHOH, -SO2N (R ⁶ ) COR ⁶ , -SO2N (R ⁶ ) 2, -N (R ⁶ ) SO2R ⁶ , C7-12 aralkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 or 6 membered heteroaryl ring, phenyl and oxo; where each 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to four ring heteroatoms independently selected from N, O and S, where each of said C _1-6 alkyl, C _1-6 alkyl portion of the moiety - (C _1-6 alkyl) -R ⁶ , C _7-12 aralkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 or 6 membered heteroaryl ring or phenyl group optionally and independently substituted up to 3 substituents halogen, C _1-4 alkyl, C _1-4 (haloalkyl), -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two R ^5d substituents attached to the same or different J ^D atoms, together with said J ^D atom or atoms to which they are attached, can optionally form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system, where the two rings of the bicyclic system are spiro connected, fused or bridged to each other; wherein said 4-6 membered heterocycle or said 5 or 6 membered heteroaryl ring contains up to four ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -NR (CO) O (C _1-4 alkyl), -C (O) NH2 , -OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{6 is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5 or 6 membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen , C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -C (O) NH2, -COO ( C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo, wherein each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring comprises up to 4 ring heteroatoms independently selected from N, O and S;

each R ^{6a is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen , C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -C (O) NH2, -C ( O) N (C1-6alkyl) 2, -C (O) NH (C1-6alkyl), -C (O) N (C1-6haloalkyl) 2, -C (O) NH (C1-6haloalkyl), C ( O) N (C _1-6 alkyl) (C _1-6 haloalkyl), -COO (C _1-6 alkyl), -COO (C _1-6 haloalkyl), -O (C _1-4 alkyl), -O (C _1-4 haloalkyl) or oxo, where each of said 5- or 6-membered heteroaryl ring or 4-7 membered heterocyclic ring contains up to 4 ring heteroatoms, independently branched from N, O and S;

each R ^{66 is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen , C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -C (O) NH2, -COO ( C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo, wherein each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring comprises up to 4 ring heteroatoms independently selected from N, O and S;

two substituents R ⁶ bonded to the same nitrogen atom R ⁵ or R ^5d , together with said atom

24 038096 MoM nitrogen R ⁵ or R ^5d , respectively, can form a 5-8 membered heterocyclic ring or a 5 membered heteroaryl ring; where each specified 5-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

two R ^6a substituents bonded to the R ^5a or R ^5b nitrogen atom, together with said nitrogen, can form a 5-8 membered heterocyclic ring or a 5-membered heteroaryl ring; where each specified 5-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

two R ^6b substituents bonded to the R ^5c nitrogen atom, together with said nitrogen, can form a 5-8 membered heterocyclic ring or a 5-membered heteroaryl ring; where each specified 5-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

Ring E is a 5-7 membered heterocycle or a 5 membered heteroaryl ring; wherein said heterocycle or heteroaryl ring contains up to 4 heteroatoms independently selected from N, O and S;

o denotes 0 or an integer selected from 1, 2, 3 or 4;

Y is either absent or is a C _1-6 alkyl chain optionally substituted with up to 6 fluoro substituents; and where in said YY, which is a C _1-6 alkyl chain, up to 3 methylene units of this alkyl chain may be replaced with a group selected from -O-, -C (O) - or -N ((Y1) -R ⁹⁰ ) -, where

Y ^{1 is} either absent or is a Cl _-6 alkyl chain optionally substituted with up to 6 fluoro substituents; and when Y ^{1 is} absent, each R ^{90 is} independently selected from hydrogen, -COR ¹⁰ , -C (O) OR ¹⁰ , -C (0) N (R ¹⁰ ) 2, -C (0) N (R ¹⁰ ) S02R ¹⁰ , -SO2R ¹⁰ , -SO2N (R ¹⁰ ) 2, -SO2N (R ¹⁰ ) COOR ¹⁰ , -SO2N (R ¹⁰ ) C (O) R ¹⁰ , - (C = O) NHOR ¹⁰ , C3-6 cycloalkyl ring, A 4-8 membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring or 5-6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and where each of said C3-6 cycloalkyl rings, each of said 4-8 membered heterocyclic rings, each of said phenyl and each of said 5-6 membered heteroaryl rings is optionally and independently substituted with up to 3 R ¹¹ substituents; and when Y ^{1 is} present, each R ^{90 is} independently selected from hydrogen, halogen, —CN, —OR ¹⁰ , —COR ¹⁰ , —OC (O) R ¹⁰ , —C (O) OR ¹⁰ , —C (O) N ( R ¹⁰ ) 2, -C (O) N (R ¹⁰ ) SO2R ¹⁰ , -N (R ¹⁰ ) C (0) R ¹⁰ , -N (R ¹⁰ ) C (O) OR ¹⁰ , -N (R ¹⁰ ) C (O) N (R ¹⁰ ) 2, -N (R ^1o ) 2, -SO2R ¹⁰ , -SO2N (R ¹⁰ ) 2, -SO2N (R ¹⁰ ) COOR ¹⁰ , -SO2N (R ¹⁰ ) C (O) R ¹⁰ , —N (R ¹⁰ ) SO2R ¹⁰ , - (C = O) NHOR ¹⁰ , C _3-6 cycloalkyl ring, 4-8 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring or 5-6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and where each of said C _3-6 cycloalkyl rings, each of said 4-8 membered heterocyclic rings, each of said phenyl and each of said 5-6 membered heteroaryl rings is optionally and independently substituted with up to 3 R ¹¹ substituents;

each R ^{9 is} independently selected from hydrogen, halogen, C1-6 alkyl, —CN, —OR ¹⁰ , —COR ¹⁰ , —OC (O) R ¹⁰ , —C (O) OR ¹⁰ , —C (0) N (R ^1o ) 2, -C (0) N (R ^1o ) S02R ¹⁰ , -N (R ^1o ) C (0) R ¹⁰ , -N (R ^1o ) C (0) 0R ¹⁰ , -N (R ^1o ) C ( 0) N (R ^1o ) 2, -N (R ^1o ) 2, -SO2R ¹⁰ , -S02N (R ^1o ) 2, -S02N (R ^1o ) C00R ¹⁰ , -S02N (R ^1o ) C (0) R ¹⁰ , -N (R ^1o ) SO2R ¹⁰ , - (C = O) NHOR ¹⁰ , C3-6 cycloalkyl ring, 4-8 membered heterocyclic ring, phenyl ring or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring or 5-6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C1-6 alkyl, each of said C _3-6 cycloalkyl rings, each of said 4 to 8 membered heterocyclic rings, each of said phenyl and each of said 5 to 6 membered heteroaryl rings are optionally and independently substituted with up to 3 substituents R ¹¹ ;

each R ^{10 is} independently selected from hydrogen, C1-6 alkyl, - (C1-6 alkyl) -R ¹³ , phenyl, benzyl, C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each A 5- or 6-membered heteroaryl ring or a 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, C _1-6 alkyl part of said fragment - (C _1-6 alkyl) -R ¹³ , each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4 A 7-membered heterocyclic ring and each 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 R ^11a ;

each R ^{13 is} independently selected from phenyl, benzyl, C _3-6 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring or 4-7 membered the heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents

- 25 038096 with R ^11b ;

each R ^{11 is} independently selected from halogen, oxo, C1-6 alkyl, -CN, -OR ¹² , -COR ¹² , -C (O) OR ¹² , -C (O) N (R ¹² ) 2, -N (R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, -SO ₂ R ¹² , —SO2N (R ¹² ) 2 or —N (R ¹² ) SO2R ¹² ; where each of said C1-6 alkyl is optionally and independently substituted with up to 6 fluoro substituents and / or 3 R ¹²¹ substituents;

each R ^{11a is} independently selected from halogen, oxo, C1-6 alkyl, -CN, -OR ¹² , -COR ¹² , -C (O) OR ¹² , -C (O) N (R ¹² ) 2, -N (R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, -SO ₂ R ¹² , —SO2N (R ¹² ) 2 or —N (R ¹² ) SO2R ¹² ; where each of said C1-6 alkyl is optionally and independently substituted with up to 6 fluoro substituents and / or 3 R ¹²¹ substituents; and each R ^{11b is} independently selected from halogen, C _1-6 alkyl, oxo, —CN, —OR ¹² , —COR ¹² , —C (O) OR ¹² , —C (O) N (R ¹² ) 2, —N (R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, - SO2R ¹² , —SO2N (R ¹² ) 2 or —N (R ¹² ) SO2R ¹² ; where each of said C1-6 alkyl is optionally and independently substituted with up to 6 fluoro substituents and / or 3 R ¹²¹ substituents;

each R ^{12 is} selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring or A 4-7 membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C _1-4 alkyl, C _1-4 (fluoroalkyl), -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH , —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 fluoroalkyl) or oxo;

each R ^{121 is} selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring or A 4-7 membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C _1-4 alkyl, C _1-4 (fluoroalkyl), -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH , —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 fluoroalkyl) or oxo;

R ^C1 is either

i) ring C; or ii) is selected from a pair of electrons on a nitrogen atom, hydrogen, halogen, oxo, -CN, C _1-6 aliphatic group, - (C _1-6 aliphatic group) - ^, -OR ⁷ , -OC (O) R ⁷ , -O (R ⁷ ) C (O) N (R ⁷ ) 2, -COR ⁷ , -C (O) OR ⁷ , -C (O) N (R ⁷ ) 2, -N (R ⁷ ) C ( O) R ⁷ , -N (R ⁷ ) C (O) OR ⁷ , -N (R ⁷ ) C (O) N (R ⁷ ) 2, -N (R ⁷ ) 2, -SR ⁷ , -S ( O) R ⁷ , -SO2R ⁷ , -SO2N (R ⁷ ) 2, -C (O) N (R ⁷ ) SO2R ⁷ , -SO2N (R ⁷ ) COOR ⁷ , -SO2N (R ⁷ ) C (O) R ⁷ or —N (R ⁷ ) SO2R ⁷ ; _{where each specified C1-6} aliphatic group, each C 1-6 aliphatic part of said - (C _1-6 aliphatic group) - ^, optionally and independently substituted with up to 6 fluoro substituents and up to 2 substituents -CN, -OR ⁸ , oxo, -N (R ⁸ ) 2, -N (R ⁸ ) C (O) R ⁸ , -N (R8) C (O) OR ⁸ , -N (R ⁸ ) C (O) N (R ⁸ ) 2, -SO ₂ R ⁸ , -SO2N (R ⁸ ) 2, -NHOR ⁸ , -SO ₂ N (R ⁸ ) COOR ⁸ , -SO2N (R ⁸ ) C (O) R ⁸ , -N (R ⁸ ) SO2R ⁸ ;

where each R ^{7 is} independently selected from hydrogen, C _1-6 alkyl, C _1-6 fluoroalkyl, C _3-8 cycloalkyl ring, phenyl, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each of said C _1-6 alkyl, each of said phenyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -COO ( C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

each R ^{8 is} independently selected from hydrogen, C _1-6 alkyl, C _1-6 fluoroalkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each of said C _1-6 alkyl, each of said phenyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C1 ₄ haloalkyl) or oxo;

each RN is independently selected from a phenyl ring, a monocyclic 5- or 6-membered heteroaryl ring, a monocyclic C _3-6 cycloaliphatic ring, or a monocyclic 4-6 membered heterocycle; where the specified monocyclic 5- or 6-membered heteroaryl ring or uc

- 26 038096 knitted monocyclic 4-6 membered heterocycle contains from 1 to 4 heteroatoms selected from N, O or S; where the specified monocyclic 5- or 6-membered heteroaryl ring is not a 1,3,5-triazinyl ring; and wherein said phenyl, said monocyclic 5-6 membered heteroaryl ring, said monocyclic C _3-6 cycloaliphatic ring, or said monocyclic 4-6 membered heterocycle is optionally and independently substituted with up to 6 fluoro substituents and / or up to 3 J ^M substituents;

each J ^{M is} independently selected from —CN, C1-6 aliphatic, —OR ^M , —SR ^M , —N (R ^M ) 2, C3-8 cycloaliphatic ring, or 4-8 membered heterocyclic ring; where the specified 4-8-membered heterocyclic ring contains 1 or 2 heteroatoms independently selected from N, O or S; where each specified ^^ aliphatic group, each specified C _3-8 cycloaliphatic ring and each specified 4-8 membered heterocyclic ring is optionally and independently substituted with up to 3 substituents R ^7c ;

each R ^{M is} independently selected from hydrogen, Cl _-6 aliphatic, C _3-8 cycloaliphatic ring, or 4-8 membered heterocyclic ring; where each specified 4-8-membered heterocyclic ring contains from 1 to 3 heteroatoms independently selected from O, N or S; and where ring C is a phenyl ring, a monocyclic 5- or 6-membered heteroaryl ring, a bicyclic 8-10 membered heteroaryl ring, a monocyclic 3-10 membered cycloaliphatic ring, or a monocyclic 4-10 membered heterocycle; wherein said monocyclic 5 or 6 membered heteroaryl ring, said bicyclic 8-10 membered heteroaryl ring or said monocyclic 4-10 membered heterocycle contains 1 to 4 heteroatoms selected from N, O or S; where the specified monocyclic 5- or 6-membered heteroaryl ring is not a 1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5-6 membered heteroaryl ring, bicyclic 8-10 membered heteroaryl ring, monocyclic 3-10 membered cycloaliphatic ring or monocyclic 4-10 membered heterocycle are optionally and independently substituted up to p with substituents J ^C ;

where p denotes 0 or an integer selected from 1, 2 or 3;

each J ^{C is} independently selected from halogen, —CN, —NO2, ^ aliphatic, —OR ^H , —SR ^H , —N (R ^h ) ₂ , C _3-8 cycloaliphatic ring, or 4-8 membered heterocyclic ring; where the specified 48-membered heterocyclic ring contains 1 or 2 heteroatoms, independently selected from N, O or S; where each specified Cl _-6 aliphatic group, each specified C _3-8 cycloaliphatic ring and each specified 4-8 membered heterocyclic ring is optionally and independently substituted with up to 3 substituents R ^7d ; or alternatively, two J ^C groups attached to two vicinal ring C atoms, taken together with said two vicinal ring C atoms, form a 5-7 membered heterocycle, which is a new ring fused to ring C; where the specified 5-7-membered heterocycle contains from 1 to 2 heteroatoms independently selected from N, O or S;

each R ^{H is} independently selected from hydrogen, a N-aliphatic group, a C3-8 cycloaliphatic ring, or a 4-8 membered heterocyclic ring; where each specified 4-8 membered heterocyclic ring contains from 1 to 3 heteroatoms independently selected from O, N or S; alternatively, two R ^H substituents bonded to the same nitrogen atom —N (R ^H ) 2 together with said nitrogen atom —N (R ^h ) ₂ form a 4-8 membered heterocyclic ring or a 5 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

each R ^{7c is} independently selected from halogen, -CN, -NO2, Cl-4alkyl, Cl-4haloalkyl, C3-8cycloalkyl ring, -OR ^8b , -SR ^8b , -N (R ^8b ) 2, -C (O) O ( Cl _-4 alkyl), -C (O) OH, -NR (CO) CO (Cl _-4 alkyl) or oxo; where each said cycloalkyl group is optionally and independently substituted with up to 3 halogen substituents;

each R ^{7d is} independently selected from halogen, -CN, -NO2, Cl-4alkyl, Cl-4haloalkyl, C3-8cycloalkyl ring, -C (O) O (Cl-4alkyl), -C (O) OH, -OR ^8c , -SR ^8c , -N (R ^8c ) 2 or oxo; where each said cycloalkyl group is optionally and independently substituted with up to 3 halogen substituents;

each R ^{8b is} independently selected from hydrogen, Cl _-6 alkyl, Cl _-6 fluoroalkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each of said Cl _-6 alkyl, each of said phenyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring, optionally and independently substituted with up to 3 substituents with halogen, Cl _-4 alkyl, OH, -NH2, -NH (Cl _-4 alkyl), -N (Cl _-4 alkyl) ₂ , -CN, -COOH, -COO (Cl _-4 alkyl), -O (Cl _-4 alkyl), -O (C1 ₄ haloalkyl) or oxo;

each R ^{8c is} independently selected from hydrogen, C _1-6 alkyl, C _1-6 fluoroalkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring

- 27 038096 contain up to 4 ring heteroatoms independently selected from N, O and S; and where each of said C _1-6 alkyl, each of said phenyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen, C _1-4 α-alkyl, OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -COO (C _1-4 αalkyl), -O (C _1-4 alkyl), -O (C ₁ .

₄ haloalkyl) or oxo; and

R ^{c2 is} selected from a pair of electrons on a nitrogen, hydrogen, halogen atom, -OH, -O (C _1-6 alkyl), -O (haloC _1-6 alkyl), -O (C _1-6 haloalkyl), -O ( cyclopropyl), cyclopropyl, C _1-6 alkyl, C _1-6 haloalkyl and —CN.

Table X

- 28 038096

(l X {I ^ 4 ^ Ν 4 ^Ν L? ^Ν Γ to ην- ^ν _ς _ ₁₅ ^Ν к ^ ΝΗ ^H2 Wo II Me 0 1-16 Ι> (I ^ Χ ^ -Ν Τ Ν V> Br NnMe Ν ΝΗ EtO ₂ C ζ-18 Α λ) X .Ν X? ”RX, .., , 4-Ν Ν u ⁰ ο 1-20 , X ° 'r. h Αι ^ ν ^ Ν ι> kC <XNN ₂ - <K θ 1-21 > Αη ^{Η2 H} W # \ νη ₂ 0 ² χ-22 ... X ° ._. N O H-N Ν \\ -Λ Ν · 4 ,% ΝΗ Η ₂ Ν 'Λ-Α λ ⁰ 1-23 ^ Λ-νη Χ ⁰ 1-24 ? λ) - ._Ν L? , χ - ^Ο _.Ν Q ¹ 4-Ν Ν _V ΝΗ XX ⁰ 1-25 Ν ⁴ Me Ν '1-26 ... Ae - ° .Ν A <X ΝΗ λ 1-27 , λ) ^U N ^Ν Γ V ΝΗ Η ° 'JVA \ ⁰ 1-28 5E ^Η0 _.Ν Ο V ° XN ^F Ο Λ y ^^ ΝΗ Χ-Ν ^Ν / K Ы ln X ⁰ 1-29 η ₂ ν ^ζ ΎΑ λ ⁰ 1-30

- 29 038096

^f О Cn С к% ΝΗ 1-31 To . V ° ^ N ^f X? xv V nh Ho RY λ ⁰ 1-32 rO -To - ...% I? -Η? Li ^N »Y ^{n N} ,% ί ^ ΝΗ RR ° 1-33 RR ⁰ 1-34 .- .. o A O V> ^E IL? A ^ NH c - ^ / NH X ^ ° 1-35 UuS 1-36 rA J \ XD --0 / - Ye N X T> N nX N l \ ⁰ 1-37 s ^V k \ ⁰ 1-38 F A-vx g 1% 0 Λ - ° x - N TA ^ N ' Ύ V ^ NH Br \ Vk V ^ NH X ^ ° 1-39 X A 1-40 "A X? about A - °, -N X? with k - <NH H ₂ N Ύ ⁰ 1-41 RV И0 Jv-I ⁰ 1-42 o CX - ° _V -N X? Vo ex - ° X ^ X? ^Cl \ e V W / NH XR 1-43 RV W / NH Χγό _ς _ _{44 K} ex, -NL? Pa XX ^{N n} R A ^ NH M ^{z /} ) ^ ΖΊμη XX 1-45 <7 ^H Υ ο k / 1 1-46

- 30 038096

- 31 038096

- 32 038096

[GU N An aA A ° 1-81 ¹ / ° 4r УЧ у - \ _ / 00 ΙΌ γΑ J 0 / Т> Ν ί ^ - ΝΗ but 'AA P ⁰ 1-83 ; o о N An AA H ₂ N AA A θ 1-84 00 (l F v> N A ^{NH H} ° ^z AA ”T ⁰ 1-86 De X ^ N X N ^NH - NH H ₂ N aA Ά ⁰ 1-87 λ) CK ^H ° ^z AA A ⁰ 1-88 Lo A -¾ 1-89 F aO NC J T> N ⁿ A AA ^NH 1-90 x - °. A Yy N Lu ^ν αΎαλ ^ 1-91 Γ / Ϊ LA An O-NH Η2Ν ^/ ) γΑ ₀ ^z \ 1-92 X ^N A ^/? ₀ ГVn ^U _t __N LA ^N Y ^ / ^ NH ^h ° vA A ⁰ 1-93 ₀ rVN - ^O - _r _-N LA N ' ^Z y .. 4 ^ 0 1-94

In some of the above embodiments, the compound is a compound selected from table. XX below.

Table XX

F ₄ aCa -v LA chi „4> La χι-z k.An n. 4 Vm · '—4 ^{N n} AOy ° F ^F n-nh

- 33 038096

- 34 038096

In some embodiments of the invention, the compound is a compound selected from table. XXX, below, or a pharmaceutical salt thereof .:

Table XXX

° 'N A , Α Q Αν he F XXI-1 F oA V \ A ° AL F XXI- 15 0-n A ν- ^Ν Q XXI-2 F / A aO X XXI- Χν ψ-γ F ' χΑο '''^ ³ F 16 Ο-Ν F rO AQN ^ _o X ° ^C F XXI-3 > A ^ A_-N W o g / X / -Ας ^N χΧ ° X F XXI- 17 θ-Ν λΧ F rO ^N aL 1? i a X) A-An LX XXI- ^N Ά aa ⁿ > w ^ o \ _ / eighteen θ'Ν Λ X F F X) Tl \ i Ci A AA ^ Tl \ i XXI- La Xn X> ^h ^ Λ ⁷ F XXI-5 X ^N Xn ( ^N -T <° ^ X F 19 θ-Ν λΧ F X) LX XXI-6 F, Ct A / a-Am O z ^ N \ NH XXI- twenty X L F F

- 35 038096

F λ ^ν aJ If fl - C0 ₂ Me F F a A i> .An A F F / ° ' ⁿ Al ·) T> AA ” ⁰ m A n A F F a. A If \ 1 — NBoc F F X / λ A ⁰ kA ⁿ nA tl ^ A ⁰ F XXI-7 XXI-8 XXI-9 XXI-10 XXI-11 AU Λ A ⁿ \ Ng ^{Z N} ^% O ^Z 0¾ F AU Q Д OMe A ⁿ ° A ^N \ A ^ _A \ A <nIn • nXn I JL ^ι: Α · ^0Η th ..... A L / ^{n 0} V ⁰ A_ F XXI- 21 XXI- 23 XXI- 24 XXI- 25 XXI- 26 f a A <Ji f W. 0 V A A ^N i) ^N ^ YcA F XXI-12 ... N ^ N 0 COOH L if U 1 ) and XXI- 27 ^F \ an a! ) / <Il ГМ LA I NH An \) N \\ A \ 7-0 F XXI-13 R A A LA N V --A \ ^ A ° F XXI- thirty ΞΓ XXI-14 AA 4 ^N A zA A ° 7Z ^CF3 F XXI- 32

- 36 038096

In some embodiments, the implementation of the above methods, uses, compositions and kits, the sGC stimulant is a compound indicated in the table. IV or tab. XIV.

Table IV

- 37 038096

(1 о _ν Αν ^ΗΝ -Λ, 0 М.0 \ 22 (1 Ύ An HN, NH 24 Ol o M% M HN, U ^Me 0 ^X N 29 {I λ) o % b θ 37 (x λ) M ^N An N \\ / N ^ ° o ^ AT (°., <A M II An M / F 109 {I ^V VN b M 110 (I AE at Mnh N V cL ° F 111 X 0-N [AVN Mj ^N 7 F 142 P ^ N Μ? D andShG ^N O M'N NV M'-OH F 143 R Pn E) vL ⁿ L / MN ^N ,% C / '- IN ₂ F 146 p ^N C AM-QH 186 6 .A? N ^ N CH-OH 189 , „,% Z% N Μ / n A F 144 OH C ^N N ^ V ^0H F 182 ^N p AM OH F 187 6, ^ ν n - ^N AM-on F 190 <Pij Ap LI \ ^ / NH ₂ 145 Λ 7 = \ Ad / —4 Ac γιΑΑ M ^{N N} V AMon F 185 A / = \ aa / II · YN M. N ^; N AMon 188 (I, Α) A _v n ^ Noh ° = <L 191

- 38 038096

l Jo o Ohl, 192 Λν dE O ^N CF ₃ 205 o D u H ^ / nh ₂ 207 An / = \ Jo / C / U-N Μ ъ H An about V / = X Jo / - ζ J ^- F ^Ν η n'N _N ON OO-he 1 H ^ y ^ -OH OD-OH 197 208 213 B ' VN 0 ^N A i ° ^N V 0 [ | D | < _N ON OjOoH TO _0H D ~ He 212 211 214 ύ, A A <° ' ^NN = \ Ei / - (\ / o X about -Y _n On OO-OH On n / a ^ / ^ - nh ₂ D _y OEt F 216 F 215 about 209

Table XIV

- 39 038096

O _V N 4 θ Λ K _NHi UhfZ ^oh F 20 A λ) A-AK.N T> Br U 0 n ^ I. A ™ H HO ^CF 3 F 25 A / A -N Λ ^Ν A \ AnA- ^CF 3 SH OH F 26 A 4 ^N h C OH 27 A L? „An 0 TsAn-Ts p OH 28 aAe N An cf _3N h ₂ ΑΑνΆΑ AH he o F 30 A u> U A ο hz ° nH ΑΑΑ a _ci 32 A A> OAA 33 th A A N A uA-nA 1 bj 34 A A about CASA H Me 35 A A ° nA kA And m7 ° n 36 _r A ^ AA V ^N ,, W'C0, H N und AA 38 F ₄ An αΓΊ? AV A ¹ An 1 CH / Λ'χο, Η X hn-A F 39 AA ^ A ⁿ Av> conh ₂ \ hnA F 40 a C ^{N Ν <ί} V '5 <- ·' 3 Λ HN — D 41 • H and _T L? A n ^N -, - NH ₂ QA ”42 * A A hAn U-N'U a An 7 F o ^z -— ^/ 43 F °. _N to jl AU A N ^ 'l N ACA ^r OH 44 A V in An t ύ ^Η V-ЛЧ H 45 A ^ ° L? O v о H O-A ^ 'αά 46 a 4 4 „Y < _z nh ₂ a 47 F / ° - ^N <J [AU A ._. N V A LS ^ ¹ * ² / N i M eh Me ^Me F 48 A 4 0 Ai xA ^0H Un \ U 49 A I? A о Am ⁰ AnA H 50

- 40 038096

Ci A 0 Αϊ to / ™? ^ ^l d / 4 51 UX X? X AO n _M > N a_J'-N 7 _0H V n Zh Y ^f f ^f 52 cvX L? „.In n Ж ^Кн ^ 4 F ~ \ - ^NH 2 0 54 th Aj 4-Жы О Xn nh ₂ N \\ О'Ж \ АЧ X χ ^ζ H k ... F 55 F / ½ Jn yX HJ A ⁿ Xk Railway / conh ₂ 1 nV ^H Me ^z 0 56 F. ° ⁿ € v _n / AJ X ^N A ' ^{c 0 N Ng F} OMe 57 l 4> 44k _N 4 "o ^{N. z} X ΚΛνη m, 59 (IX X - \, N T? X ^ Ov F NH ₂ 60 Ci A) T? 4 ° x ^H X χΧι XX / ^N yf ^{cl = 3 F} nn 62 L O. _N Г4 ur ^ О 'N'T 41 “^ Mih he 64 a 4 Г, /; / α h but cf ₃ F 65 Λ) a-a, n Xx AvX- 4 = / L Me Me 66 Cl X 44k n iX Vn, nh ₂ να 67 Ci XX Xn, nh ₂ ^N 'W. a- <C z NO H F 68 f! .-Oh „X? A 1-NX? V "X ^h 69 F and / 0, .. N 4 "A-Zhm j. ^H Ό 70 .1 4 Α_ν ΙΛν ^ 4 NH F λ CF ₃ 71 F _x ? x3 A ^ n lx ^ Χν ^ ^0Η X / h _Z V— 72 ? DZ -4 / .N X? Λ ⁰ _M X XoH \ / 73 F !? rO -41 n X? A 0 Xn \ / - 74 a '' '> Il N 4 ^ 1/4 ° a-./N 75 F ° vO -4 /. N L> A ° 1 O- _n ^ 'NH ₂ Λ HF 76 ϊ 4 XX ^N 1 A / 1 NH F 77 F? AE -Ά_.ν LX A vA-n ^ a X </ ^so * 78

- 41 038096

- 42 038096

<Ά_-Ν An NH ₂ \ _An - \ A F ^F 106 F P'N DD} ^ Vn HO * к -к AkAk T ^H a 107 ^a k An ukNAVF A \ <F 108 Λ nk AA ^N А / F - ^/ 112 A kk A ^ Ay F A / V 113 a kk and L tk'N yF to F 114 : A A A AF 115 A kk A An oh Ά < 116 A v A ^H0 VAn ^ A v / A F 117 A ik chk Akch F ^V 118 A kk kv D F 119 l ke ik VA-na A '--A ^ 120 A _r N A A ^ Ah ^F (Ar 121 A λ> V ΐ ΑνΛ A x ° n "H 122 A k) kA q _n Q% H ₀ > 0H 123 A D> > 4 t ΑνΛ A V N ^ F 124 A kk kl nk ^ on ΐ / An λ ⁿ F 125 ! Λ 4 nA As ^ ³ Au ^s F 126 E / ° 'N AA Al', cf ₃ I? A ^N (, 0H АЧ Y ^H 127 , 0-N А <к / Anh АА F 128 i / О ^ VN An, nh ₂ AAA 129 (1 λ) л ^ ιΑ ^Η0 ^ θ An NH N 'VA Γ7 U / N / A h' d 130 A kE ^ kts'm ^Η ° <γθ An nh ^N 'A z— < _Γ u / N aA A h -A 131 A X) 4k% kk A A h 132

- 43 038096

u> Q ₀ D Di F 133 / ⁿ oJJ Y A AAA HO ^ A_, n A T _z N D ⁰ b O- N \\ / -V l An \ ^H F 134 F. o aJJ Α, ν o ^N f An ^ A ^0H AH 135 and O -A_-N JO nA? ⁿ F O ^ 136 l A О O ⁿ Ν Λ HO U> NH \ ' _d - 137 o o ^ A Ayr ⁵ ° d L A TO Ν X ^ x TsAN 1 F OO ^С00Н О 139 l 0 oA ^ I L> o ^ A / -n F 140 x> 4 ⁿ apA ^Fi F 141 jo Ο-n € OO a ⁿ dao ,. F 147 F · .- JO 0-NJ A JL N MeS ^ OO) i OH> - ⁷ ANH F 150 ^F -xx Jo pN GAL A jOA O 'nh ₂ } = N / -AA N ^ / A ^NH F 153 ^F X ---- X JO PN I ² - · 'OAO A) ^N O nh ₂ / = N _/ —A AnH F ¹ 156 JO 0-N YES AAn o _) = n _y —ζ Anh ₂ n Anh A (A (OH F 159 ,. D oo OJ / M - <OH / - / Anh F 148 ^Fx X- ^ X JO к jLA (AN) MJ OH> - ⁷ Ν _λ Anh f 151 ^F X, ---- X JO PN [> An nh ₂ ) = n _/ -A n ^ AnhJ ^ F 154 0 4 О (° = </) = N) - (N ^ ^ N ^ _p F 157 JO 0-N 4Aa Ay _ 0 ../) = ^N / - (AinDz ^N Anh ⁴ - (OH F 160 ^F X ^ x JO 0-N xJAa \ A Ox / - ^{/ N} \ y ^NH F 149 F, - JO pN% D _N \ ^ O ^N ) A i OH A '/ - ^{/ N} \ y ^NH F 152 ^F x - x JcJ 0-N ^ JAx AN A? _N h ₂ A / —YES p> —NH IF 155 JO ο-NA ^w rQ vo <> у NN— ^/ О, ° l A A a N ^^ i— ^NH F 158 20 0-NC YES ^ A _ o ^ PA ⁿ / -YES ^1-1 '' N p-NH \ - (A OH 161

- 44 038096

p- O c °) EZEa XT L. A o / = Ν / - ^/ γ ~ NH F 162 JO pN xXX A An / - N ^ ^ ^NH F 163 JO 0-N y ₀ E) = N _g - ^Z y γ NH 164 JO ON / (Hell yA N ^ O ^NH F 165 XJ pN r ¹ ^ Oj: en χ ^{7 N} O ^N 1 F 166 Fx ^ X) pN y JE.n ^ 0 ⁿ X, ^ OH OX F 167 Fv.-. 0-N XX OH VAa ./A, Y Y C Voh An / - (Y ^0H F 168 F._ XJ pN JOT> = N ^ OH ⁿ O ⁿ O \ ΌΗ F 169 X) pN Ϋ zeeE X ^N / - \ p ~ ^0H N, __ N— ^/ F 170 Fv ^ JO pN Ae ........- n A ^N / -У N _y i-N AcCyMe F 171 XJ pN ί ^:: · - Ё jk.N E ⁿ о '- (V0Me) = ^N f ^{f n} O \ F 172 n X X X ⁿ / ~ \ ⁿ \% ⁿ / ° F ΰ NH ₂ 173 Fx ^ JO pN 4 AA Y OMe 0 ^N / - 'Ό \ A ^nh F 174 Fv ^. XJ pN Y Ё ЗЕТ, X _Z N C0 ₂ Me X ^N ^ NH F 175 JO pN У 3E.A / ^0H X ⁿ / - y — NH F 176 Fv ^ X) 0-N r ^: > C E and o nh ₂ % _r N A ⁿ _x / - ^z P — NH F 177 XL? O ~ N Έ3Ε ^ ν / —nh ₂ ^ E ^N / 7 X ^N / - ν. ^ Υ ^νη 178 F „j? yO OO ⁿ EEn ^ -X XV ^ XCOOH F 179 .l te x? U / ^k NA Af HF 180 F ₄ ? DE X \ ^ N O ^ Οχ. -L. A ZN V E ___ / - COOH F 181 L O on X ^N Xn p ^H N l HAUL E / En / X. E xy 183 F ^^ r ^ OH z ° -N XT E Η f N (J On oh eayA 184 / = ^ ⁵ y 'Y F ⁰ On χο about A _g ^on YX ^nhz 194

- 45 038096

In some embodiments of the above methods, uses, pharmaceutical compositions, and kits, the sGC stimulant is a compound according to Formula IA, or a pharmaceutically acceptable salt thereof

Formula IA where X is selected from N, CH, C (C _1-4 alkyl), C (C _1-4 haloalkyl), CCl and CF;

ring B is a phenyl or 6-membered heteroaryl ring containing 1 or 2 ring nitrogen atoms, or ring B is thiophene;

n is 0 or an integer selected from 1 to 3;

each J ^{B is} independently selected from halogen, —CN, C1-6 aliphatic, —OR ^B, or C3-8 cycloaliphatic; wherein each of said C _1-6 aliphatic group and each of said C _3-8 cycloaliphatic ring are optionally substituted with up to 3 halogen substituents;

each R ^{B is} independently selected from hydrogen, a C1-6 aliphatic group, or a C3-8 cycloaliphatic ring; where each of said R ^B , which is a C1-6 aliphatic group, and each of said R ^B , which is a C3-8 cycloaliphatic ring, optionally substituted with up to 3 halogen substituents;

J ^{A is} selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or —NR ^a R ^b , where R ^a and R ^b are each independently selected from hydrogen, C _1-6 alkyl, or a 3-6 cycloalkyl ring;

J ^D is hydrogen or selected from halogen, —CN, —CF ₃ , methoxy, trifluoromethoxy, nitro, amino, or methyl;

R ¹ and R ² , together with the nitrogen atom to which they are attached, form a 4-8 membered heterocyclic ring or a 5- or 6-membered heteroaryl ring; wherein said 4-8 membered heterocyclic ring or said 5 or 6 membered heteroaryl ring optionally contains, in addition to the nitrogen atom to which R ¹ and R ^{2 are} attached, up to 3 heteroatoms independently selected from N, O or S, and optionally substituted with up to 5 substituents R ⁵ ; or alternatively, R ¹ and R ² are each independently selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl

- 46 038096 rings, 4-8 membered heterocyclic ring, 5- or 6-membered heteroaryl or C _1-6 alkyl-R ^Y ; where each of the specified 4-8-membered heterocyclic ring and each of the specified 5- or 6-membered heteroaryl ring contain up to 3 heteroatoms independently selected from N, O and S; and where each of said C1-6 alkyl, each of said C3-8 cycloalkyl ring, each of said 4-8 membered heterocyclic ring group, each of said 5 or 6 membered heteroaryl, and each of said C1-6 alkyl portion of each of said C1-6 alkyl —R ^{Y is} optionally and independently substituted with up to 5 R ^5a ; with the proviso that R ¹ and R ² are not simultaneously hydrogen; and with the proviso that when X is one of CH, C (C1-4 alkyl), C (C _1-4 haloalkyl), CCl, or CF, none of R ¹ and R ² is pyridine or pyrimidine; or alternatively, J ^D and one of R ¹ or R ² can form a 5-6 membered heterocyclic ring containing up to two heteroatoms selected from O, N and S and optionally substituted with up to 3 oxo or - (Y) -R substituents ⁹ ;

where Y is either absent or represents a bond in the form of a C _1-6 alkyl chain optionally substituted with up to 6 fluoro substituents;

each R ^{9 is} independently selected from hydrogen, fluorine, -CN, -OR ¹⁰ , -SR ¹⁰ , -COR ¹⁰ , -OC (O) R ¹⁰ , -C (O) OR ¹⁰ , -C (0) N (R ¹⁰ ) 2, -C (0) N (R ¹⁰ ) S02R ¹⁰ , -N (R ¹⁰ ) C (0) R ¹⁰ , -N (R ¹⁰ ) C (0) OR ¹⁰ , -N (R ¹⁰ ) C ( 0) N (R ¹⁰ ) 2, -N (R ¹⁰ ) 2, -SO2R ¹⁰ , -SO2N (R ¹⁰ ) 2, -SO2N (R ¹⁰ ) COOR ¹⁰ , -S02N (R ¹⁰ ) C (0) R ¹⁰ , -N (R ¹⁰ ) SO2R ¹⁰ , - (C = O) NHOR ¹⁰ , C3-6 cycloalkyl ring, 4-8 membered heterocyclic ring or 5-6 membered heteroaryl ring;

where each said 4-8 membered heterocyclic ring and each said 5-6 membered heteroaromatic ring contain up to 4 ring heteroatoms independently selected from N, O or S; and where each said C _3-6 cycloalkyl ring, each said 4-8 membered heterocyclic ring, and each said 5-6 membered heteroaromatic ring are optionally substituted with up to 3 R ¹¹ substituents;

each R ^{11 is} independently selected from halogen, C1-6 alkyl, —CN, —OR ¹² , —SR ¹² , —COR ¹² , —OC (O) R ¹² , —C (O) OR ¹² , —C (O) N ( R ¹² ) 2, -C (O) N (R ¹² ) SO2R ¹² , -N (R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, -SO2R ¹² , -SO2N (R ¹² ) 2, -SO2N (R ¹² ) COOR ¹² , -SO2N (R ¹² ) C (O) R ¹² , -N (R ¹² ) SO2 R ¹² and -N = OR ¹² ; where each of said C1-6 alkyl is optionally and independently substituted with up to 3 fluoro substituents, —OH, —O (C14 alkyl), phenyl, or —O (C _1-4 fluoroalkyl);

where each R ^{10 is} independently selected from hydrogen, C1-6 alkyl, phenyl, benzyl, C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring, and each said 4-7 membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C1-6 alkyl, each said phenyl, each said benzyl, each said C3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C1-4alkyl, C1-4 (fluoroalkyl), -OH, -NH2, -NH (C1-4alkyl), -N (C1-4alkyl) 2, -CN, -COOH, -COO (C1-4alkyl), -O (C1-4alkyl), -O (C1-4fluoroalkyl) or oxo; and where each R ^{12 is} independently selected from hydrogen, C1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring and each said 4-7 membered heterocyclic ring contain up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C _1-4 alkyl, C _1-4 (fluoroalkyl), -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH , —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 fluoroalkyl) or oxo;

R ^{Y is} selected from C _3-8 cycloalkyl ring, 4-8 membered heterocyclic ring, phenyl, or 56 membered heteroaromatic ring; where each of said 4-8 membered heterocyclic ring and each of said 5-6 membered heteroaromatic ring contain up to 4 ring heteroatoms independently selected from N, O or S; and where each of said C _3-8 cycloalkyl ring, each of said 4-8 membered heterocyclic ring, each of said phenyl and each of said 5-6 membered heteroaromatic ring is optionally substituted with up to 5 R ^5c substituents;

each R ^{5c is} independently selected from halogen, —CN, C1-6 alkyl, —OR6 ^b , —SR6 ^b , —COR ^6b , —OC (O) R6 ^b , —C (O) OR ^6b , —C (O) N ( R ^6b ) 2, -C (O) N (R ^6b ) SO2R ^bb , -N (R ^bb ) C (O) R ^6b , -N (R ^6b ) C (O) OR ^bb , -N (R ^6b ) С (O) N (R ^6b ) 2, -N (R ^6b ) 2, -SO2R6 ³ , -SO2N (R6 ^b ) 2, -SO2N (R ^6b ) COOR6 ^b , -SO2N (R ^bb ) С (O) R ^bb , -N (R ^6b ) SO2R ^6b , - (C = O) NHOR ^6b , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, phenyl, benzyl, oxo group or a bicyclic group; where each of said 5- or 6-membered heteroaryl ring and each of said 4-7-membered heterocyclic ring contain up to 4 ring heteroatoms independently selected from N, O and S; and where each of said C1-6 alkyl, each of said C _3-8 cycloalkyl ring, each of said 4-7 membered heterocyclic ring, each of said 5- or 6-membered heteroaryl ring, each of said benzyl and each of said phenyl group is optionally and independently substituted with up to 3

- 47 038096 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -H (C _1-4 alkyl) 2, -CN, -COOH, -COO (C _{1 -4} alkyl), -O (C _1-4 alkyl), -O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains a first ring and a second ring fused or bridged, wherein said first ring is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said second ring is phenyl a ring or a 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

each R ^{ft is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring and each of said 4-7 membered heterocyclic ring contain up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -COO (C _{1- 4} alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; or two R ^5c substituents attached to the same and different ring atoms RY together with said ring atom or atoms can form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system where the two rings are spiro-linked, fused or bridged, wherein said 4-6-membered heterocycle or said 5- or 6-membered heteroaryl ring contains up to three heteroatoms independently selected from N, O, or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkoxy, C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -NR (CO) CO (C _1-4 alkyl), -OH or halogen ; where R "is hydrogen or C _1-2 alkyl;

each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, —OR ^6a , —SR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , —C (O) N ( R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) C (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, phenyl, benzyl, oxo group or a bicyclic group; where each 5- or 6-membered heteroaryl ring and each of said 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, where each of said C1-6 alkyl, C _3-8 cycloalkyl ring , 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, benzyl or phenyl group optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -NH2, - NH (C _1-4 alkyl), -N (C _1-4 alkyl) _2, -CN, -COOH, -COO (C 1-4 alkyl), -O (C _1-4 alkyl), -O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is phenyl a ring or 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

each R ^{6a is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -C (O) NH ₂ , -C (O) N (C _1-6 alkyl) ₂ , -C (O) NH (C _1-6 alkyl), -C (O) N (C _1-6 haloalkyl) ₂ , -C (O) NH (C _1-6 haloalkyl), C (O) N (C _1-6 alkyl) (C _1-6 haloalkyl), -COO (C _1-6 alkyl), -COO (C _1-6 haloalkyl), -O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo, wherein each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; or when one of R ¹ or R ² is a C3-8 cycloalkyl ring, a 4-8 membered heterocyclic ring, or a 5 or 6 membered heteroaryl substituted with up to 5 R ^5a substituents, two R ^5a substituents attached thereto and different ring atoms of said R ¹ or R ² , together with said atom or atoms, optionally can form a C3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5- or 6-membered heterocyclic ring, in re

- 48 038096 resulting in a bicyclic system where the two rings are spiro connected, fused or bridged, wherein said 4-6 membered heterocycle or said 5 or 6 membered heterocyclic ring contains up to two ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5- or 6-membered heterocyclic ring is optionally substituted with up to 2 substituents C _1-4 alkyl, C _1-4 haloalkyl, oxo, - (CO ) CO (C _1-4 alkyl), —NR '(CO) CO (C _1-4 alkyl) or halogen; where R 'is hydrogen or C _1-2 alkyl;

each R ^{5 is} independently selected from halogen, —CN, C1-6 alkyl, —OR ⁶ , —SR ⁶ , —COR ⁶ , —OC (O) R ⁶ , —C (O) OR ⁶ , —C (O) N ( R ⁶ ) 2, -C (O) N (R ⁶ ) SO2R ⁶ , -N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) C (O) OR ⁶ , -N (R ⁶ ) C (O) N (R ⁶ ) 2, -N (R ⁶ ) 2, -SO2R ⁶ , -SO2N (R ⁶ ) 2, -SO2N (R ⁶ ) COOR ⁶ , -SO2N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) SO2R ⁶ , - (C = O) NHOR ⁶ , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic groups; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each of said C1-6 alkyl, each of said C _3-8 cycloalkyl ring, each of said 4-7 membered heterocyclic ring, each of said 5 or 6 membered heteroaryl ring, each of said benzyl or each of said phenyl group is optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is phenyl a ring or 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

each R ^{6 is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, or 4-7 membered heterocyclic ring, 5 or 6 membered heteroaryl ring; where each of said 5- or 6-membered heteroaryl ring and each of said 4-7-membered heterocyclic ring contain up to 4 ring heteroatoms independently selected from N, O and S; and where each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6- member heteroaryl ring optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH , —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; or when R ¹ and R ² attached to a nitrogen atom form a 4-8 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring substituted with up to 5 substituents R ⁵ , two R ⁵ substituents attached to the same or different atoms of the specified ring, together with the specified atom or atoms, can optionally form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; phenyl or 5- or 6-membered heteroaryl ring, resulting in the formation of a bicyclic system, where the two rings of the bicyclic system are connected spiro, fused or linked by a bridge, where the specified 4-6-membered heterocycle or the specified 5- or 6-membered heteroaryl ring contain up to three ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, said 4-6 membered heterocyclic ring, said phenyl or said 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -NR (CO) CO (C _1-4 alkyl), - OH or halogen; where R represents hydrogen or C _1-2 alkyl;

p denotes an integer selected from 0, 1 or 2;

ring C is a monocyclic 5-membered heteroaryl ring containing up to 4 ring heteroatoms selected from N, O, or S; where the specified monocyclic 5-membered heteroaryl ring is not a 1,3,5-triazinyl ring;

each J ^{C is} independently selected from halogen or a C _1-4 aliphatic group optionally and independently substituted with up to 3 C _1-4 alkoxy, C _1-4 haloalkoxy, oxo, —C (O) O (C _1-4 alkyl) substituents, —C (O) OH, —NR (CO) CO (C _1-4 alkyl), —OH, or halogen.

In other embodiments of the above methods, uses, compositions, and kits, the sGC stimulant is a compound of Formula IB

- 49 038096

Formula IB;

where J ^{D is} selected from hydrogen or halogen;

J ^B is halogen, and

R ¹ and R ² together with the nitrogen atom to which they are attached form a 4 to 8 membered heterocyclic ring or a 5 membered heteroaryl ring; wherein said 4-8 membered heterocyclic ring or said 5-membered heteroaryl ring optionally contain, in addition to the nitrogen atom to which R ¹ and R ^{2 are} attached, up to 3 heteroatoms independently selected from N, O or S, and optionally substituted with up to 5 substituents R ^5e ;

each R ^{5e is} independently selected from halogen, —CN, C1.6 alkyl, - (C1.4 alkyl) —R ⁶ , C3. ₈ cycloalkyl ring, C1-4cyanoαlkylα, -OR ⁶ , -SR ⁶ , -OCOR ⁶ , -COR ⁶ , -C (O) OR ⁶ , -C (O) N (R ⁶ ) 2, -N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) 2, -SO2R ⁶ , -SO2OH, -SO2NHOH, -SO2N (R ⁶ ) COR ⁶ , -SO2N (R ⁶ ) 2, -N (R ⁶ ) SO2R ⁶ , benzyl, phenyl or oxo; where each said phenyl ring and each said benzyl group is optionally and independently substituted with up to 3 substituents with halogen, -OH, -NH2, -NH (C1.4alkyl), -N (C1.4alkyl) 2, -CN, C1.4alkyl, C1 .4haloalkyl, —O (C1.4alkyl) or —O (C1.4haloalkyl); and wherein each said C1.6alkil each C1-4 alkyl moiety of said - (C1.4alkil) -R ⁶ fragment and each designated C3. _{The 8} cycloalkyl ring is optionally and independently substituted with up to 3 halogen substituents; where each R ^{6 is} independently selected from hydrogen, C ₁ . ₆ alkyl, C ₂ . ₄ alkenyl, phenyl, benzyl or C ₃ . ₈ cycloalkyl ring; where each specified C ₁ . ₆ alkyl, each specified C ₂ . ₄ alkenyl, each specified phenyl, each specified benzyl and each specified C ₃ . _{An 8} cycloalkyl group is optionally and independently substituted with up to 3 halogen substituents;

two R ^5e substituents attached to the same or different atoms of said ring formed by R ¹ , R ² and the nitrogen atom to which R ¹ and R ^{2 are} attached, together with said atom or atoms, can optionally form C ₃ . ₈ cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring resulting in a bicyclic system, where the two rings of the bicyclic system are spiro-fused, fused or bridged, wherein said 4-6-membered heterocycle or said 5- or 6-membered heteroaryl ring contain up to three ring heteroatoms independently selected from N, O, or S; and where the specified C ₃ . _{An 8} cycloalkyl ring, a 4-6 membered heterocyclic ring, a phenyl or a 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 C _1-4 alkyl, C ₁ substituents. ₄ haloalkyl, C ₁ . ₄ alkoxy, C ₁ . ₄ haloalkoxy, oxo, -C (O) O (C _{1. 4} alkyl), -C (O) OH, -C (O) NH ₂ , -NR (CO) O (C _{1. 4} alkyl), -OH or halogen; where R is hydrogen or C ₁ . ₂ alkyl;

alternatively, R ¹ and R ² are each independently selected from hydrogen, C1.6 alkyl, C3.8 cycloalkyl ring, 4-10 membered heterocyclic ring, 5 or 6 membered heteroaryl, phenyl, or C1-6αalkylRY; where each of said 4-10 membered heterocyclic ring and each of said 5 or 6 membered heteroaryl ring contain up to 3 heteroatoms independently selected from N, O and S; and where each of said C1.6 alkyl, each of said C1.6 alkyl portion of each of said C1.6 alkyl-R ^Y moiety, each of said C3. ₈ cycloalkyl ring, each of said 4-10 membered heterocyclic ring group, each of said 5- or 6-membered heteroaryl, each of said phenyl is optionally and independently substituted with up to 5 R ^5f substituents; with the proviso that none of R ¹ or R ² is pyridine or pyrimidine;

RY is selected from C ₃ . ₈ cycloalkyl ring, 4-8 membered heterocyclic ring, phenyl or 56 membered heteroaryl ring; where each of said 4-8 membered heterocyclic ring and each of said 5-6 membered heteroaromatic ring contain from 1 to 4 ring heteroatoms independently selected from N, O or S; and where each of the specified C ₃ . ₈ cycloalkyl ring, each of said 4-8 membered heterocyclic ring, each of said phenyl and each of said 5-6 membered heteroaryl ring are optionally substituted with up to 5 R ^5g substituents;

each R ^{5f is} independently selected from halogen, —CN, C1.6 alkyl, - (C1.4 alkyl) —R ^6a , C7. ₁₂ aralkyl, C ₃ . ₈ cycloalkyl ring, C ₁ . ₄ cyanoalkyl, -OR ^6a , -SR ^6a , -OCOR ^6a , -COR ^6a , -C (O) OR ^6a , -C (O) N (R ^6a ) 2, -N (R ^6a ) C (O) R ^6a , —N (R ^6a ) 2, —SO2R ^6a , —SO2N (R ^6a ) 2, —N (R ^6a ) SO2R ^6a , —SO2OH, —SO2NHOH, —SO2N (R ^6a ) COR ^6a , phenyl and oxo; where each said phenyl group is optionally and independently substituted with up to 3 substituents with halogen, -OH, -NH2, -NH (C _{1. 4} alkyl), -N (C _{1. 4} alkyl) ₂ , -NO ₂ , -CN, C ₁ ... _{4 by} alkyl, C ₁ . ₄ haloalkyl, —O (C _{1 4} alkyl) or —O (C _{1 4} haloalkyl); and where each specified C ₇ . ₁₂ aralkyl, each specified C ₁ . ₆ alkyl, each specified C ₁ . _{4 the} alkyl portion of each of said - (C _{1. 4} alkyl) -R ^6a and each

- 50 038096 indicated C ₃ . _{An 8} cycloalkyl group is optionally and independently substituted with up to three halo substituents;

each R ^{6a is} independently selected from hydrogen, C _1-6 alkyl, C _2-4 alkenyl, phenyl, benzyl, or C ₃ . ₈ cycloalkyl ring; where each specified C _1-6 alkyl, each specified C _2-4 alkenyl, each specified phenyl, each specified benzyl and each specified C _3-8 cycloalkyl group is optionally and independently substituted with up to 3 halogen substituents;

when one of R ¹ or R ² is a C3-8 cycloalkyl ring, a 4-8 membered heterocyclic ring or a 5 or 6 membered heteroaryl substituted with up to 5 substituents R ^5f , two substituents R ^5f attached to the same and different ring atoms of the specified R ¹ or R ² , together with the specified atom or atoms form a C3-8 cycloalkyl ring, 4-6-membered heterocyclic ring, phenyl or 5- or 6-membered heterocyclic ring, resulting in the formation of a bicyclic system, where two rings are spiro-linked, fused or bridged, wherein said 4-6 membered heterocycle or said 5- or 6-membered heterocyclic ring contains up to two ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heterocyclic ring are optionally substituted with up to 2 C _1-4 alkyl, C ₁ substituents. ₄ haloalkyl, oxo, - (CO) O (C _1-4 alkyl), —NR '(CO) O (C _1-4 alkyl) or halogen; where R 'is hydrogen or C _1-2 alkyl;

each R ^{5g is} independently selected from halogen, —CN, C1-6 alkyl, - (C1-4 alkyl) —R ^6b , benzyl, C3-8 cycloalkyl ring, C _1-4 cyanoalkyl, —OR ^6b , —SR ^6b , —OCOR ^6b , -COR ^6b , -C (O) OR ^6b , -C (O) N (R ^6b ) 2, -N (R ^6b ) C (O) R ^6b , -N (R ^6b ) 2, -SO2R ^6b , - SO2N (R ^6b ) 2, —N (R ^6b ) SO2R ^6b , —SO2OH, —SO2NHOH, —SO2N (R ^6b ) COR ^6b , phenyl and oxo; wherein each of said phenyl and said benzyl group each optionally and independently substituted with up to 3 substituents halogen, -OH, -NH2, -NH (C1. ₄ alkyl), -N (C _{1. 4} alkyl) _2, -NO2, -CN, C ₁ . _{4 by} alkyl, C ₁ . ₄ haloalkyl, —O (C _{1 4} alkyl) or —O (C _{1 4} haloalkyl); and where each specified C ₁ . ₆ alkyl, C ₁ . _{4 the} alkyl portion of each of said (C _{1. 4} alkyl) -R ^{6b moieties} and each of said C ₃ . _{An 8} cycloalkyl group is optionally and independently substituted with up to 3 halogen substituents;

each R ^{6b is} independently selected from hydrogen, C ₁ . ₆ alkyl, C ₂ . ₄ alkenyl, phenyl, benzyl or C ₃ . ₈ cycloalkyl ring; where each specified C ₁ . ₆ alkyl, each specified C ₂ . ₄ alkenyl, each said phenyl, each said benzyl, and each said C _3-8 cycloalkyl group are optionally and independently substituted with up to 3 halo substituents;

alternatively, two R ^5g substituents attached to the same and different ring atoms RY together with said ring atom or atoms form C ₃ . ₈ cycloalkyl ring, 46 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system where the two rings are spiro-linked, fused or bridged, wherein said 4-6-membered heterocycle or said 5- or 6-membered heteroaryl ring contains up to three heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 C ₁ substituents. _{4 with} α alkul, C ₁ . ₄ haloalkyl, C ₁ . ₄ alkoxy, C ₁ . ₄ haloalkoxy, oxo, -C (O) O (C _{1. 4} alkyl), -C (O) OH, -C (O) NH ₂ , -NR (CO) O (C _{1. 4} alkyl), -OH or halogen; and

R ″ is hydrogen or C ₁ . ₂ alkyl.

In some embodiments of the above methods, uses, compositions, and kits, the sGC stimulant is a compound of Formula IC

F

Formula IC where JB is halogen;

R ¹ is hydrogen or C ₁ . ₆ αalkyl;

R ² is C ₁ . ₆ an alkyl group optionally and independently substituted with up to three substituents R ^5a , where R ^5a was defined in the previous paragraphs as part of the description of formula IA.

In some embodiments of the above methods, uses, compositions, and kits, the sGC stimulant is a compound selected from those listed below:

- 51 038096

- 52 038096

In some embodiments of the above methods, uses, compositions, and kits, the sGC stimulant is a compound of Formula XZ

Formula XZ;

where W is either

i) is absent and J ^B is bonded directly to a carbon atom bearing two J groups; where each J group is independently selected from hydrogen or methyl, n is 1, and J ^B is a C _2-7 alkyl chain independently substituted with 2 to 9 fluoro substituents; where, optionally, one unit —CH ₂ - of said C _2-7 alkyl chain may be replaced with —O— or —S—;

ii) is a ring B selected from phenyl, a 5 or 6 membered heteroaryl ring containing 1 or 2 ring heteroatoms independently selected from N, O or S, a C _3-7 cycloalkyl ring and a 4-7 membered heterocyclic compound containing up to 3 heteroatoms independently selected from O, N or S;

where when W is ring B, each J is hydrogen;

n is 0 or an integer selected from 1, 2 or 3;

each J ^{B is} independently selected from halogen, —CN, C1-6 aliphatic, —OR ^B, or C3-8 cycloaliphatic; where each said C _1-6 α aliphatic and each said C _3-8 cycloaliphatic group is optionally and independently substituted with up to 3 substituents R ³ ;

each R ^{B is} independently selected from hydrogen, a ^^ aliphatic group, or a C3-8 cycloaliphatic ring; where each of said R ^B , which is a ^^ aliphatic group, and each of said R ^B , which is a C3-8 cycloaliphatic ring, is optionally and independently substituted with up to 3 substituents R ^3a ;

each R ^{3 is} independently selected from halogen, —CN, C _1-4 alkyl, C _1-4 haloalkyl, —O (C _1-4 alkyl), or —O (C _1-4 haloalkyl);

each R ^{3a is} independently selected from halogen, —CN, C _1-4 alkyl, C _1-4 haloalkyl, —O (C _1-4 alkyl), or —O (C _1-4 haloalkyl);

Z ¹ in ring D is selected from CH or N; Z is selected from C or N; where if Z ¹ is CH, then Z must be C; and if Z ¹ is N, then Z can be C or N;

each JD is independently selected from J ^A , -CN, -NO ₂ , -ORD, -SRD, -C (O) RD, -C (O) ORD, -OC (O) RD, -C (O) N (R ^d ) 2, -N (R ^d ) 2, -N (R ^d ) C (O) R ^D , -N (R ^d ) C (O) OR ^D , -N (R ^d ) C (O) N ( R ^D ) 2, -OC (O) N (R ^d ) 2, -SO2RD -SO2N (R ^d ) 2, -N (R ^d ) SO2RD, -N (R ^d ) SO2NHRD, -N (R ^d ) SO2NHC (O) ORD, -N (R ^d ) SO2NHC (O) RD, C1-6alipha

- 53 038096 tic group, - (C _1-6 aliphatic group) -R ^D , C3-8 cycloaliphatic ring, 6-10-membered aryl ring, 4-8-membered heterocyclic ring or 5-10-membered heteroaryl ring; where each said 4-8 membered heterocyclic ring and each said 5-10 membered heteroaryl ring contain from 1 to 3 heteroatoms independently selected from O, N or S; and where each said C1-6 aliphatic group, each said C1-6 aliphatic part of a fragment - (C1-6 aliphatic group) -R ^D , each said C3-8 cycloaliphatic ring, each said 6-10 membered aryl ring, each said 4-8- a membered heterocyclic ring and each of said 5-10 membered heteroaryl ring is optionally and independently substituted with up to 5 R ^5d substituents;

J ^{A is} selected from a pair of electrons on nitrogen, hydrogen, halogen, oxo, methyl, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, or —NR ^a R ^b ; where R ^a and R ^b are each independently selected from hydrogen, C1-6 alkyl or 3-6-cycloalkyl ring; or where R ^a and R ^b together with the nitrogen atom to which they are both attached form a 4-8 membered heterocyclic ring or a 5 membered heteroaryl ring optionally containing up to two additional heteroatoms selected from N, O and S; where each of said 4 to 8 membered heterocyclic ring and 5 membered heteroaryl ring is optionally and independently substituted with up to 6 fluoro substituents;

each R ^{d is} independently selected from hydrogen, C1-6 aliphatic, - (C1-6 aliphatic α group) -R ^f , C3-8 cycloaliphatic ring, 4-10 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each said 4-10 membered heterocyclic ring and each said 5-6 membered heteroaryl ring contain from 1 to 3 heteroatoms independently selected from O, N or S; and where each said C _1-6 aliphatic group, each said C _1-6 aliphatic part of the fragment - (Cl _-6 aliphatic group) -R ^f , each said C3-8 cycloaliphatic ring, each said 4-10 membered heterocyclic ring, each said phenyl and each said 5-6 membered heteroaryl ring are optionally and independently substituted with up to 5 R ^5a substituents; where, when any R ^D is one of a C1-6 aliphatic group or - (C _1-6 aliphatic α group) -R ^f group, one or two -CH2- that form said Cl _-6 aliphatic chains may optionally be replaced by a group independently selected from —N (R ^d ) -, —CO—, or —O—;

each Rd is independently selected from hydrogen, C _1-6 aliphatic, - (C _1-6 aliphatic α) -R ^f , C3-8 cycloaliphatic ring, 4-8 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring and each specified 5- or 6-membered heteroaryl ring contain from 1 to 3 heteroatoms independently selected from O, N or S; and where each said C1-6 aliphatic group, each said C1-6 aliphatic part of the fragment - (Cl-6 aliphatic α group) -R ^f , each said C3-8 cycloaliphatic ring, each said 4-8 membered heterocyclic ring, each said phenyl and each said The 5-6 membered heteroaryl ring is optionally and independently substituted with up to 5 R ^5b substituents; where, when any Rd is one of a C1-6 aliphatic group or a - (C1-6 aliphatic α group) -R ^f group, one or two -CH2- that form said Cl-6 aliphatic chains may optionally be replaced with a group, independently selected from -N (R ^dd ) -, -CO-, or -O-;

each R ^{dd is} independently selected from hydrogen, C1-6 aliphatic, - (C1-6 aliphatic) -R ^f , C3-8 cycloaliphatic ring, 4-8 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring and each specified 5- or 6-membered heteroaryl ring contain from 1 to 3 heteroatoms independently selected from O, N or S; and where each said C _1-6 aliphatic group, each said C _1-6 aliphatic moiety - (Cl _-6 aliphatic α group) -R ^f , each said C _3-8 cycloaliphatic ring, each said 4-8 membered heterocyclic ring each said phenyl and each said 5-6 membered heteroaryl ring is optionally and independently substituted with up to 5 _R 5b _{substituents;} each R ^{f is} independently selected from C _1-3 alkyl, C _3-8 cycloαliphatic ring, 4-10 membered heterocyclic ring, phenyl, or 5-6 membered heteroaryl ring; where each said 4-10 membered heterocyclic ring and each said 5-6 membered heteroaryl ring contain from 1 to 4 heteroatoms independently selected from O, N or S; and where each said C _3-8 cycloaliphatic ring, each said 4-10 membered heterocyclic ring, each said phenyl and each said 5-6 membered heteroaryl ring is optionally and independently substituted with up to 5 R ^5c substituents;

when J ^D is -C (O) N (R ^D ) 2, -N (R ^D ) 2, N (R ^d ) C (O) N (R ^D ) 2, -OC (O) N (R ^D ) 2 or —SO2N (R ^D ) 2, two R ^D groups together with a nitrogen atom attached to two R ^D groups can form a 4-8 membered heterocyclic ring or a 5 membered heteroaryl ring; where each said 4-8 membered heterocyclic ring and each said 5-membered heteroaryl ring optionally contain up to 3 additional heteroatoms independently selected from N, O or S, in addition to the nitrogen atom to which the two R ^D groups are attached; and where each said 4-8 membered heterocyclic ring and each said 5 membered heteroaryl ring are optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D is -N (R ^d ) C (O) R ^D , the group R ^D together with a carbon atom attached to

- 54 038096 a group R ^d, together with the nitrogen atom attached to the group R ^D, and R ^D group 4-8chlennoe may form a heterocyclic ring or a 5-membered heteroaryl ring; where each specified 4-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S, in addition to the nitrogen atom to which the group R ^D is attached; and where each said 4-8 membered heterocyclic ring and each said 5 membered heteroaryl ring are optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D is -N (R ^d ) C (O) OR ^D , the R ^D group together with the oxygen atom attached to the R ^d group, together with the carbon atom of the -C (O) - part of the -N (R ^d ) group C (O) OR ^D , together with the nitrogen atom attached to the group R ^D and with said group R ^d , can form a 4-8 membered heterocyclic ring; wherein said 4-8 membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O, or S, and is optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D is —N (R ^d ) C (O) N (R ^D ) ₂ , one of the R ^D groups attached to the nitrogen atom together with said nitrogen atom and with the N atom attached to the R ^D group, and said R ^d group can form a 4-8 membered heterocyclic ring; wherein said 4-8 membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O, or S, and is optionally and independently substituted with up to 5 R ⁵ substituents;

when J ^D is —N (R ^d ) SO ₂ R ^D , the R ^D group together with the sulfur atom attached to the R ^D group together with the nitrogen atom attached to the R ^D group and with the specified R ^d group can be combined to form a 4-8 membered heterocyclic ring; wherein said 4-8 membered heterocyclic ring optionally contains up to 2 additional heteroatoms independently selected from N, O, or S, and is optionally and independently substituted with up to 5 R ⁵ substituents;

each R ^{5 is} independently selected from halogen, -CN, C1-6alkyl, - (C1-6alkyl) -R ⁶ , -OR ⁶ , -SR ⁶ , -COR ⁶ , -OC (O) R ⁶ , -C (O) OR ⁶ , -C (O) N (R ⁶ ) 2, -C (O) N (R ⁶ ) SO2R ⁶ , -N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) C (O ) OR ⁶ , -N (R ⁶ ) C (O) N (R ⁶ ) 2, -N (R ⁶ ) 2, -SO2R ⁶ , -SO2OH, -SO2NHOH, -SO2N (R ⁶ ) 2, -SO2N ( R ⁶ ) COOR ⁶ , -SO2N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) SO2R ⁶ , - (C = O) NHOR ⁶ , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, A 5- or 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each specified C _1-6 alkyl, C _1-6 alkyl part of the fragment - (C _1-6 alkyl) -R ⁶ , C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, benzyl or phenyl group are optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , - CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring, or A 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two R ⁵ substituents attached to the same or different J ^D atoms, together with the indicated atom or atoms to which they are attached, can optionally form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring resulting in a bicyclic system, where the two rings of the bicyclic system are spiro-fused, fused or bridged, wherein said 4-6-membered heterocycle or said 5- or 6-membered heteroaryl ring contain up to four ring heteroatoms independently selected from N, O, or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkoxy, C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -NR (CO) O (C _1-4 alkyl), -CONH2, - OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{5a is} independently selected from halogen, -CN, C1-6alkyl, - (C1-6alkyl) R ^6a , -OR ^6a , -SR ^6a , -COR ^6a , -OC (O) R ^6a , -C (O) OR ^6a , -C (O) N (R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) С (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2OH, -SO2NHOH, -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 - or a 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, where each of said C _1-6 alkyl, C _1-6 alkyl moiety of the moiety - (C _1-6 alkyl) R ^6a , C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, benzyl or phenyl group optionally and independently substituted with up to 3 halogen substituents, C _1-4 alcohol,

- 55 038096

C _1-4 haloalkyl, -OH, -NH2, -NH (C _1-4 alkyl), -H (C _1-4 alkyl) 2, -CN, -COOH, -CONH2, -COO (C _1-4 alkyl ), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two, fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is phenyl a ring or 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O, or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

each R ^{5b is} independently selected from halogen, —CN, C1-6 alkyl, - (C1-6 alkyl) R ^6a , —OR ^6a , —SR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , -C (O) N (R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) С (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2OH, -SO2NHOH, -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 - or a 6-membered heteroaryl ring, phenyl, benzyl, oxo group or bicyclic group; where each 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S, where each of said C1-6 alkyl, C1-6 alkyl moiety is (C1- 6alkyl) R ^6a , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring, benzyl or phenyl group optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, C _1-4 haloalkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -CONH2, -COO (C _1-4 alkyl), O (C _{1 -4} alkyl), -O (C _1-4 haloalkyl) or oxo; wherein said bicyclic group contains ring one and ring two fused or bridged, wherein said ring one is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring or a 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two substituents R ^5a or two substituents R ^5b attached to the same or different atoms RD or Rd, respectively, together with the indicated atom or atoms to which they are attached, can optionally form a C _3-8 cycloalkyl ring, 4- 6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system, where the two rings of the bicyclic system are spiro connected, fused or bridged to each other; wherein said 4-6 membered heterocycle or said 5 or 6 membered heteroaryl ring contains up to four ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _{1- 4} alkoxy, C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -C (O) NH2, -NR (CO) O (C _1-4 alkyl), -OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{5c is} independently selected from halogen, -CN, C1-6alkyl, - (C1-6alkyl) -R ^6b , -OR ^6b , -SR ^6b , -COR6b, -OC (O) R ^6b , -C (O) OR6b , -C (O) N (R ^6b ) 2, -C (O) N (R ^6b ) SO2R ^6b , -N (R ^6b ) C (O) R ^6b , -N (R ^6b ) C (O) OR ^6b , -N (R ^6b ) С (O) N (R ^6b ) 2, -N (R ^6b ) 2, -SO2R6b, -SO2OH, -SO2NHOH, -SO2N (R ^6b ) 2, -SO2N (R ^6b ) COOR ^6b , -SO2N (R ^6b ) C (O) R ^6b , -N (R ^6b ) SO2R ^6b , - (C = O) NHOR ^6b , C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or A 6-membered heteroaryl ring, phenyl, benzyl, oxo or bicyclic group; where each of said 5- or 6-membered heteroaryl ring and each of said 4-7-membered heterocyclic ring contain up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, C _1-6 alkyl portion of said fragment - (C _1-6 alkyl) -R ^bb , each of said C _3-8 cycloalkyl ring, each of said 4-7 membered heterocyclic ring , each of said 5- or 6-membered heteroaryl ring, each of said benzyl and each of said phenyl group is optionally and independently substituted with up to 3 substituents with halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _{1- 4} alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -CONH2, -COO (C _1-4 alkyl), -O (C _1-4 alkyl), -O (C _{1- 4} haloalkyl) or oxo; wherein said bicyclic group contains a first ring and a second ring fused or bridged, said first ring is a 4-7 membered heterocyclic ring, a 5 or 6 membered heteroaryl ring, phenyl or benzyl, and said second ring is a phenyl ring or a 5- or 6-membered heteroaryl ring containing up to 3 heteroatoms selected from N, O or S; and wherein said bicyclic group is optionally and independently substituted with up to six substituents with halogen, C _1-4 alkyl, —OH, —NH2, —NH (C _1-4 alkyl), —N (C _1-4 alkyl) ₂ , —CN, —COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two R ^5c substituents attached to the same or different Rf atoms, together with the indicated atom or atoms to which they are attached, can optionally form C _3-8

56 038096 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system, where the two rings of the bicyclic system are spiro connected, fused or bridged to each other; wherein said 4-6 membered heterocycle or said 5 or 6 membered heteroaryl ring contains up to four ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -CONH2, -NR (CO) O (C _1-4 alkyl), -OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{5d is} independently selected from halogen, -CN, C1-6alkyl, - (C1-6alkyl) -R ⁶ , -OR ⁶ , -SR ⁶ , -COR ⁶ , -OC (O) R ⁶ , -C (O) OR ⁶ , -C (O) N (R ⁶ ) 2, -N (R ⁶ ) C (O) R ⁶ , -N (R ⁶ ) C (O) OR ⁶ , -N (R ⁶ ) C (O ) N (R ⁶ ) 2, -N (R ⁶ ) 2, -SO2R ⁶ , -SO2OH, -SO2NHOH, -SO2N (R ⁶ ) COR ⁶ , -SO2N (R ⁶ ) 2, -N (R ⁶ ) SO2R ⁶ , C7-12 aralkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5 or 6 membered heteroaryl ring, phenyl and oxo; where each 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to four ring heteroatoms independently selected from N, O and S, where each of said C _1-6 alkyl, C _1-6 alkyl moiety - (C _1-6 alkyl) -R ⁶ , C _7-12 aralkyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, 5- or 6-membered heteroaryl ring or phenyl group optionally and independently substituted up to 3 substituents halogen, C _1-4 alkyl, C _1-4 (haloalkyl), -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo;

two R ^5d substituents attached to the same or different J ^D atoms, together with said J ^D atom or atoms to which they are attached, can optionally form a C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring; a phenyl or 5- or 6-membered heteroaryl ring, resulting in a bicyclic system, where the two rings of the bicyclic system are spiro connected, fused or bridged to each other; wherein said 4-6 membered heterocycle or said 5 or 6 membered heteroaryl ring contains up to four ring heteroatoms independently selected from N, O or S; and wherein said C _3-8 cycloalkyl ring, 4-6 membered heterocyclic ring, phenyl or 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy , C _1-4 haloalkoxy, oxo, -C (O) O (C _1-4 alkyl), -C (O) OH, -NR (CO) O (C _1-4 alkyl), -C (O) NH2 , -OH or halogen; where R represents hydrogen or C _1-2 alkyl;

each R ^{6 is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen , C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -C (O) NH2, -COO ( C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo, wherein each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring comprises up to 4 ring heteroatoms independently selected from N, O and S;

each R ^{6a is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring, and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen , C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, -C (O) NH2, -C ( O) N (C1-6alkyl) 2, -C (O) NH (C1-6alkyl), -C (O) N (C1-6haloalkyl) 2, -C (O) NH (C1.6haloalkyl), C ( O) N (C _1-6 alknl) (C _1-6 haloalkyl), -COO (C _1-6 alkyl), -COO (C _1-6 haloalkyl), -O (C _1-4 alkyl), -O (C _1-4 haloalkyl) or oxo, wherein each of said 5- or 6-membered heteroaryl ring or 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms, independently branched from N, O and S;

each R ^{66 is} independently selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, wherein each of said C _1-6 alkyl, each of said phenyl, each of said benzyl, each of said C _3-8 cycloalkyl group, each of said 4-7 membered heterocyclic ring and each of said 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C _1-4 alkyl, -OH, -NH2, -NH (C _1-4 alknl), -N (C _1-4 alknl) ₂ , -CN, -COOH, -C (O) NH ₂ , -COO (C _1-4 alkyl), -O (C _1-4 alkyl), -O (C _1-4 haloalkyl) or oxo, wherein each of said 5- or 6-membered heteroaryl ring or a 4-7 membered heterocyclic rings contain up to 4 ring heteroatoms independently selected from N, O and S;

two substituents R ⁶ bonded to the same nitrogen atom R ⁵ or R ^5d , together with said nitrogen atom R ⁵ or R ^5d , respectively, can form a 5-8 membered heterocyclic ring or 5

- 57 038096 membered heteroaryl ring; where each specified 5-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

two R ^6a substituents bonded to the R ^5a or R ^5b nitrogen atom, together with said nitrogen, can form a 5-8 membered heterocyclic ring or a 5-membered heteroaryl ring; where each specified 5-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

two R ^ft substituents bonded to the R ^5c nitrogen atom, together with said nitrogen, can form a 5-8 membered heterocyclic ring or a 5-membered heteroaryl ring; where each specified 5-8 membered heterocyclic ring and each specified 5-membered heteroaryl ring optionally contain up to 2 additional heteroatoms independently selected from N, O or S;

Y is either absent or is a C _1-6 alkyl chain optionally substituted with up to 6 fluoro substituents; and where in said Y, which is a C _1-6 alkyl chain, up to 3 methylene units of this alkyl chain may be replaced with a group selected from -O-, -C (O) - or -N ((Y1) -R ⁹⁰ ) -, where

Y ^{1 is} either absent or is a C _1-6 alkyl chain optionally substituted with up to 6 fluoro substituents; and when Y ^{1 is} absent, each R ^{90 is} independently selected from hydrogen, -COR ¹⁰ , -C (O) OR ¹⁰ , -C (0) N (R ¹⁰ ) 2, -C (0) N (R ¹⁰ ) S02R ¹⁰ , -SO2R ¹⁰ , -SO2N (R ¹⁰ ) 2, -SO2N (R ¹⁰ ) COOR ¹⁰ , -S02N (R ¹⁰ ) C (0) R ¹⁰ , - (C = O) NHOR ¹⁰ , Cs-6 Cycloalkyl ring, 4 An 8-membered heterocyclic ring, a phenyl ring, or a 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring or 5-6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and where each of said C3-6 cycloalkyl rings, each of said 4-8 membered heterocyclic rings, each of said phenyl and each of said 5-6 membered heteroaryl rings is optionally and independently substituted with up to 3 R ¹¹ substituents; and when Y ^{1 is} present, each R ^{90 is} independently selected from hydrogen, halogen, —CN, —OR ¹⁰ , —COR ¹⁰ , —OC (O) R ¹⁰ , —C (O) OR ¹⁰ , —C (O) N ( R ¹⁰ ) 2, -C (O) N (R ¹⁰ ) SO2R ¹⁰ , -N (R ¹⁰ ) C (0) R ¹⁰ , -N (R ¹⁰ ) C (0) OR ¹⁰ , -N (R ¹⁰ ) C (O) N (R ¹⁰ ) 2, -N (R ^1o ) 2, -SO2R ¹⁰ , -SO2N (R ¹⁰ ) 2, -SO2N (R ¹⁰ ) COOR ¹⁰ , -SO2N (R ¹⁰ ) C (O) R ¹⁰ , —N (R ¹⁰ ) SO2R ¹⁰ , - (C = O) NHOR ¹⁰ , C _3-6 cycloalkyl ring, 4-8 membered heterocyclic ring, phenyl ring, or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring or 5-6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and where each of said C3-6 cycloalkyl rings, each of said 4-8 membered heterocyclic rings, each of said phenyl and each of said 5-6 membered heteroaryl rings is optionally and independently substituted with up to 3 R ¹¹ substituents;

each R ^{9 is} independently selected from hydrogen, halogen, C1-6 alkyl, —CN, —OR ¹⁰ , —COR ¹⁰ , —OC (O) R ¹⁰ , —C (O) OR ¹⁰ , —C (0) N (R ^1o ) 2, -C (0) N (R ^1o ) S02R ¹⁰ , -N (R ^1o ) C (0) R ¹⁰ , -N (R ^1o ) C (0) OR ¹⁰ , -N (R ^1o ) C ( 0) N (R ^1o ) 2, -N (R ^1o ) 2, -SO2R ¹⁰ , -S02N (R ^1o ) 2, -SO2N (R ¹⁰ ) COOR ¹⁰ , -S02N (R ^1o ) C (0) R ¹⁰ , -N (R ¹⁰ ) SO2R ¹⁰ , - (C = O) NHOR ¹⁰ , C3-6 cycloalkyl ring, 4-8 membered heterocyclic ring, phenyl ring or 5-6 membered heteroaryl ring; where each specified 4-8-membered heterocyclic ring or 5-6-membered heteroaryl ring contains up to 4 ring heteroatoms independently selected from N, O or S; and wherein each of said C1-6 alkyl, each of said C _3-6 cycloalkyl rings, each of said 4 to 8 membered heterocyclic rings, each of said phenyl and each of said 5 to 6 membered heteroaryl rings are optionally and independently substituted with up to 3 substituents R ¹¹ ;

each R ^{10 is} independently selected from hydrogen, C1-6 alkyl, - (C1-6 alkyl) -R ¹³ , phenyl, benzyl, C3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each A 5- or 6-membered heteroaryl ring or a 4-7-membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, C _1-6 alkyl part of said fragment - (C _1-6 alkyl) -R ¹³ , each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4 A 7-membered heterocyclic ring and each 5- or 6-membered heteroaryl ring is optionally and independently substituted with up to 3 R ^11a ;

each R ^{13 is} independently selected from phenyl, benzyl, C _3-6 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring or 4-7 membered the heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said phenyl, each of said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 R ^11b ;

each R ^{11 is} independently selected from halogen, oxo, C _1-6 alkyl, —CN, —OR ¹² , —COR ¹² , —C (O) OR ¹² , —C (O) N (R ¹² ) 2, —N ( R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, -SO2R ¹² , —SO2N (R ¹² ) 2 or —N (R ¹² ) SO2R ¹² ; where each of said C1-6 alkyl is optionally and independently substituted with up to 6 fluoro substituents and / or 3 R ¹²¹ substituents;

- 58 038096 each R ^{11a is} independently selected from halogen, oxo, C1-6 alkyl, -CN, -OR ¹² , -COR ¹² , -C (O) OR ¹² , -C (O) N (R ¹² ) 2, -N (R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, - SO2R ¹² , —SO2N (R ¹² ) 2 or —N (R ¹² ) SO2R ^{1 2} ; where each of said C1-6αalkyl is optionally and independently substituted with up to 6 fluoro substituents and / or 3 R ¹²¹ substituents; and each R ^{11b is} independently selected from halogen, C1-6αalkyl, oxo, —CN, —OR ¹² , —COR ¹² , —C (O) OR ¹² , —C (O) N (R ¹² ) 2, —N (R ¹² ) C (O) R ¹² , -N (R ¹² ) C (O) OR ¹² , -N (R ¹² ) C (O) N (R ¹² ) 2, -N (R ¹² ) 2, -SO ₂ R ¹² , —SO2N (R ¹² ) 2 or —N (R ¹² ) SO2R ^{1 2} ; where each of said C _1-6 α-alkyl is optionally and independently substituted with up to 6 fluoro substituents and / or 3 R ¹²¹ substituents;

each R ^{12 is} selected from hydrogen, C _1-6 αalkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring or A 4-7 membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, each said phenyl, each said benzyl, each said C _3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents halogen, C _1-4 alkyl, C _1-4 (fluoroalkyl), -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH , —CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 fluoroalkyl) or oxo;

each R ^{121 is} selected from hydrogen, C _1-6 alkyl, phenyl, benzyl, C _3-8 cycloalkyl ring, 4-7 membered heterocyclic ring, or 5- or 6-membered heteroaryl ring, where each 5- or 6-membered heteroaryl ring or A 4-7 membered heterocyclic ring contains up to 4 ring heteroatoms independently selected from N, O and S; and where each said C _1-6 alkyl, each said phenyl, each said benzyl, each said C3-8 cycloalkyl group, each said 4-7 membered heterocyclic ring, and each 5 or 6 membered heteroaryl ring is optionally and independently substituted with up to 3 substituents with halogen , C _1-4 alkyl, C _1-4 (fluoroalkyl), -OH, -NH ₂ , -NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -CN, -COOH, - CONH2, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 fluoroalkyl) or oxo; and each J ^{C is} independently selected from hydrogen or C _1-6 alkyl.

In some embodiments of the above methods, uses, compositions, and kits, the sGC stimulant is a compound of Formula XY

Formula XY;

where n denotes 0 or an integer selected from 1 to 3;

each J ^{B is} independently selected from halogen, —CN, C1-6 aliphatic, —OR ^B, or C3-8 cycloaliphatic; where each of said C _1-6 aliphatic group and each of said C _3-8 cycloaliphatic ring are optionally substituted with up to 3 halogen substituents;

each R ^{B is} independently selected from hydrogen, a C1-6 aliphatic group, or a C3-8 cycloaliphatic ring; where each of said R ^B , which is a C1-6 aliphatic group, and each of said R ^B , which is a C3-8 cycloaliphatic ring, optionally substituted with up to 3 halo substituents;

each J ^C , if present, is independently selected from halogen;

R ¹ is hydrogen or C _1-6 alkyl; and

R ² is C _1-6 alkyl.

In some embodiments of Formula XY, n is 1 or 2. In some embodiments, n is 1.

In some embodiments of Formula XY, each J ^B is halogen. In some such embodiments, each J ^B is fluorine. In some embodiments of the formula XY, n is 1 and J ^B is fluoro.

In some embodiments of Formula XY, one or two J ^C substituents are present. In other embodiments, only one substituent J ^C is present. In some such embodiments, J ^C is fluoro.

In some embodiments of Formula XY, R ^{1 is} selected from hydrogen, methyl, or ethyl. V

59 038096 in other embodiments, R ¹ is hydrogen. In still other embodiments, R ¹ is methyl.

In some embodiments of Formula XY, R ² is methyl or ethyl. In yet other embodiments, R ² is methyl.

In some embodiments of Formula XY, the compound is vericiguat or riociguat as mentioned above.

In some embodiments of the above methods, compositions, and kits, the sGC stimulant is a compound that achieves multiple times higher concentrations in the liver than in plasma in an animal model. In some of these embodiments, the sGC stimulant is a compound that concentrates in the liver of a rat in an animal model such as described for the rat in Example 5 below. In some embodiments, the concentration is defined as the ratio of the liver concentration of the compound to the plasma concentration of the compound greater than 50: 1. In some embodiments, the liver concentration is defined as the ratio of the concentration of the compound in the liver to the concentration of the compound in plasma greater than 40 to 1. In some embodiments, the concentration in the liver is defined as the ratio of the concentration of the compound in the liver to the concentration of the compound in plasma greater than 30: 1. In some embodiments, the concentration is defined as the ratio of the liver concentration of the compound to the plasma concentration of the compound greater than 20: 1. In other embodiments, this ratio is greater than 15: 1. In other embodiments, the ratio is higher than 10: 1. In other embodiments, the ratio is higher than 5: 1. In other embodiments, the ratio is at least greater than 4: 1.

In some embodiments of the above methods, compositions, and kits, the sGC stimulant is a compound that, when administered to a subject or patient, results in a liver concentration of the compound and a plasma concentration of the compound in a ratio greater than 40: 1. In other embodiments, this ratio is greater than 30: 1. In other embodiments, this ratio is greater than 20: 1. In other embodiments, this ratio is greater than 15: 1. In other embodiments, the ratio is higher than 10: 1. In other embodiments, the ratio is higher than 5: 1. In other embodiments, the ratio is at least greater than 4: 1. In some embodiments, the liver concentration is determined by liver biopsy.

In some embodiments of the above methods, compositions, and kits, the sGC stimulant is a compound that, when administered orally to a healthy subject, does not result in hypotension. In some embodiments, hypotension is defined as a blood pressure reading of less than 90/60.

In some embodiments of the above methods, compositions, and kits, the sGC stimulant is a compound that, when administered orally to a subject, does not result in a decrease of at least 10 mmHg. in systolic or diastolic blood pressure readings, or both at the same time.

In some embodiments of the above methods, compositions, and kits, the sGC stimulant is a compound that, when administered orally to a subject exhibiting normal blood pressure, does not result in a decrease of at least 10 mmHg. in terms of systolic or diastolic blood pressure, or both at the same time. In some embodiments, normal blood pressure is defined as less than 120/80 (systolic / diastolic) or less.

Pharmaceutically acceptable salts.

In some embodiments of the methods, uses, pharmaceutical compositions, and kits, the sGC stimulant may be present as (i) the compound itself (eg, as a free base); (ii) a pharmaceutically acceptable salt of the compound; or (iii) part of a pharmaceutical composition. In some embodiments of the above methods, uses, pharmaceutical compositions, and kits, the additional therapeutic agent may be provided as (i) the compound itself (eg, as the free base); (ii) a pharmaceutically acceptable salt of compound (iii) or part of a pharmaceutical composition.

The expression pharmaceutically acceptable salt, as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein. For medical use, the salts of the compounds described herein will be pharmaceutically acceptable salts. However, other salts may be used in the preparation of the compounds described herein or their pharmaceutically acceptable salts. The pharmaceutically acceptable salt may contain the inclusion of another molecule such as an acetate ion, succinate ion, or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt can have more than one charged atom in its structure. In the case where part of the pharmaceutically acceptable salt is several charged

- 60 038096 atoms, they can have several counterions. Therefore, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

Pharmaceutically acceptable salts of the compounds described herein include those derived from the corresponding inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments, the salts can be prepared from the free form of the compound in a separate synthetic step.

When a compound described herein is acidic or contains a sufficiently acidic bioisoster, suitable pharmaceutically acceptable salts refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium, zinc, etc. ... Specific embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine , diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morphinocamines, piperine theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

When a compound described herein is basic or contains a sufficiently basic bioisoster, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. These acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, almond, methanesulfonic, mucinic, pamphoric, pamphoric, pamphoric, pamino sulfuric, tartaric, p-toluenesulfonic acid, etc. Specific embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. Other illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisatin, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene bis- ( 2-hydroxy-3-naphthoate)).

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described in Berg et al., Pharmaceutical Salts, J. Pharm. Sci., 1977: 66: 1-19, which is incorporated herein by reference in its entirety. The compounds, compositions and kits of the invention can also be used for the veterinary treatment of companion animals, exotic animals and farm animals, including dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs, and cattle.

Methods of administration and joint administration.

In some embodiments of the above methods and uses, the sGC stimulant is administered before a symptom or clinical manifestation of NASH is fully developed or detected in said patient. In other embodiments of the above methods and uses, the sGC stimulant is administered after one or more symptoms or clinical manifestations of NASH develop or become apparent in said patient.

As used herein, the term in combination or co-administration may be used interchangeably with reference to the use of more than one therapeutic agent (eg, an sGC stimulant and one or more additional therapeutic agents). The use of the terms does not limit the order in which the therapeutic agents (eg, the sGC stimulant and additional therapeutic agents) are administered to the subject.

In some embodiments, the sGC stimulant is administered before, at the same time, or after the initiation of treatment with another therapeutic agent.

In some embodiments of the above methods and uses, the additional therapeutic agent and the sGC stimulant are administered simultaneously. In other embodiments of the above methods and uses, the additional therapeutic agent and sGC stimulant is administered sequentially or separately.

In some embodiments, the aforementioned pharmaceutical compositions or kits comprise (a) an sGC stimulant as discussed above, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, drug vehicle, or excipient. In some embodiments, the pharmaceutical composition or kit comprises (a) one or more additional therapeutic agents, as discussed above, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, medium for the drug

- 61 038096 or auxiliary substance. In some embodiments, the pharmaceutical composition comprises (i) an sGC stimulant, as discussed above, or a pharmaceutically acceptable salt thereof, (ii) one or more additional therapeutic agents, as discussed above, or a pharmaceutically acceptable salt thereof, and (iii) a pharmaceutically acceptable carrier , a drug carrier or excipient.

The sGC stimulants and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combined treatment with more than one active agent, the additional active agents can be in the same dosage form or in separate dosage forms. In the event that additional active agents are present in separate dosage forms, the active agents can be administered alone or in combination with an sGC stimulant. In addition, the administration of one agent can be carried out before, simultaneously with, or after the administration of the other agent.

When co-administered with other agents, for example, when co-administered with another sGC stimulant, arginine, etc., the effective amount of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition (s) being treated, and the amount of compound used herein. In cases where the amount is not explicitly indicated, an effective amount should be used. For example, the compounds described herein can be administered to a subject at a dosage range of from about 0.001 to about 100 mg / kg body weight per day, from about 0.001 to about 50 mg / kg body weight per day, from about 0.001 to about 30 mg / kg body weight per day, from about 0.001 to about 10 mg / kg body weight / day.

When combination therapy is used, an effective amount can be achieved using a first amount of an sGC stimulant or a pharmaceutically acceptable salt thereof and a second amount of an additional suitable therapeutic agent (e.g., another sGC stimulant, arginine, NO modulator, cGMP modulator, a therapeutic agent that increases synthase function nitric oxide, etc.).

In one embodiment of the present invention, the sGC stimulant and the additional therapeutic agent are administered in an effective amount (ie, each in an amount that will be therapeutically effective if administered separately). In another embodiment, the sGC stimulant and the additional therapeutic agent are administered in an amount that, by itself, has no therapeutic effect (sub-therapeutic dose). In yet another embodiment, the sGC stimulant can be administered in an effective amount, while the additional therapeutic agent is administered at a subtherapeutic dose. In yet another embodiment, the sGC stimulant can be administered at a sub-therapeutic dose, while an additional therapeutic agent, eg, a suitable anti-inflammatory agent, is administered in an effective amount.

Co-administration includes administering the first and second amounts of the compounds substantially simultaneously, for example, in the same pharmaceutical composition, for example, a capsule or tablet having a fixed ratio of the first and second amounts, or several separate capsules or tablets for each. In addition, co-administration also includes the use of each compound sequentially in any order. When co-administration includes the separate administration of the first amount of the sGC stimulant and the second amount of the additional therapeutic agent, the compounds are administered close enough in time to obtain the desired therapeutic effect. For example, the time interval between each administration that can lead to the desired therapeutic effect can vary from minutes to hours and can be determined based on the properties of each compound, such as efficacy, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the sGC stimulant and the second therapeutic agent can be administered in any order within about 24 hours after each other, within about 16 hours after each other, within about 8 hours after each other, within about 4 hours after each other, in within about 1 hour after each other or within about 30 minutes after each other, within about 5 minutes after each other, etc.

More specifically, the first therapeutic agent (e.g., prophylactically or therapeutically used sGC stimulant) can be administered to the subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours , 24 h, 48 h, 72 h, 96 h, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), simultaneously or after (e.g. after 5 min, 15 min , 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later) administration of a second therapeutic agent (eg, an additional therapeutic agent or prophylactic agent described herein).

Combined therapeutic agents.

In some embodiments of the above methods, uses, compositions and kits, the additional therapeutic agent or agents can be selected from one or more

- 62 038096 of the following:

(1) endothelial relaxing factor (EDRF) or NO gas;

(2) NO donors such as nitrosothiol, nitrite, sydnone imine, NONOaT, N-nitrosamine, N-hydroxylnitrosamine, nitrosimine, nitrotyrosine, diazetindioxine, oxatriazole-5-imine, oxime, hydroxylamine, N-hydroxyguanidine, hydroxane. Some examples of these types of compounds include glyceryl trinitrate (also known as GTN, nitroglycerin, nitroglycerin, and trinitroglycerin), glycerin nitrate ester; sodium nitroprusside (SNP), where the nitric oxide molecule is coordinated with metallic iron to form a square bipyramidal complex; 3morpholinosidnone imine (SIN-1), a zwitterionic compound formed by combining morpholine and sydnone imine; S-nitroso-N-acetylpenicillamine (SNAP), a derivative of an N-acetylated amino acid with a nitrosotile functional group; diethylenetriamine / NO (DETA / NO), a nitric oxide compound covalently linked to diethylenetriamine; m-nitroxymethylphenyl ester of acetylsalicylic acid. More specific examples of some of these classes of NO donors include classic nitrovasodilators such as organic nitrate and nitrite esters including nitroglycerin, amyl nitrite, isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil; isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Isordil®, Titradose®, Monoket®), 3-morpholinosidnone imine; linsidomin hydrochloride (SIN-1); S-nitroso-N-acetylpenicillamine (SNAP); S-nitrosoglutathione (GSNO), sodium nitroprusside, S-nitrosoglutathione monoethyl ester (GSNO-ester), 6- (2-hydroxy-1-methylnitrosohydrαzino) -N-methyl-1-hexanamine or diethylamine-NONOaT;

(3) other substances that increase the concentration of cGMP, such as derivatives of protoporphyrin IX, arachidonic acid and phenylhydrazine;

(4) nitric oxide synthase substrates, for example N-hydroxyguanidine analogs such as N [G] -hydroxy-L-arginine (NOHA), 1- (3,4-dimethoxy-2-chlorobenzylideneamino) -3-hydroxyguanidine, and PR5 (1- (3,4-dimethoxy-2-chlorobenzylideneamino) -3-hydroxyguanidine); L-arginine derivatives (such as homo-Arg, homo-NOHA, N-tert-butyloxy and N- (3-methyl-2-butenyl) oxy-L-arginine, canavanine, epsilon guanidine-caproic acid, agmatine, hydroxyl -agmatine and L-tyrosyl-L-arginine); N-αalkyl-N'-hydroxyguanidines (such as N-cyclopropyl-N'-hydroxyguanidine and N-butyl-N'-hydroxyguanidine), N-aryl-N'-hydroxyguanidines (such as N-phenyl-N'-hydroxyguanidine and its para-substituted derivatives bearing substituents —F, —Cl, —methyl, —OH, respectively); guanidine derivatives such as 3- (trifluoromethyl) propylguanidine;

(5) compounds that enhance transcription of eNOS;

(6) NO-independent heme-independent activator of sGCs, including, but not limited to,

BAY 58-2667 (described in patent publication DE 19943635)

HMR-1766 (sodium ataciguat described in patent publication WO 2000002851)

S 3448 (2- (4-chloro-phenylsulfonylamino) -4,5-dimethoxy-N- (4- (thiomorpholine-4-sulfonyl) phenyl) benzamide (described in patent publications DE 19830430 and WO 2000002851)

HMR-1069 (Sanofi-Aventis);

(7) Heme-dependent, NO-independent stimulant sGCs including, but not limited to, YC-1 (see patent publications EP 667345 and DE 19744026)

- 63 038096

riotsiguat (BAY 63-2521, Adempas® described in DE 19834044)

unliciguat (BAY 60-4552 described in WO 2003095451)

veriziguat (BAY 1021189)

BAY 41-2272 (described in DE 19834047 and DE 19942809)

BAY 41-8543 (described in DE 19834044)

- 64 038096 etriciguat (described in WO 2003086407)

CFM-1571 (described in patent publication WO 2000027394)

А-344905, its acrylamide analogue А-350619 and aminopyrimidine analogue А-778935

and other sGC stimulants described in one of the publications US 20090209556, US 8455638, US 20110118282 (WO 2009032249), US 20100292192, US 20110201621, US 20147664, US 8053455 (WO 2009094242), US 20100216764, US 8509954 20110218202 (WO 2010065275), US 20130012511 (WO 2011119518), US 20130072492 (WO 2011149921), US 20130210798 (WO 2012058132), and other compounds described in Tetrahedron Letters (2003), 44 (48): 8661-8663;

(8) compounds that inhibit cGMP degradation such as PDE5 inhibitors such as, for example, sildenafil (Viagra®) and related agents such as

- 65 038096 avanafil, lodenafil, myrodenafil, sildenafil citrate (Revatio®), tadalafil (Cialis® or Adcirca®), vardenafil (Levitra®) and udenafil; alprostadil; dipyridamole and PF-00489791; and PDE9 inhibitors such as, for example, PF-04447943;

(9) calcium channel blockers of the following types: dihydropyridine calcium channel blockers such as amlodipine (Norvasc®), aranidipine (Sapresta®), azelnidipine (Calblock®), barnidipine (NuroCa®), benidipine (Coniel®), Cilnidipine ( , Cinalong®, Siscard®), clevidipine (Cleviprex®), diltiazem, efonidipine (Landel®), felodipine (Plendil®), lacidipine (Motens®, Lacipil®), lercanidipine (Zanidip®), manidipine (Calslot®, Madipine® ), nicardipine (Cardene®, Carden SR®), nifedipine (Procardia®, Adalat®), nilvadipine (Nivadil®), nimodipine (Nimotop®), nisoldipine (Baymycard®, Sular®, Syscor®), nitrendipine (Cardif®, Nitrepin®, Baylotensin®), pranidipine (Acalas®), isradipine (Lomir®);

phenylalkylamine calcium channel blockers such as verapamil (Calan®, Isoptin®)

non-selective calcium channel inhibitors such as mibefradil, bepridil, fluspirilene, and fendilin;

(10) endothelin receptor antagonists (ERA), such as the dual endothelin receptor antagonist (ETA and ETV) bosentan (Tracleer®), sitaxentan (Thelin®) or ambrisentan (Letairis®);

(11) prostacyclin derivatives or analogs such as prostacyclin (prostaglandin I2), epoprostenol (synthetic prostacyclin, Flolan®), treprostinil (Remodulin®), iloprost (Ilomedin®), iloprost (Ventavis®); and oral and inhaled forms of Remodulin® in development;

(12) antihyperlipidemic agents such as the following:

bile acid sequestrants such as cholestyramine, colestipol, colistilan, kosevelam, or sevelamer;

statins such as atorvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, rosuvastatin, and pravastatin;

cholesterol absorption inhibitors such as ezetimibe;

other lipid lowering agents such as icosapenta ethyl ester, omega-3 acid ethyl esters, reduole;

fibric acid derivatives such as clofibrate, bezafibrate, clinofibrate, gemfibrozil, ronifibrate, binifibrate, fenofibrate, ciprofibrate, choline fenofibrate;

nicotinic acid derivatives such as acipimox and niacin;

combinations of statins, niacin and supplements that inhibit the absorption of cholesterol in the intestine (ezetimibe and others), and fibrates; and antiplatelet therapeutic agents such as clopidogrel bisulfate;

(13) anticoagulants, such as the following:

coumarins (vitamin K antagonists) such as warfarin (Coumadin®), acenocoumarol, phenprocoumon, and phenindione;

heparin and derivatives such as low molecular weight heparin, fondaparinux and idraparinux;

direct thrombin inhibitors such as argatroban, lepirudin, bivalirudin, dabigatran, and ximelagatran (Exanta®); and tissue plasminogen activators used to dissolve clots and unblock arteries, such as alteplase;

(14) antiplatelet drugs such as, for example, clopidogrel, ticlopidine, dipyridamole and aspirin;

(15) ACE inhibitors, for example of the following types:

sulfhydryl-containing agents such as captopril (Capoten®) and zofenopril;

dicarboxylate agents such as enalapril (Vasotec / Renitec®), ramipril (Altace® /

- 66 038096

Tritace® / Ramace® / Ramiwin®), quinapril (Accupril®), perindopril (Coversyl® / Aceon®), lisinopril (Lisodur® / Lopril® / Novatec® / Prinivil® / Zestril®) and benazepril (Lotensin®);

agents containing phosphonate such as fosinopril;

natural ACCE inhibitors such as casokinins and lactokinins, which are breakdown products of casein and whey and which naturally occur after the consumption of dairy products, especially fermented milk products;

lactotripeptides Val-Pro-Pro and Ile-Pro-Pro, which are derived from the probiotic Lactobacillus helveticus or derived from casein, also having ACE inhibitory and antihypertensive effects;

other ACE inhibitors such as alacepril, delapril, cilazapril, imidapril, trandolapril, temocapril, moexipril and spirapril;

(16) supplemental oxygen therapy;

(17) β-blockers, such as the following: non-selective agents such as alprenolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, penbutolol, pindolol, oxprenonol, acebutolol, sotalol, mepindolol, celiprolol, amyradosatulaatolol, , propranolol and timolol;

βι-selective agents such as acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, dobutamine hydrochloride, irsogladine maleate, carvedilol, talinolol, esmolol, metoprolol and nebivolol; and B2 selective agents such as butaximan;

(18) antiarrhythmic drugs, such as the following:

type I (sodium channel blockers) such as quinidine, lidocaine, phenytoin, propafenone;

type III (potassium channel blockers) such as amiodarone, dofetilide, and sotalol; and type V such as adenosine and digoxin;

(19) diuretics such as thiazide diuretics, for example chlorothiazide, chlorthalidone and hydrochlorothiazide, bendroflumethiazide, cyclopentiazide, methiclothiazide, polythiazide, quinethasone, sipamide, metalazone, indapamide, cycletanin; loop diuretics such as furosemide and torasemide; potassium-sparing diuretics such as amiloride, spironolactone, potassium canreonate, eplerenone, and triamterene; combinations of these agents; other diuretics such as acetazolamide and carperitide;

(20) direct vasodilators such as hydrolazine hydrochloride, diazoxide, sodium nitroprusside, cadralazine; other vasodilators such as isosorbide dinitrate and isosorbide 5-mononitrate;

(21) exogenous vasodilators such as Adenocard® and α-blockers;

(22) α-1 adrenergic receptor antagonists such as prazosin, indoramine, urapidil, bunazosin, terazosin, and doxazosin; atrial natriuretic peptide (ANP), ethanol, histamine inducers, tetrahydrocannabinol (THC) and papaverine;

(23) bronchodilators of the following types:

short-acting β2-agonists such as salbutamol or albuterol (Ventolin®) and terbutaline;

long-acting β2 agonists (LABA) such as salmeterol and formoterol;

anticholinergics such as ipratropium and tiotropium; and theophylline, a bronchodilator and phosphodiesterase inhibitor;

(24) corticosteroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, prednisolone, triamcinolone, dexamethasone, fluticasone, flunisolide, hydrocortisone, and corticosteroid analogs such as budesonide;

(25) nutritional supplements such as, for example, omega-3 oils; folic acid, niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark, Tribulus terrestris, arginine, Avena sativa, epimedium, poppy root, muira puama, saw palmetto, and Swedish pollen; vitamin C, vitamin E, vitamin K2; testosterone supplements, testosterone transdermal patch formulation, zoraxel, naltrexone, bormelanoid and melanotan II;

(26) PGD2 receptor antagonists;

(27) immunosuppressants such as cyclosporin (cyclosporin A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (Sirolimus®, Rapamune®) and other immunosuppressants such as FK506, mycophenolate such as mycophenolate mofetil (Cell ®);

(28) non-steroidal anti-asthma drugs such as β2 agonists such as terbutaline, metaproterenol, fenoterol, isoetarin, albuterol, salmeterol, bitolterol, and pirbuterol; combinations of β2agonists and corticosteroids such as salmeterol-fluticasone (Advair®), formoterol-budesonide (Symbicort®), theophylline, cromolyn, cromolyn sodium, nedocromil, atropine, ipratropium, ipratropium bromide and inhibitors of biosynthesis of leukotropium (zile5);

(29) non-steroidal anti-inflammatory drugs (NSAIDs), propionic acid derivatives such as alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, pentoprofen, miroprofen, suprofen, pirprofen, pirprofen tiaprofenic acid and thioxaprofen); derivatives of acetic

- 67 038096 acids such as indomethacin, acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclosic acid, fentiazac, furofenac, ibufenac, isoxepac, oxypinac, sulindac, thiopinac, tolmetin, zepidometacin and zepidiometacin; fenamic acid derivatives such as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid; biphenylcarboxylic acid derivatives such as diflunisal and flufenisal; oxicams such as isoxicam, piroxicam, sudoxicam and tenoxicam; salicylates such as acetylsalicylic acid and sulfasalazine; and pyrazolones such as apazone, bezpiperilone, feprazone, mofebutazone, oxyphenbutazone, and phenylbutazone;

(30) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib, and lumiracoxib; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, desocine, nalbuphine, and pentazocine;

(31) antidiabetic agents such as insulin and insulin mimetics; sulfonylureas such as glyburide, glibenclamide, glipizide, gliclazide, glyvidone, glimepiride, meglinatide, tolbutamide, chlorpropamide, acetohexamide, and tolazamide; biguanides such as metformin (Glucophage®); α-glucosidase inhibitors such as acarbose, epalrestat, voglibose, miglitol; triazalidinone compounds such as rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) and englitazone; insulin sensitizers such as pioglitazone and rosiglitazone; insulin secretion stimulants such as repaglinide, nateglinide and mitiglinide; incretin mimetics such as exenatide and liraglutide; amylin analogs such as pramlintide; glucose lowering agents such as chromium picolinate, optionally in combination with biotin; DPP-IV inhibitors such as sitagliptin (Januvia®), vildagliptin (Galvus®), saxagliptin (Onglyza®), linagliptin (Tradjenta®), anagliptin (Sanwa®), teneligliptin, alogliptin, trelagliptin, hemigliptin and MK -3102); GLP-1 agonists such as exenatide (Byetta® / Bydureon®), liraglutide (Victoza®, Saxenda®), lixisenatide (Lyxumia®), albiglutide (Tanzeum®), dulaglutide (Trulicity®);

(32) agents that increase HDL cholesterol levels such as anacetrapib and dalcetrapib;

(33) antiobesity drugs such as methamphetamine hydrochloride (Desoxyn®), amfepramone hydrochloride (Tenuate®), phentermine (Ionamin®), benzfetamine hydrochloride (Didrex®), phendimetrazine tartrate (Bontril®, Prelu-2®, Plegine® ), mazindol (Sanorex®), orlistat (Xenical®), sibutramine hydrochloride monohydrate (Meridia®, Reductil®), rimonabant (Acomplia®), amfepramone, chromium picolinate; combinations such as phentermine / topiramate, bupropion / naltrexone, sibutramine / metformin, bupropion SR / zonisamide SR, salmeterol, xinafoate / fluticasone propionate; lorkeserin hydrochloride, phentermine / topiramate, cetylistat, exenatide, liraglutide, metformin hydrochloride, sibutramine / metformin, bupropion SR / zonisamide SR, CORT-108297, canagliflozin, chromium picolinate, GSK15214604, LYEP-57N-57N -821, salmeterol xinafoate / fluticasone propionate, sodium tungstate, somatropin (recombinant), tesamorelin, tesofensin, welnerit, zonisamide, beloranib hemioxalate, insulinotropin, resveratrol, sobetirome, tetrahydrocannabachine;

(34) angiotensin receptor blockers such as losartan, valsartan, candesartan, cilexetil, eprosartan, irbesartan, telmisartan, olmesartan, medoxomil, azilsartan, and medoxomil;

(35) renin inhibitors such as aliskiren hemifumarate;

(36) centrally acting α-2 -adrenoceptor agonists such as methyldopa, clonidine and guanfacine;

(37) adrenergic neuron blockers such as guanethidine and guanadrel;

(38) I-1 imidazoline receptor agonists such as rilmenidine dihydrogen phosphate and moxonidine hydrochloride hydrate;

(39) aldosterone antagonists such as spironolactone and eplerenone;

(40) potassium channel activators such as pinacidil;

(41) dopamine D1 agonists such as fenoldopam mesylate; other dopamine agonists such as ibopamine, dopexamine, and docarpamine;

(42) 5-HT2 antagonists such as ketanserin;

(43) vasopressin antagonists such as tolvaptan;

(44) calcium channel sensitizers such as levosimendan or activators such as nicorandil;

(45) PDE-3 inhibitors such as amrinone, milrinone, enoximone, vesarinone, pimobendan, and olprinone;

(46) adenylate cyclase activators such as colforsin daropat hydrochloride;

(47) positive inotropic agents such as digoxin and methyldigoxin; metabolic cardiotonic agents such as ubidecarenone; brain natriuretic peptides such as nesiritide;

(48) drugs used to treat erectile dysfunction, such as alprostadil, aviptadil, and phentolamine mesylate;

68 038096 (49) PPAR agonists such as fibrates (clofibrate, gemfibrozil, ciprofibrate, bezafibrate and fenofibrate); thiazolidinediones; saroglitazar;

(50) FXR agonists such as cafeestol, chenodeoxycholic acid, obeticholic acid, and fexaramine;

(51) caspase inhibitors;

(52) LOXL2 monoclonal antibodies;

(53) acetyl Co-A carboxylase (ACC) inhibitors;

(54) CCR2 / CCR5 antagonists;

(55) conjugates of fatty acids / bile acids;

(56) inhibitors of galectin-3;

(57) ursodeoxycholic acid (UDCA);

(58) DGAT1 inhibitors;

(59) neprilysin inhibitors (NEPs) such as sacubitrile;

(60) combinations of NEP inhibitors with angiotensin receptor antagonists such as entresto (LCZ696), a combination of valsartan and sacubitrile; and (61) IMM-124E (bovine colostrum powder from cows immunized with LPS).

Pharmaceutical compositions and methods of administration.

The compounds described herein and their pharmaceutically acceptable salts can be presented in the form of pharmaceutical compositions or formulations.

A typical formulation is prepared by mixing a compound described herein, or a pharmaceutically acceptable salt thereof, and a carrier, diluent, or excipient. Suitable carriers, diluents and auxiliaries are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purposes for which the composition described herein is formulated. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (eg, as described in the GRAS (Generally Recognized Safe)) for administration to a mammal. Typically safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include other types of adjuvants, such as one or more buffers, stabilizing agents, release agents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release), preservatives, antioxidants, opacifiers, glidants, manufacturing aids, colorants, sweeteners, fragrances, flavors and other known additives to provide the aesthetic presentation of a drug (i.e., the compound described herein , or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug).

The formulations can be prepared using conventional dissolution and mixing techniques. For example, a bulk drug substance (i.e., one or more of the compounds described herein, a pharmaceutically acceptable salt thereof, or a stabilized form of the compound such as a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more auxiliary substances described above. The compound having the required purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers in the form of a lyophilized composition, a milled powder, or an aqueous solution. The composition can be formulated by mixing at ambient temperature, at an appropriate pH and in the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular application and the concentration of the compound, but can range from about 3 to about 8.

The compound described herein, or a pharmaceutically acceptable salt thereof, is typically formulated into pharmaceutical dosage forms to provide an easily controlled dose of the drug and to ensure patient compliance with a prescribed regimen. Pharmaceutical formulations of the compounds described herein, or pharmaceutically acceptable salts thereof, can be prepared for a variety of routes and types of administration. Different dosage forms can exist for the same compound. The amount of active ingredient that can be combined with carrier materials to produce a unit dosage form may vary depending on the subject being treated and the particular route of administration. For example, a sustained release formulation for oral administration to humans can be formulated with

69 038096 contain about 1 to 1000 mg of active material mixed with a suitable and convenient amount of carrier material, which can range from about 5 to about 95% of the total weight of the composition (weight: weight). The pharmaceutical composition can be formulated to provide readily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per ml of solution so that an appropriate volume of infusion can be carried out at a rate of about 30 ml / h.

The pharmaceutical compositions described herein will be formulated, dosed, and administered by a method, i. E. quantities, concentrations, schedules, courses, with carrier media for medicines and by administration in accordance with good medical practice. Factors to be considered in this context include the specific disorder to be treated, the specific human or mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site for delivery of the agent, the route of administration, the schedule of administration, and other factors known to the practitioner. such as the age, weight and response of the individual patient.

Acceptable diluents, carriers, excipients and stabilizers are those that are non-toxic to the recipient at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g. octadecyldimethylbenzylammonium chloride hexamethonium chloride, benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol); and mcresol proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt forming counter ions such as sodium; metal complexes (eg Zn protein complexes); and / or nonionic surfactants such as TWEEN ™, PLURONICS ™ or polyethylene glycol (PEG). Active pharmaceutical ingredients can also be encapsulated in microcapsules obtained, for example, by coacervation or interfacial polymerization methods, for example, microcapsules of hydroxymethylcellulose or gelatin and microcapsules of poly (methyl methacrylate), respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres , microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such methods are described in a review by Remington's: The Science and Practice of Pharmacy, 21 ^st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereinafter Remington's).

Controlled drug delivery systems deliver the drug to the body in a manner that is precisely controlled according to the drug and treatment conditions. The main goal is to achieve a therapeutic concentration of the drug at the site of action over a desired period of time. The term controlled release is often used to refer to various methods that modify the release of a drug from a dosage form. This term includes formulations designated as sustained release, delayed release, modified release, or sustained release.

Sustained release formulations are the most common controlled release embodiments. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compound, the matrices being in the form of shaped articles, such as films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactides (US Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene vinyl acetate, degradable copolymers of lactic acid and glycolic acid and poly-E - (-) - 3-hydroxybutyric acid.

Gastro-retentive formulations are preparations designed to increase the retention time in the stomach cavity. In some cases, they are used when the drug is predominantly or primarily absorbed through the stomach, are intended to directly treat the stomach, or when dissolution or absorption of the drug promotes absorption of the drug, providing a lasting effect on stomach acids. Examples of gastro-retentive formulations include, but are not limited to, high-density formulations, where the formulation density is higher than that of the liquid in the stomach; floating formulations that can float on top of fluids in the stomach due to increased buoyancy or lower density of the drug; temporarily expandable formulations that are larger than the opening of the stomach for a time; flour and bio-adhesive compositions; swellable gel formulations; and in situ gelling compositions (see, for example, Bhardwaj, L. et al. African J. of Basic & Appl. Sci. 4 (6): 300-312 (2011)).

Rapid release formulations can also be prepared. The purpose of these formulations is to conclude

- 70 038096 is to deliver the drug into the bloodstream and to the site of its action as quickly as possible. For example, for fast dissolution, most tablets are designed to disintegrate quickly into granules and then disaggregate into small particles. This provides more surface area available to the dissolution medium, resulting in a faster dissolution rate.

Implantable devices coated with a compound of the present invention are another embodiment of the present invention. The compounds can also coat implantable medical devices, such as beads, or are formulated with a polymer or other substance to provide a drug depot, which allows the drug to be released over a longer period of time than the administration of an aqueous solution of the drug. Suitable coatings and a general method for making coated implantable devices are described in US Pat. Nos. 6,099,562, 5,886,026 and 5,304,121. The coatings are generally biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings can be further coated with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids, or combinations thereof to impart controlled release characteristics in the composition.

Formulations include those that are suitable for the routes of administration described herein. The formulations can conveniently be presented in unit dosage form and can be prepared by any means well known in the pharmaceutical art. Descriptions of methods and formulations can usually be found in Remington's. Such methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

The terms “administration”, “administered” or “administration” in relation to a compound, composition or composition of the invention means the introduction of the compound into the body of an animal in need of treatment. When a compound of the invention is presented in combination with one or more other active agents, administration and variations thereof will be understood to include the simultaneous and / or sequential administration of the compound and other active agents.

The compositions described herein can be administered systemically or topically, for example, orally (for example, using capsules, powders, solutions, suspensions, tablets, sublingual tablets, etc.), by inhalation (for example, using an aerosol, gas, inhaler, nebulizer or the like), into the ears (for example, using ear drops), topically (using creams, gels, liniment, lotions, ointments, pastes, transdermal patches, etc.), ophthalmologically (for example, with eye drops, eye gels, ophthalmic ointments), rectally (for example, using enemas or suppositories), nasally, buccal, vaginally (for example, using douching, intrauterine devices, vaginal suppositories, vaginal rings or tablets, and etc.), through an implanted reservoir or the like, or parenterally, depending on the severity and type of disease being treated. The term parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In certain embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, wheat germ oil, olive, castor and sesame oil), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and esters of sorbitan and fatty acids their mixtures. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or dry diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders

- 71 038096 mi, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, algal starch acid, certain silicates and sodium carbonate, e) agents retarding dissolution, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known methods, including microencapsulation, to mask an unpleasant taste or slow down disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a substance such as glyceryl monostearate or glyceryl distearate can be used to delay the release. A water-soluble taste masking material such as hydroxypropyl methylcellulose or hydroxypropylcellulose can be used.

Formulations of the compound described herein suitable for oral administration can be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, for example, gelatine capsules, syrups or elixirs. Formulations of the compound for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions.

Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the compound powder moistened with an inert liquid diluent.

Formulations for oral administration can be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, where the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol, or an oily medium such as peanut oil, liquid paraffin, or olive oil.

The active compounds can also be in microencapsulated form with one or more excipients, as indicated above.

If aqueous suspensions are required for oral use, the active ingredient is combined with an emulsifier and suspending agent. Certain sweetening and / or flavoring agents can be added if desired. Syrups and elixirs can be formulated with sweeteners such as glycerin, propylene glycol, sorbitol, or sucrose. Such formulations may also contain an anti-irritant, a preservative, a flavoring and coloring agent, and an antioxidant.

Sterile injectable forms of the compositions described herein (eg, for parenteral administration) can be an aqueous or oily suspension. These suspensions can be prepared according to methods known in the art using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable media for drugs and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are typically used as a solvent or suspension medium. For this, any soft, non-volatile oils can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, for example natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol as a diluent or dispersing agent such as carboxymethyl cellulose, or similar dispersing agents that are traditionally used to prepare pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tween, Span, and other emulsifiers or bioavailability enhancers that are commonly used to prepare pharmaceutically acceptable solid, liquid, or other dosage forms can also be used to prepare formulations.

Oily suspensions can be prepared by suspending a compound described herein in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those described above and flavorings can be added to provide

- 72 038096 for an acceptable oral preparation. These compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or α-tocopherol.

Aqueous suspensions of the compounds described herein contain the active agents in admixture with adjuvants suitable for preparing aqueous suspensions. Such adjuvants include a suspending agent such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, as well as dispersing or wetting agents such as alkylene phosphinide (for example, natural with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose or saccharin.

Injectable formulations can be sterilized, for example, by filtration through a bacterial filter or by including sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.

In order to prolong the effect of a compound described herein, it is often desirable to slow down absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low water solubility. The rate of drug absorption further depends on the rate of its dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, absorption of a parenterally administered dosage form is slowed down by dissolving or suspending the drug in an oily drug carrier. Depot injectable forms are prepared by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide polyglycolide. Depending on the ratio of compound to polymer, as well as the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Drug-based depot formulations are also prepared by trapping the compound in liposomes or microemulsions that are compatible with body tissues.

Injectable solutions or microemulsions can be injected into the patient's bloodstream by local bolus injection. Alternatively, it may be successful to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the compound. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Model 5400 Deltec CADDPLUS ™ intravenous pump.

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or suppository wax that are solid at temperature environment, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays.

The pharmaceutically acceptable compositions described herein can also be administered topically, especially if the target of treatment includes sites or organs readily accessible upon topical application, including diseases of the eyes, skin, or lower intestines. Suitable topical formulations can be easily obtained for each of the indicated sites or organs.

Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulation, ear drops and eye drops are also contemplated as being within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be obtained by dissolving or dispensing a compound in an appropriate medium. Additionally, absorption enhancers can be used to increase the absorption of the compound through the skin.

The speed can be adjusted either by using a speed control membrane,

- 73 038096 either by dispersing the compound in a polymer matrix or gel. Local administration to the lower intestine can be carried out using a rectal suppository formulation (see above) or a suitable enema formulation. Topical percutaneous patches can also be applied.

For topical administration, the pharmaceutically acceptable compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions can be formulated as a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

Alternatively, the active ingredients can be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i. E. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400); and mixtures thereof. Topical formulations may optionally include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of emulsions prepared using the compounds described herein can be prepared from known ingredients in a known manner. Although the phase may contain only an emulsifier (otherwise known as an emulsifier), it desirably contains a mixture of at least one emulsifier with a fat or oil or both with a fat and oil. A hydrophilic emulsifier can be included along with a lipophilic emulsifier that acts as a stabilizer. In some embodiments, the emulsifier includes both oil and fat. Together, the emulsifier (emulsifiers) with or without stabilizer (s) form the so-called emulsifying wax, and the wax together with oil and fat form the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream composition. Emulsifiers and emulsion stabilizers suitable for use in the compounds described herein include Tween ™ -60, Span ™ -80, ketostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

The pharmaceutical composition (or formulation) for use can be packaged in various ways depending on the method used to administer the drug. Typically, the product for distribution includes a container containing the pharmaceutical composition in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also contain a tamper-proof assembly to prevent inadvertent access to the contents of the package. In addition, a label is placed on the container that describes the contents of the container. The label may also contain appropriate warnings.

The formulations can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Injection solutions and suspensions can be prepared from the sterile powders, granules and tablets described above. Preferred unit dosage forms are formulations containing a daily dose or a single daily dose as defined above, or a corresponding portion of the active ingredient. In another aspect, a compound described herein, or a pharmaceutically acceptable salt, co-crystal, solvate or prodrug thereof, can be formulated as a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials that can be used to administer the composition and can be solid, liquid or gaseous materials which, when inert or acceptable in veterinary medicine, can be inert or compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or any other route desired.

Sets.

The pharmaceutical formulations described herein may be contained in a kit. The kit may include one or more doses of two or more agents, each packaged or formulated individually, or a single or multiple dose of two or more agents packaged or formulated in combination. Thus, one or more agents may be present in the first container, and the kit may optionally include one or more agents in the second container. The container or containers are placed in a package, and the package may optionally include instructions for administration or dosage. The kit may include additional components such as

- 74 038096 syringes or other means for administering agents, as well as diluents or other means for preparation. Thus, the kits may contain: a) a pharmaceutical composition containing a compound described herein and a pharmaceutically acceptable carrier, a drug carrier or diluent; and b) another therapeutic agent and a pharmaceutically acceptable carrier, a drug carrier or diluent in one or more containers or separate packaging. The kits may optionally contain instructions describing how to use the pharmaceutical compositions in one or more of the methods described herein (eg, preventing or treating one or more of the diseases and disorders described herein). The pharmaceutical composition containing the compound described herein and the second pharmaceutical composition contained in the kit may optionally be combined in the same pharmaceutical composition.

The kit includes a container or package for containing pharmaceutical compositions and may also include split containers such as a split bottle or split foil pouch. The container can be, for example, a paper or cardboard box, glass or plastic bottle or jar, a resealable pouch (for example, to hold a refill of tablets for placement in another container), or a custom dose blister pack to be compressed from a package according to a therapeutic schedule. It is possible that more than one container can be used together in one package to sell a single dosage form. For example, pills can be contained in a bottle, which in turn is contained in a box.

An example of a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs usually consist of a sheet of relatively rigid material covered with foil, preferably transparent plastic. Depressions are formed in the plastic foil during the packaging process. The recesses are sized and shaped as single tablets or capsules for packaging, or may be sized and shaped to accommodate multiple tablets and / or capsules for packaging. The tablets or capsules are then placed in the recesses, respectively, and a sheet of relatively rigid material is sealed against a plastic foil on the face of the foil that is opposite to the direction in which the recesses are formed. As a result, the tablets or capsules are individually sealed or collected together, as desired, in the recesses between the plastic film and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the recesses, whereby an opening is formed on the sheet at the location of the recess. The tablet or capsule can then be removed through the indicated opening.

It may be desirable to provide a written reminder containing information and / or instructions for the physician, pharmacist, or subject as to when to take the medication. The daily dose can be one tablet or capsule, or multiple tablets or capsules to be taken on a specific day. When the kit contains separate compositions, the daily dose of one or more of the compositions of the kit may consist of one tablet or capsule, while the daily dose of the other one or the other composition of the kit may consist of several tablets or capsules. The kit may take the form of a dispenser designed to dispense daily doses one at a time in the order of intended use. The dispenser can be equipped with a reminder to further facilitate compliance. An example of such an auxiliary memo is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of such a reminder is a battery-powered microchip memory associated with a liquid crystal readout or audible reminder that, for example, reads the date the last daily dose was taken and / or reminds of when the next dose is due.

Examples of

Example 1. Animal models of NASH.

Several NASH animal models have been described in the literature (see review of Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame, Ibrahim SH et al., Dig Dis Sci.published on line 01 ^st Dec 2015; DOI 10.1007 / sl0620-015-3977 -1).

In one model, NASH is induced in male mice according to the method used by Fujii et al. (Fujii M., Shibazaki Y., Wakamatsu K., et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma, Med. Mol. Morphol., 2013, 46, 14152), consisting of one subcutaneous injection of 200 mcg streptozotocin 2 days after birth (1st dose) and feeding a high fat diet (HFD, 57 kcal% fat, cat #: HFD32, CLEA Japan, Japan) starting at 4 weeks (2 -th dose). In this experimental model, fatty liver and major histological features of NASH are evident 5 and 7 weeks after birth, respectively. In this model, animals are kept on HFD for 2-16 weeks.

In another model, NASH is induced in Sprague-Dawley rats by intravenous administration of 20% intralipid (IL) for three weeks (Abu-Serie et al., Lipids in Health and Disease, 14: 128 (2015)).

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These or similar animal models of NASH can be used to determine the effect of the sGC stimulant compounds described herein on the clinical manifestations of NASH.

For example, NASH will be induced in male C57BL / 6J mice (using N = 4-12 animals per group) with a single subcutaneous injection of ~ 200 μg streptozotocin 2 days after birth and fed a high fat ad libitum diet 4 weeks later. Male mice without any treatment and male mice treated with STZ alone could be used as controls. Then the animals were treated with the stimulant sGC, starting from the second day. The sGC stimulant can be dosed daily or more frequently throughout the study by oral gavage, food or water, or parenteral administration. A number of analyzes have been performed, which are described below:

Biochemical analyzes.

Fasting blood sugar, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglyceride (TG) were measured. In addition, levels of albumin, urea, and creatinine will also be used to determine liver status and degree of function.

Historical analysis.

Liver sections from one lobe (eg, left lobe) were embedded, quickly frozen in liquid nitrogen, and stored for analysis. Then the sections were cut, dried in air, and fixed in acetone. For staining with hematoxylin and eosin, sections of the liver were preliminarily fixed in Buin's solution, and then stained with Lilly-Mayer's hematoxylin solution and eosin. The degree (zone-3) of liver fibrosis could be assessed by sirius red staining or silver impregnation staining. To visualize macro- and microvesicular adipose tissue, sections fixed with 4% PFAPBS were stained with oil red O.

Immunohistochemistry.

Endogenous peroxidase activity can be blocked using 0.03% H2O2-PBS followed by incubation with Block Ace (Dainippon Sumitomo Pharm. Osaka, Japan). The sections were incubated with optimal dilutions of antibodies against F4 / 80 ER-TR7, against CD68, against BrdU, against CD31, against glial fibrillar acidic protein (GFAP), against type IV collagen and antibodies against glutamine synthetase overnight at 4 ° C. After incubation with the appropriate secondary antibodies, the substrate was reacted using a solution of 3 ', 3'-diaminobenzidine (DAB). For double staining, Alkaline Phosphatase Substrate Kit 1, Vector Labs, Burlingame, CA, USA, can be used. For negative control, samples were processed using primary antibody dilution buffer.

For quantitative analysis of ER-TR7-, F4 / 80- and Sirius red positive areas, bright-field images of stained sections were captured with a digital camera around the central veins at 200x magnification, and positive areas in several fields (~ 5) were measured using software ImageJ (National Institute of Health, Bethesda, MD, USA). Results were defined as the mean of several (~ 5) different fields for each section.

Non-alcoholic fatty liver activity indices (NAFLD) (NAS estimate) can be calculated according to Kleiner, et al. (Hepatology 41: 1313-1321 (2005)). Liver histology was used to determine NAFLD scores. Assessment components include the degree of steatosis, localization of steatosis and presence of microvesicular steatosis, stage of fibrosis, endpoints of inflammation including lobular inflammation, presence of microgranulomas and large lipogranulomas, and portal inflammation. Liver cell endpoints, including hepatocyte ballooning, acidophilus bodies, pigmented macrophages, and megamitochondria, are also components of the assessment. Other histological indicators, including Mallory grade, hyaline and glycogenized nuclei, are also used in the assessment.

Lobular inflammation can be detected in several ways, including lobular accumulation of F4 / 80 + macrophages.

Histological oil red O staining can be used to assess steatosis / body fat.

Fibrosis can be defined in several ways. Histologically, for example, by quantifying ER-TR7 + fibroblasts using Sirius red staining to detect collagen deposition and pericellular fibrosis found around the central vein, or using silver impregnation staining.

The effect of the sGC stimulant on the NAFLD score, or on one or more components of the NAFLD scores, including steatosis, fibrosis, inflammation, or damage to liver cells, would be indicative of usefulness in treating NASH. In addition, evidence of an effect on these endpoints at a dose associated with little to no effect on blood pressure could be indicative of usefulness in the treatment of NASH.

Example 2 Carbon tetrachloride (CCl ₄ ) -induced changes in liver fibrosis markers in C57BL / 6 mice in the presence and absence of the sGC stimulator.

Experimental animal models of liver fibrosis using CCl ₄ in mice have previously been

- 76 038096 are described in the literature (see, for example: Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation, Fu Y. et al., Mol. Pharmacol., 73 (2): 399409 (2008)).

An experimental study using C57BL / 6 mice was conducted to investigate changes in the biomarker of liver fibrosis after a single injection of carbon tetrachloride (CCl ₄ ) administered intraperitoneally (IP) and the action of several substances, including the stimulant sGC, in this model. Injection of CCl ₄ mice leads to an increase in the expression of α-SMA (α-smooth muscle actin) mRNA, and this can be used as a biomarker of fibrosis in the liver. The decrease in expression levels of this biomarker and return to normal levels upon administration of the stimulant sGC can be used to assess the potential usefulness of the compound in the treatment of liver fibrosis.

The mice used at delivery were 8 weeks old, healthy and not used in other experimental procedures. Housing and care was as specified in the USDA Animal Conservation Act (9 CFR Parts 1 and 3) and as described in the National Research Council's Laboratory Animal Care and Handling Guidelines. The living environment was set within the following ranges for acclimatization and untreated groups: temperature: 68 ± 5 ° F (22 ± 4 ° C), humidity: 50 ± 20%; light cycle: 12-hour light / 12-hour dark; air change: ten or more changes per hour with 100% HEPA filtered air. The mice were given regular food and water ad libitum and were not fasted overnight prior to compound administration.

The sGC stimulant used in this experiment is Compound A depicted below:

Compound A

The preparation and characterization of this compound was described in patent application publication WO 0201144100, published September 18, 2014.

CCl ₄ was administered once to all animals by intraperitoneal injection (IP) at a concentration of 15 μl (dissolved in 85 μl of corn or olive oil) and a dose volume of 100 μl per mouse weighing 30 g. Compound A was administered to mice by oral administration (PO, oral probe) twice a day for 3 days at a concentration of 3 mg / ml (0.5% methylcellulose) and a dose of 300 μl / 30 g mouse. A single dose of CCl ₄ was administered 2 hours after the first dose of Compound A. A second dose of Compound A was administered 7 hours after the first dose. After three days of dosing, animals were sacrificed and plasma and liver samples were obtained for analysis.

Homogenization of tissues.

Total RNA was extracted from the isolated tissues by adding 1 ml of Trizol and a stainless steel bead to each sample and homogenized using a TissueLyser II at maximum speed (30 Hz) for 2 min at room temperature. After homogenization, 200 μl of chloroform was added to each homogenized sample. The homogenate was quickly shaken and left upright at room temperature for 2-5 minutes until phase separation became visible. Samples were centrifuged for 15 min at maximum speed (13200 rpm) at 4 ° C in an Eppendorf centrifuge.

Complete purification of RNA.

For RNA purification, a Qiagen RNeasy Mini Kit (Qiagen, Cat #: 74106) was used.

After 15 min centrifugation at maximum speed (13200 rpm) at 4 ° C, the supernatant of each sample (~ 500 μL) was transferred to a new tube without RNase. An equal volume of 70% ethanol (prepared with nuclease-free water) was added to each sample and immediately mixed by pipetting up and down. The RNeasy-labeled spin column was placed on a tube rack. 700 μl of 70% ethanol / sample, including any precipitate, was transferred to an RNeasy spin column placed in a 2 ml collection tube (supplied by Qiagen). The lid was closed and the RNeasy back column was centrifuged for 30 seconds at 10,000 rpm at room temperature and the filtrate in a 2 ml collection tube was discarded. The remainder of the ethanol / sample mixture (~ 300 μl) was added to the same spin column and the previous procedure repeated (steps 3 and 4). After the completion of the above two steps, the total RNA was bound to the spin column membrane and the filtrate was discarded. 350 μl of wash buffer (RW1) was added to the RNeasy spin column, the lid was closed and the RNeasy spin column was centrifuged for 30 s at 10,000 rpm at room temperature. Filtrate from

- 77 038096 thrown. A DNase I stock solution (Qiagen) was prepared by injecting 550 μl of RNase-free water into a DNase I flask using an RNase-free needle and syringe. The mixture was gently mixed by inverting the vial rather than by shaking. 10 μl of DNase I stock solution was added to 70 μl of RDD buffer (Qiagen) and the mixture was gently mixed. 80 μl of RNase-free DNA was added to each spin column to digest the DNase on the column (15 min incubation at room temperature). After a 15 minute incubation step, the RNeasy spin column was washed with an additional 350 μl of RW1 buffer, the lid was closed and the RNeasy spin column was centrifuged for 30 s at 10,000 rpm at room temperature and the filtrate discarded. The spin column was then washed twice with 500 μl RPE buffer, centrifuged for 30 seconds between wash steps at 10,000 rpm at room temperature, and the filtrate was discarded. The RNeasy spin column was placed in a new 2 ml collection tube, centrifuged at maximum speed for 1 min at room temperature to dry the membrane, and the RNeasy spin column was then placed in a new 1.5 ml collection tube (Qiagen). After the above step, 15 μl of nuclease-free water was added to the spin column twice, and the column was centrifuged after each of the two steps of adding 15 μl of nuclease-free water at a maximum speed (14800 rpm) in a Sorvall Legand Micro 21 centrifuge. (ThermoFisher) at room temperature for RNA elution. The eluted total RNA was placed on ice until RNA was quantified. Total RNA was determined using a NanoDrop 2000c (ThermoFisher) and the concentration and quality of RNA was recorded.

CDNA synthesis.

For the synthesis of cDNA, 1 μg of total RNA was used. Single-stranded complementary DNA (cDNA) was synthesized in a volume of 20 μl using the high capacity reverse transcription kit (Life Technologies) described in table. 1 to obtain a concentration of 50 ng / μl.

After completion of the cDNA synthesis, an additional 20 μl of nuclease-free water was added to the cDNA to obtain a final cDNA concentration of 25 ng / μl.

Relative expression of RT-qPCR.

For TaqMan® real-time quantitative polymerase chain reaction (RT-qPCR) gene expression analysis, 25 ng cDNA was used. The taqman probes of murine α-smooth muscle actin (Life Technologies) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Life Technologies) were obtained from Life Technologies. The reaction mixture, placed in an optical 96-well MicroAmp plate (Life Technologies) for RT-qPCR in a fast mode, is shown in table. 2. A total of 20 μl of PCR reaction was added to each well. The plate was sealed with a sealed lid and the reaction mixture was centrifuged at 2000 rpm at 4 ° C for 2 min, then the plate was placed in a real-time PCR instrument (Applied Biosystems StepOnePlus ™). All samples were tested in duplicate using no negative control (NTC) cDNA template on each plate, and reactions were carried out under the thermal cycle conditions shown in table. 3. After the completion of the PCR run, the data was exported to an Excel file for analysis of relative mRNA expression. The 2-ΔΔCt method (Livak & Schmittgen, Methods (2001) 25: 402-408) was used to calculate the relative expression of mRNA.

Table 1 Synthesis of cDNA

Preparation of reagents

Reagents 1 reaction Ix RT buffer (μl) 2 Yux RT random primers (μl) 2 25x dNTP mix (100 mM) (μl) 0, 8 MultiScribe Reverse Transcriptase (μl) 1 Rnase inhibitor (μl) 1 total RT Mix per well (μl) 6.8 Total RNA @ 1 μg (μl) H ₂ O (μl) Total volume (μl) twenty

PCR program for generating cDNA

25 ° C 10 min 37 ° C 120 minutes 85 ° C 5 minutes 4 ° C always

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table 2

Reaction mixture RT-qPCR

human intestinal tissue cDNA One reaction (μl) 2Ox Analysis of Taqman gene expression (μl) Acta2 (Life Technologies) 1 GAPDH (Life Technologies) 1 2x Taqman Gene Expression Master Mix (Life Technologies, PN 4369016) (μl) ten CDNA template (μl) 1 H ₂ O (μl) 7

Table 3

Thermal Cycling Conditions RT-qPCR

Thermal cycling conditions Stage Temperature (° C) Time (min: sec) Retention 50 2:00 Retention 95 10:00 Cycle (4 0 cycles) 95 0: 15 60 100

Compound A administration in this pilot study resulted in a statistically significant reduction in elevated α-SMA levels compared to samples treated with drug carrier (0.5% methylcellulose). The decrease observed in the samples treated with Compound A was significantly greater than the decrease observed in the samples treated with pirfenidone, a marketed antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis.

More specifically, the 30 mg / kg dose of Compound A caused a relative decrease in α-SMA mRNA expression levels of about 66%, while pirfenidone at a dose of 400 mg / kg resulted in a decrease of about 20%.

These data support the hypothesis that an sGC stimulant (eg, Compound A) exhibits antifibrotic activity in the liver in vivo, and also demonstrate the usefulness of this model for investigating the mechanism of action of sGC stimulants on fibrosis, one of the indicative characteristics of NASH.

Example 3. LPS model of acute inflammation in mice.

Murine models of acute inflammation have previously been described (see, for example, Engelberts I. et al., Lymphokine Cytokine Res. 10 (1-2): 127-31 (1991), and Durez P. et al., J. Exp. Med. 177: 551-5 (1993)). In these models, the compound of interest is administered to mice or rats followed by an injection of LPS one hour later (LPS stands for lipopolysaccharide, intravenous administration 100 ng). LPS is a component of the bacterial cell wall and induces a rapid and strong systemic inflammatory response. Blood was collected 2 hours after LPS injection, plasma and serum were isolated and cytokine levels measured. Blood concentrations of TNFa and IL-6 increase after stimulation with bacterial lipopolysaccharide (LPS). Measurement of cytokine production is carried out either by ELISA assay or by cytokine bead assay (CBA).

The sGC stimulant compound B was evaluated in this animal model using C57BL / 6 mice. The structure of connection B is shown below.

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The preparation and characterization of this compound was described in patent application publication WO 0201144100, published September 18, 2014.

The ability of compound B to modulate the release of cytokines in vivo was evaluated. Compound B was administered by oral gavage (formulated with methylcellulose as a carrier) at doses of 1 and 10 mg / kg and the levels of the pro-inflammatory cytokines TNFa and IL-6, as well as the anti-inflammatory cytokine IL-10, were determined. Drug vehicle (V) and dexamethasone (dex, 5 mg / kg) were used as negative and positive controls, respectively, and 10 mice were used per group.

In this study, Compound B at 10 mg / kg significantly reduced IL-6 and TNFa levels while increasing IL-10 levels. These data support the hypothesis that the sGC stimulant (eg, Compound B) has anti-inflammatory activity in vivo, and also demonstrate the usefulness of this model for investigating the mechanism of action of sGC stimulants on the inflammatory response, which is one of the indicative characteristics of NASH.

Example 4: Effect of sGC stimulant treatment in a mouse model of diet-induced obesity (DIO) with hepatic steatosis.

NASH is common in people who are overweight or obese. Obesity is characterized by an excess fat / energy ratio and excessive expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) burns energy to produce heat. Hoffman et al. (Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue, Linda S. Hoffmann et al., Nature Communications 6: 7235 (2015)) showed that BAY 41-8543, a low molecular weight stimulant soluble guanylyl cyclase (sGC) , protects against diet-induced weight gain and hepatic steatosis, induces weight loss in established obesity, and improves the diabetic phenotype. BAY 41-8543 enhances lipid uptake in BAT and increases total body energy expenditure, while ablation of the heme-containing sGC B1 subunit severely impairs BAT function. BAY 418543 enhances differentiation of human brown adipocytes and induces browning of primary white adipocytes. These results indicate that sGC is a possible pharmacological target for the treatment of obesity and its associated diseases, including NASH.

In the above study, transgenic mice were generated by removing the β1 subunit of sGC (sGC1e- / '), a subunit that contains the heme / NO-binding domain. The addition of NO increases cGMP in brown adipocytes (BA) isolated from wild-type (WT) mice, but not in sGCe17'BA isolated from transgenic mice. This demonstrates that sGCe1 is required for NO-dependent cGMP formation in VA.

When WT mice were fed a high-fat diet (HFD), they were obese and displayed all the metabolic characteristics of obesity, including decreased insulin sensitivity, increased plasma insulin levels, and increased total fat storage. They also showed abnormal levels of fat accumulation in the liver (i.e., steatosis).

BAY 41-8543 (dosage for 8 weeks at 300 mg / kg / 24 h food and intraperitoneally at 1 mg / kg to ensure high plasma levels) increases lipid absorption in BAT and increases energy expenditure by the whole body. BAY 41-8543 enhances differentiation of human brown adipocytes and induces roasting of primary white adipocytes. In the livers of WT mice injected with HFD, showing an obesity phenotype, administration of BAY 41-8543 resulted in a significant reduction in triglyceride content compared to mice fed a regular meal.

These data support the hypothesis that the sGC stimulant has the ability to reduce hepatic steatosis in vivo, and also demonstrate the usefulness of this model for investigating the mechanism of action of sGC stimulants on steatosis, which is one of the indicative characteristics of NASH.

Example 5. Distribution of sGC stimulants in tissues, studies in rats.

The purpose of this experiment was to determine the concentration of compounds in the plasma and tissues of animals that were administered stimulants sGC for 5 days once a day.

In a first experiment, the sGC stimulant compound B (described previously in Example 2) was dosed for 5 days once a day to male Wister rats. The rats were divided into four study groups and dosed according to the table below:

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Experimental group Group A Group B Group D Compound and dose Drug carrier Compound B 1 mg / kg (in carrier) Compound B 10 mg / kg (in carrier) #Rats / Group 12 males 6 males 6 males Dose volume 5 ml / kg PO 5 ml / kg PO 5 ml / kg PO

The carrier medium is 1% HPMC, 0.2% Tween 80 in 0.5% methylcellulose.

The animals were dosed daily for five consecutive days according to the table above. On each dosing day, frozen aliquots of each dosing solution were thawed and the animals were weighed and dosed accordingly. On the 5th day, 2 hours after the fifth dose, blood was collected using orbital bleeding. Blood samples were collected in EDTA tubes pre-filled with 5 μl of 100 mM IBMX. Plasma was separated by centrifugation for 10 min at 4 ° C and then stored at -80 ° C.

A solution of ketamine / xylazine / pbs in a ratio of 5: 1: 4 was injected IP at 1 μl per 1 g. Once the rat was completely anesthetized (as determined by checking its reflexes) and when the heart was still beating, a needle was inserted into the left ventricle. Then, approximately 20 ml of PBS / IBMX / heparin solution was perfused. The right atrium was cut off and perfusion was continued for about 10 ml more (30 ml total). At this point, the femoral artery was cut off and perfusion was continued until there was no more blood collecting in the abdominal cavity (clear fluid only). Some tissues, including the liver, were isolated and weighed, followed by freezing.

A second separate and similar experiment was carried out with Compound C. The structure of Compound C is depicted below. The preparation and characterization of this compound was described in patent application publication WO 0201144100, published September 18, 2014.

NH ₂

Compound C

For this second experiment, the rats were divided into four study groups and dosed according to the table below:

Experimental group Group A Group B Group D Compound Medium for the drug Compound C 1 mg / kg (in medium for the drug) Compound C 10 mg / kg (in drug medium) The consignment #Rats / Group 6 males 6 males 6 males Dose volume 5 ml / kg PO 5 ml / kg PO 5 ml / kg PO

The carrier medium is 1% HPMC, 0.2% Tween 80 in 0.5% methylcellulose.

Quantification of Compound B and Compound C in Rat Liver by LC-MS / MS.

Samples were analyzed using liquid chromatography (LC) using tandem mass spectrometric detection (MS / MS) using positive electrospray ionization. The standard curve range was 0.1 to 400 ng / ml. The reference materials used were: Compound B, Compound C, Compound B Smechennoe ¹³ and ¹³ Smechennoe compound C.

To prepare tissues for measurement, untreated liver and liver isolated after treatment were taken from an 80 ° C freezer and placed in liquid nitrogen. Liver weight was recorded and then

- 81 038096 tissue was placed in a Geno grinding tube containing two 7/16 steel beads. The liver was homogenized using Geno / Grinder 2010 for 3 minutes at 1500 rpm. Approximately 200 mg of tissue from each sample was weighed and recorded. A 4x volume of 100 μM IBMX in 20% acetic acid was added to each pre-weighed sample and shaken (eg 200 mg liver powder / 800 μl 100 μM IBMX in 20% acetic acid). A standard curve was obtained on untreated liver matrix by diluting 100x DMSO stock solutions (5 μl of each 100x standard in 495 μl of liver matrix). 300 microliters of acetonitrile containing internal standard (20 ng / ml ¹³ C-labeled compound B or ¹³ C-labeled compound C) was added to a 96-well plate Phenomenex Phree for removing phospholipids. To acetonitrile was added 100 μl of 1X standards and treatment group samples, then pipetted up and down several times to ensure mixing and settling. A Phree phospholipid removal plate was placed on top of the immunoassay plate and pressurized at 5 psi using a positive pressure manifold. The samples were dried under nitrogen in a TurboVap at 55 ° C. Each sample was resuspended in 50 μl of 0.1% formic acid, covered and shaken. Samples were analyzed using LC-MS / MS.

The following LC / MS / MS conditions were used for the analysis.

LC / MS / MS conditions

Chromatography conditions Speaker Hypersil Gold, 2.1x50mm, 3um Safety column Hypersil Gold javelin guard (2.1x10) Column temperature 25 ° C Injection volume 10 μl Temperature autosampler 4 ° C Flow rate 1.0 ml / min. Mobile phases Mobile phase A: 0.1% formic acid in H ₂ O Mobile phase B: 0.1% formic acid in ACN Detection method Ion detection mode TurboIon Spray, positive Compound MRM Transition Compound B 535.0> 109.0 ¹³ C-labeled compound B 541.0> 115.0 Compound C 510> 109 ¹³ C-labeled compound C 516> 115

Total liver and plasma concentrations were determined, and liver concentrations were adjusted for total liver weight. Liver: The plasma ratio was determined by dividing the liver concentration of the compound by the plasma concentration of the compound. Liver: The observed liver: plasma ratios were the same for both dosages (1 mg / kg and 10 mg / kg). The total liver: plasma ratio for Compound B was 19 at 1 mg / kg and 20 at 10 mg / kg. The total liver: plasma ratio for Compound C was 6 at 1 mg / kg and 8 at 10 mg / kg. All compounds showed dose proportional increases in total tissue and plasma concentrations.

These data support the notion that some sGC stimulants, such as structures similar to Compound B and Compound C or others described herein, are capable of spreading to the liver, where they can influence aspects of NASH while still being able to minimize systemic effects such as lowering blood pressure.

Using liver microdialysis, these compounds have also been shown to bind to target sGC in the liver, in particular to increase cGMP and pVASP, both of which are markers of interactions

- 82 038096 sGC targets.

Example 6. Distribution of sGC stimulants in tissues, clinical studies.

In a randomized, double-blind, placebo-controlled, single dose escalating phase I study in 46 healthy volunteers, participants were randomly assigned 3: 1 to receive a single dose of Compound B or placebo administered via an oral capsule. Clinically relevant clinical data results were in agreement with the preclinical data described in Example 5 above and included evidence of widespread tissue distribution.

Example 7 Mice on a high fat methionine / choline depleted diet.

Research plan.

The study was conducted in mice on a high-fat diet low in choline and methionine (MCD-HFD or MCD diet), a model that mimics the clinical manifestations of human steatohepatitis and fibrosis in mice. These mice received the sGC stimulant compound B prophylactically (at two doses of 1 and 3 mg / kg / day in food), starting at the same time as the high fat diet, low in choline / methionine, and before the animals began to show clinical signs of steatohepatitis.

Compound B prophylactic treatment was continued for a total of 9 weeks concurrently with a high-fat choline / methionine-poor diet. At the end of treatment, the degree of inflammation was assessed in the liver by determining the gene expression levels for IL-6, TNFa, IL10, MCP-1, IL-1e and IL-1ra using real-time PCR. Inflammation levels were also determined by assessing the inflammatory infiltrate using F4 / 80 immunohistochemistry, and necrotic inflammation was assessed by hematoxylin-eosin staining. Liver fibrosis was determined by measuring the levels of gene expression for collagen types I and II, MMP-2, TIMP-1 and TGFe1 at the mRNA level. Histological analysis was performed on tissue sections stained with Masson's trichrome and Sirius red.

The study included the following experimental groups.

Group I (n = 5): Food control group received a matched sugar diet equivalent to a high fat diet (HFD) for 9 weeks.

Group II (n = 15): Choline / methionine depleted HFD control group (MCD control group) received choline / methionine depleted HFD diet for 9 weeks.

Group III (n = 10): received HFD depleted in choline / methionine supplemented with food grade Compound B for 9 weeks (1 mg / kg bw / day) (group IW1).

Group IV (n = 10): Received HFD depleted in choline / methionine supplemented with food grade Compound B for 9 weeks (3 mg / kg bw / day) (group IW3).

Analysis.

After treatment, the animals were sacrificed and liver and blood samples were collected. The effect of the sGC stimulant on liver weight, steatosis, inflammation and fibrosis was assessed as follows.

Analysis of mRNA expression using real-time PCR.

Total RNA was obtained using the RNA aqueous kit. RNA concentration was assessed on a UV spectrophotometer and RNA integrity tested on a 6000 LabChip in a 2100 Bioanalyzer (Agilent Technologies, Palo Alto, Calif.). The first strand of cDNA was synthesized by incubating 1 μg of total RNA with 2.5 μl of 10x RT buffer, 1 μl of 25x dNTP, 2.5 μl of 10x primers, and 1.25 μl of reverse transcriptase (25 μl final volume) for 10 min at 25 ° C for 2 h at 37 ° C in an ABI thermal cycler. Ready-to-use primer and probe samples previously developed by Applied Biosystems (TaqMan gene expression assays) were used to quantify gene expression using β-actin as an endogenous control. Briefly, PCR reactions were performed in duplicate using a Universal TaqMan 2x PCR master mix in a volume of 20 μl containing 1.25 μl of cDNA. Real-time quantitative PCR was performed using an ABI Prism 7900 sequence detection system (Applied Biosytems) using TaqMan fluorescence technology. Real-time PCR results were analyzed using Sequence Detection Software Version 2.1 (Applied Biosystems), and relative quantification of gene expression was performed using the 2-ΔΔ Ct method.

(User Bulletin # 2; http://docs.appliedbiosystems.com/pebiodocs/04303859.pdf). Masson Trichrome and Sirius red staining: Tissue samples fixed in 10% formalin were embedded in paraffin, cut into 5 μm sections, stained with H&E and analyzed by a registered pathologist unaware of treatment. Tissue sections were incubated for 10 min in 0.5% thiosemicarbazide and stained with 0.1% Sirius red F3B in saturated picric acid solution for 1 h and then washed with acetic acid solution (0.5%). Masson's trichrome staining was performed at the Pathology Department of the Hospital Clinic, Barcelona, Spain. Sections were visualized under a Nikon Eclipse E600 microscope (Kawasaki, Kanagawa, Japan), and the relative areas of steatosis and fibrosis were quantified by histomorphometry using Olympus Cell

- 83 038096 (Olympus Soft Imaging Solution GmbH, Munster, Germany) and Image J software (Macbiophotonics, McMaster University, Hamilton, ON, Canada), respectively. At least 6-20 independent regions were assessed.

Masson's trichrome stained sections were scored by examining randomly selected areas of view for each tissue section as follows.

Stage 0. None. Normal lobular architectonics.

Stage I. Pericentral fibrosis (increased thickness of the central vein).

Stage II. Central anastomosis (some fibrous septa connecting central veins).

Stage III. Precirrhotic stage (fibrous septa with pronounced distortion of the lobular structure of the liver).

Stage IV. Cirrhosis (regeneration in the nodes surrounded by wide cords of fibrous septa).

Evaluation of inflammatory infiltrate using immunohistochemistry F4 / 80.

Tissue sections were dewaxed, rehydrated and pretreated with trypsin 0.05% -CaCl ₂ 0.1% for 20 min at 37 ° C to detect antigen, then incubated with 3% H ₂ O ₂ for 25 min at room temperature and in the dark to block endogenous peroxidase activity and with 2% BSA for 20 min at room temperature to avoid non-specific binding of the primary antibody. The sections were then incubated overnight at 4 ° C with primary rat anti-mouse F4 / 80 antibody (1/100), followed by incubation for 90 min at room temperature using biotinylated rabbit anti-rat IgG antibody (1/200) and incubation with ABC for 45 min at room temperature. The color was developed using DAB substrate and the areas were contrasted with hematoxylin.

Assessment of necrotic inflammation.

Tissue samples fixed in 10% formalin were embedded in paraffin and cut into 2 µm sections for hematoxylin-eosin staining. Necrotizing inflammation was analyzed by a registered pathologist unaware of treatment according to the histological scoring system used on a regular basis in the Hospital Clinic pathology laboratory: grade 0 (none), grade 1 (macular necrosis, one or more necrotic hepatocytes), grade 2 (confluent necrosis) and grade 3 (bridging necrosis).

Results.

Control groups.

After 9 weeks, animals in group II (control group on the MCD diet) showed a significant increase in the ratio of liver tissue mass to total body weight compared to animals in the control group food (group I). The ratio of liver tissue mass to total body weight in MCD animals almost doubled compared to the nutritional control group. Using hematoxylin / eosin staining, fat accumulation in the liver of animals in group II was clearly seen as compared with animals in group I.

Based on Picrosirius Red staining, fibrosis (in the form of collagen accumulation) was clearly increased by about 8-fold in group II compared to the liver of animals in group I. This observation was confirmed when fibrosis was determined by analysis of the trichromic stain and also by deposition of α-SMA (Fig. 4, comparison of columns of food groups with MCD).

The mRNA expression levels were strongly increased in animals in group II compared to animals in group I for the following genes associated with liver fibrosis: COL1A1, COL1A2, TIMP-1, MMP2 and TGFP1.

The mRNA expression levels were strongly increased in animals in group II compared to animals in group I for the following genes associated with liver inflammation: TNF-α, IL-6, IL-10, MCP-1 and IL-1ra.

Treatment groups.

After 9 weeks, animals treated with 3 mg / kg of Compound B (group IV) showed a statistically significant decrease in liver tissue weight relative to total body weight compared to animals in control group II. After 9 weeks, animals treated with 3 mg / kg of Compound B (Group IV) showed a statistically significant reduction in the percentage of white adipose tissue in the liver compared to animals in the control group II. These results are summarized in FIG. 5. This supports the view that sGC stimulants such as Compound B are able to reduce hepatic steatosis.

After 9 weeks, fibrosis, as determined using Picrosirius Red staining, was significantly reduced in animals treated with 1 mg / kg Compound B (Group III) and in animals treated with 3 mg / kg Compound B (Group IV). The decrease was proportional to the dose of Compound B as shown in FIG. 1. This was confirmed as shown in FIG. 4 by analysis using trichrome staining as well as α-SMA precipitation.

After 9 weeks of treatment, mRNA expression levels for all markers of liver fibrosis assessed in this study were statistically significantly reduced in both group III and group IV compared to

- 84 038096 with their levels in the control group II. These results are summarized in FIG. 2. These results support the view that sGC stimulants such as Compound B are able to reduce liver fibrosis.

After 9 weeks of treatment, the levels of mRNA expression for all markers of liver inflammation assessed in this study were statistically significantly reduced in both group III and group IV compared to their levels in control group II. These results are summarized in FIG. 3.

Evaluation of the inflammatory infiltrate by immunohistochemistry F4 / 80 (Fig. 6) showed a decrease in the number of liver macrophages in treatment groups III and IV compared to the liver in the control group II. The effect was statistically significant for both doses of compound B used (1 and 3 mg / kg).

These results support the notion that sGC stimulants such as Compound B are able to reduce liver inflammation in an animal model of NASH.

The total amount of NAS (defined above) was reduced after administration of Compound B at 1 mg / kg (group III) or 3 mg / kg (group IV) compared to the NAS score in control group II (FIG. 7).

Example 8. Model of liver fibrosis in rats caused by thioacetamide (TAA).

Male Sprague-Dawley rats (280-300 g, Envigo) were injected with 150 mg / kg TAA or phosphate buffered saline (PBS) 3 times a week by intraperitoneal (ip) injection throughout the study (8 weeks) in a volume of 5 ml / kg. TAA was prepared fresh on the day of each injection. Four weeks after the initial TAA injection, animals were dosed with Compound B mixed into the food prepared by Research Diets at a dose equivalent of 1, 3, or 10 mg / kg / day. Animals were weighed weekly and overall health changes were closely monitored throughout the experiment.

At the end of the in vivo study, the medial lobe of the liver was harvested in 10% neutral buffered formalin (Sigma, HT501128) and fixed at 4 ° C overnight with gentle stirring. The tissues were then washed with phosphate buffered saline (x2) and transferred into 70% ethanol. The samples were then cut into three pieces and inserted into one block and cut into 5 µm sections to obtain single section slides (three liver pieces). Slides were subjected to collagen staining using 0.1% Sirius red in picric acid (Rowley Biochemical, SO-674).

Images were captured with a Nikon DS-QiMc camera mounted on a Nikon Eclipse E400 equipped with an automatic stage (Prior Optiscan III). For each part of the liver, a 2x2 random image was scanned at 100x magnification (3 per animal). A binary threshold was set to capture positively colored (red) pixels in the image and the percentage of positive pixels was calculated (NIS Elements, v.4.40).

Data was analyzed using GraphPad Prism (v6.07). Differences between groups were assessed using one-way ANOVA followed by Student's t-test. The data were considered statistically significant at p <0.05. Data are presented as mean ± SEM.

The liver of rats treated with TAA showed a significantly larger collagen deposition area compared to the vehicle control (1.27 ± 0.14 versus 13.25 ± 1.53, p <0.0001). Compared with the TAA control, treatment with compound B significantly reduced collagen staining at a concentration of 1 mg / kg / day (7.08 ± 1.13, p <0.0001), 3 mg / kg / day (9.36 ± 0.89 , p <0.05) and 10 mg / kg / day (9.00 ± 1.28, p <0.05).

FIG. 8 shows sirius red liver slides depicting collagen accumulation. Staining, a measurement of tissue fibrosis, was reduced in the TAA groups that were treated with 1, 3, or 10 mg / kg of Compound B compared to control TAA animals (FIG. 8).

FIG. 9 shows the decrease in% collagen accumulation in control animals treated with TAA, also treated with 1, 3 or 10 mg / kg of Compound B.

The method described in Antifibrotic Activity of Sorafenib in Experimental Hepatic Fibrosis - Refinement of Inhibitory Targets, Dosing and Window of Efficacy In Vivo; Feng Hong *, Hsin Chou *, Isabel Fiel, and Scott L. Friedman; Dig Dis Sci. 2013 January; 58 (1): 257-264. doi: 10.1007 / sl0620-012-2325-y .; was used with minor modifications.

Various embodiments of the invention can be described in the text below. As explained above, it should be understood that in these embodiments, the implementation includes pharmaceutically acceptable salts, although the phrase pharmaceutically acceptable salt is not indicated.

[1] . A method of treating NASH in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an sGC stimulant or a pharmaceutically acceptable salt thereof.

[2]. The method according to [1] above or in accordance with other embodiments of the invention, wherein said sGC stimulant or a pharmaceutically acceptable salt thereof is administered as monotherapy.

[3]. The method according to [1] above or in accordance with other embodiments of the invention, wherein said sGC stimulant or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically or prophylactically effective amount of one or more additional tera

- 85 038096 singing agents.

[4] . The method of [3] above or in accordance with other embodiments of the invention, wherein the additional therapeutic agent is a compound known as a NO pathway regulator.

[5] . The method according to [4] above or in accordance with other embodiments of the invention, wherein said additional therapeutic agent known as a NO pathway regulator is selected from arginine, nitric oxide, NO donor, sGC stimulant, sGC activator, or PDE5 inhibitor.

[6]. The method according to [5] above or in accordance with other embodiments of the invention, wherein said additional therapeutic agent is an NO donor.

[7]. The method according to [6] above or in accordance with other embodiments of the invention, wherein the NO donor is selected from nitrate, nitrite, NONOaTa or nitrosothiol.

[eight] . The method according to [5] above or in accordance with other embodiments of the invention, wherein the additional therapeutic agent is an sGC stimulant and is selected from riociguat, nonliciguat, vericiguat, BAY-41-2272, BAY 41-8543, or etriciguat.

[nine] . The method of [8] above or in accordance with other embodiments of the invention, wherein the additional therapeutic agent is an sGC stimulant and is selected from riociguat or vericiguat.

[ten] . The method according to [5] above or in accordance with other embodiments of the invention, wherein the additional therapeutic agent is an sGC activator selected from ataciguat or cynaciguat.

[eleven] . The method according to [3] above or in accordance with other embodiments of the invention, wherein the additional therapeutic agent is selected from statin, PPAR agonist, FXR agonist, DPP-IV inhibitor, caspase inhibitor, GLP-1 agonist, LOXL2 monoclonal antibody, acetylCo-A inhibitor β-carboxylase (ACC), CCR2 / CCR5 antagonist, fatty acid / bile acid conjugate, galectin-3 inhibitors, ursodeoxycholic acid (UDCA), DGAT1 inhibitor or IMM-124E.

[12] . The method according to any of [1] to [11] above or in accordance with other embodiments of the invention, wherein the patient in need thereof is an adult.

[13] . The method according to any of [1] to [11] above, or in accordance with other embodiments of the invention, wherein the patient in need thereof is a child.

[fourteen] . The method according to any one of [1] to [13] above, or in accordance with other embodiments of the invention, wherein the patient in need thereof is a human who has been diagnosed with NASH.

[15] . The method according to any one of [1] to [13] above or in accordance with other embodiments of the invention, wherein the patient in need thereof is a human who exhibits a characteristic clinical picture associated with NASH.

[16] . The method according to any one of [1] or from [3] to [13] above or in accordance with other embodiments of the invention, wherein the sGC stimulant is administered before, at the same time, or after the initiation of treatment with another therapeutic agent.

[17]. The method according to any one of [1] to [16] above or in accordance with other embodiments of the invention, wherein a patient in need thereof is clinically obese.

[eighteen] . The method according to any one of [1] to [16] above, or in accordance with other embodiments of the invention, wherein a patient in need thereof has been diagnosed with diabetes or prediabetes.

[19] . The method according to any of [1] to [16] above, or in accordance with other embodiments of the invention, wherein a metabolic syndrome has been diagnosed in a patient in need thereof.

[twenty] . The method according to any of [1] to [16] above, or in accordance with other embodiments of the invention, wherein the patient in need thereof is of normal weight.

[21]. The method according to any one of [1] to [16] above, or in accordance with other embodiments of the invention, wherein the patient in need thereof is clinically overweight.

[22]. The method according to any of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable decrease in the level of steatosis, or abnormal accumulation of fat in the liver.

[23]. The method of any one of [1] to [22] above or in accordance with other embodiments of the invention, wherein a measurable decrease in the degree of steatosis or abnormal fat accumulation in the liver is determined by tissue biopsy.

[24]. The method according to any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable reduction in the degree of liver inflammation or hepatitis.

[25]. The method of any one of [1] to [21] or [24] above or in accordance with other embodiments of the invention, wherein a measurable reduction in liver inflammation or hepatitis is determined by tissue biopsy or magnetic resonance elastography.

- 86 038096

[26]. The method according to any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable decrease in the degree of fibrosis, cirrhosis or sclerosis of the liver.

[27]. The method according to any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein the administration of the stimulant sGC or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable concurrent decrease in steatosis levels , inflammation and fibrosis of the liver.

[28]. The method of any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable reduction in fatigue.

[29]. The method of any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable reduction in the feeling of fatigue.

[thirty] . The method according to any of [1] to [21] above or in accordance with other embodiments of the invention, wherein the administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable decrease in the increase in enzyme levels liver.

[31]. The method according to any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in an observable or measurable decrease in the increase in inflammatory cytokines.

[32]. The method according to any of [1] to [21] above or in accordance with other embodiments of the invention, wherein administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, results in observable or measurable inhibition of weight loss.

[33]. The method according to any of [1] to [21] above or in accordance with other embodiments of the invention, wherein the administration of an sGC stimulant or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing an sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, a patient in need of it, has the goal or leads to the complete or partial relief of NASH, which is determined by the partial or complete normalization of one or more clinical pictures.

[34]. The method according to any one of [1] to [21] above, or in accordance with other embodiments of the invention, wherein the administration of the sGC stimulant, or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, to a patient in need thereof, aims or slows or stops the progression of NASH in cirrhosis.

[35]. The method according to any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein the administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, to a patient in need thereof is intended to either leads to an increase in the survival time of the patient diagnosed with NASH.

[36]. The method according to any one of [1] to [21] above or in accordance with other embodiments of the invention, wherein the administration of the sGC stimulant or a pharmaceutically acceptable salt thereof, alone or in combination with another therapeutic agent, to a patient in need thereof is intended to either leads to a decrease or complete abandonment of the need for a patient to undergo liver transplantation.

[37]. The method according to any one of [1] to [36] above or in accordance with other embodiments of the invention, wherein the sGC stimulant is a compound of Formula IA or a pharmaceutically acceptable salt thereof.

[38]. The method according to any one of [1] to [37] above or in accordance with other embodiments of the invention, wherein the sGC stimulant is a compound of Formula IB, or a pharmaceutically acceptable salt thereof.

[39]. The method according to any one of [1] to [38] above or in accordance with other embodiments of the invention, wherein the sGC stimulant is a compound of Formula IC or a pharmaceutically acceptable salt thereof.

[40]. The method according to any one of [1] to [39] above or in accordance with other embodiments of the invention, wherein the sGC stimulant is selected from a compound specified below, or a pharmaceutically acceptable salt thereof:

- 87 038096

- 88 038096

[41]. The method according to any one of [1] to [36] above or in accordance with other embodiments of the invention, wherein the sGC stimulant is selected from a compound indicated in any of the table. X, XX, XXX, IV or XIV.

[42]. A pharmaceutical composition containing an sGC stimulant or a pharmaceutically acceptable salt thereof for use in the treatment of NASH in a patient in need thereof.

[43]. The pharmaceutical composition according to [42] above or in accordance with other embodiments of the invention, wherein said sGC stimulant is selected from a compound specified in any of [37], [38], [39], [40] or [41] above or in in accordance with other embodiments of the invention.

[44]. A pharmaceutical composition comprising an sGC stimulant or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents for use in treating NASH in a patient in need thereof.

[45]. The pharmaceutical composition according to [44] above or in accordance with other embodiments of the invention, wherein said sGC stimulant is selected from a compound specified in any of [37], [38], [39], [40] or [41] above or in in accordance with other embodiments of the invention.

Other options for implementation.

All publications and patents mentioned in this description are incorporated herein by reference to the same extent as if each individual publication or patent application were specifically and separately indicated for inclusion by reference. If the meaning of the terms in any of the patents or publications incorporated by reference conflicts with the meaning of the terms used in this description, the meaning of the terms in this description is determinative. In addition, the above discussion discloses and describes only exemplary embodiments of the present invention. A person skilled in the art will readily understand from such discussion and accompanying drawings and claims that various changes, modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the following claims.

Claims (15)

CLAIM 1. A method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an sGC stimulant or a pharmaceutically acceptable salt thereof, wherein the sGC stimulant is a compound of formula IC or a pharmaceutically acceptable salt thereof where J ^B represents halogen; R ¹ is hydrogen or C _1-6 alkyl; R ² represents a C _1-6 alkyl group optionally and independently having up to three substituents selected from R ^5a ; each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, —OR ^6a , —SR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , —C (O) N ( R ^6a ) 2, -C (O) N (R ^6a ) SO2R ^6a , -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) C (O) OR ^6a , -N (R ^6a ) C (O) N (R ^6a ) 2, -N (R ^6a ) 2, -SO2R ^6a , -SO2N (R ^6a ) 2, -SO2N (R ^6a ) COOR ^6a , -SO2N (R ^6a ) C (O) R ^6a , -N (R ^6a ) SO2R ^6a , - (C = O) NHOR ^6a and a C3-8 cycloalkyl ring, wherein each of said C _1-6 alkyl group optionally and independently has - 89 038096 up to 3 substituents selected from halogen, C1.4 alkyl, C1.4 haloalkyl, -OH, -NH ₂ , -NH (C _{1. 4} alkyl), -N (C _{1. 4} alkyl) ₂ , -CN, —COOH, —COO (C _1-4 alkyl), —O (C _1-4 alkyl), —O (C _1-4 haloalkyl) or oxo; and each R ^{6a is} independently selected from hydrogen and C _1-6 alkyl. 2. The method of claim 1, wherein each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, —OR ^6a , —COR ^6a , —OC (O) R ^6a , —C (O) OR ^6a , —C (O) N (R ^6a ) 2, -N (R ^6a ) C (O) R ^6a , -N (R ^6a ) 2, - (C = O) NHOR ^6a and C3-8 cycloalkyl ring, where each of said group C _1-6 alkyl optionally and independently has up to 3 substituents selected from halogen, C _1-4 alkyl, C _1-4 haloalkyl, —OH, —NH2, —NH (C _1-4 alkyl), or —CN. 3. The method of claim 1, wherein each R ^{5a is} independently selected from halogen, —CN, C1-6 alkyl, —OR ^6a , —C (O) N (R ^6a ) 2, —N (R ^6a ) C (O) R ^6a , -N (R ^6a ) 2, - (C = O) NHOR ^6a and C3-8 cycloalkyl ring, where each of said C _1-6 alkyl group optionally and independently has up to 3 substituents selected from halogen, Cl _-4 alkyl, Cl _-4 haloalkyl, -OH, -NH2, -NH (Cl _-4 alkyl) or -CN. 4. The method of claim 1, wherein each R ^{5a is} independently selected from CF3, —C (O) NH _2, and —OH. 5. The method of claim 1, wherein the sGC stimulant is or a pharmaceutically acceptable salt thereof. 6. The method of claim 1, wherein the sGC stimulant is or a pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the sGC stimulant is or a pharmaceutically acceptable salt thereof. 8. A method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an sGC stimulant or a pharmaceutically acceptable salt thereof, wherein the sGC stimulant is a compound of formula XY where n denotes 0 or an integer selected from 1 to 3; each J ^{B is} independently selected from halogen, —CN, Cl-6 aliphatic, —OR ^B, or C3-8 cycloaliphatic; where each of the specified C1. ₆ aliphatic group and each of the specified C ₃ . ₈ cycloaliphatic ring optionally has up to 3 substituents selected from halogen; 90 038096 each R ^{B is} independently selected from hydrogen, a C1-6 aliphatic group, or a C3-8 cycloaliphatic ring; where each of said R ^B , which is a C1-6 aliphatic group, and each of said R ^B , which is a C _3-8 cycloaliphatic ring, optionally has up to 3 substituents selected from halogen; each JC, if present, is independently selected from halogen; R ¹ is hydrogen or C _1-6 αalkyl; and R ² is C _1-6 alkyl. 9. The method according to claim 8, where n represents 1; J ^B is fluorine; JC is fluorine; R ¹ is hydrogen or methyl; and R ² is methyl or ethyl. 10. The method of claim 8, wherein the sGC stimulant is riociguat or vericiguat (riociguat), or θ ~ β (vericiguat). 11. A method according to any one of claims 1-10, wherein the patient in need thereof is an adult. 12. A method according to any one of claims 1-10, wherein the patient in need thereof is a child. 13. A method according to any one of claims 1-10, wherein the patient in need thereof is clinically obese, has been diagnosed with diabetes or prediabetes, or has been diagnosed with metabolic syndrome. 14. A method according to any one of claims 1-13, wherein the administration of the sGC stimulant or a pharmaceutically acceptable salt thereof results in (i) an observable or measurable decrease in the level of steatosis or abnormal accumulation of fat in the liver, (ii) an observable or measurable decrease in the degree of liver inflammation, or hepatitis, (iii) an observed or measurable decrease in the degree of fibrosis, cirrhosis, or sclerosis of the liver, (iv) an observed or measured concurrent decrease in the levels of steatosis, inflammation and fibrosis of the liver, (v) an observed or measurable decrease in feelings of fatigue, (vi) an observed or measurable decrease feelings of fatigue, an observable or measurable decrease in elevated liver enzymes, (vii) an observable or measurable decrease in an increase in inflammatory cytokines, (viii) an observable or measurable inhibition of weight loss. 15. The method of claim 1, wherein the sGC stimulant is selected from one of the following or a pharmaceutically acceptable salt thereof