Soluble guanylate cyclase activators for treating portal hypertension - Patents.com

Abstract

The present invention relates to a method of treating a patient with compensated cirrhosis, comprising administering to a patient in need thereof a therapeutically effective amount of a soluble guanylate cyclase (sGC) activator, or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to the use of certain soluble guanylate cyclase activators for treating certain disorders, including portal hypertension. The present invention further relates to the combination of a soluble guanylate cyclase activator with a sodium glucose cotransporter-2 (SGLT2) inhibitor. [Background technology]

[0002] Cirrhosis is an end-stage liver condition caused by multiple chronic diseases, including hepatitis C virus infection (HCV), chronic alcohol abuse, or metabolic syndrome with nonalcoholic fatty liver disease (NAFLD). Cirrhosis itself is a chronic condition with a high mortality rate. It is a heterogeneous disease classified into two main prognostic stages: compensated and decompensated cirrhosis. This classification depends on the presence or absence of clinically evident decompensation events (specifically ascites [abdominal fluid beyond the perihepatic area]), variceal bleeding (VH) and / or overt hepatic encephalopathy (HE). (See, for example, G. Garcia-Tsao et al., “Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management”: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65(1):310-335). Currently, there is no treatment available for cirrhosis of the liver that involves reducing fibrotic tissue or regenerating liver cells. The main treatment goals are to delay decompensation, improve quality of life, and treat cirrhosis, especially the symptoms of decompensation. Portal hypertension (PH) is an early and major consequence of cirrhosis and is responsible for the majority of its complications (see, for example, GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385(9963):117-171). The only currently recommended clinical approach to prevent PH-related decompensation events in patients with compensated cirrhosis is endoscopic variceal ligation or off-label use of nonselective beta-blockers (NSBBs) or carvedilol to prevent initial variceal bleeding.

[0003] However, not all patients with PH achieve hemodynamic response with these current treatment options. NSBBs and carvedilol are currently used to prevent cirrhosis complications and improve survival in patients, but these benefits occur in less than half of treated patients, mainly in patients who achieve significant reduction in portal vein pressure. There is still an unmet need for a significant number of patients who cannot tolerate treatment with NSBBs or carvedilol due to reduction in systolic blood pressure (BP) and heart rate (HR) and are at higher risk for further progression to decompensation. Thus, there is an unmet medical need to reduce portal vein pressure and improve hepatic perfusion in this patient population with PH and especially with clinically significant portal hypertension (CSPH) and compensated cirrhosis. CSPH is associated with varices, overt clinical decompensation (ascites, VH and HE), postsurgical decompensation and an increased risk of developing hepatocellular carcinoma. (For example, C. Villanueva et al., “Development of hyperdynamic circulation and response to betablockers in compensated cirrhosis with portal hypertension. Hepatology, 2016;63(1):197-206; G. D'Amico et al., “Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. 2014;39(10):1180-1193; and G. Garcia-Tsao et al., “Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65(1):310-335). Summary of the Invention

[0004] The present invention relates to a method of treating a patient with compensated cirrhosis, comprising administering to the patient a pharma- ceutical effective amount of a soluble guanylate cyclase (sGC) activator, or a pharma- ceutical acceptable salt thereof. The present invention also relates to an sGC activator, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a patient with compensated cirrhosis. In another embodiment, the present invention relates to a method for treating a patient with clinically significant portal hypertension in compensated cirrhosis, comprising administering to the patient a therapeutically effective amount of an sGC activator or a pharma- ceutically acceptable salt thereof. In another embodiment, the present invention relates to an sGC activator, or a pharma- ceutically acceptable salt thereof, for use in the treatment of patients with clinically significant portal hypertension in compensated cirrhosis. In another embodiment, the present invention relates to a method for reducing portal pressure in a patient with clinically significant portal hypertension in compensated cirrhosis, comprising administering to the patient a therapeutically effective amount of an sGC activator or a pharma- ceutically acceptable salt thereof. In one embodiment, CSPH in compensated cirrhosis is caused or caused by Hepatitis B virus (HBV), Hepatitis C virus (HCV) or non-alcoholic steatohepatitis (NASH).

[0005] In another embodiment, the present invention relates to a method for treating a patient with clinically significant portal hypertension in compensated cirrhosis, comprising administering to the patient a therapeutically effective amount of an sGC activator or a pharma- ceutically acceptable salt thereof, wherein the CSPH in compensated cirrhosis is caused or caused by HBV, HCV, or NASH. In one embodiment, the present invention relates to a method of treating patients with clinically significant portal hypertension in compensated cirrhosis due to HBV. In another embodiment, the invention relates to a method of treating patients with clinically significant portal hypertension in compensated cirrhosis due to HCV. In another embodiment, the present invention relates to a method of treating patients with clinically significant portal hypertension in compensated cirrhosis due to NASH. In another embodiment, the present invention relates to a method of treating a patient with clinically significant portal hypertension in compensated cirrhosis due to NASH, wherein said patient has type 2 diabetes. In another embodiment, the present invention relates to a method of treating a patient with clinically significant portal hypertension in compensated cirrhosis due to NASH, wherein said patient does not have type 2 diabetes.

[0006] In another embodiment, the invention relates to any of the above methods or uses, further comprising administering a pharma- ceutically effective amount of a SLGT2 inhibitor, or a pharma- ceutically acceptable salt thereof. In another embodiment, the present invention relates to a method for treating a patient with compensated cirrhosis due to NASH, comprising administering to the patient a pharma- ceutical effective amount of an sGC activator of the present invention or a pharma- ceutical acceptable salt thereof in combination with a pharma- ceutical effective amount of an SLGT2 inhibitor or a pharma- ceutical acceptable salt thereof. In another embodiment, the present invention relates to a method for treating a type 2 diabetes patient with CSPH in compensated cirrhosis due to NASH, comprising administering to the patient a pharmacologic effective amount of an sGC activator of the present invention or a pharmacologic acceptable salt thereof in combination with a pharmacologic effective amount of an SGLT2 inhibitor or a pharmacologic acceptable salt thereof. In another embodiment, the SLGT2 inhibitor, if used, is selected from the group consisting of empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, sotagliflozin, licogliflozin and ipragliflozin.

[0007] In another embodiment, the invention relates to the immediately preceding embodiment, wherein the SGLT2 inhibitor is selected from the group consisting of: empagliflozin, dapagliflozin and canagliflozin. In another embodiment, the invention relates to the immediately preceding embodiment, wherein the SGLT2 inhibitor is empagliflozin. In another embodiment, the present invention relates to a method for treating a patient with CSPH in compensated cirrhosis due to NASH, comprising administering to the patient a pharmacologic effective amount of an sGC activator of the present invention or a pharmacologic acceptable salt thereof in combination with a pharmacologic effective amount of empagliflozin. In another embodiment, the present invention relates to a method for treating a type 2 diabetes patient with CSPH in compensated cirrhosis due to NASH, comprising administering to the patient a pharmacologic effective amount of an sGC activator of the present invention or a pharmacologic acceptable salt thereof in combination with a pharmacologic effective amount of empagliflozin.

[0008] Within the scope of the present invention, the SGLT2 inhibitor can also inhibit SGLT1, i.e. is a dual SGLT1 / SGLT2 inhibitor. In one embodiment, the SGLT2 inhibitor, when used, is an SGLT1 / SGLT2 inhibitor selected from the group consisting of sotagliflozin and licogliflozin. WO 2014 / 039434 and WO 2020 / 011804 describe oral small molecule activators of sGC ("sGC activators of the present invention") that are useful in the methods of the present invention. Unless otherwise specified herein, the terms "sGC activators of the present invention," "compounds of the present invention," and "compounds of formula (I)" are used interchangeably. In one embodiment of the present invention, the sGC activator used in the methods of the present invention is a compound of formula (I) or a salt thereof.

[0009] [ka] I (In the formula, A is a 5-7 membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, one carbon of said heterocyclyl group being C 1-3 optionally substituted with one or two groups selected from alkyl and oxo; R 1 C optionally substituted with a methoxy group1-4 is alkyl, R 2 are H, F, Cl, and C. 1-3 selected from alkyl, -CN, -OMe and -CF3; R 3 is selected from H and -CH3; R 4 is selected from H, F, -CH3 and -OMe; R 5 is selected from H, Cl, -CH3, -CH2CH3, -CF3, F and -OMe; R 6 is bonded to the nitrogen of A, H, C 1-6 Alkyl, -(CH2) n C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -(CH2) n Heterocyclyl, -(CH2) n Aryl-(CH2) n Heteroaryl, -SO2aryl, SO2C 1-6 alkyl, 1-6 Alkyl, -(CH2) n Heterocyclyl, -(CH2) n Cycloalkyl, -(CH2) n Aryl and -(CH2) n Heteroaryl is C 1-3 Alkyl, halogen, C 1-3 Alkoxy, -CF3, -OH, oxo, -(CH2) 1-3 O(CH2) 2-3 optionally substituted with 1 to 4 groups independently selected from OH and -SO2CH3; R 7 is selected from H, -CH3, -CH2CH3, -CF3, F and -CN; n is 0, 1 or 2.

[0010] In another embodiment, the present invention relates to the method described in the above embodiment, or a salt thereof. (In the formula, A is a 5-7 membered saturated heterocyclyl group containing one nitrogen atom, and one carbon atom of the heterocyclyl group is substituted with one or two C 1-3 may be substituted with an alkyl group, R 1 is C 1-3 is alkyl, R 2 are H, F, Cl, and C. 1-3 selected from alkyl, -CN, -OMe and -CF3; R 3 is selected from H and -CH3; R 4 is selected from H and F; R 5 is selected from H, Cl and -CH3; R 6 is bonded to the nitrogen of A, H, C 1-6 Alkyl, -(CH2) n C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -(CH2) n Heterocyclyl, -(CH2) n Aryl and -(CH2) n heteroaryl, 1-6 Alkyl, -(CH2) n Heterocyclyl, -(CH2) n Cycloalkyl, -(CH2) n Aryl and -(CH2) n Heteroaryl is C 1-3 Alkyl, halogen, C 1-3 optionally substituted with 1 to 4 groups independently selected from alkoxy, -CF3, -OH, and -SO2CH3; R 7 is H, n is 0, 1 or 2.

[0011] In another embodiment, the present invention relates to a method or a salt thereof as described in any of the above embodiments. (In the formula, R 1 is methyl, ethyl or isopropyl; base [ka] teeth, [ka] (selected from

[0012] In another embodiment, the present invention relates to a method or a salt thereof as described in any of the above embodiments. (In the formula, R 2 is selected from -CH3, F, Cl and -CF3; R 6 , H, C 1-6 Alkyl, -(CH2) n C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl and -(CH2) n heterocyclyl, 1-6 Alkyl, -(CH2) n Cycloalkyl and -(CH2) n Heterocyclyl is C 1-3 Alkyl, halogen, C 1-3 and optionally substituted with 1 to 4 groups independently selected from alkoxy, -CF3, -OH, and -SO2CH3. In another embodiment, the present invention relates to a method as described in any of the above embodiments or a salt thereof, wherein R 6 said heterocyclyl is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [1,4]dioxanyl, 8-oxabicyclo[3.2.1]octanyl, 1-oxaspiro[4.5]decanyl and pyrrolidin-2-one; R 6 wherein the heteroaryl referred to in the formula (I) is selected from imidazolyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl and 4,5,6,7-tetrahydrobenzothiazolyl; R 6wherein the aryl mentioned in is phenyl.

[0013] In another embodiment, the present invention relates to a method or a salt thereof as described in any of the above embodiments. (In the formula, R 6 Ha-(CH2) n heterocyclyl, said heterocyclyl being selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [1,4]dioxanyl, 8-oxabicyclo[3.2.1]octanyl and 1-oxaspiro[4.5]decanyl. In another embodiment, the present invention relates to a method or a salt thereof as described in any of the above embodiments. (In the formula, R 2 is -CH3, R 3 is H, R 4 is H or -CH3, R 5 is H or -CH3, R 7 is R 5 and is H, -CH3, or -CH2CH3.

[0014] In another embodiment, the present invention relates to a method or a salt thereof as described in any of the above embodiments. (In the formula, base [ka] teeth [ka] is)

[0015] In another embodiment, the present invention relates to a method or a salt thereof as described in any of the above embodiments. (In the formula, R 3 is H, R 4 is H)

[0016] Table 1 provides representative compounds of the invention that can be used according to the methods of the invention. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28]

[0017] In one embodiment, the sCG activator used in the methods of the present invention is selected from any of the compounds shown in Table 1 above, and pharma- ceutically acceptable salts thereof. In another embodiment, the sCG activator used in the methods of the present invention is selected from the group consisting of compound numbers 1, 2, 3, 4, 5, 7, 8, 9, 12, 15, 16, 18, 21, 27, 28, 30, 31, 35, 36, 39, 41, 42, 44, 45, 46, 47, 48, 57, 59, 62, 68, 77, 78, 79, 80, 82, 83, 84, 85, 86, 88, 92, 93 and 94 as shown in Table 1, and pharma- ceutically acceptable salts thereof.

[0018] In another embodiment, the sCG activator used in the method of the present invention is a compound number 95, 97, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 3, 124, 125, 126, 127, 128, 129, 130, 131, 132, 136, 137, 139, 140, 141, 142, 145, 146, 152, 153, 154, 155, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 2 5, 176, 177, 178, 179, 180, 181, 184, 185, 186, 187, 188, 189, 191, 193, 194, 195, 196, 197, 198, 199, 201, 202, 203, 204, 205, 206, 207, 208, 210, 211, 212, 213, 214, 215, 216, 220, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 28 3, 224, 225, 227, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, and pharma- ceutically acceptable salts thereof.

[0019] In one embodiment, the SLGT2 inhibitor, when used in the methods of the invention, is selected from the group consisting of empagliflozin, dapagliflozin and canagliflozin. In another embodiment, the SLGT2 inhibitor when used in the methods of the present invention is empagliflozin. [Brief description of the drawings]

[0020] [Figure 1] 1 is a schematic diagram showing the study design of a four-arm clinical trial to investigate the effect of the oral sGC activator of the present invention alone and in combination with empagliflozin on portal hypertension after 8 weeks of treatment in patients with clinically significant portal hypertension (CSPH) in compensated cirrhosis. As shown in FIG. 1, the four arms or treatment arms are as follows: HBV arm (BID treatment with sGC activator alone), HCV arm (BID treatment with sGC activator alone), NASH arm without type 2 diabetes (BID treatment with sGC activator alone), and NASH arm with type 2 diabetes (BID treatment with sGC activator alone and QD treatment with empagliflozin). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Abbreviation [Table 2] JPEG2025510685000036.jpg175168

[0022] As used herein, the term "compensated cirrhosis" refers to the absence of clinically evident decompensation events, such as ascites [abdominal fluid beyond the perihepatic area], variceal hemorrhage (VH) and / or overt hepatic encephalopathy (HE). As used herein, the term "clinically significant portal hypertension" (CSPH) refers to a hepatic venous pressure gradient (HVPG) greater than or equal to 10 mmHg. In addition to this quantitative measurement of CSPH, the term "CSPH" may also refer to clinical signs of CSPH, such as esophagogastric varices, splenomegaly, thrombocytopenia, portosystemic shunt, and further clinical signs of CSPH. Methods for measuring HVPG, esophagogastric varices, splenomegaly, thrombocytopenia, portosystemic shunt, and further clinical signs of CSPH are known in the art and / or described herein. Unless specifically indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of different ratios of the separate enantiomers, mixtures of diastereomers or any of the aforementioned forms in which such isomers and enantiomers exist, as well as salts, including pharma- ceutically acceptable salts thereof, and solvates thereof, such as, for example, hydrates, including solvates of the free compounds or solvates of the salts of the compounds.

[0023] Some of the compounds of formula 1 may exist in more than one tautomeric form and the present invention includes methods of using all such tautomers. The present invention includes pharma- ceutically acceptable derivatives of the compounds of formula (I). "Pharmaceutically acceptable derivatives" refers to any pharma- ceutically acceptable salt or ester, or any other compound that, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful in the present invention, or a pharmacologically active metabolite or a pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound of the present invention that can be enzymatically or chemically metabolized. This includes, for example, hydroxylated or oxidized derivative compounds of formula (I).

[0024] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds where the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. For example, such salts include acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide / hydrobromide, edetate, camsylate, carbonate, chloride / hydrochloride, citrate, edisylate, ethanedisulfonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilates, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothioate, lact ... These include bionate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamide, sulfate, tannate, tartrate, theoclate, toluenesulfonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Further pharma-ceutically acceptable salts can be formed with cations derived from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 66, 1-19).

[0025] The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of an appropriate base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of acids other than those mentioned above, which are useful, for example, for purifying or isolating the compounds of the invention (eg, trifluoroacetates), also form part of the invention. In addition, the use of prodrugs of the compounds of formula (I) is within the scope of the present invention. Prodrugs include compounds that, upon simple chemical transformation, are modified to produce the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. Specifically, prodrugs, when administered to a patient, can be transformed into the compounds disclosed herein above, thereby imparting the desired pharmacological effect. The compounds of the present invention are only those that are contemplated to be "chemically stable" as would be understood by one of ordinary skill in the art. For example, compounds that have "dangling valences" or "carbanions" are not compounds contemplated by the inventive methods disclosed herein.

[0026] For all compounds disclosed hereinabove in this application, in the event that the nomenclature conflicts with the structural formula, it shall be understood that the compound is defined by the structural formula. All terms used herein are to be understood in their ordinary sense as known in the art unless otherwise specified. For example, "C 1-4 "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, or t-butyl. 1-4 "Alkoxy" refers to C alkyl groups with terminal oxygen such as methoxy, ethoxy, propoxy, and butoxy. 1-4Alkyl. All alkyl, alkenyl and alkynyl groups, where structurally possible, are understood to be branched or unbranched, cyclic or acyclic, unless otherwise specified. Other more specific definitions are as follows. "C 1-n The term "alkyl", alone or in combination with another group, denotes an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, C 1-5 The term alkyl encompasses the groups HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH-, HC-CH-CH-CH- and HC-CH-CH(CHCH)-.

[0027] "C 1-n The term "alkylene", alone or in combination with another group, refers to a divalent acyclic, straight or branched chain alkyl group containing 1 to n carbon atoms. For example, C 1-4 The term alkylene refers to the terms -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2 -CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2- CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CHCH(CH3)2)- and -C(CH3)(CH2CH3)-. "C 3-n The term "cycloalkyl", alone or in combination with another group, denotes a cyclic, saturated, unbranched hydrocarbon group having 3 to n C atoms. For example, C 3-7 The term cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0028] As used herein, the term "heteroatom" shall be understood to mean atoms other than carbon, such as O, N, S and P. In any alkyl group or carbon chain, one or more carbon atoms may be replaced with a heteroatom O, S or N, where if N is unsubstituted it is understood to be NH, and it is understood that the heteroatom may replace either a terminal or internal carbon atom in a branched or unbranched carbon chain. Such groups may be substituted as described herein above with groups such as oxo to provide definitions such as, but not limited to, alkoxycarbonyl, acyl, amido and thioxo. The term "aryl" as used herein, alone or in combination with another group, refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further fused to a second 5- or 6-membered carbocyclic group, which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

[0029] The term "heteroaryl" means an aromatic 5-6 membered monocyclic heteroaryl or an aromatic 7-11 membered bicyclic heteroaryl ring in which at least one of the rings is aromatic, the heteroaryl ring containing 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5-6 membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7-11 membered heteroaryl bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl, and benzothiazolyl.

[0030] The term "heterocyclyl" refers to a stable non-aromatic 4-8 membered monocyclic heterocyclic group or a stable non-aromatic 6-11 membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic group. The 5-11 membered heterocyclic ring consists of carbon atoms and one or more, preferably 1-4, heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4-8 membered monocyclic heterocyclic groups include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ ... 6-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl and azepinyl. Non-limiting examples of non-aromatic 6- to 11-membered fused bicyclic groups include octahydroindolyl, octahydrobenzofuranyl and octahydrobenzothiophenyl. Non-limiting examples of non-aromatic 6- to 11-membered bridged bicyclic groups include 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of non-aromatic 6- to 11-membered spirocyclic heterocyclic groups include 7-azaspiro[3,3]heptanyl, 7-spiro[3,4]octanyl and 7-azaspiro[3,4]octanyl. The term "heterocyclyl" is intended to include all possible isomeric forms.

[0031] The term "halogen" as used herein shall be understood to mean bromine, chlorine, fluorine or iodine. The definitions "halogenated", "partially or fully halogenated", partially or fully fluorinated, "substituted with one or more halogen atoms" include, for example, mono-, di- or trihalo derivatives on one or more carbon atoms. Non-limiting examples of alkyl are -CH2CHF2, -CF3, etc. It is to be understood that each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl, or the like, described herein may be partially or fully halogenated. As used herein, "nitrogen" or N and "sulfur" or S include all oxidized forms of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, -SC 1-6 For an alkyl group, unless otherwise specified, this is -S(O)-C 1-6 Alkyl and S(O)2-C 1-6 Similarly, -SR a is R a is phenyl, then phenyl-S(O) m -, where m is 0, 1 or 2.

[0032] Basic synthesis method Compounds of formula (I) for use in the methods of the present invention may be prepared by the methods and examples described in WO2014 / 039434. Therapeutic uses For therapeutic use, the compound of formula (I) and the SGLT2 inhibitor, respectively, when used, may be administered via a pharmaceutical composition in any conventional pharmaceutical dosage form in any conventional manner. Conventional dosage forms typically include a pharma- ceutically acceptable carrier suitable for the particular dosage form selected. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, injection, sublingual, transdermal, oral, topical or inhalation. Preferred modes of administration are oral and intravenous.

[0033] The compounds of formula (I) and optionally the SGLT2 inhibitor, when used, may be administered alone or in combination with adjuvants, including other active ingredients, that enhance the stability of the inhibitor, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide improved solubility or dispersibility, enhance inhibitory activity, provide adjunctive therapy, etc. In one embodiment, for example, multiple compounds of the invention may be administered. Advantageously, such combination therapy utilizes lower dosages of conventional therapeutic agents, thus avoiding potential toxic and adverse side effects incurred when these agents are used as monotherapy. The compounds of the invention may be physically combined with conventional therapeutic agents or other adjuvants into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, pharmaceutical compositions containing such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of the compound of formula (I) (w / w) or combinations thereof. The optimal percentage (w / w) of the compounds of the invention may vary and is within the skill of the art. Alternatively, the compounds of the invention and conventional therapeutic agents or other adjuvants may be administered separately (sequentially or concurrently). Separate dosing allows for great flexibility in dosing regimens.

[0034] In one embodiment, the present invention relates to a method for treating compensated cirrhosis, comprising administering to a patient in need thereof a pharmaceutical composition comprising a pharma- ceutical effective amount of the sGC activator of the present invention or a pharma- ceutical acceptable salt thereof. In another embodiment, the present invention relates to a pharmaceutical composition comprising an sGC activator of the present invention for use in the treatment of patients with compensated cirrhosis. As mentioned above, the dosage forms of the compounds of formula (I) and SGLT2 inhibitors of the present invention may contain pharma- ceutically acceptable carriers and adjuvants, if used, known to those skilled in the art and appropriate to the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstitutable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, for example, HC Ansel and NG Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). The specific dosage and treatment regimen will depend on factors such as the patient's overall health profile, the severity and course of the patient's disorder or predisposition thereto, and the judgment of the attending physician.

[0035] It should be understood that within the scope of the present invention, the combination or combination of an sGC activator and an SGLT2 inhibitor according to the present invention may envisage simultaneous, sequential or separate administration of the therapeutic components. In this context, "combination" or "combined" within the meaning of the present invention may include, but is not limited to, fixed and non-fixed (e.g., free) forms (including kits, or other administration, application or dosage forms) and uses such as simultaneous, sequential or separate use of, for example, an sGC activator and an SGLT2 inhibitor. In this context, "combination" or "combined" within the meaning of the present invention may further include additional therapeutic agents or combination therapies as described herein. The combined administration or application of the present invention may be performed by administering the therapeutic components together, e.g., by administering the therapeutic components simultaneously in one single or two separate formulations. Alternatively, administration may be performed by administering the therapeutic components sequentially, e.g., consecutively in two separate formulations.

[0036] For the combination therapy of the present invention, the therapeutic components may be administered separately (meaning that the therapeutic components are formulated separately) or together (meaning that the therapeutic components are formulated in the same preparation). Thus, the administration of one element of the combination of the present invention may be prior to, simultaneous to, or subsequent to the administration of the other element of the combination. In one embodiment, the method of the present invention comprises administering to a patient a daily dose of 0.1 mg to about 50 mg of an sGC activator of the present invention or a pharma- ceutically acceptable salt thereof. In another embodiment, the method of the present invention comprises administering to a patient a daily dose of 1 mg to about 30 mg of an sGC activator of the present invention or a pharma- ceutically acceptable salt thereof. In another embodiment, the sGC activator of the present invention or a pharma- ceutically acceptable salt thereof is administered to a patient in a daily dose of 0.1 to 100 mg, 1 to 25 mg, 1 to 10 mg, or 2 to 5 mg, or a pharma- ceutically acceptable salt thereof.

[0037] In another embodiment, the sGC activator of the present invention or a pharma- ceutically acceptable salt thereof is administered to a patient in an amount selected from the group consisting of 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg. In another embodiment, the sGC activator of the present invention or a pharma- ceutically acceptable salt thereof is administered to a patient in an amount selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg. In another embodiment, the methods of the present invention comprise administering to a patient up to 3 mg of an sGC activator of the present invention, or a pharma- ceutically acceptable salt thereof. In another embodiment, the method of the present invention comprises administering to a patient 1 mg of an sGC activator of the present invention or a pharma- ceutically acceptable salt thereof. In another embodiment, the method of the present invention comprises administering to the patient 2 mg of an sGC activator of the present invention or a pharma- ceutically acceptable salt thereof. In another embodiment, the method of the present invention comprises administering to the patient 3 mg of an sGC activator of the present invention or a pharma- ceutically acceptable salt thereof.

[0038] The vasodilatation of sGC activators can lead to orthostatic dysregulation and hypotensive episodes. Titration of sGC activators may allow for a higher total daily exposure to sGC activators while avoiding high peak concentrations. In one embodiment, the present invention relates to a method of preventing or reducing the severity of orthostatic dysregulation caused by, resulting from, or associated with administration of an sGC activator or a pharma- ceutically acceptable salt thereof, comprising administering a daily dose of an sGC activator BID, TID, or QID to a patient. In another embodiment, the invention relates to the method described immediately above, wherein the sGC activator is administered BID. In another embodiment, the methods of the present invention comprise administering to a patient up to 3 mg of an sGC activator of the present invention, or a pharma- ceutically acceptable salt thereof, twice daily. In another embodiment, the method of the present invention comprises administering to a patient 3 mg of an sGC activator of the present invention, or a pharma- ceutically acceptable salt thereof, twice daily to provide a total daily dose of 6 mg of sGC activator. In another embodiment, the method of the present invention comprises administering to a patient 2 mg of an sGC activator of the present invention, or a pharma- ceutically acceptable salt thereof, twice daily to provide a total daily dose of 4 mg of sGC activator.

[0039] In another embodiment, the method of the present invention comprises administering to a patient 1 mg of an sGC activator of the present invention, or a pharma- ceutically acceptable salt thereof, twice daily to provide a total daily dose of 2 mg of sGC activator. In another embodiment, the method of the present invention comprises administering to the patient 3 mg of an sGC activator of the present invention or a pharma- ceutically acceptable salt thereof. In one embodiment, the SGLT2 inhibitor, if used, is administered to the patient in a daily dose of 0.1 to 500 mg. In another embodiment, the SLGT2 inhibitor, if used, is empagliflozin. In another embodiment, empagliflozin, if used, is administered to a patient in a daily dose of 1, 2.5, 5, 10 or 25 mg. In another embodiment, empagliflozin, if used, is administered to a patient in a daily dose of 10 or 25 mg.

[0040] In another embodiment, empagliflozin, if used, is administered to a patient in a daily dose of 10. In another embodiment, empagliflozin, if used, is administered to a patient in an amount of 5 mg twice daily to provide a total daily dose of 10 mg empagliflozin. In another embodiment, the present invention relates to a method for treating a type 2 diabetes patient with CSPH in compensated cirrhosis due to NASH, comprising administering to the patient up to 3 mg twice daily of an sGC activator of the present invention or a pharma- ceutical acceptable salt thereof in combination with empagliflozin. In another embodiment, the invention relates to the method as described immediately above, wherein empagliflozin is administered in a daily dose of 10 mg or in an amount of 5 mg twice a day.

[0041] The patient being treated with the sGC activator of the present invention or the combination of the sGC activator and the SGLT2 inhibitor may be treated with one or more additional therapeutic agents. Non-limiting examples of such one or more additional therapeutic agents include compounds for improving the metabolic (e.g., obesity, diabetes, inflammation) condition of the patient. Non-limiting examples of such compounds include, for example, DPP-IV inhibitors (e.g., linagliptin, sitagliptin, saxagliptin, vildagliptin, and alogliptin), glitazones / thiazolidinediones (e.g., pioglitazone and rosiglitazone), glucagon-like peptide 1 (GLP-1) based therapies (e.g., GLP-1 receptor agonists), metformin, insulin, and other metabolic disease medications, such as antihypertensives (e.g., diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs), adrenergic receptor antagonists, vasodilators, renin inhibitors, aldosterone receptor antagonists, and alpha-2 adrenergic receptor agonists) and statins (e.g., atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin).

[0042] For patients with NASH, treatment with an sGC activator or a combination of an sGC activator and an SGLT2 inhibitor of the present invention may further include treatment with compounds useful for treating NASH, including metabolic regulators, RAAS inhibitors, lipid regulators, anti-fibrotic agents, anti-inflammatory agents and immunomodulators.Non-limiting examples of such NASH combination partners include PF-05221304 (Pfizer), obeticholic acid (Intercept), GS-0976 (Gilead), GS-9674 (Gilead), LJN452 (Novartis), LMB763 (Novartis), MSDC-0602K / Metabolic Solutions (Octeca), EDP-305 (Enanta), INT-767 (Intercept), O304 (Betagenon), PF-06835919 (Pfizer), Semaglutide (NovoNordisk), BMS-98603 6(BMS), NGM282(NGM), BMS-986171(BMS), PF-06865571(Pfizer), LIK066(Novartis), ORMD0801(Oramed), CER-209(Cerenis), TVB-2640(3-V Bioscience), DS102 (Afiimmune), MGL-3196 (Madrigal, Roche), VK2809 (Viking), Vorixibut (Sanofi, Shire), IONIS-DGAT2Rx (Ionis), AKCEA-ANGPTL3-LRx (Akcea), Gemkabene (Gemphire), MT-3995 (Mitsubishi Tanabe), DUR-928 (Durect), CORT118335 (Corcept), amacizumab (BirdRock / Janssen), elafibranor (Genfit), GRI-0621 (GRI Bio), selonsertib (Gilead), cenicriviroc (Takeda, Allergan), JKB121 (Taiwan), saroglitazar (Zydus), IMM-124E (Immuron), lanifibranor (IVA337) (Inventiva), GR-MD-02 (Galectin), emricasan (VAY785) (Novartis), tipelukast (Kyorin, MediciNova), BMS986263 (ND-L02-s201) ​​(BMS), PF-06667272 (Pfizer), foralumab (Tiziana), and DRX-065 (DeuteRx).

[0043] In another embodiment, the NASH combination partner is selected from the following: Acetyl-CoA carboxylase (ACC) inhibitors (e.g., GS-0976), Amine oxidase, copper-containing 3 (AOC3) inhibitors (e.g., BI 1467335 (formerly known as PXS-4728A)); Farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), Apoptosis signal-regulating kinase 1 (ASK1) inhibitors (e.g., selonsertib), CC chemokine receptor 2 (CCR2) and 5 (CCR5) antagonists (e.g., ceniriviroc), Caspase inhibitors (e.g. emricasan), peroxisome proliferator-activated receptor-gamma (PPAR) agonists (e.g., elafibranor), Stearoyl-CoA desaturase 1 inhibitors (e.g., aramchol), Vascular adhesion protein-1 (VAP-1) inhibitors (e.g., PXS4728A), and Pioglitazone / vitamin.

[0044] Clinical Trial Protocol Clinical Trials Described below is a clinical trial protocol targeted at treating patients with CSPH in compensated cirrhosis due to HBV, HCV, and NASH with or without T2DM. Study objectives and evaluation items Primary objectives, primary and secondary endpoints Main purpose This study investigates the safety and tolerability of sGC activators in patients with CSPH in compensated cirrhosis due to NASH with or without HBV, HCV, and T2DM, and the combination of sGC activators and empagliflozin in patients with CSPH in compensated cirrhosis due to NASH with T2DM, respectively, added to standard of care. The primary objective is to estimate the percentage change in HVPG from baseline measured after 8 weeks. The primary analysis will be performed on treated patients with baseline HVPG measurements as if all patients had been treated for the duration of the study (full analysis set, FAS).

[0045] Primary endpoint The primary endpoint was the percentage change in HVPG (measured in mmHg) from baseline after 8 weeks of treatment. Secondary endpoints Secondary endpoints include: - Incidence of response, defined as a >10% reduction from baseline HVPG (measured in mmHg) after 8 weeks of treatment - Incidence of one or more decompensation events (i.e., ascites, VH and / or overt HE) during the 8-week treatment period - Incidence of CTCAE grade 3 (or higher) hypotension or syncope during the 8-week treatment period as judged by the investigator. Incidence of discontinuation due to hypotension or syncope during the 8-week treatment period.

[0046] Further objectives and further evaluation items Further Objectives In addition to the primary objective defined above, further objectives of this study include gaining further insight into general safety, PK, PD, evaluation of disease activity biomarkers, and the use of non-invasive methods to investigate liver function and portal vein pressure.

[0047] Further evaluation items Further evaluation items include (but are not limited to) the following: - Change from baseline in spleen stiffness (kPa) by FibroScan® Expert 630 after 8 weeks of treatment - Change from baseline in liver fat content (dB / m) by FibroScan® Expert 630 CAP after 8 weeks of treatment - Change from baseline in liver stiffness (kPa) by FibroScan® Expert 630 LSM after 8 weeks of treatment - Change from baseline in metabolic function after 8 weeks of treatment as measured by: HbA1c Plasma glucose HOMA-IR - Change from baseline in body weight after 8 weeks of treatment: - Change from baseline in liver function after 8 weeks of treatment as measured by: PT / INR, aPTT Bilirubin (direct and indirect) Liver enzymes (ALT, AST, γ-GT and alkaline phosphatase) albumin - Change from baseline in renal function after 8 weeks of treatment as measured by eGFR - Changes from baseline across disease-specific and mechanism-exploratory biomarkers after 8 weeks of treatment and at EoS Fibrosis markers (e.g. PRO-C3, ELF score) Inflammatory markers (e.g. hs-CRP) Cardiac and renal biomarkers (e.g., brain natriuretic peptide (BNP), troponin I, eGFR, creatinine) - PK endpoints for sCG activators and empagliflozin will be determined, if feasible. C max (maximum measured concentration of analyte in plasma) t max (time from dose to maximum measured concentration of analyte in plasma) AUC t1-t2(area under the concentration-time curve of an analyte in plasma over the time interval t1 to t2 after administration of a single dose) C max、N (Maximum measured concentration of analyte in plasma following N doses) t max、N (time from last dose to maximum measured concentration of analyte in plasma after administration of N doses) AUC t1-t2、N (area under the concentration-time curve of an analyte in plasma over the time interval t1 to t2 after administration of the Nth dose) C max、ss (the maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ) t max、ss (Time from last dose to maximum measured concentration of analyte in plasma at steady state over a uniform dose interval τ) AUC t1-t2、ss (area under the concentration-time curve of an analyte in plasma over the time interval t1 to t2 at steady state) C pre、N (Pre-dose concentration of analyte in plasma immediately prior to administration of the Nth dose after N-1 doses have been administered) C pre、ss (Pre-dose concentration of analyte in plasma at steady state, immediately prior to administration of the next dose) C t、N (Concentration of analyte in plasma at time t following N doses) Further PK parameters may be calculated as appropriate.

[0048] The following additional endpoints will be measured based on data collected in countries where respective regulatory conditions are appropriate and implementation has been performed via country-specific local amendments to this protocol. - Change from baseline in liver function after 8 weeks of treatment as measured by Disease Severity Index (DSI) and related parameters using the HepQuant® Dual Cholate Clearance Test Additional further endpoints may be defined in the Trial Statistical Analysis Plan (TSAP).

[0049] Description of Design and Study Population Overall Study Design This phase II multicenter, randomized, open-label, and parallel-group study to investigate the effect of oral sGC activators alone and in combination with empagliflozin on portal hypertension after 8 weeks of treatment in patients with clinically significant portal hypertension (CSPH) in compensated cirrhosis. Patients are enrolled in the study once they have signed the informed consent and are screened for eligibility. The screening period consists of a maximum of three visits (Visits 1a, b, and c) and lasts a maximum of four weeks. Patients can progress from one visit to the next if eligibility at the previous visit is confirmed. Evaluations include gastroscopy, liver and spleen ultrasound, liver and spleen FibroScan®, and HVPG measurements. Patients who are still eligible and successfully complete this period will progress to an 8-week open-label active treatment period. A total of 80 patients entered the study, 20 in the HBV group (Treatment Arm 1), 20 in the HCV group (Treatment Arm 2), and 40 in the NASH group (Treatment Arms 3 and 4). Two types of NASH patients (either with or without a diagnosis of T2DM) will enter treatment arms 3 or 4. NASH patients without a diagnosis of T2DM can only enter treatment arm 3 (high dose BID sGC activator alone) at visit 2. NASH patients with a diagnosis of T2DM will be randomized in a 1:1 ratio to either treatment arm 3 (high dose BID sGC activator alone) or treatment arm 4 (high dose BID sGC activator + empagliflozin QD) at visit 2. Once the number of patients in treatment arm 3 reaches 20, enrollment of NASH patients without T2DM will stop, and only NASH patients with T2DM will be enrolled in treatment arm 4 until the number of patients in treatment arm 4 reaches 20. Although randomization is applied, patients, investigators, and sponsors will remain unblinded due to the open-label nature of this study.

[0050] Following enrollment and randomization at Visit 2, patients begin taking study medication and enter a dose titration period of sGC activator. All patients in all four treatment groups begin this period with a low dose of sGC activator BID. If the low dose is tolerable, one week later (Visit 3, Day 8), the dose for all patients is titrated to a medium dose of sGC activator BID. If this medium dose is tolerable, a second titration to a high dose of sGC activator BID occurs another week later (Visit 4, Day 15). Following the dose titration period, and if the dose is tolerable, patients remain on the highest dose of sGC activator for the remainder of the treatment period until the end of treatment (EoT) visit and 8 weeks of treatment. If the dose is not tolerable, study medication may be discontinued or the dose may be reduced / tapered. Patients in treatment group 4 receive a fixed dose of empagliflozin QD in addition to the sGC activator started at Visit 2. Ultrasound and FibroScan® of the liver and spleen, as well as HVPG measurements, will be repeated during the treatment period (see FIG. 1). After the 8-week treatment period, all patients will enter a 4-week follow-up period without study medication. Patient participation in the study will be completed when they attend their last scheduled visit (i.e., end of study [EoS], 4 weeks after EoT).

[0051] Study design considerations, including choice of control group A randomized, open-label and parallel-group design was chosen for this exploratory study with a very short treatment period in addition to standard of care. The parallel groups allow for the comparison of four different patient groups, and the open-label design benefits all patients participating in it. The 8-week treatment period was chosen to allow for evaluation of short-term efficacy and indirect comparison with week 8 results from study NCT05161481 (first published on December 17, 2021). The patient population in this study (patients with HBV, HCV and NASH with and without T2DM) was chosen to represent a subset of the intended patient population for sGC activators (patients with clinically significant portal hypertension in compensated cirrhosis due to non-cholestatic liver disease). In arm 4, the combination of an sGC activator with empagliflozin will be investigated in patients with NASH and T2DM to evaluate the additional benefit of metabolic improvement with an SGLT2 inhibitor, in this study empagliflozin.

[0052] Measurement of HVPG was chosen as the primary endpoint because it is the gold standard for estimating portal venous pressure, i.e., assessing the severity of sinusoidal PH, in patients with cirrhosis (see T. Reiberger et al., “Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III),” Wien Klin Wochenschr 2017;129(Suppl 3):S135-158). It is used as an established surrogate marker for improvement and / or worsening of liver fibrosis / function, since a reduction in HVPG translates into clinically meaningful benefit (see M. Mandorfer et al., “Changes in hepatic venous pressure gradient predict hepatic decompensation in patients who achieved sustained virologic response to interferon-free therapy,” Hepatology 2020;71(3);1023-1036).The prognostic value of HVPG has been clearly demonstrated by several landmark studies, showing that an HVPG of ≥ 10 mmHg (i.e., CSPH) is predictive of varicose vein formation (see RJ Groszmann et al. “Portal Hypertension Collaborative Group. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis,” N Engl J Med 2005;353(21);2254-2261), whereas a (pharmacologically induced) reduction in HVPG modulates the risk of varicose vein growth and decompensation, respectively (C. Merkel et al., “Gruppo Triveneto per l'Ipertensione Portale. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004;127(2);476-484; and M. Mandorfer et al., “Hepatic venous pressure (See Curr Hepatol Rep 2019;18;174-186). Therefore, this also informs the selection of secondary endpoints related to the occurrence of one or more decompensation events.

[0053] Other secondary endpoints (incidence of significant hypotension or syncope, and incidence of discontinuation due to hypotension or syncope) were selected because they are relevant based on the mechanism of action of sGC activators. Patients are screened for the study based on eligibility criteria. These include the selection of patients with endoscopically confirmed documented gastroesophageal varices or documented esophageal varices treated endoscopically as a prophylactic procedure, since varices only occur in patients with CSPH. At Visit 1c (the last visit within the screening period), patients who are still eligible after Visits 1a and 1b undergo an initial HVPG measurement. Those with an HVPG ≥ 10 mmHg (based on local interpretation of the pressure curve) remain eligible. With this approach, the study is designed to enroll patients with CSPH but reduce the burden of the invasive HVPG procedure, which is only performed for patients who successfully reach Visit 1c, rather than all screened patients.

[0054] Non-invasive assessments (i.e. liver and spleen ultrasound and FibroScan® and liver function tests) were chosen as part of the screening procedure to further explore the patient's status and establish baseline values ​​for comparison with treatment, as well as to gain further insight into the use of non-invasive methods to investigate liver function and portal vein pressure. These assessments will be repeated to assess the time dependency of treatment (see FIG. 1). Following enrollment / randomization, the study design includes a dose-escalation period. Mechanism-related vasodilation of sGC activators can result in orthostatic dysregulation and hypotensive episodes. Orthostatic dysregulation is dose limiting, and clinical tolerability improves when doses are titrated. BID dosing also allows for a higher total daily exposure to sGC activators while avoiding high peak concentrations. Therefore, a dose-escalation regimen of low- to medium- to high-dose BID will be followed in this study.

[0055] Selection of study population Eighty patients with CSPH in compensated cirrhosis due to HBV, HCV, and NASH with or without T2DM will be enrolled in the study. Approximately 42 centers are planned across multiple countries. Two patients are expected to be randomized at each center. In the event of delayed enrollment, additional centers may be recruited. Screening of patients for this study is competitive, i.e., screening for one of the study or treatment groups will stop simultaneously at all sites once a sufficient number of patients have been screened to result in the required number of randomized patients. Investigators will be notified about screening completion and will then be unable to screen additional patients for this study. Patients already screened at this point may continue with randomization if eligible. Retesting during the screening period is permitted only once (e.g., if the investigator believes that a disqualifying laboratory test is the result of an error or extenuating circumstances, the test may be repeated without the need to rescreen the patient). This excludes gastroscopy and HVPG measurements. Rescreening is also permitted only once, provided that, based on the investigator's judgment, the reason for the screening failure is reversible and has been resolved. A patient is considered a "rescreenee" if he / she is initially ineligible for the study and subsequently rescreened, undergoes a second informed consent process, receives a new unique patient number, and repeats the screening period assessments.

[0056] Main diagnosis for study participation The study included patients with compensated cirrhosis due to HBV, HCV and NASH (with or without T2DM) with HVPG of ≥ 10 mmHg and endoscopic evidence of gastroesophageal varices as an indication of CSPH or esophageal varices treated endoscopically as a prophylactic measure.

[0057] Inclusion criteria - Sign and date written informed consent in accordance with ICH-GCP and local law prior to study participation. - Males or females who are ≥ 18 (or of legal age in countries where the legal age is greater than 18) and ≤ 75 years of age at Screening (Visit 1a) - Clinical signs of CSPH as described by any one of the following points: Each study patient must undergo a gastroscopy during the screening period (Visit 1b) or within 3 months prior to screening (Visit 1b). Documented endoscopic evidence of esophageal and / or gastric varices at Screening (Visit 1b) or within 3 months prior to Screening (Visit 1b) Documented esophageal varices treated endoscopically as a prophylactic measure - CSPH defined as baseline HVPG ≥ 10 mmHg (measured at Visit 1c) based on local interpretation of the pressure curve - Diagnosis of compensated cirrhosis due to HCV, HBV, or NASH with or without T2DM. Diagnosis of cirrhosis must be based on medical history (historical data is available) or clinical evidence of cirrhosis (e.g., platelet count <150 x 109 / L [150 x 103 / μL], nodular liver surface or splenomegaly on imaging, etc.). A diagnosis of NASH based on any of the following: Either current or past histological diagnosis of NASH or adiposity or Clinical diagnosis of NASH based on previous or current imaging diagnosis of fatty liver (FibroScan®, US, MRI, CT) and at least two current or previous comorbidities of metabolic syndrome (overweight / obesity, T2DM, hypertension, hyperlipidemia)

[0058] - Willingness and ability to undergo protocol-specific HVPG measurement (based on the investigator's judgment) - If taking a statin, must be on a stable dose for at least 3 months prior to screening (Visit 1b) and no dose changes are planned throughout the study - If receiving treatment with NSBB or carvedilol, must be on a stable dose for at least 3 months prior to screening (Visit 1b) and no dose changes are planned throughout the study - If receiving pioglitazone, GLP1 agonists or vitamin E, they must be on a stable dose for at least 3 months prior to screening (Visit 1b) and no dose changes are planned throughout the study - WOCBP must be willing and able to use a highly effective method of contraception per ICH M3(R2) that results in a low failure rate of less than 1% per year when used consistently and correctly from the randomization visit (Visit 2) until 7 days after the last treatment in the study. Patients must agree to undergo regular pregnancy testing during their participation in the study. - Men who are capable of fathering children and have a female sexual partner in CBP must use condoms with or without spermicide, or must embrace complete abstinence, or must undergo a vasectomy (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate) from the randomization visit (Visit 2) until 7 days after their last treatment in the study.

[0059] 3.3.3 Exclusion criteria - Previous clinically significant decompensation events (e.g. ascites [extending beyond the pericep- tial fluid]), VH and / or overt / overt HE - History of other forms of chronic liver disease (e.g., alcohol-related liver disease (ARLD), autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, alpha-1 antitrypsin [A1At] deficiency) - Patients who are not adequately treated for HBV, HCV or NASH according to local guidance (e.g. antiviral therapy for chronic HBV or HCV infection, or lifestyle modifications in NASH) - Receiving curative antiviral therapy for HCV, no sustained virologic response (SVR) or sustained SVR for less than 2 years prior to screening, or detectable HCV RNA If receiving curative antiviral therapy for HBV, they must have been on a stable dose for <6 months prior to screening, have a dose modification planned during the study, and have detectable HBV DNA Weight change of ≥ 5% within 6 months prior to screening

[0060] - Must take or wishes to continue taking any restricted concomitant medication, or any concomitant medication that (in the investigator's judgment) may interfere with the safe conduct of the study - SBP<100mmHg and DBP<70mmHg at Screening (Visit 1a) - Model for End-Stage Liver Disease (MELD) score >15 at screening (Visit 1a) as calculated by a central laboratory - Liver dysfunction defined as a Child-Turcotte-Pugh score ≥ B8 at screening (Visit 1a) as calculated by the institution using central laboratory results - ALT or AST >5x upper limit of normal (ULN) at Screening (Visit 1a) as measured by a central laboratory - eGFR (CKD-EPI formula) < 20 mL / min / 1.73 m2 at Screening (Visit 1a) as measured by a central laboratory - Alpha-fetoprotein >50 ng / mL (>50 μg / L) at Screening (Visit 1a) measured by a central laboratory - Active SARS-CoV-2 infection (or known to have a positive test between Screening [Visit 1a] and Randomization [Visit 2]) - Previous orthotopic liver transplant - Previous or planned TIPS or other portosystemic bypass procedures - Known portal vein thrombosis - History of clinically relevant orthostatic hypotension, syncope, or loss of consciousness due to hypotension or of unknown origin (based on investigator judgment) - QTcF interval at screening (Visit 1a) >450 ms in men and >470 ms in women, family history of long QT syndrome, or concomitant use of medications with known risk of polymorphic ventricular tachycardia, or planned initiation of such medications during the study

[0061] - History of type 1 diabetes mellitus or other autoimmune diabetes mellitus (e.g. LADA) - Patients who, in the opinion of the investigator, are at high risk for ketoacidosis. - Contraindication to any of the study evaluations (e.g. lack of patient cooperation for gastroscopy, cardiac pacemaker for FibroScan® [if contraindicated based on local marketing approval], etc.) - Major surgery (significance as assessed by the investigator) performed 12 weeks prior to randomization (Visit 2) or planned during the study, e.g. hip replacement. - Active or suspected malignancy, or any documented history of malignancy within 5 years prior to screening (Visit 1), except for adequately treated basal cell carcinoma of the skin or in situ cervical cancer - History of chronic substance abuse (within 6 months prior to randomization [Visit 2]) or ongoing chronic substance abuse, or not anticipated to comply with protocol requirements due to any other reason that, in the investigator's judgment, would make the patient an unreliable study participant or less likely to complete the study as planned - Previous randomization in this study, previous exposure to an SGC activator, or allergy / contraindication to any of the sGC activators and / or excipients - Currently enrolled in a study of another investigational device or investigational drug, or less than 30 days or 5 half-lives (whichever is longer) since completing another investigational device or investigational drug or receiving any other investigational treatment before randomization (Visit 2) - Women who are pregnant, breastfeeding or planning to become pregnant during the study - Any other medical condition that, in the opinion of the investigator, may pose a safety risk to the patient or interfere with the objectives of the study.

[0062] treatment The investigational drugs being tested are an sGC activator and empagliflozin. Methods for Allocating Patients to Treatment Groups After evaluation of all inclusion and exclusion criteria, each eligible patient enters the treatment phase at Visit 2. HBV patients are assigned to treatment arm 1 and HCV patients are assigned to treatment arm 2 by an interactive response technology (IRT) system. NASH patients with T2DM are randomized in a 1:1 ratio by the IRT system to treatment arms 3 or 4. NASH patients without a diagnosis of T2DM are assigned by IRT only to treatment arm 3. Once the number of patients enrolled in treatment arm 3 reaches 20, the IRT system will continue to only enroll NASH patients with T2DM into treatment arm 4 until the total number of patients in this group also reaches 20. Assignment of drugs to each patient and administration of doses Study medications are dispensed at the investigational site according to a flow chart. At the dispensing visit, patients are given a medicine kit for the appropriate number of sGC activators (range 1-2) and empagliflozin (range 1-2) depending on the interval between visits. The last dose of sGC activators is administered in the evening before the EoT visit and the last dose of empagliflozin is administered in the morning before the EoT visit.

[0063] All patients start on a low dose of sGC activator BID at Visit 2. Treatment group 4 additionally receives a fixed dose of empagliflozin QD. Seven days later, at Visit 3, and again 7 days after Visit 3, at Visit 4, all patients are titrated to a medium dose of sGC activator BID, then to a maintenance high dose of sGC activator BID. Patients will be informed of the dose titration period and will be informed that titration of the sGC activator will be used. From Visit 4 onwards, patients in treatment groups 1, 2, 3 and 4 will continue to receive the maximum dose of high-dose sGC activator (group 4 only will add empagliflozin QD) until the EoT visit (8 weeks after initiation of study medication) is reached. From the start of the treatment period (i.e., from visit 2) until the EoT visit 8 weeks later, patients are instructed to take the sGC activator orally twice daily (BID) and empagliflozin orally once daily (QD). Each dose of the sGC activator consists of one film-coated tablet. It is recommended that the first daily dose be taken in the morning and the second dose in the evening. Ideally, there should be at least 10 hours between the intake of each dose. The sGC activator should be taken at approximately the same time each day. In case of a missed dose, this should not be corrected by taking two doses (i.e., a double dose) at the next time point; in case of a missed dose of more than 6 hours, the dose should be skipped altogether and the next dose should be taken as scheduled. The study medication should be taken with a glass of water and can be taken with or without food.

[0064] Patients in treatment group 4 will take one film-coated tablet of empagliflozin in the morning plus the first daily dose of an sGC activator. To ensure an approximate 24-hour dose interval for empagliflozin, the medications should be taken at approximately the same time each day in the morning. If a dose of empagliflozin is missed by more than 12 hours, the dose will be skipped and the next dose will be taken as scheduled. Double doses should not be taken. Both medications should be taken together with a glass of water and may be taken with or without food.

[0065] limit Restrictions on Concomitant Treatments The following concomitant treatments must not be administered to patients with a diagnosis of NASH. These restrictions apply from prior to enrollment (Visit 2) until the EoS visit, and within 5 half-lives after concomitant treatment is stopped: - Other SGLT2 or SGLT-1 / 2 inhibitors The following concomitant treatments should not be administered simultaneously with sGC activators: - NO-sGC-cGMP pathway activating therapies such as NO donors (e.g. nitroglycerin, isosorbide dinitrate or mononitrate, molsidomine), PDE-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) non-specific PDE inhibitors such as dipyridamole and theophylline, or sGC stimulants (e.g. riociguat): These restrictions apply from before enrollment (Visit 2) until the EoS visit and within 5 half-lives after concomitant treatment is stopped. - Concomitant medication with known risk of polymorphic ventricular tachycardia. These restrictions apply from Screening Visit 1a through the EoS Visit. In case of temporary concomitant use of such medication, study medication must be temporarily stopped and then may be resumed at least 5 half-lives after the concomitant medication with known risk of polymorphic ventricular tachycardia has been stopped.

[0066] Concomitant administration of concomitant treatment with any of the following study medications, sGC activators and empagliflozin, is not permitted from before enrollment (Visit 2) through the EoS visit and within 5 half-lives after the concomitant treatment is stopped. - Clinically relevant OATP1B1 / 3 inhibitors - Clinically relevant concomitant therapies known to inhibit or induce UGT enzymes In case of temporary concomitant use of unauthorized medications, sGC activators and / or empagliflozin must be temporarily stopped and may be resumed after a period of at least 5 half-lives after concomitant treatment is stopped. If permanent use of any of the above prohibited treatments is required, both study medications should be stopped. Additionally, patients receiving treatment with statins or NSBBs / carvedilol, pioglitazone, GLP1 agonists, or vitamin E must be on a stable dose for at least 3 months prior to screening (Visit 1b) and no dose modifications are scheduled throughout the study. In addition, these concomitant treatments should not be initiated during the study as they may interfere with the efficacy of the study medication. If receiving antiviral therapy for HBV, patients must be on a stable dose for at least 6 months prior to screening, and no dose modifications are scheduled throughout the study. Close monitoring for combination treatment-based AEs Close monitoring for AEs is recommended in this study if patients are taking concomitant therapy that has a narrow therapeutic window and / or is metabolized by CYP3A4, a sensitive substrate.

[0067] evaluation Efficacy assessment Hepatic venous pressure gradient The HVPG procedures during the study will be performed in a standardized manner at all sites and training will be provided. Each study site will be asked to provide a sample of acceptable HVPG tracings before starting patient recruitment if not already provided for Study 1366-0021. Obstructed hepatic venous pressure (WHVP) and open hepatic venous pressure (FHVP) measurements will be performed in triplicate and tracings will be provided to an external source and read centrally by an independent PH expert, with the central read including a subjective assessment of the overall tracing quality as well as a reading of the relevant pressures. The independent expert will be blinded as to the time point to which the tracing is relevant. The central read will include tracings from Visit 1c that are also interpreted locally. The results of the central read will be communicated to the sponsor and will be considered as the formal assessment of the study. In case of discrepancy between the local interpretation (e.g. of the Visit 1c tracing) and the central assessment, the central assessment will remain valid.

[0068] HVPG measurements should be performed using the same hepatic vein before ingestion of study medication, after an overnight fast, and ideally in the morning. If it is not possible to perform the measurement at Visit 1c in the morning, an alternative time can be chosen, in which case a fast of at least 4 hours is required. All subsequent HVPG measurements must then be performed for each individual patient at approximately the same time as the Visit 1c measurement. If Visits 1b and 1c are performed on the same day, the HVPG measurement must be performed after gastroscopy (i.e., it is confirmed only once that the patient is still eligible for the study). During the treatment period, following randomization, HVPG measurements should be performed on the day of the scheduled visit or within 7 days (if this latter approach is taken, the measurement should still be performed after an overnight fast / at least 4 hours fast). A summary of the HVPG procedure is as follows (see T. Reiberger et al., “Measurement of the hepatic venous pressure gradient and transjugular liver biopsy,” J Vis Exp 2020 (160); e58819): Under local anesthesia and ultrasound guidance, a catheter introducer sheath is placed in the right internal jugular vein. Under fluoroscopic guidance, a balloon catheter is advanced into the inferior vena cava (IVC) and inserted into the large hepatic vein. Contrast is injected while the balloon is blocking the outflow of the cannulated hepatic vein to ensure accurate and adequate wedge positioning of the catheter. After calibrating the external pressure transducer, continuous pressure recordings are obtained by triplicate recordings of WHVP and FHVP. The difference between FHVP and WHVP is called HVPG, and a value of ≥ 10 mmHg indicates CSPH. Before removing the catheter, pressure readings obtained in the IVC at the same level are recorded, as well as the right atrial pressure.

[0069] FibroScan® Measurements The liver and spleen will be assessed using the FibroScan® Expert 630 instrument, a non-invasive, advanced technology that uses vibration-controlled transient elastography (VCTE™) technology. Liver FibroScan® has been available for several years and is a standard procedure used to screen and manage patients with liver disease. The ability to assess splenic stiffness using FibroScan® has only recently become possible after the introduction of the FibroScan® Expert 630 model, and therefore splenic stiffness measurement is not yet a standard part of clinical practice in the patient population planned for this study.

[0070] Assessments will be performed after an overnight fast. At screening, FibroScan® can be performed at either Visit 1b or 1c. During the treatment period, following randomization, assessments should be performed on the day of the scheduled visit or within 7 days (if this latter approach is taken, measurements should still be performed after an overnight fast). The following evaluations will be performed: - Liver Stiffness Measurement (LSM) using VCTE™ - Liver fat using controlled attenuation parameters (CAP) - Spleen hardness measurement using VCTE™

Claims

1. A method of treating a patient with compensated cirrhosis, comprising administering to the patient a therapeutically effective amount of a soluble guanylate cyclase (sGC) activator of formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 I (In the formula, A is a 5-7 membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, one carbon of said heterocyclyl group being C 1-3 optionally substituted with one or two groups selected from alkyl and oxo; R 1 is C optionally substituted with a methoxy group 1-4 is alkyl, R 2 is H, F, Cl, C 1-3 Alkyl, -CN, -OMe and -CF 3 is selected from R 3 is H and -CH 3 is selected from R 4 is H, F, -CH 3 and -OMe; R 5 is H, Cl, -CH 3 , -CH 2 CH 3 , -CF 3 , F and -OMe; R 6 is bonded to the nitrogen of A, H, C 1-6 Alkyl, -(CH 2 ) n C 3-6 Cycloalkyl, —C(O)C 1-6 Alkyl, -(CH 2 ) n Heterocyclyl, -(CH 2 ) n Aryl-(CH 2 ) n Heteroaryl, -SO 2 Aryl, SO 2 C 1-6 alkyl, 1-6 Alkyl, -(CH 2 ) n Heterocyclyl, -(CH 2 ) n Cycloalkyl, -(CH 2 ) n Aryl and -(CH 2 ) n Heteroaryl is C 1-3 Alkyl, halogen, C 1-3 Alkoxy, -CF 3 , -OH, oxo, -(CH 2 ) 1-3 O (CH 2 ) 2-3 OH and -SO 2 CH 3 and optionally substituted with 1 to 4 groups independently selected from R 7 is H, -CH 3 , -CH 2 CH 3 , -CF 3 , F and -CN; n is 0, 1 or 2.

2. 2. The method of claim 1, wherein the patient has clinically significant portal hypertension in compensated cirrhosis.

3. 3. The method of claim 2, wherein the compensated cirrhosis is caused or caused by Hepatitis B virus (HBV), Hepatitis C virus (HCV) or non-alcoholic steatohepatitis (NASH).

4. 4. The method of claim 3, wherein the compensated cirrhosis is caused or caused by HBV.

5. 4. The method of claim 3, wherein the compensated cirrhosis is caused or caused by HCV.

6. 4. The method of claim 3, wherein the compensated cirrhosis is caused or caused by NASH.

7. 7. The method of claim 6, wherein the patient has type 2 diabetes.

8. The method of any one of claims 1 to 7, further comprising administering to the patient a pharma- ceutical effective amount of an SGLT2 inhibitor or a pharma- ceutical acceptable salt thereof.

9. 9. The method of claim 8, wherein the SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin and canagliflozin.

10. 10. The method of claim 9, wherein the SGLT2 inhibitor is empagliflozin.

11. The method of any one of claims 8 to 10, wherein the SGLT2 inhibitor is administered to the patient twice daily.

12. The method of any one of claims 8 to 10, wherein the SGLT2 inhibitor is administered to the patient once daily.

13. 1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a patient with compensated cirrhosis. 【Chemistry 2】 I (In the formula, A is a 5-7 membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, one carbon of said heterocyclyl group being C 1-3 optionally substituted with one or two groups selected from alkyl and oxo; R 1 is C optionally substituted with a methoxy group 1-4 is alkyl, R 2 is H, F, Cl, C 1-3 Alkyl, -CN, -OMe and -CF 3 is selected from R 3 is H and -CH 3 is selected from R 4 is H, F, -CH 3 and -OMe; R 5 is H, Cl, -CH 3 , -CH 2 CH 3 , -CF 3 , F and -OMe; R 6 is bonded to the nitrogen of A, H, C 1-6 Alkyl, -(CH 2 ) n C 3-6 Cycloalkyl, —C(O)C 1-6 Alkyl, -(CH 2 ) n Heterocyclyl, -(CH 2 ) n Aryl-(CH 2 ) n Heteroaryl, -SO 2 Aryl, SO 2 C 1-6 alkyl, 1-6 Alkyl, -(CH 2 ) n Heterocyclyl, -(CH 2 ) n Cycloalkyl, -(CH 2 ) n Aryl and -(CH 2 ) n Heteroaryl is C 1-3 Alkyl, halogen, C 1-3 Alkoxy, -CF 3 , -OH, oxo, -(CH 2 ) 1-3 O (CH 2 ) 2-3 OH and -SO 2 CH 3 and optionally substituted with 1 to 4 groups independently selected from R 7 is H, -CH 3 , -CH 2 CH 3 , -CF 3 , F and -CN; n is 0, 1 or 2.

14. 14. A compound according to claim 13 for use in the treatment of patients with clinically significant portal hypertension in compensated cirrhosis.

15. 14. The compound of claim 13 for use in the treatment of patients with clinically significant portal hypertension in compensated cirrhosis, wherein the compensated cirrhosis is caused by or is caused by Hepatitis B virus, Hepatitis C virus or non-alcoholic steatohepatitis.

16. 14. A compound according to claim 13 for use in the treatment of patients with clinically significant portal hypertension in compensated cirrhosis, wherein the compensated cirrhosis is due to or caused by the Hepatitis B virus.

17. 14. A compound according to claim 13 for use in the treatment of patients with clinically significant portal hypertension in compensated cirrhosis, wherein the compensated cirrhosis is due to or caused by the Hepatitis C virus.

18. 14. The compound of claim 13 for use in the treatment of patients with clinically significant portal hypertension in compensated cirrhosis, wherein the compensated cirrhosis is due to or caused by non-alcoholic steatohepatitis.

19. 14. The compound of claim 13 for use in treating type 2 diabetes patients with clinically significant portal hypertension in compensated cirrhosis, wherein the compensated cirrhosis is due to or caused by non-alcoholic steatohepatitis.

20. The compound of claim 13 and the use of any one of claims 12 to 18, wherein the compound of claim 13 is administered to a patient twice daily.

21. The compound according to claim 13 and the use according to any one of claims 13 to 20, wherein the patient is further treated with an SGLT2 inhibitor.

22. 22. The use according to claim 21 , wherein the SGLT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin and canagliflozin.

23. 23. The use according to claim 22, wherein the SGLT2 inhibitor is empagliflozin.

24. The use according to any one of claims 21 to 23, wherein the SGLT2 inhibitor is administered to the patient twice daily.

25. The use according to any one of claims 21 to 23, wherein the SGLT2 inhibitor is administered to the patient once daily.

26. The method according to any one of claims 1 to 12 or the use according to any one of claims 13 to 25, wherein the compound of formula (I) is selected from the group consisting of any of the compounds shown in Table 1 and pharma- ceutically acceptable salts thereof.

27. The method according to any one of claims 1 to 12 or the use according to any one of claims 13 to 25, wherein the compound of formula (I) is selected from the group consisting of compound numbers 18, 27, 84, 114, 133, 134, 136, 148, 154, 165 and 167, and pharma- ceutically acceptable salts thereof. 【Chemistry 3-1】 【Chemistry 3-2】

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