Soluble guanylate cyclase activators for treating systemic sclerosis

Abstract

The present invention provides a therapeutically effective amount of a compound of formula (I) [Case 1] JPEG2025537141000048.jpg6955(I) (In the formula, R 1 ~R 7 and A are as defined in the specification), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

Description

[Technical Field]

[0001] The present invention relates to the use of certain soluble guanylate cyclase activators for the treatment of systemic sclerosis. [Background technology]

[0002] Systemic sclerosis (SSC) is a devastating disease of unknown etiology. It is a rare, chronic, heterogeneous connective tissue disorder with vascular, inflammatory, and fibrotic features, primarily affecting women. The estimated global prevalence of SSC is 17.6 per 100,000 people, ranging from 6.8 per 100,000 in Asia to 25.9 per 100,000 in North America. (M. Bairkdar et al. “Incidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysis,” Rheumatology 2021;60(7):3121-3133.) It is considered an incurable disease, with a prevalence of approximately 50–300 per million in the United States, 20–50 per million in Asia, and 100–200 per million in Europe. (See, e.g., J. Barnes et al., “Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers,” Curr Opin Rheumatol 2012;24(2):165-170 and A. Gabrielli et al., N Engl J Med 2009;360(19):1989-2003.) Disease progression is variable and unpredictable, with cumulative survival rates from diagnosis estimated at 74.9% at 5 years and 62.5% at 10 years. (B. Thoreau et al., “Treatment of systemic sclerosis,” Presse Med (Paris) 2021:50(1):104088.) Median survival for systemic sclerosis-associated interstitial lung disease (SSc-ILD) is 5 to 8 years.(EL Herzog et al. “Interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct?” Arthritis and Rheumatology, 2014. p. 1967-1978.)

[0003] Systemic sclerosis (SSC) is characterized by potentially widespread, progressive skin fibrosis and vascular abnormalities, the early development of Raynaud's phenomenon (RP), and potential involvement of the musculoskeletal, gastrointestinal, pulmonary, cardiac, renal, neuromuscular, and genitourinary systems. Clinical features are heterogeneous and encompass a wide range of disease severity and manifestations. Raynaud's phenomenon is a common initial symptom, followed by arthralgia and myalgia, fatigue, skin tightening, calcinosis, and DU. Patients with these symptoms struggle to manage their daily lives and may be stigmatized for facial and limb deformities. These external features are associated with internal organ involvement, including gastrointestinal disorders, renal failure, and pulmonary disease; interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the most common causes of death. Due to the heterogeneity of clinical manifestations and organ involvement, current disease management involves individualized, organ-based supportive care. Supportive care for SSc-related organ complications includes immunosuppressants, dihydropyridine calcium antagonists, endothelin receptor antagonists, the soluble guanylate cyclase (sGC) stimulator riociguat, prostacyclin analogs, and PDE-5 inhibitors (O. Kowal-Bielecka et al., “Update of EULAR recommendations for the treatment of systemic sclerosis,” Ann Rheum Dis 2017;76:1327-1339). Immunosuppressive and antifibrotic therapies have been proposed for the treatment of SSc, but controlled data are limited. Nintedanib and tocilizumab are approved for SSc-ILD. Currently, there are no disease-modifying therapies that address the underlying vascular damage and the prevention of organ damage resulting from vascular damage. Summary of the Invention

[0004] The present invention relates to a method for treating a patient with systemic sclerosis, comprising administering to the patient a pharmaceutically effective amount of a soluble guanylate cyclase (sGC) activator, or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention relates to a method for treating a patient with diffuse cutaneous systemic sclerosis (dcSSc) and vascular disorders, comprising administering to the patient a therapeutically effective amount of an sGC activator, or a pharmaceutically acceptable salt thereof. The present invention also relates to an SGC activator, or a pharmaceutically acceptable salt thereof, for use in treating patients with dcSSc and vascular disorders. In another embodiment, the present invention relates to a method for treating a patient with early progressive dcSSc and vascular disease, comprising administering to the patient a therapeutically effective amount of an sGC activator, or a pharmaceutically acceptable salt thereof.

[0005] The present invention also relates to an SGC activator, or a pharmaceutically acceptable salt thereof, for use in treating patients with early progressive dcSSc and vascular disorders. WO 2014 / 039434 and WO 2020 / 011804 describe oral small molecule activators of sGC ("sGC activators of the invention") that are useful in the methods of the invention. In one embodiment of the present invention, the sGC activator used in the method of the present invention is a compound represented by formula (I):

[0006] [ka] I (In the formula, A is a 5- to 7-membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, and one carbon of the heterocyclyl group is C 1-3 optionally substituted with one or two groups selected from alkyl and oxo; R 1 is optionally substituted with a methoxy group 1-4 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 on A, and 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, wherein C 1-6Alkyl, -(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) or a salt thereof.

[0007] Unless otherwise specified herein, the terms "compound of formula (I)", "sGC activator of the present invention", and "compound of the present invention" are used interchangeably. In another embodiment, the present invention provides the method described in the above embodiment, comprising: A is a 5- to 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 on A, and H, C 1-6 Alkyl, -(CH2) n C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -(CH2) nHeterocyclyl, -(CH2) n Aryl and -(CH2) n heteroaryl, wherein C 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; or a salt thereof.

[0008] In another embodiment, the present invention provides the method described in any of the above embodiments, comprising: R 1 is methyl, ethyl or isopropyl, base [ka] teeth,

[0009] [ka] Selected from: or a salt thereof.

[0010] In another embodiment, the present invention provides the method described in any of the above embodiments, comprising: 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, wherein C 1-6Alkyl, -(CH2) n Cycloalkyl and -(CH2) n Heterocyclyl is C 1-3 Alkyl, halogen, C 1-3 optionally substituted with 1 to 4 groups independently selected from alkoxy, -CF3, -OH, and -SO2CH3; or a salt thereof. In another embodiment, the present invention provides the method described in any of the above embodiments, further comprising: 6 wherein the heterocyclyl mentioned in 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; and R 6 wherein the heteroaryl referred to in R is selected from imidazolyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, and 4,5,6,7-tetrahydrobenzothiazolyl; 6 wherein the aryl mentioned in the formula (I) is phenyl, or a salt thereof.

[0011] In another embodiment, the present invention provides the method described in any of the above embodiments, further comprising: 6 Ha-(CH2) n heterocyclyl, wherein the heterocyclyl is 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, or a salt thereof. In another embodiment, the present invention provides the method described in any of the above embodiments, comprising: 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 is in the para position to H, -CH3, or -CH2CH3; or a salt thereof.

[0012] In another embodiment, the present invention provides the method described in any of the above embodiments, comprising: base [ka] teeth,

[0013] [ka] That is, or a salt thereof. In another embodiment, the present invention provides the method described in any of the above embodiments, comprising: R 3 is H, R 4 is H, or a salt thereof.

[0014] Table 1 provides representative compounds of the invention that can be used in accordance with 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]

[0015] In one embodiment, the sGC activator used in the methods of the present invention is selected from any of the compounds set forth in Table 1 above, and pharmaceutically acceptable salts thereof. In another embodiment, the sGC activator used in the methods of the present invention is selected from the group consisting of Compound Nos. 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, and pharmaceutically acceptable salts thereof; such compounds are shown in Table 1.

[0016] In another embodiment, the sGC activator used in the methods of the present invention is compound Nos. 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 7, 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, 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, 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 pharmaceutically acceptable salts thereof; such compounds are shown in Table 1. In one embodiment, the sGC activator used in the methods of the present invention is Compound No. 114. In the figure, "Ex114" refers to compound 114, "Ninte" or "Nin" refers to nintedanib, "bleo" refers to bleomycin, and "EX637" or "EX76637" refers to riociguat. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows hypoxia-induced TGFb2 production in primary human microvascular endothelial cells by compound 114. [Figures 2A-2C]Figure 2A shows the effect of bleomycin-induced skin fibrosis on dermal thickness (Figure 2A), reduced myofibroblast count (Figure 2B), and lower hydroxyproline content (Figure 2C) compared to bleomycin / vehicle mice. A P-value of less than 0.05 was considered statistically significant, and p-values ​​are expressed as follows: * for 0.05>p>0.01, ** for 0.01>p>0.001, *** for 0.001>p>0.0001, and **** for p<0.0001. [Figure 3A-3C] Figure 3 shows the effect of bleomycin-induced pulmonary fibrosis on Ashcroft score (Figure 3A), collagen-covered area (Figure 3B), and hydroxyproline content (Figure 3C). A P-value of less than 0.05 was considered statistically significant, and p-values ​​are represented as follows: 0.05>p>0.01 = *, 0.01>p>0.001 = **, 0.001>p>0.0001 = ***, p<0.0001 = ****, and no significant difference = ns. [Figure 4] FIG. 1 shows that ADP-induced CXCL4 secretion is reduced by compound 114 (Ex114). [Figure 5] Figure 1 shows that the sGC activator compound 114 (Ex114) significantly reduced ADP-induced CXCL4 production in a dose-dependent manner, and that compound 114 is more potent / effective than nintedanib (Nin), mycophenolate (MMF), and riociguat (EX637). [Figure 6] FIG. 1 shows the overall study design, including a randomized, placebo-controlled, double-blind, parallel-group efficacy and safety comparison of two groups (treatment and placebo) over 48 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0018] [Table 2-1] [Table 2-2] [Table 2-3]

[0019] Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name encompasses tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) thereof, as well as racemates and mixtures of different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof, and solvates, such as hydrates, including, for example, solvates of the free compounds or solvates of the salts of the compounds. Some of the compounds of formula (I) can exist in more than one tautomeric form and the present invention includes methods for using all such tautomers. The present invention includes pharmaceutically acceptable derivatives of compounds of formula (I). "Pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable salt or ester, or any other compound that, upon administration to a patient (directly or indirectly), can provide a compound useful in the present invention, or a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite is 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).

[0020] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. For example, such salts include acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, acid tartrate, bromide / hydrobromide, edetate, camsylate, carbonate, chloride / hydrochloride, citrate, edisylate, ethanedisulfonate, estolatesylate, etc. esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilate, hexylresorcinate, hydrabamates, hydroxymaleates, hydroxynaphthoates, iodides, isethionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucates ate), napsylate, nitrate, oxalate, pamoate, pantothenate, phenylacetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamide, sulfate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Further pharmaceutically acceptable salts can be formed with cations derived from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. (See also "Pharmaceutical Salts," Birge, SM et al., J. Pharm. Sci., (1977), 66, 1-19.)

[0021] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which 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 the 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 (eg, trifluoroacetates), which are useful, for example, for purifying or isolating the compounds of the invention, are also part of this invention. Additionally, within the scope of the present invention is the use of prodrugs of the compounds of formula (I). Prodrugs include compounds that change upon simple chemical transformation to produce the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be converted to the compound disclosed above, thereby providing the desired pharmacological effect.

[0022] The compounds of the present invention are only those that are contemplated as "chemically stable," as will be appreciated by those skilled in the art. For example, compounds with "dangling valences," or "carbanions," are not compounds that are contemplated by the methods of the present invention disclosed herein. For any compound disclosed herein in this application, in the event that the nomenclature conflicts with the structure, it is to be understood that the compound is defined by the structure. All terms used herein should be understood in their ordinary sense as known in the art unless otherwise specified. For example, "C 1-4 "Alkyl" means a saturated aliphatic hydrocarbon monovalent radical containing 1 to 4 carbon atoms, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, or t-butyl; "C 1-4 "Alkoxy" is a C with a terminal oxygen 1-4Alkyl, for example, methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl, and alkynyl groups are to be understood as being structurally possible and branched or unbranched, cyclized or uncyclized unless otherwise specified. Other more specific definitions are as follows:

[0023] The term “C 1-n "-alkyl" (n is an integer from 2 to n), alone or in combination with another group, means an acyclic, saturated, branched or linear hydrocarbon group having 1 to n C atoms. For example, the term C 1-5 -Alkyl is the group H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH 2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. The term “C 1-n The term "-alkylene" (n is an integer from 1 to n), alone or in combination with another group, means an acyclic, straight or branched chain divalent alkyl group containing 1 to n carbon atoms. For example, the term C 1-4-Alkylene is -(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-C H2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-C Includes H(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CHCH(CH3)2)- and -C(CH3)(CH2CH3)-.

[0024] The term “C 3-n "-cycloalkyl" (n is an integer from 4 to n), alone or in combination with another group, means a cyclic, saturated, unbranched hydrocarbon group having 3 to n C atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "heteroatom" as used herein 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 optionally be replaced by a heteroatom: O, S, or N; if N is unsubstituted, it shall be understood to be NH; and it shall also be understood that a heteroatom may replace either a terminal or internal carbon atom within a branched or unbranched carbon chain. Such groups may be substituted, as described herein above, with groups such as oxo, resulting in definitions such as, but not limited to, alkoxycarbonyl, acyl, amido, and thioxo.

[0025] The term "aryl," as used herein, alone or in combination with another group, means 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. The term "heteroaryl" means an aromatic 5- to 6-membered monocyclic heteroaryl or an aromatic 7- to 11-membered heteroaryl bicyclic ring in which at least one ring is aromatic, and the heteroaryl ring contains 1 to 4 heteroatoms, such as N, O, and S. Non-limiting examples of 5- to 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.

[0026] The term "heterocyclyl" refers to a stable non-aromatic 4- to 8-membered monocyclic heterocyclic group or a stable non-aromatic 6- to 11-membered fused bicyclic, bridged bicyclic, or spirocyclic heterocyclic group. The 5- to 11-membered heterocyclic ring consists of carbon atoms and one or more, preferably 1 to 4, heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocyclic ring may be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4- to 8-membered monocyclic heterocyclic groups include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ ... 6Examples 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-aza-spiro[3.3]heptanyl, 7-spiro[3.4]octanyl, and 7-aza-spiro[3.4]octanyl. The term "heterocyclyl" is intended to include all possible isomeric forms.

[0027] The term "halogen" as used herein should be understood to mean bromine, chlorine, fluorine, or iodine. The definitions "halogenated," "partially or fully halogenated," "partially or fully fluorinated," and "substituted by one or more halogen atoms" include, for example, mono-, di-, or trihalo derivatives on one or more carbon atoms. In the case of alkyl, non-limiting examples are -CH2CHF2, -CF3, etc. It should be understood that each alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl, or analog thereof, described herein may be partially or fully halogenated. As used herein, "nitrogen" or N and "sulfur" or S include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, -SC 1-6 With respect to alkyl groups, 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 and m is 0, 1 or 2, then phenyl-S(O) m - can be expressed as:

[0028] General synthesis method The compounds of formula (I) used in the methods of the present invention may be prepared by the methods and examples described in WO 2014 / 039434. Therapeutic uses For therapeutic use, the compounds of formula (I) can be administered by any conventional method using pharmaceutical compositions in any conventional pharmaceutical dosage form. Conventional dosage forms typically contain a pharmaceutically acceptable carrier appropriate for the particular dosage form selected. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical, or inhalation. Preferred administration methods are oral and intravenous.

[0029] The compounds of Formula (I) may be administered alone or in combination with adjuvants, including other active ingredients, to enhance the stability of the inhibitor, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide enhanced dissolution or dispersion, enhance inhibitory activity, provide adjunctive therapy, etc. For example, in one embodiment, multiple compounds of the present invention may be administered. Advantageously, such combination therapy utilizes lower doses of conventional therapeutic agents, thus avoiding potential toxic and adverse side effects incurred when those agents are used as monotherapy. The compounds of the present 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%, more preferably at least about 20%, of a compound of Formula (I) (w / w) or combination thereof. The optimal percentage (w / w) of the compounds of the present invention may vary and is within the skill of those in the art. Alternatively, the compounds of the present invention and the conventional therapeutic agents or other adjuvants may be administered separately (sequentially or simultaneously). Separate dosing allows for greater flexibility in the administration schedule.

[0030] As described above, dosage forms of the compounds of formula (I) of the present invention can contain pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for 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, H.C. Ansel and N.G. 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, and the judgment of the treating physician. 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), as well as uses such as simultaneous, sequential, or separate use of, for example, an sGC activator and a further therapeutic agent or combination therapy described herein.

[0031] The combined administration or application of the present invention may be carried out by administering the therapeutic components together, such as by administering them simultaneously in one single or two separate formulations, or by administering the therapeutic components sequentially, such as successively in two separate formulations. The therapeutic agent components of the combination therapy of the present invention may be administered separately (implying separately formulated) or may all be formulated together (implying formulated in the same formulation). Thus, the administration of one element of the combination of the present invention may occur prior to, concurrently with, or following the administration of other elements of the combination. Non-limiting examples of additional therapeutic agents include cyclophosphamide, mycophenolate mofetil, tocilizumab, nintedanib, and prednisone. In one embodiment, the method of the present invention comprises administering to a patient an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, in a daily dose of 0.1 mg to about 50 mg. 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 pharmaceutically acceptable salt thereof.

[0032] In another embodiment, the sGC activator of the present invention, or a pharmaceutically acceptable salt thereof, is administered to a patient in a daily dose of 0.1 to 100 mg, or 1 to 25 mg, or 1 to 10 mg, or 2 to 5 mg. In another embodiment, the sGC activator of the present invention, or a pharmaceutically 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 pharmaceutically 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 method of the present invention comprises administering to a patient up to 3 mg of an SGC activator of the present invention, or a pharmaceutically 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 pharmaceutically acceptable salt thereof.

[0033] 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 pharmaceutically acceptable salt thereof. 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 pharmaceutically acceptable salt thereof. The vasodilatory effects of sGC activators can cause orthostatic intolerance and hypotensive episodes. Titration of sGC activators can avoid high peak concentrations while allowing for further increases in total daily exposure to sGC activators. In one embodiment, the present invention relates to a method for preventing or reducing the severity of orthostatic dysregulation caused by, resulting from, or associated with administration of an sGC activator, or a pharmaceutically acceptable salt thereof, the method comprising administering a daily dose of an sGC activator to a patient QD, BID, or TID. In another embodiment, the sGC activator is administered QD to the patient. In another embodiment, the sGC activator is administered to the patient BID. In another embodiment, the sGC activator is administered to the patient TID. In another embodiment, the method of the present invention comprises administering up to 3 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient twice daily.

[0034] In another embodiment, the method of the present invention comprises administering 3 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient 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 2 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient twice daily to provide a total daily dose of 4 mg of sGC activator. In another embodiment, the method of the present invention comprises administering 1 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient 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 a patient TID doses of up to 3 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof. In another embodiment, the method of the present invention comprises administering 3 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient TID to provide a total daily dose of 9 mg of sGC activator.

[0035] In another embodiment, the method of the present invention comprises TID dosing of 2 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient to provide a total daily dose of 6 mg of sGC activator. In another embodiment, the method of the present invention comprises TID dosing of 1 mg of an SGC activator of the present invention, or a pharmaceutically acceptable salt thereof, to a patient to provide a total daily dose of 3 mg of sGC activator. In another embodiment, the present invention relates to a method for initiating treatment of a patient with an sGC activator. Non-limiting examples of initial treatment include titrating the patient from a low dose to a target dose. In one embodiment, the initial treatment of the patient includes: administering the sGC activator at a dose of 1 mg TID for 2 weeks (weeks 1 and 2 of treatment); sGC activator administered at a dose of 2 mg TID for 2 weeks (weeks 3 and 4); and sGC activator will be administered at a dose of 3 mg TID after the fourth week.

[0036] In another embodiment, the present invention relates to a method for treating patients with systemic sclerosis, including patients with diffuse cutaneous systemic sclerosis (dcSSc) and vasculopathy, wherein the treatment results in the following improvements: Rate of decline in FVC (mL) relative to placebo over 48 weeks Change from baseline in mRSS at week 48 revised CRISS score at week 48 (achievement of ≥20% improvement from baseline to week 48 in at least three of the five core set measures, excluding ≥5% in percent predicted FVC); Change from baseline in HAQ-DI score at week 48 Change from baseline in PGA VAS score at week 48 Change from baseline in CGA VAS score at week 48 Composite index of RP activity at 48 weeks Change from baseline in DU net burden at week 48, and / or Time to treatment failure, defined as the time to one of the following events (whichever occurs first) occurring over the 48-week and extended treatment periods: death, an absolute decline in percent predicted FVC of 10% or more compared to baseline; An increase in mRSS of 25% or more and an increase in mRSS of more than 5 points, and Initiation or dose modification of immunomodulatory / immunosuppressive therapy for clinically significant worsening of dcSSc.

[0037] In another embodiment, the present invention relates to a method for treating patients with systemic sclerosis, including patients with diffuse cutaneous systemic sclerosis (dcSSc) and vasculopathy, wherein the treatment results in the following improvements: Absolute change from baseline in FACIT-Fatigue scale score at week 48 Absolute change from baseline in SSPRO score at week 48 Absolute change from baseline in EQ-5D-5L score at week 48 Absolute change from baseline in Worst Pain NRS at week 48 Absolute change from baseline in six individual SHAQ domain scores at week 48 (pain, bowel problems, respiratory problems, RP, digital ulcers, and disease severity); PGIC score at 48 weeks, Change from baseline in percent predicted DLCO at week 48 Global Rank Composite Score (GRCS) at the end of the extended treatment period or, for patients not participating in the extended treatment period, at the end of the 48-week primary evaluation treatment period; Annual rate of decline in FVC (mL) over the primary and extended treatment periods Change from baseline in the presence or absence of tendon friction rubs at week 48 Change from baseline in joint damage (tender joint count and swollen joint count-28) at week 48, and / or Absolute change from baseline in RCS at week 48.

[0038] Patients treated with the sGC activators of the present invention may be treated with one or more additional therapeutic agents, non-limiting examples of which include cyclophosphamide, mycophenolate mofetil, tocilizumab, nintedanib, and prednisone. Clinical Trial Protocol Clinical trials The following describes a clinical trial protocol for the treatment of patients with early progressive dcSSc and vasculopathy. The study will evaluate the efficacy, safety, and tolerability of a compound of the present invention compared to placebo on a background of local standard of care (SOC) therapy in adult patients with early progressive dcSSc and vasculopathy. Diffuse cutaneous systemic sclerosis (dcSSc) is a subtype of systemic sclerosis (systemic sclerosis) characterized by hardened skin (fibrosis) and problems in many organs of the body. Symptoms include Raynaud's phenomenon, skin fibrosis that begins in the fingers and face and rapidly spreads throughout the body; "spider veins" (telangiectasia) on the chest, face, lips, tongue, and fingers; gastroesophageal reflux; and difficulty eating (dysphagia) accompanied by weight loss, vomiting, diarrhea, or constipation. Dry mouth and dental lesions may occur. Joint pain (arthralgia), muscle pain, weakness, muscle cramps, and destruction of the tips of the fingers or toes (acroostosis) often occur. More serious problems involving the lungs and kidneys may also occur. The exact cause of the condition is unknown.

[0039] Study objectives and evaluation items Primary Objective: This study will evaluate the efficacy, safety, and tolerability of compound 114 3 mg TID compared with placebo on a background of topical SOC therapy in adult patients with early progressive dcSSc and vascular disease. The primary objective is to demonstrate superiority of Compound 114 at a target dose of 3 mg TID over placebo based on the mean difference in annual rate of decline in FVC over 48 weeks. The treatment effect of primary interest is based on all randomized patients, including the impact of any changes in treatment, i.e., treatment policy strategy, used. Secondary objectives are to demonstrate superiority of compound 114 over placebo with respect to absolute change from baseline in mRSS, FVC (% predicted), patient and physician global assessment, HAQ-DI, RP activity, and DU net burden, ACR-CRISS, revised CRISS, and time to treatment failure at week 48. Additional objectives are to evaluate safety, PK, PD, and exploratory biomarkers.

[0040] Primary endpoint: The primary endpoint was the rate of decline in FVC (mL) over 48 weeks. Key secondary endpoints included: Absolute change from baseline in mRSS at week 48 Revised CRISS score at week 48 (achievement of a 20% or greater improvement from baseline to week 48 in at least three of the five core set measures, excluding a 5% or greater improvement in percent predicted FVC) Absolute change from baseline in HAQ-DI score at week 48.

[0041] Secondary endpoints were: ACR-CRISS score at 48 weeks Absolute change from baseline in FVC (% predicted) at week 48 Absolute change from baseline in PGA VAS score at week 48 Absolute change from baseline in CGA VAS score at week 48 Composite index of RP activity at 48 weeks Absolute change from baseline in DU net load at week 48 Time to treatment failure, defined as the time to one of the following events (whichever occurs first) occurring over 48 weeks and extended treatment periods: death, Absolute decline in percent predicted FVC of 10% or more relative to baseline Increase in mRSS of 25% or more and increase in mRSS of more than 5 points, Initiation or dose modification of immunomodulatory / immunosuppressive therapy for clinically significant worsening of dcSSc as outlined herein.

[0042] Further objectives and further evaluation items Additional Objectives: Additional objectives include efficacy, PK, and changes in biomarkers after 48 weeks of treatment with Compound 114 compared to placebo in adults with early dcSSc. Further evaluation items: Further evaluation items are as follows: Efficacy: Absolute change from baseline in FACIT-Fatigue scale score at week 48 Absolute change from baseline in SSPRO score at week 48 Absolute change from baseline in EQ-5D-5L score at week 48 Absolute change from baseline in worst pain NRS at week 48 Absolute change from baseline in six individual SHAQ domain scores (pain, bowel problems, respiratory problems, RP, digital ulcers, disease severity) at week 48 PGIC score at 48 weeks Absolute change from baseline in percent predicted DLCO at week 48 Global Rank Composite Score (GRCS) at the end of the extended treatment period or, for patients not participating in the extended treatment period, at the end of the 48-week primary evaluation treatment period. Proportion of patients who have treatment failure (as defined above) or discontinue treatment (non-respondents) over 48 weeks and extended treatment periods Annual rate of decline in FVC (mL) over the primary and extended treatment periods Change from baseline in the presence or absence of tendon friction sounds at 48 weeks Change from baseline in joint damage (tender joint count and swollen joint count-28) at week 48 Absolute change from baseline in RCS at week 48

[0043] Pharmacokinetics: Additional PK parameters will be calculated up to and including week 36 whenever possible and may include, but are not limited to: Cmax (maximum measurable concentration of the analyte in plasma) tmax (time from administration to maximum measured concentration of the plasma analyte) AUCt1~t2 (area under the concentration-time curve of an analyte in plasma over the time interval t1~t2) Biomarkers: Changes in blood biomarkers from baseline up to week 48, including but not limited to KL-6, CRP, CCL18, ProC3, C3M, ProC6, C6M, CXCL4, 8-isoprostane, 8-hydroxydG, sICAM-1, endothelin-1, endostatin, connective tissue growth factor (CTGF), CXCL9, and CXCL10 Changes in gene expression from baseline up to 48 weeks in skin biopsies and blood (RNA gene expression sub-study, see Section 5.4.1). Changes from baseline up to 48 weeks in the number of SMA-positive fibroblasts, skin thickness, and other histopathological parameters based on immunohistochemical analysis of skin biopsies (RNA gene expression substudy, see Section 5.4.1). Change from baseline up to 48 weeks in Digital Artery Volume Index (DAVIX®), a novel quantitative MRI-based score for assessment of intra-arterial blood flow (MRA sub-study, see Section 5.4.1). More details and additional endpoints may be defined in the Trial Statistical Analysis Plan (TSAP).

[0044] Description of design and study population Overall Test Plan This is a multicenter, multinational, prospective, randomized, placebo-controlled, double-blind, parallel-group, Phase II clinical trial to investigate the efficacy and safety of oral compound 114 at a target dose of 3 mg TID in adult patients with early-progressive dcSSc and vascular disease. Patients will be enrolled in the study and screened for eligibility after signing informed consent. The screening period will last up to 5 weeks. Eligible patients will proceed to the 48-week treatment period. Compound 114 vs. placebo will be established in a 1:1 randomization after the screening period. The treatment period involves a 4-week titration of Compound 114 from 1 mg to 3 mg TID. 1 mg of Compound 114 is given TID for 2 weeks. If tolerated, 2 mg of Compound 114 TID is given for 2 weeks, then increased to 3 mg TID. If the patient develops symptomatic orthostatic hypotension at 2 mg TID, they must discontinue study medication and contact the study site for a dose adjustment. After increasing the dose to 2 mg to 3 mg TID, the same procedure is followed. All dose adjustments require a patient visit to the study site. It is estimated that approximately 10% of patients may not be fully titrated up to the 3 mg TID dose.

[0045] The primary efficacy analysis will be assessed at Week 48. After completing the initial 48 weeks of treatment, patients may continue to receive their assigned study treatment for an extended treatment period until the last patient completes the treatment period. Patients then enter a 4-week follow-up period without study treatment for ongoing safety and efficacy data collection. Patient participation in the study will be completed upon completion of the last scheduled visit (i.e., EOS, 4 weeks after EOT). An overview of the overall study plan is shown in Figure 6. Compound 114 will be formulated IR and, if tolerated during the primary treatment period, will be titrated from 1 mg TID to 2 mg TID after 2 weeks, then from 2 mg TID to 3 mg TID after an additional 2 weeks. It is expected that approximately 10% of patients may not be able to fully titrate up to the 3 mg TID dose.

[0046] Study design considerations, including choice of control group This is a randomized, placebo-controlled, double-blind trial. The rationale for a blinded, placebo-controlled treatment group is that patients with SSc may have waxing and waning symptoms and signs. Therefore, the benefit of the experimental treatment must be judged against a clear response (or lack thereof) in the placebo group. To minimize bias, patients must be randomly assigned to either placebo or the study drug, and neither patients nor study personnel should be aware of the assignment. With exceptions noted herein, individuals involved in data collection, cleaning, programming, and analysis will remain blind to the treatment assignment until all patients have completed the study.

[0047] One of the most challenging aspects of studying SSc is the lack of validated endpoints. A variety of endpoints have been used in previous clinical trials, including skinfold thickness reduction using the mRSS, slowing of lung function decline as indicated by FVC, and composite endpoints including the mRSS, FVC, patient and physician global assessments, and the HAQ-DI. While changes in lung function have been used to register products for the treatment of interstitial lung disease in patients with SSc, none of these have been successfully used to register products for the broader symptoms of SSc. On this basis, FVC is chosen as the primary endpoint, with the understanding that it is important to also demonstrate efficacy in non-pulmonary endpoints (secondary endpoints). In the absence of a reliable composite endpoint, we suggest the inclusion of a number of secondary endpoints, including, but not limited to, RCS, reduction in the number of digital ulcers (net ulcer burden), assessment of skin thickening (mRSS), and patient and clinician global assessments, as well as patient-reported outcomes such as the HAQ-DI, FACIT, and SSPRO. These endpoints were selected based on publications demonstrating their ability to detect meaningful change in patients with SSc.

[0048] Additionally, the trial will use currently available composite endpoints, including the ACR-CRISS, the revised CRISS, and the GRCS (see, e.g., D Khanna et al., "The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis," Arthritis Rheumatol 2016;68(2):299-311; D. Khanna et al., "New composite endpoint in early diffuse cutaneous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis," Ann Rheum Dis 2021;80:641-650; and KM Sullivan et al., "Myeloablative autologous stem-cell transplantation for severe scleroderma," N Engl J Med 2018;378(1):35-47). The primary evaluation treatment period duration of 48 weeks will be selected to allow time for titration to 3 mg TID and to allow evaluation of the efficacy, safety, and tolerability of 3 mg Compound 114 TID compared with placebo on the background of topical SOC therapy in adult patients with early progressive dcSSc and vascular disease. An extended treatment period was included to provide continued treatment and evaluation for study patients and to gather additional efficacy and safety assessments.

[0049] Data cleaning, central medical review, and quality assessment of the data and reporting plan will be performed in a blinded manner. The study will include an external DMC to review blinded and unlabeled safety data quarterly throughout the duration of the study, and at interim and final analyses. Selection of study population A total of approximately 200 patients with early-progressive diffuse cutaneous systemic sclerosis will participate in the trial. Approximately 150 study sites are planned across approximately 30 countries. Approximately 1-2 patients will be randomized to each study site. If enrollment is delayed, additional study sites may be recruited. Screening of patients for this study will be competitive, i.e., screening for the study will stop simultaneously at all study sites once a sufficient number of patients have been screened. Investigators will be notified of screening completion and will not be permitted to screen additional patients thereafter. Patients already screened at this point will be allowed to continue randomization if eligible. Retesting will be permitted once during the screening period (e.g., if the investigator believes that an inappropriate laboratory test is the result of an error or extenuating circumstances, the test can be repeated once without the patient having to be rescreened).

[0050] Rescreening is also permitted once if the reason for the screening failure is reversible and resolved based on the investigator's judgment. A patient is considered a "re-screener" if they were initially ineligible for the study but were subsequently re-screened, went through a second informed consent process, received a new unique patient number, and underwent a repeat screening period assessment. A log of all patients enrolled in the study (i.e., those who signed informed consent) will be maintained in the ISF, whether or not they are treated with the study drug. If retrospectively, a patient is found to have been incorrectly randomized (i.e., did not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or representative will be contacted immediately, and a decision will be made regarding continued participation based on an individual benefit-risk assessment. Primary diagnosis for study participation The primary diagnosis for study inclusion was SSc (according to the American College of Rheumatology / European League Against Rheumatism [ACR / EULAR] criteria, 2013), subtype diffuse cutaneous sclerosis as defined by LeRoy et al., “Scleroderma (systemic sclerosis): classification, subsets and pathogenesis,” J Rheumatol 1988;15(2):202-205.

[0051] The study population should be enriched by patients with earlier, more progressive disease. This will be achieved by using criteria historically associated with "active disease" in both clinical (criterion #6) and biomarker (criterion #7) inclusion criteria. In addition to standard biomarkers associated with active inflammation, such as CRP and ESR, the biomarker criteria were strengthened with the addition of KL-6. Elevated KL-6 (>1000 U / mL) has been associated with active, progressive ILD in several studies. M. Kawana et al., “Elevated serum Krebs von den Lungen-6 in early disease predicts subsequent deterioration of pulmonary function in patients with systemic sclerosis and interstitial lung disease,” J Rheumatol 2016;43(10 ):1825-1831; GA Salazar et al., “KL-6 but not CCL-18 is a predictor of early progression in systemic sclerosis)-related 2018. p. 1153-1158, and H. Satoh et al., “Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases,” J Intern Med See 2006;260:429-434.

[0052] Inclusion criteria for patients Signed and dated written informed consent in accordance with ICH-GCP and local laws prior to study participation Male or female patients who are 18 years of age (or over the legal age, e.g. 16 years or over in the UK) at the time of consent. Patients must meet the 2013 ACR / EULAR classification criteria for SSc. Patients must be diagnosed with diffuse cutaneous scleroderma (SSc) (extensive cutaneous fibrosis with skin involvement proximal to the elbows and / or knees) as defined by LeRoy et al., “Scleroderma (systemic sclerosis): classification, subsets and pathogenesis,” J Rheumatol 1988;15(2):202-205. SSc disease onset (defined by first non-RP symptom) must be within 5 years of Visit 1.

[0053] Evidence of active disease, defined as having at least one of the following: New onset of SSc within the 2 years immediately preceding Visit 1, or New skin lesions or worsening in 2 new body areas (out of 17 body areas defined by mRSS assessment and recorded in the clinical file) within 6 months of Visit 1, or New lesions or worsening of any one new body area in the chest or abdomen within 6 months of Visit 1, or Worsening of skin thickening (≥2 mRSS points) within 6 months of Visit 1, or One or more tendon friction sounds. Elevated biomarkers at Visit 1 (Screening), defined as at least one of the following: CRP 6 mg / L or higher (0.6 mg / dL or higher), or Erythrocyte sedimentation rate (ESR) 28mm / h or higher, or KL-6 1000U / mL or more. Evidence of significant vascular impairment as defined below: Active DU at Visit 1, or A documented medical history of DU, or Previous treatment of RP with one or more other medications, such as prostacyclin analogues or calcium channel blockers, nitrates, any form of NO donor, including topical; phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil); nonspecific PDE5 inhibitors (theophylline, dipyridamole), or Elevated CRP 6mg / L or more RP If none of the above four criteria are met, the patient may participate if the diagnosis of ILD is confirmed.

[0054] Evidence of early fibrosis at Visit 1 defined as: mRSS of 10 points or more, and FVC ≥ 50% of predicted normal. If patients receive combination therapies for dcSSc, these should be at stable doses as follows: Mycophenolate mofetil / sodium: stable dose for at least 4 months before randomization Methotrexate: stable dose and route of administration for at least 4 months before randomization; folic acid supplementation with topical SOC should be administered before randomization and during the study Azathioprine: stable dose for at least 4 months before randomization Oral corticosteroids (up to 10 mg / day prednisone or equivalent): stable dose for at least 2 weeks before randomization NSAID: stable dose for at least 2 weeks before randomization ACE inhibitors: stable dose for at least 2 weeks before randomization Calcium channel blockers: stable dose for at least 2 weeks before randomization Male patients of childbearing potential must be willing to use condoms with sexual partners who are women of childbearing potential (WOCBP). WOCBP must be able to obtain and use highly effective methods of contraception in accordance with ICH M3(R2). Such methods should be used throughout the study. A list of contraceptive methods that meet these criteria is provided in the Patient Information and in Section 4.2.2.3.

[0055] Exclusion criteria All known forms of pulmonary hypertension. Pulmonary disease with FVC less than 50% predicted at screening. Localized cutaneous SSc at screening. Other autoimmune connective tissue diseases excluding fibromyalgia, scleroderma-related myopathy, and secondary Sjögren's syndrome. Diffusing capacity for carbon monoxide (DLCO) less than 40% of predicted value at screening (corrected for hemoglobin). Any history of scleroderma renal crisis within the previous 6 months. -Estimated glomerular filtration rate (eGFR) less than 30 mL / min / 1.73 m2 (CKD-EPI formula) or receiving dialysis at the time of screening. Any Child-Pugh class cirrhosis (A, B, or C) (Appendix 10.9). Current cholestasis or ALP >4xULN or ALP >2xULN and GGT >3xULN at screening.

[0056] Known severe gastric antral vascular ectasia (watermelon stomach). Any history of bronchial artery embolization or massive hemoptysis (defined as acute bleeding of more than 240 mL within a 24-hour period or recurrent bleeding of more than 100 mL / day for consecutive days). Active hemoptysis or pulmonary hemorrhage, including events managed by bronchial artery embolization. Unstable cardiovascular disease, pulmonary disease (other than study indications), or other diseases (e.g., acute coronary artery disease, heart failure, and pulmonary embolism) within the 6 months prior to Visit 1 and / or during the screening period. Systolic blood pressure less than 100 mmHg or known history of moderate or severe symptomatic orthostatic dysregulation as determined by the investigator prior to the start of study treatment. Sitting heart rate <50 bpm at screening visit. Laboratory values: Hemoglobin less than 9.0 g / dL, white blood cell (WBC) count less than 3000 / mm3 (3 x 10 9 / L), platelet count less than 100,000 / mm3 (100 × 10 9 / L) Known heart failure with left ventricular ejection fraction less than 40% before screening. Marked baseline prolongation of the QT / QTc interval as evidenced by repeated evidence on at least two ECG measurements within triplicates or two triplicates of the QTc interval (>450 ms in male patients and >470 ms in female patients). History of additional risk factors for Torsade de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome).

[0057] Use in the following treatments and therapies: Any form of nitrate or NO donor, including topical use, within 2 weeks prior to randomization (e.g., amyl nitrate); phosphodiesterase (PDE) 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil); and nonspecific PDE5 inhibitors (theophylline, dipyridamole) Prostacyclin analogues within 2 weeks prior to randomisation (short-term / intermittent treatment for up to 21 days with oral beraprost for digital ulcers / Raynaud's disease and intravenous prostacyclin analogues for digital / vascular injuries is permitted) Nintedanib, pirfenidone, elguride, tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib), or Janus kinase inhibitors within 2 weeks prior to randomization sGC-stimulators / activators (other than Compound 114) within 4 weeks prior to randomization Treatment with clinically relevant OATP1B1 / 3 inhibitors and clinically relevant UGT inhibitors / inducers within 4 weeks prior to randomization Medications with a known risk of torsade de pointes within 5 half-lives before randomization Other investigational drugs within 1 month or 5 half-lives (whichever is longer) prior to randomization UV therapy within 6 weeks prior to randomization

[0058] Use of immunomodulatory / immunosuppressive treatments and corticosteroids, including: Anakinra within 1 week prior to randomization Etanercept within 2 weeks prior to randomization Cyclophosphamide, cyclosporine A, hydroxychloroquine, tacrolimus, sirolimus, colchicine, D-penicillamine, mizoribine, and intravenous immunoglobulin within 4 weeks prior to randomization Infliximab, certolizumab, golimumab, adalimumab, abatacept, tocilizumab, brodalumab, and leflunomide within 8 weeks prior to randomization Rituximab or other anti-CD20 antibodies within 6 months prior to randomization Non-investigational or investigational cytoablative therapy, including but not limited to alemtuzumab, anti-CD4, anti-CD5, anti-CD3, and anti-CD19, within 18 months prior to randomization Previous treatment with chlorambucil, bone marrow transplant, total body lymphoid irradiation, thalidomide, antithymocyte globulin, plasma exchange, or extracorporeal photopheresis Oral prednisone >10 mg / day or equivalent, intravenous and intramuscular corticosteroids within 2 weeks prior to randomization

[0059] Standard of care in the local context must not be discontinued for patients who are eligible to participate in the study. Patients with SSc-ILD who, in the opinion of the investigator, require approved treatments that are not permitted in this study (if such treatments are available and considered SOC) should not be included in this study. Relevant chronic or acute infectious diseases, including but not limited to human immunodeficiency virus (HIV) and viral hepatitis. Corresponding laboratory tests will be performed during screening. Once the patient is treated and cleared of the acute infection, the patient may be rescreened. The patient has an active infection with SARS-CoV-2 (or is known to have a positive test) from screening to randomization. · Major surgery scheduled during the study (major surgery as assessed by the investigator). Any documented active or suspected malignancy or history of malignancy within the 5 years prior to screening, excluding adequately treated basal or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia.

[0060] History of clinically relevant allergies / hypersensitivities that may preclude study participation, including allergies to the investigational drug / placebo or its excipients. Any other medical condition that, in the opinion of the investigator, may pose a safety risk to the patient or interfere with the purpose of the study. Patients who are not expected to comply with protocol requirements or complete the planned study (e.g., chronic alcohol or drug abuse or any other condition that makes the patient an unreliable study participant in the investigator's opinion). · Previous randomization / treatment in this study. Currently enrolled in another investigational device or clinical trial, or less than 1 month or 5 half-lives (whichever is longer) since randomization, completion of another investigational device or clinical trial, or receipt of another investigational treatment. Women who are pregnant, nursing, or planning to become pregnant during the study. MRA sub-study: Contraindications to MRI or inability to undergo MRI (e.g., implanted medical devices that are contraindicated to MRI and cannot be removed (e.g., cardiac pacemakers, neurostimulation systems), severe claustrophobia). Patients who are legally institutionalized in accordance with national legislation.

[0061] treatment The investigational medicinal product in the study is an sGC activator formulated as an immediate release (IR) formulation. Method of assigning patients to treatment groups: After assessment of all inclusion and exclusion criteria, each eligible patient will be randomized 1:1 to a treatment group according to the randomization plan at Visit 2. Randomization codes will be generated by validated software and will be blinded to the study team, site, and patient. An automated response technology (IRT) system will be used to screen patients, perform medication allocation, manage initial / resupply orders for medication supply, and handle emergency unblinding.

[0062] The investigator will receive all necessary instructions from the sponsor to access the IRT. Detailed IRT functionality and procedures are documented in a user requirement specification mutually agreed upon by the sponsor and the IRT supplier. Note that the medication number is different from the patient number (the latter is generated by the IRT system during screening). Drug assignment and administration of doses to each patient: Patients are randomized to participate in either the active treatment group or the placebo control group (Table 3). Dose is escalated from 1 mg TID to 3 mg TID or a matching dose of placebo. All patients start on a dose of 1 mg TID of Compound 114 or a matching dose of placebo. Escalation occurs after 14 and 28 days. Patients who cannot tolerate escalation, for example, due to orthostatic intolerance, should follow the guidance provided herein. These patients continue to receive 2 mg or 1 mg (or placebo).

[0063] [Table 3]

[0064] It is recommended that the first daily dose be taken in the morning, the middle dose around lunchtime, and the third dose in the evening (one tablet at each time point). There must be at least four hours between doses of study treatment. A missed dose should not be corrected by taking two doses at the next time point. Study treatment should be taken with a glass of water and may be taken with or without food. Tablets may be broken or crushed to make them easier to swallow. Crushed tablets may be suspended in tap water. Crushed or suspended tablets must be used within 2 hours of being crushed. Ensure the entire dose is taken. The last dose of study treatment will be administered the evening before the EOT visit. All study treatment assignments, including titration / tapering and exchange kits, will be managed through the IRT system. Patients will be informed that the medication can be either the active study treatment or placebo.

[0065] During coronavirus disease 2019 or similar pandemics, physical visits to the study site may need to be limited to ensure patient safety. Based on a thorough assessment of benefits and risks, the investigator may still decide to continue with study treatment, which may be shipped to the patient's home if permissible according to local laws and regulations. Potential tapering (dose reduction) can be performed by the investigational site. This will be managed via the IRT system. Dose reduction must not be performed by instructing patients to take less than three doses per day. Patients will be informed that tapering may be necessary as determined by the investigator. Tapering will require an (unscheduled) visit to the investigational site.

[0066] Dose titration rules in the event of discontinuation of study treatment Because discontinuation of study treatment may affect tolerance, the following rules apply for patient safety: Discontinuation of study treatment after 4 or more consecutive doses * This is defined as any event in which a medication was not administered (i.e., a medication failure or temporary discontinuation). *A dose refers to a discrete time point, for example a morning dose, or a mid-day dose or an evening dose. If fewer than 4 consecutive doses of study treatment are missed, the next dose of study treatment should be taken as scheduled. After discontinuation of study treatment, patients should resume Compound 114 1 mg / placebo TID, independent of the dose the patient was previously receiving, unless the patient is tapering due to an adverse event (see Section 4.1.4.2), in which case: If receiving Compound 114 2 mg / 3 mg / placebo, resume at Compound 114 1 mg / placebo. If receiving Compound 114 1 mg / placebo, they should resume at Compound 114 1 mg / placebo. Before any escalation can occur, patients must have taken the previous dose for at least 10 consecutive days. This applies throughout the treatment period. This could mean that patients who are due to be titrated at Visit 3 or 4 (per Table 4.1.4:1) will be kept on their current dose until their next scheduled visit. They could also be titrated at an unscheduled visit if this requirement is met. If discontinuation occurs for any reason after Visit 4, subsequent titration will be permitted at scheduled or unscheduled visits. Patients who discontinue Compound 114 2 mg or 3 mg or matching placebo must return to the clinic at their next scheduled or unscheduled visit to receive Compound 114 1 mg / placebo tablets before continuing study treatment.

[0067] Tapering rules in case of intolerance to the test treatment If a patient has an AE that the investigator believes may be related to study treatment, the investigator may discontinue the patient's study treatment (with resumption per the rules above) or reduce the patient's dose as described below. If a patient reports symptomatic orthostatic hypotension between scheduled visits, the investigator should consider interrupting study treatment until the unscheduled visit. Patients will be removed from study treatment if they are taking Compound 114 1 mg TID or a matching placebo dose. If a patient is taking Compound 114 2 mg TID or 3 mg TID (or matching placebo dose) and discontinues study treatment: After no more than four consecutive doses, the patient is then tapered one step, i.e.: Compound 114 2 mg / placebo to Compound 114 1 mg TID / placebo. Compound 114 3 mg / placebo to Compound 114 2 mg TID / placebo. After four or more consecutive doses, patients are then tapered to Compound 114 1 mg TID or placebo. Dose reduction should not be achieved by taking fewer than 3 daily doses or by splitting tablets so that not a whole tablet is taken. If a patient has already discontinued / tapered due to an AE and experiences a second AE that the investigator believes is related and will require further tapering, the patient should permanently discontinue study treatment. In the case of AEs that persist despite dose reduction or serious adverse effects at any dose, permanent treatment discontinuation should be considered.

[0068] Escalation is not permitted in patients who have tapered or discontinued for a related AE. Any change in study treatment dose will require a scheduled or unscheduled visit to the study site and an IRT call. Blinding and unblinding procedures Blinding With the exceptions noted below, patients, investigators, central reviewers, and all persons involved in the conduct or analysis of the study or with any other interest in this double-blind study will remain blinded to the randomized treatment assignment until the database is declared ready for analysis according to the sponsor's standard operating procedures (SOPs). Further details regarding when the database will be unblinded for analysis will be documented in the TSAP.

[0069] The randomization code will be provided to bioanalytics before the last patient completes the first 48-week treatment period of the study, and placebo samples will be excluded from the PK analysis. The randomization code or results of the measurements will not be disclosed until database lock. An external independent statistician will receive the data and procedure codes and generate quarterly safety reports for the DMC. The external independent statistician will also receive the data and procedure codes to perform a planned interim analysis after approximately 80% of patients have completed the first 24 weeks of treatment. The DMC and project team will have access to the aggregate results of the interim analysis. To expedite population PK and PK-PD analyses and ensure timely handover of PK / PD results after database lock, certain data must be unblinded and treatment information must be made available to selected individuals. It should be noted that PK / PD results will not be communicated to the project and study teams prior to database lock. Prior to the interim analysis, the logistics and access plan will document details of data transfer, timelines, and individual functions related to both the interim analysis and the population PK and PK-PD analyses.

[0070] Unblinding and breaking the code Emergency unblinding is available to the investigator through the IRT. It should only be used in emergency situations where the identity of the study medication must be known to the investigator to provide appropriate medical treatment or otherwise ensure the safety of study participants. The reason for unblinding should be recorded on the source document and / or the appropriate CRF page. Suspicion of unexpected serious side effects Due to the requirement to report Suspected Unexpected Serious Adverse Reactions (SUSARs), it may be necessary to have access to individual patient randomization codes during the conduct of the study. Access to the codes will only be given to Pharmacovigilance representatives authorized to process them in the PV database system and will not be shared further. Other Procedures, Emergency Procedures and Restrictions Other Procedures and Emergency Procedures The following immunomodulatory / immunosuppressive medications are permitted and should be on a stable dose for at least 4 months prior to randomization and until EOT during the study:

[0071] Dose reductions of concomitant medications may be permitted in exceptional circumstances. Mycophenolate mofetil / sodium MTX - Patients taking MTX should receive folic acid supplementation according to the local SOC before randomization and during the study to minimize the possibility of MTX-related toxicity. (For MTX, stable dose means a stable dose and stable route of administration of this drug.) Concomitant use of azathioprine-allopurinol and xanthine oxidase inhibitors such as febuxostat should be avoided. If coadministration of a xanthine oxidase inhibitor is necessary, the azathioprine dose should be reduced to one-quarter of the usual dose because xanthine oxidase inhibitors reduce the metabolism of azathioprine. If these medications were not used concomitantly but previously, they should be stopped at least 4 weeks before randomization (Visit 2). In addition, the following concomitant medications are permitted and should be at stable doses for at least 2 weeks prior to randomization and until the EOT visit during the study (dose reductions of these medications are permitted for safety reasons): Oral corticosteroids (up to 10 mg / day of prednisone or equivalent) NSAIDs ACE inhibitors Calcium channel blockers Endothelin-receptor antagonists

[0072] These treatments will also be permitted to be initiated de novo during the study at the investigator's discretion to treat adverse events specific to SSc (e.g., Raynaud's phenomenon, arthritis, first renal crisis). For patients receiving corticosteroids and / or NSAIDs, prophylaxis with proton pump inhibitors or histamine-2 receptor blockers may be added at the investigator's discretion according to the local SOC. Pain medications up to the maximum recommended dose may be used as needed for pain, but patients must stop using pain medications, including NSAIDs, within 12 hours prior to performance of the outpatient efficacy assessment.

[0073] In cases of worsening dcSSc In the event of clinically significant worsening of dcSSc, initiation of treatment or dose changes of immunomodulatory / immunosuppressive therapy and corticosteroids >10 mg / day prednisone or equivalent will be permitted after the Week 24 visit. Use of these medications before Week 24 is not recommended except in cases of clinically significant worsening. However, if new therapy is initiated to treat significant worsening, study drug should be discontinued. Use of these medications before Week 24 is not recommended except in cases of clinically significant worsening. Clinically significant deterioration observed at any time during the course of the study is defined as follows: An absolute decline from baseline in percent predicted FVC of 10% or more (e.g., a change in percent predicted FVC from 70% at baseline to less than 60%, excluding other causes, e.g., respiratory infection), or A relative change from baseline in the mRSS of 25% or more and an absolute change from baseline of 5 points or more; Clinically significant deterioration of other organ systems or clinical parameters at the investigator's discretion

[0074] Individually ordered medications at the investigator's discretion are permitted subject to the medication restrictions set forth herein and in the inclusion / exclusion criteria. If unauthorized therapy is initiated, the investigational product must be discontinued. In case of serious AE or overdose There are no special emergency procedures to follow. There is no specific antidote for Compound 114, but symptomatic treatments to reverse its effects are widely available and should be applied. All concomitant and / or rescue therapies will be recorded on the appropriate page of the electronic case report form (eCRF).

[0075] limit Restrictions on Combination Therapy Potential risk mitigation can be achieved by close patient monitoring and prohibiting coadministration of drugs with a similar mechanism of action (i.e., activators of the NO-sGC-cGMP pathway). Particular caution is required when administering compound 114 in combination with NTIs and / or sensitive CYP3A4 substrates, as exposure to such drugs may potentially be increased in a clinically relevant manner. Furthermore, compound 114 should not be coadministered with OATP1B1 / 3 inhibitors and drugs known to inhibit or induce UGT enzymes, as this may affect compound 114 exposure in a clinically relevant manner. A list of relevant drugs can be found in the ISF. Additionally, treatments with a known risk of TdP must not be administered concomitantly with Compound 114. These restrictions apply from screening (Visit 1) throughout the study, including the treatment and follow-up periods, to the EOS visit. In the case of temporary concomitant use of such treatments, study treatment must be temporarily interrupted and may then be resumed after a period of at least 5 half-lives, as long as the interruption rules are followed after the concomitant treatment with a known risk of TdP is discontinued.

[0076] Table 4 summarizes medications and treatments that should not be taken for specified periods. [Table 4-1] [Table 4-2]

[0077] Dietary and lifestyle restrictions Patients must fast for at least 8 hours from Visit 2 prior to collection of safety laboratory samples. Contraception Requirements WOCBP study participants must use highly effective contraception during the study and for at least 7 days after their last dose of study medication if their sexual partner is a man of childbearing potential. Contraception is not required for WOCBP participants' partners. Highly effective methods according to ICH M3(R2) that, when used consistently and correctly, result in low failure rates of less than 1% per year are listed below (examples depend on national approval status): Combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) that blocks ovulation. · Progestogen-only hormonal contraception (oral, injectable, implantable) that blocks ovulation. · Intrauterine contraceptive devices or intrauterine hormone-releasing systems. · Bilateral tubal ligation.

[0078] Male study participants must have a proven sperm-free vasectomy or use condoms for at least 7 days after their last dose of study drug if their sexual partner is a WOCBP. Contraception is not required for the partners of male participants. Alternatively, WOCBP participants and male participants of child-bearing potential must abstain from male-female sexual activity, as defined according to the patient's desired usual lifestyle. Periodic abstinence methods, such as calendar, ovulation, symptom-temperature, or post-ovulation methods; declaration of abstinence for the duration of exposure to the clinical trial drug; and withdrawal are not permitted.

[0079] evaluation Efficacy assessment forced vital capacity Spirometry will be performed according to the ATS / ERS 2019 guidelines. BL Graham et al., "American Thoracic Society, European Respiratory Society. Standardization of spirometry 2019 update: an official American Thoracic Society and European Respiratory Society technical statement," Am J Respir Crit Care Med 2019;200(8):e70-e88. FVC will be assessed using a standardized spirometer equipped with a centralized supply of pre-calibrated disposable flow sensors. These sensors meet the International Organization for Standardization (ISO) 26782 standard, with a maximum allowable accuracy error of ±2.5% per the ATS / ERS Technical Statement. Therefore, routine calibration before use is not required. Only these spirometers will be used in this study. Spirometry will be performed with the subject in a seated position. Preferably, the same trained individual will perform PFTs for a given subject. The best of three attempts (out of a maximum of eight attempts) is defined as the highest FVC obtained in any of three expirations that meets the 2019 ATS / ERS criteria. Predicted norms will be calculated according to the Global Lung Initiative.

[0080] Efforts should be made to schedule spirometry at approximately the same time on the same day as the baseline measurement (Visit 2). On the day of the clinic visit, patients should refrain from strenuous activity for at least 12 hours prior to PFT. Smoking is discouraged throughout the entire visit and is not permitted 30 minutes prior to spirometry. Patients should also avoid cold temperatures, secondhand smoke, dust, or strong odors (e.g., perfume). If treated with bronchodilators, a 24-hour washout period for long-acting bronchodilators and an 8-hour washout period for short-acting bronchodilators should be observed before spirometry. A decline of 15% (relative) or more in FVC% predicted from baseline should be confirmed by another FVC test within 1 month. If the diagnosis of ILD was not established by HRCT obtained at screening, a new HRCT of the chest should be performed to confirm ILD. Spirometry results will be transmitted electronically. A central spirometry review will be implemented to ensure the quality of primary endpoint measurements and provide feedback to study sites and CRAs on the quality of data received from sites. Further instructions regarding FVC measurement will be provided to the ISF.

[0081] Modified Rodnan Skin Score The mRSS consists of an assessment of a patient's skin thickness by clinical palpation in 17 superficial anatomical regions of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of the hands, and dorsum of the feet, graded using a scale of 0 to 3 (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness where the skin cannot be pinched and folded). These individual values ​​are summed, and the sum is defined as the total skin score. (D. Khanna et al., "Scleroderma Clinical Trials Consortium, World Scleroderma Foundation. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis," J Scleroderma Rel Disord 2017;2(1):11-18.) This evaluation should be performed by a physician experienced and trained in skin scoring. Efforts should be made to have skin scoring performed by the same rater for a given patient throughout the study to prevent inter-observer variability. Further instructions regarding mRSS evaluation will be provided to ISF.

[0082] Carbon monoxide diffusing capacity Each institution uses its own DLCO machine, and all measurements are performed on the same DLCO machine (e.g., even if several machines are available at the institution). Single-inspiration DLCO measurements are performed according to the ATS / ERS guidelines for DLCO measurement (N. Macintyre et al., “Standardization of the single-breath determination of carbon monoxide uptake in the lung,” Eur Respir J 2005;26(4):720-735). The procedure should be presented and patients carefully instructed before starting the test. DLCO values ​​are adjusted for the most recent hemoglobin value. For predicted normal values, different institutions may use different prediction formulas based on the method used to measure DLCO. In any case, the calculation method used must conform to the ATS / ERS guidelines for DLCO measurement and the prediction formula appropriate for that method. The raw data (gas mixture, formula used to predict normal, and further adjustments, if any) must be traced.

[0083] DLCO assessments should be performed after FVC assessments and should always begin at approximately the same time of day, ie, with a maximum difference of less than 90 minutes between the start of the test. Further instructions regarding DLCO measurements will be provided to the ISF. Oxygen saturation measurement Oxygen saturation (SPO2) is measured by standard pulse oximetry (earlobe or unaffected skin on the forehead) at rest, and the recorded value is entered into the eCRF. Digital ulcer net burden The net digital ulcer burden is defined as the total number of "active" and indeterminate digital ulcers at the time of assessment. Digital ulcers are defined according to the proposed WSF (World Scleroderma Foundation) definition: "Loss of epidermal covering with a break in the basement membrane (which separates dermis from epidermis). It appears clinically as visible blood vessels, fibrin, granulation tissue, and / or underlying deeper structures (e.g., muscle, ligament, fat) or as it would appear on debridement." YA Suliman et al., "Defining skin ulcers in systemic Sclerosis: Systematic literature review and proposed World Scleroderma Foundation (WSF) definition," J Scleroderma Relat Disord 2017;2(2):115-1204.

[0084] Ideally, ulcer counts are performed by the same healthcare professional at each visit. Further instructions regarding DU evaluation will be provided to the ISF. Raynaud's Attack Assessment (composite index of RP activity) Raynaud's attacks will be assessed using a composite of six individual outcome measures to minimize measurement variability and placebo response, as described in H. Gladue et al., "Evaluation of test characteristics for outcome measures used in Raynaud's phenomenon clinical trials" Arthritis Care & Res. 2013: 65(4):630-636: Raynaud's symptom score (RCS), patient assessment of RP, physician assessment of RP, attack symptoms, attack duration, and average number of attacks per day. The RCS is a daily patient self-assessment of RP activity using an ordinal scale of 0 to 10 ranging from "no difficulty" to "extreme difficulty." It incorporates the cumulative frequency, duration, severity, and impact of RP attacks and reflects the overall extent to which RP affects the patient's use of their hand. See PA Merkel et al., "Scleroderma Clinical Trials Consortium. Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon," Arthritis Rheum 2002;46(9):2410-2420.

[0085] The RCS, details of the frequency and duration of Raynaud's attacks, and attack symptoms such as pain, numbness, and tingling, each measured on a 0-100 VAS, are incorporated into a daily diary that patients are asked to complete for seven consecutive days leading up to their visit. Patient and physician assessments will measure the severity of RP over the past week using a 0-100 VAS assessed at each visit. Tendon friction Anatomical sites including the hands, wrists, elbows, shoulders, knees and ankles are examined for the presence of tendon rubs. Number of tender and swollen joints This physician-reported tool assesses swelling and tenderness in 28 joints. This outcome measure should be administered by the same physician to assess the burden of joint disease from SSc-associated polyarthritis and myopathy.

[0086] Questionnaire and results obtained Patients should complete all items on the PRO questionnaire themselves in a quiet place / room prior to any other study-related testing. Site personnel will check the patient's responses to the questionnaire for completeness before the patient leaves the site but should not review the response to each item. If the patient is unable to respond or cannot determine the answer, the response should not be recorded. Scores will then be transcribed into the eCRF by designated site personnel. Chronic Disease Therapy - Functional Assessment of Fatigue The FACIT-Fatigue scale is a 13-item measure that assesses self-reported fatigue and its impact on daily activities and function. M. Hinchcliff et al., "Validity of two new patient-reported outcome measures in systemic sclerosis: Patient-Reported Outcomes Measurement Information System 29-item Health Profile and Functional Assessment of Chronic Illness Therapy-Dyspnea short form," Arthritis Care Res (Hoboken) 2011;63(11):1620-1628. Health Status Questionnaire-Disability Index (HAQ-DI) The HAQ is a questionnaire frequently used in rheumatic diseases, including systemic sclerosis, and assesses function / activities of daily living with 20 items in eight categories: dressing and grooming, hygiene, rising, reaching, eating, grasping, walking, and general daily activities. See J. Pope, "Measures of systemic sclerosis (scleroderma)," Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S98-S111; and B. Bruce et al, "The Health Assessment Questionnaire (HAQ)," Clin Exp Rheumatol 2005;23(Suppl 39):S14-S18.

[0087] Each category has at least two subcategory questions. Within each category, patients report the amount of difficulty they have in performing a particular subcategory item. There are four response options ranging from no difficulty to unable, scored from 0 to 3. An overall score (HAQ Disability Index, or HAQ-DI) is calculated from the category scores. Scleroderma Health Questionnaire The SHAQ includes the HAQ-DI and six additional VAS that are relevant to patients with systemic sclerosis. VD Steen et al., "The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time," Arthritis Rheum 1997;40(11):1984-1991. Six additional VAS that are relevant to patients with systemic sclerosis are pain, patient's global assessment of limitations, vascular involvement, DU, pulmonary involvement, and gastrointestinal involvement. Scores from these scales are not incorporated into the HAQ-DI global score.

[0088] The SHAQ will be self-administered by patients at the clinic visit. Further detailed instructions regarding SHAQ administration to patients and scoring method will be provided in the ISF. EuroQol 5-dimensional quality of life questionnaire The EQ-5D was developed by the European Quality of Life (EuroQol) group and is a standardized instrument used as a measure of health outcomes. M. Herdman et al., "Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)," Qual Life Res 2011;20:1727-1736. The version used in this study is the new five-level version (EQ-5D-5L). The questionnaire basically consists of two pages. The first page is a descriptive system with five questions about the patient's current health status. Each question captures one dimension of health (e.g., mobility, self-care) and has five levels for responses. The second page records the patient's current self-rated health status on a vertically graded (0-100) visual analog scale.

[0089] Patient and clinician global assessment The tool incorporates patient self-assessment (PGA VAS) and clinician global assessment (CGA VAS) of general health one week prior using an ordinal scale of 0 to 10, as well as ratings of overall SSc-related health progression compared with one month and one year prior. Scleroderma Skin Patient-Reported Outcomes The SSPRO is a validated PRO instrument assessing health-related quality of life (HRQOL) related to skin involvement in SSc. A. Man et al., "Development and validation of a patient-reported outcome instrument for skin involvement in patients with systemic sclerosis," Ann Rheum Dis 2017; 76:1374-1380. The SSPRO has 18 items representing four HRQOL scales: physical impact, emotional impact, physical function, and social impact. All items are scored from 0 (better) to 6 (worse). Worst Pain Numeric Rating Scale The Worst Pain NRS is a horizontal line with an 11-point numerical range. It is graded from 0 to 10, with 0 being the embodiment of no pain and 10 being the worst possible pain.

[0090] Patient Global Impression of Change (PGI-C) The Patient Global Impression scale (PGI) is a PRO counterpart to the Clinical Global Impression scale (CGI) published by the National Institute of Mental Health (USA) in 1976. It is based on the CGI and consists of one patient-adapted item. Used as the PGI-C, it primarily measures changes in clinical status. Combined Response Index in Systemic Sclerosis, ACR-CRISS Version and Revised Version The CRISS is a two-step composite index that includes the mRSS, percent predicted FVC, HAQ-DI, patient global assessment, and clinician global assessment in step 2. Step 1 in the ACR-CRISS version defines the absence of significant worsening of interstitial lung disease, new scleroderma renal crisis, left ventricular failure, or pulmonary arterial hypertension. (D Khanna et al., “The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis,” Arthritis Rheumatol 2016;68(2):299-311). In step 1, worsening ILD is defined as a relative decline of 15% or more of predicted FVC, confirmed by another FVC test within 1 month, confirmed by HRCT to confirm ILD if not already confirmed at screening, and an FVC less than 80% of predicted. Left ventricular failure is defined as a left ventricular ejection fraction of 45% or less and requires intervention. New PAH should be confirmed by right-sided cardiac catheterization. Patients with any of the above are considered not improved and are assigned a probability score of 0.0.

[0091] In step 2 of the ACR-CRISS, a weighted probability score (0.0 to 1.0, inclusive) is calculated that incorporates absolute change from baseline in five core set indices: mRSS, percent predicted FVC, HAQ-DI, patient global assessment, and clinician global assessment. In the revised version, significant gastrointestinal motility disturbances requiring parenteral or enteral nutrition and significant digital ischemia requiring hospitalization, gangrene, or amputation are added to Step 1. (D. Khanna et al., “New composite endpoint in early diffuse ceous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis,” Ann Rheum Dis 2021;80:641-650.) These patients are considered to have not improved and are not included in Step 2.

[0092] In Step 2 of the revised CRISS, the proportion of patients who achieve a defined percentage improvement in at least 1, 2, 3, 4, or 5 core set measures is assessed. Global Rank Composite Score (GRCS) The GRCS is a composite score that reflects how study participants compare with each other based on ordered outcomes: death, event-free survival (survival without respiratory, renal, or heart failure), FVC, scores on the Health Status Questionnaire Disability Index, and stratification of the Modified Rodnan Skin Score. KM Sullivan et al., "Myeloablative autologous stem-cell transplantation for severe scleroderma," N Engl J Med 2018;378(1):35-47. [Example]

[0093] Example 1 Example 1 describes experiments used to demonstrate the inhibition of hypoxia-induced TGFβ2 production in primary human microvascular endothelial cells by compound 114. TGFβ and hypoxia are thought to be important promoters of vascular remodeling and fibrosis associated with the development of SSc. Materials and Methods The assay uses the following materials and reagents: Human dermal microvascular endothelial cells are obtained from (Lonza, 2543). All experiments are performed with cells from passages 4 to 8. Four donors are utilized in these experiments. EBM™-2 (Lonza, 3156 or 00190860) EGM(trademark)-2MV Singlequotes(Lonza, 4147) FBS (Gibco, A4766801) Reagent pack (Lonza, 5034) Pen / Strep (Gibco, 15140122) Glutamax (Gibco, 35050061) T175 flask (Corning, 431466) DMSO (Sigma D2650-5X5ML) Compound 114 (Sample ID 30295026, Batch 5, Molecular Weight 582.689) ODQ(Enzo Life sciences, ALX270034M010) 96-well culture plate (Corning Costar 3595) Hypoxic chamber (water-jacketed incubator (Thermo Scientific, 3110) set at 37°C and 1% O2)

[0094] Medium preparation: Standard culture medium: EBM-2 supplemented with EGM-2MV singlequots, 10% Premium Plus FBS, 1% Glutamax, and 1% Pen-strep. Basal medium: EBM-2 supplemented with 2% FBS. Endothelial cell culture: Dermal endothelial cells from each donor indicated were cultured in a T175 flask containing standard culture medium in a 37°C / 5% CO2 incubator. When cells reached 80-90% confluence, they were subcultured by trypsinization with trypsin from the reagent pack at 37°C for 5 minutes. Cells were counted and seeded into new T175 flasks for further expansion or used for experiments as described in the protocol below. Compound preparation: 5.2 mg of compound 114 was dissolved in 446.2 μL of 100% DMSO to a concentration of 20 mM. The compound solution was then diluted to 10 mM with 100% DMSO. The 10 mM compound solution was then diluted to 1 mM and 100 mM with 100% DMSO, followed by serial dilutions to 100 μM, 10 μM, and 1 μM with HEPES-Tyrode's BSA buffer to create a 10x stock.

[0095] Hypoxia Assay: Day 0: Cells were trypsinized and counted, with each well containing 8 x 10 3 The cells are seeded in a volume containing 100 μl of medium and placed in an incubator (37° C.) overnight. Day 1: Aspirate medium and replace with basal medium left at 37°C overnight-24 hours. Day 2: Replace the basal medium with 90 μL of fresh basal medium. Add 10 μL of ODQ (12x) to reach a final concentration of 10 μM (or 3-fold serial dilutions). Incubate plates at 37° C. for 45 minutes. Add 20 μL aliquots of compound solution at 6x concentrations per well for a final well volume of 120 μL. After treatment, plates are placed in normoxia at 37° C. or hypoxia at 1% O 2 at 37° C. for 48 hours. Supernatants are collected and TGFβ2 levels are measured using an MSD ELISA. MSD Elisa: The MSD ELISA is performed according to the manufacturer's protocol. Dermal microvascular endothelial cells from three normal donors were seeded and grown to confluence. Cells were serum-starved and treated with DMSO / ODQ / Compound 114. After addition of DMSO / ODQ / Compound 114, cells were incubated in a hypoxic chamber (1% O2). After 48 hours, cells and supernatants were collected and TGF-β2 levels were measured by MSD-ELISA. MSD plates were read using an MSD QuickPlex SQ120 instrument. Standard curves and TGF-β2 concentrations were determined using Discovery Workbench Version 4.0. Normoxia was used as a control for hypoxia.

[0096] TGFβ and hypoxia are thought to be important drivers of vascular remodeling and fibrosis associated with the development of SSc. As shown in Figure 1, elevated TGFβ2 levels are produced in primary human microvascular endothelial cells under hypoxic conditions (1% O2) compared with normoxic control conditions. Compound 114 inhibits hypoxia-induced TGFβ2 levels in primary human microvascular endothelial cells. Using hypoxia (1% O2) as a disease-relevant stimulus, the results show that elevated TGF-β2 levels are produced in primary human microvascular endothelial cells under hypoxic conditions compared with normoxic control conditions. The data also show that sGC activation by compound 114 concentration-dependently reduced hypoxia-driven TGF-β2 production in primary human microvascular endothelial cells derived from three donors (see Figure 1). A statistically significant reduction was achieved at 10 μM compound 114. Therefore, compound 114 is expected to provide significant vasoprotective and antifibrotic benefits to patients with SSc by reducing hypoxia-mediated endothelial cell activation. References: JPEG2025537141000041.jpg109167

[0097] Example 2 Example 2 demonstrates the therapeutic effect of BI sGC activators in models of bleomycin-induced pulmonary and dermal fibrosis. Materials and Methods Compounds and Formulations: Compounds: Compound 114 (Sample ID 30295026), Batch 5 and EX00076637 (EX76637 / riociguat), Sample ID 17810950, Batch 5, both are dissolved in methylcellulose solution. The concentrations are 10 mg / kg, 3 mg / kg, and 1 mg / kg in a volume of 0.1 ml po. Nintedanib ethanesulfonate is prepared fresh every two days. The concentration is 60 mg / kg in a volume of 0.1 ml po.

[0098] Bleomycin-induced dermal fibrosis Skin fibrosis is induced by subcutaneous injection of bleomycin (2.5 mg / kg) every other day for 6 weeks. First, to evaluate the effect of therapeutic medication, fibrosis is induced by injection of bleomycin for 3 weeks without treatment. Then, treatment is initiated while bleomycin injections are continued. Outcomes are analyzed 6 weeks after the first injection of bleomycin. Mice injected with 0.9% NaCl, the vehicle for bleomycin, serve as non-fibrotic controls. The following groups of female C57B1 / 6 mice, each with n=8, are analyzed: Group 1 NaCl / vehicle Group 2 Bleomycin / vehicle Group 3 Bleomycin / nintedanib Group 4: Bleomycin / Cpd114 1mg / kg bid po Group 5: Bleomycin / Cpd114 3mg / kg bid po Group 6 Bleomycin / Cpd114 10mg / kg bid po Group 7 Bleomycin / EX76637 1mg / kg bid po Group 8: Bleomycin / nintedanib + Cpd114 3mg / kg bid po Group 9: Bleomycin / nintedanib + Cpd114 10mg / kg bid po

[0099] Quantification of dermal thickening: Skin from a defined area of ​​the upper back is excised, then fixed in 4% formalin for 6 h and embedded in paraffin. Skin sections are cut and stained with hematoxylin / eosin. Dermal thickness (measured in arbitrary units as the distance between the epidermal-dermal junction and the dermal-subcutaneous junction) is quantified in four different sections from different sites using two measurements per section as described in 1, 2, 4-7. Analysis is performed in a blinded manner. Myofibroblast detection: Myofibroblasts are characterized by the expression of α-smooth muscle actin (αSMA). αSMA-positive fibroblasts are detected in paraffin-embedded slides from the upper back by incubation with a monoclonal anti-αSMA antibody (clone 1A4, Sigma-Aldrich, Steinheim, Germany). Expression is visualized with a horseradish peroxidase-conjugated secondary antibody and 3,3-diaminobenzidine tetrahydrochloride (DAB) (Sigma-Aldrich). A monoclonal mouse IgG antibody (Calbiochem, San Diego, CA, USA) is used for controls 4, 8–10. Analysis is performed by a blinded reviewer who evaluates myofibroblasts in four sections per sample.

[0100] Hydroxyproline assay: The amount of collagen protein in skin samples is determined by the hydroxyproline assay. Full-thickness skin punch biopsies (3 mm diameter) from the upper back are digested in 6 M HCl at 120°C for 3 hours, after which the pH of the samples is adjusted to 6 with 6 M NaOH. For lung analysis, the median lobe is analyzed. Each sample is then added with 0.06 M chloramine T and incubated for 20 minutes at room temperature. Next, 3.15 M perchloric acid and 20% p-dimethylaminobenzaldehyde are added, and the samples are further incubated at 60°C for 20 minutes. Absorbance is measured at 557 nm using a Spectra MAX190 microplate spectrophotometer with a standard curve generated with purified type I collagen (Sigma-Aldrich). Bleomycin-induced pulmonary fibrosis In the bleomycin-induced pulmonary fibrosis model, fibrosis is induced by a single intratracheal injection of 50 μl of bleomycin on day 0. Mice injected with an equal volume of 0.9% NaCl served as controls. Outcomes are analyzed after 28 days. Treatment begins 15 days after intratracheal administration of bleomycin, thus at a time when fibrosis is already pre-established.

[0101] The following groups of female C57B1 / 6 mice, each with n=8, are analyzed: Group 1 NaCl / vehicle Group 2 Bleomycin / vehicle Group 3 Bleomycin / nintedanib Group 4: Bleomycin / Cpd114 1mg / kg bid po Group 5: Bleomycin / Cpd114 3mg / kg bid po Group 6 Bleomycin / Cpd114 10mg / kg bid po Group 7 Bleomycin / EX76637 1mg / kg bid po Group 8: Bleomycin / nintedanib + Cpd114 3mg / kg bid po Group 9: Bleomycin / nintedanib + Cpd114 10mg / kg bid po

[0102] Two mice (one from group 3 and one from group 9) died during the pretreatment phase and were therefore unavailable for analysis. Histological assessment of pulmonary fibrosis: Whole lungs were excised, fixed in 4% formalin for 6 h, and embedded in paraffin. Five-micrometer sections were cut and stained with Sirius Red. Images were recorded using a Hamamatsu Nano Sumo S60 slide scanner microscope (Hamamatsu, Herrsching am Ammersee, Germany). Histological changes in pulmonary fibrosis were quantified by Ashcroft scoring. Analysis was performed in a blinded manner. Furthermore, whole lung sections were stained with Sirius Red (Sigma-Aldrich), and the fibrotic area was measured as the percentage of Sirius Red-covered area per total area using ImageJ (v.1.42q, National Institutes of Health, USA).

[0103] Missing Samples / Values: As outlined above, two mice with bleomycin-induced pulmonary fibrosis died and therefore samples are unavailable. In addition, the following values ​​are missing: Ashcroft scoring: 1 sample in the NaCl group (tissue was washed off the slide); hydroxyproline lung: 1 sample each for Cpd114 3 mg / kg, Cpd114 10 mg / kg, and Cpd114 10 mg / kg + nintedanib (assay-related issue); dermal thickness: 1 mouse each for Cpd114 1 mg / kg and Cpd114 10 mg / kg + nintedanib (embedding not in a completely upright position). Statistics: All data are presented as median ± range, and differences between groups are tested for statistical significance by the Mann-Whitney U nonparametric test for unrelated samples.

[0104] Results: The results demonstrate that therapeutic dosing with compound 114 (Cpd114) and EX76637 ameliorates bleomycin-induced dermal fibrosis and pulmonary fibrosis. Mice challenged with bleomycin for 6 weeks (bleomycin / vehicle) developed dermal fibrosis compared with control mice. As expected, treatment with nintedanib at a dose of 60 mg / kg qd for the final 3 weeks ameliorated bleomycin-induced dermal fibrosis, reducing dermal thickness (Figure 2A), myofibroblast count (Figure 2B), and hydroxyproline content (Figure 2C) compared with bleomycin / vehicle mice. Treatment with compound 114 at doses of 1, 3, or 5 mg / kg for the final 2 weeks also ameliorated bleomycin-induced dermal fibrosis (Figures 2A-B). However, because the effects of even the lowest dose were already quite pronounced, no clear dose-dependence was observed, despite certain trends for dermal thickness and myofibroblast count. The effects are within the range of those observed with nintedanib. EX76637 at a dose of 1 mg / kg also ameliorated bleomycin-induced dermal fibrosis, with effects comparable to those of compound 114 (Figures 2A-B). The combination of nintedanib with compound 114 at doses of 3 mg / kg or 10 mg / kg bid was well tolerated and demonstrated antifibrotic effects. However, no additive effects of the combination therapy were observed compared with monotherapy with either nintedanib or compound 114.

[0105] Intratracheal instillation of bleomycin induced severe pulmonary fibrosis. Consistent with previous reports, treatment with nintedanib, starting 2 weeks after bleomycin instillation and continuing through the end of the experiment, reduced the Ashcroft score (Figure 3A), collagen-covered area (Figure 3B), and hydroxyproline content (Figure 3C). Treatment with compound 114 at doses of 1, 3, or 10 mg / kg also significantly improved fibrotic readings. Although there was a trend toward a more pronounced effect at higher doses with respect to the Ashcroft score, the difference did not reach statistical significance. Regarding bleomycin-induced dermal fibrosis, EX76637 also improved bleomycin-induced pulmonary fibrosis. Combination therapy of nintedanib and compound 114 did not demonstrate increased efficacy compared with the individual monotherapies.

[0106] The results show that activation of sGC signaling significantly ameliorates bleomycin-induced dermal and pulmonary fibrosis. References JPEG2025537141000042.jpg201165 JPEG2025537141000043.jpg40165

[0107] Example 3 Example 3 describes studies used to evaluate the in vitro efficacy of compound 114 in reducing platelet activation as measured by CXCL4 release. CXCL4 is a chemokine highly expressed by platelets. It is elevated in the blood and skin of patients with SSc and is associated with the progression of pulmonary fibrosis and pulmonary arterial hypertension. NO-sGC-cGMP is a central pathway that keeps platelets inactive. Dysregulation of this pathway could result in increased systemic CXCL4. Therefore, reducing human platelet activation as measured by CXCL4 release can be used to evaluate the efficacy of a treatment regimen.

[0108] Materials and Methods: Compound 114 (Sample ID: 30295026, Batch: 5) EX0076637 (Sample ID: 17810950, Batch: 5) Nintedanib esylate (Boehringer Ingelheim, Manufacturing #67653, Lot #1078235) EX0000076 (Sample ID: 15614118, Batch: 1) Blood from healthy volunteer donors Plastic blood collection tubes with sodium citrate (BD biosciences, 363083) 50ml conical tube (Corning, 430828) BSA solution, 30% in saline, fatty acid free, sterile filled (Sigma, A9205) ADP (Sigma, 01905-250MG-F) Tyrode's buffer (Sigma, T2397) HEPES (Gibco, 15630-080) DMSO (Sigma, D2650) 1 ml deep well plate (Thermo Scientific, 260251) Sterile 0.22 μm PVDF filter plates (Millipore, MAGVS2210) 96-well microplate (Thermo Scientific, 249946) CXCL4 ELISA kit (Abcam, ab189573 and R&D Systems, DPF40)

[0109] Buffer preparation: HEPES-Tyrode's BSA buffer: Tyrode's buffer supplemented with 0.35% BSA and 5 mM HEPES Platelet-Rich Plasma (PRP) Generation: Blood is collected from healthy donor volunteers into plastic sodium citrate tubes. The first two tubes are discarded. The remaining blood is processed within 30 minutes of collection. The blood is aliquoted into 50 ml conical tubes, no more than 35 ml per tube, and centrifuged at 200 x g for 16 minutes at room temperature with acceleration and deceleration set to half maximum. After centrifugation, the upper layer (PRP) is carefully transferred to a new tube, avoiding the buffy coat. The PRP is allowed to stand at room temperature for 5-15 minutes. The PRP is now ready for use in the experiments described in the protocol below. Compound preparation: 5.2 mg of compound 114 was dissolved in 446.2 μl of 100% DMSO to a concentration of 20 mM. The compound solution was then diluted to 10 mM with 100% DMSO. The 10 mM compound solution was then diluted to 1 mM and 100 μM with 100% DMSO, followed by serial dilutions to 100 μM, 10 μM, and 1 μM with HEPES-Tyrode's BSA buffer to create a 10x stock solution.

[0110] Preparation of Compound 114 and EX76637: 5.2 mg of Compound 114 was dissolved in 446.2 μl of 100% DMSO at a concentration of 20 mM. 9 Compounds are dissolved in 10 μl of 100% DMSO to a concentration of 50 mM. The compound solutions are then diluted to 10 mM with 100% DMSO. The 10 mM compound solutions are then diluted to 1 mM and 100 μM with 100% DMSO, followed by serial dilutions to 100 μM, 10 μM, and 1 μM with HEPES-Tyrode's BSA buffer to make 10x stock solutions. Preparation of Nintedanib: Dissolve 2.9 mg of Nintedanib in 446.3 μl of 100% DMSO to a concentration of 10 mM. The compound solution is then diluted to 100 μM in 100% DMSO. The 100 μM compound solution is then diluted to 1 μM in HEPES-Tyrode's BSA buffer to create a 10x stock solution. Preparation of EX00000776 (MMF): Dissolve 2.3 mg of EX00000776 in 530.5 μl of 100% DMSO to a concentration of 10 mM. The compound solution is then diluted to 5 mM in 100% DMSO. The 5 mM compound solution is then diluted to 50 μM in HEPES-Tyrode's BSA buffer to make a 10x stock solution.

[0111] ADP is dissolved in distilled water to a concentration of 100 mM. The 100 mM ADP is further diluted to 10 mM with HEPES-Tyrode's BSA buffer, and then diluted a second time to 100 μM with HEPES-Tyrode's BSA buffer to make a 10x stock. Activation of PRP with ADP and CXLC4 detection by ELISA 80 or 40 microliters of PRP is added to wells of a 1 ml deep-well plate containing 560 μl or 280 μl of HEPES-Tyrode's BSA buffer. 80 or 40 microliters of 10x compound solution is added per well and incubated for 30 min at 37°C / 5% CO2 before the addition of ADP. 80 or 40 microliters of 100 μM ADP is added per well and the plate is incubated for 5 min at 37°C / 5% CO2. After the 5 min incubation, 300 microliters of stimulated PRP per well is transferred to a sterile 0.22 μm PVDF 96-well filter plate. The 96-well microplate is placed under the filter plate and centrifuged at 1100 rpm for 5 min before collecting the supernatant. The flow-through supernatant is collected and diluted 1:50 with sample diluent NS from the Abcam CXCL4 ELISA kit or 1:4 with calibrator diluent RD6-13 from the R&D Systems CXCL4 Quantikine ELISA kit. The CXCL4 ELISA is performed according to the supplier's instructions.

[0112] Data analysis Raw data from the Victor Nivo plate reader was generated and analyzed using Microsoft Excel 2016. A standard curve was generated using XLfit 5.5.0 model 205. The concentration of CXCL4 in the sample was determined by interpolating the absorbance values ​​against the standard curve. The resulting value was multiplied by 50 or 4 (dilution factor) to obtain the concentration of CXCL4 in the sample. The percentage of Max CXCL4 was calculated by dividing the sample concentration value by the DMSO / ADP concentration value and then multiplying by 100. result PRP prepared from fresh blood is stimulated for 5 minutes with 10 μM ADP with or without the addition of 10 μM, 1 μM, 0.1 μM Compound 114 or DMSO. Platelets were filtered through a filter plate, and the supernatant was collected for CXCL4 ELISA. The CXCL4 percentage of Max was calculated by dividing the sample value by the DMSO / ADP value and multiplying by 100. ADP induced CXCL4 production in all 10 donors tested. Addition of the sGC activator compound 114 at 1 μM and 10 μM attenuated ADP-induced CXCL4 production in all 10 donors. A low dose (0.1 μM) of compound 114 also reduced ADP-induced CXCL4 production in 9 of the 10 donors (Figure 4). Figure 5 shows the percentage of Max for all donors compared to ADP / DMSO. The sGC activator compound 114 significantly reduced ADP-induced CXCL4 production in a dose-dependent manner.

[0113] The results show that very low levels of CXCL4 secretion are observed in PRP without activation. As shown in Figure 4, ADP-induced CXCL4 secretion is reduced by the sGC activator Compound 114. Ten donors of PRP were stimulated with 10 μM, 1 μM, or 0.1 μM Compound 114 or 10 μM ADP with or without the addition of DMSO. Ex114 = Compound 114. As shown in Figure 5, the sGC activator Compound 114 significantly reduced ADP-induced CXCL4 production in a dose-dependent manner. Furthermore, minimal effects on CXCL4 production were observed after treatment with riociguat (EX76637, designated EX637 in the figure) at a dose equivalent to Compound 114. Similarly, treatment with nintedanib or MMF was ineffective. Max CXCL4 percentage was calculated by dividing the variable value by the DMSO / ADP value and then multiplying by 100. All values ​​are expressed as means; T bars represent standard deviations. Statistical analysis is determined using a paired t-test.

[0114] Addition of 10 μM of ADP, a known platelet agonist, caused massive release of CXCL4. Data show that sGC activation with compound 114 concentration-dependently inhibited agonist-induced CXCL4 release from PRP from 10 donors. Addition of compound 114 significantly and dose-dependently attenuated ADP-induced CXCL4 production in all 10 donors. Minimal to no effect was observed after treatment with riociguat, nintedanib, or MMF, suggesting that compound 114 possesses differential activity on CXCL4 release in activated human platelets relative to the sGC stimulator riociguat or standard treatment. Results indicate that platelet activation is associated with fibrosis, inflammation, and microvascular injury. CXCL4, significantly produced by activated platelets, directly correlates with SSc disease activity. Inhibition of CXCL4 release is demonstrated by ADP-activated PRP with the sGC activator compound 114.

Claims

1. A method of treating a patient with systemic sclerosis, comprising administering a therapeutically effective amount of a compound of formula (I) 【Chemistry 1】 I (In the formula, A is a 5- to 7-membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, and one carbon of said heterocyclyl group is C 1-3 optionally substituted with one or two groups selected from alkyl and oxo; R 1 is optionally substituted with a methoxy group 1-4 is alkyl, R 2 are H, F, Cl, and 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 on A, and 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, wherein C 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. or a pharmaceutically acceptable salt thereof to a patient.

2. 10. The method of claim 1, wherein the patient has early diffuse cutaneous systemic sclerosis (dcSSc) and / or vasculopathy.

3. 3. The method of claim 1 or 2, wherein the compound of formula (I) is administered to the 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.

4. The method of any one of claims 1 to 3, wherein the compound of formula (I) is administered to the patient three times daily (TID).

5. The method of any one of claims 1 to 4, wherein the compound of formula (I) is administered to the patient in an amount selected from the group consisting of 1 mg, 2 mg, and 3 mg.

6. 6. The method of claim 5, wherein the compound of formula (I) is administered to the patient in an amount of 1 mg TID, or in an amount of 2 mg TID, or in an amount of 3 mg TID.

7. 3. The method of claim 1 or 2, wherein the treatment comprises an initial treatment comprising administering the compound of formula (I) in an amount of 1 mg TID at weeks 1 and 2, followed by 2 mg TID at weeks 3 and 4, followed by 3 mg at week 5 through the end of treatment.

8. The method of any one of claims 1 to 7, wherein the amount of the compound of formula (I) is reduced if the patient develops symptomatic orthostatic hypotension.

9. 1. A compound for use in treating a patient with systemic sclerosis, the compound having formula (I): 【Chemistry 2】 I (In the formula, A is a 5- to 7-membered saturated heterocyclyl group containing one nitrogen and optionally one oxygen, and one carbon of said heterocyclyl group is C 1-3 optionally substituted with one or two groups selected from alkyl and oxo; R 1 is optionally substituted with a methoxy group 1-4 is alkyl, R 2 are H, F, Cl, and 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 on A, and 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, wherein C 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. or a pharmaceutically acceptable salt thereof.

10. 5. The compound of formula (I) having the structure: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

11. The treatment is as follows: Percent reduction in FVC (mL) relative to placebo over 48 weeks Change from baseline in mRSS at week 48 Revised CRISS score at week 48 (achievement of 20% or greater improvement from baseline to week 48 in at least three of the five core set measures, excluding 5% or greater improvement in percent predicted FVC); Change from baseline in HAQ-DI score at week 48; Change from baseline in PGA VAS score at week 48, Change from baseline in CGA VAS score at week 48, Composite index of RP activity at week 48; Change from baseline in DU net burden at week 48, and / or Time to treatment failure, defined as the time to one of the following events (whichever occurs first) occurring over the 48-week and extended treatment periods: death, an absolute decline in percent predicted FVC of 10% or more relative to baseline; 25% or greater increase in mRSS and >5 point increase in mRSS; and Initiation or dose modification of immunomodulatory / immunosuppressive therapy for clinically significant worsening of dcSSc 11. The method of any one of claims 1 to 10, which results in an improvement in

12. The treatment is as follows: Absolute change from baseline in FACIT-Fatigue scale score at week 48; Absolute change from baseline in SSPRO score at week 48; Absolute change from baseline in EQ-5D-5L scores at week 48; Absolute change from baseline in worst pain NRS at week 48 Absolute change from baseline in six individual SHAQ domain scores at week 48 (pain, bowel problems, respiratory problems, RP, digital ulcers, disease severity), PGIC score at week 48, Change from baseline in percent predicted DLCO at Week 48; For patients not participating in the extended treatment period, the Global Rank Composite Score (GRCS) at the end of the extended treatment period or at the end of the 48-week primary evaluation treatment period; Annual rate of decline in FVC (mL) over the primary and extended treatment periods Change from baseline in the presence or absence of tendon friction rubs at week 48 Change from baseline in joint damage (tender joint count and swollen joint count-28) at week 48, and / or Absolute change from baseline in RCS at week 48 11. The method of any one of claims 1 to 10, which results in an improvement in

13. 5. The compound of formula (I) having the structure: 【Chemistry 4】 2. The method of claim 1, comprising:

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