EA042973B1 - Alkoxypyrazoles as Activators of Soluble Guanylate Cyclase - Google Patents

Description

Field of invention

This invention relates to heterocyclic compounds which are useful as activators of soluble guanylate cyclase and thus useful in the treatment of various diseases that are mediated or caused by reduced or decreased activity of soluble guanylate cyclase, such as chronic liver disease, non-alcoholic steatohepatitis (NASH), cirrhosis , portal hypertension, and related disorders.

Prerequisites for the invention

Soluble guanylate cyclase (sGC) is a nitric oxide (NO) receptor found in the cytoplasm of many cell types. In humans, functional rGC is a heterodimer consisting of an alpha 1 or alpha 2 subunit in combination with a beta 1 subunit that has a heme prosthetic group. Under nonpathophysiological conditions, binding of NO to the heme of rGC activates the enzyme, catalyzing the conversion of guanosine 5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is a second messenger that exerts its effect by modulating cGMP-dependent protein kinase (PC-G) isoforms, phosphodiesterases, and cGMP-gated ion channels. In doing so, rHC has been shown to modulate numerous disease-associated pathways, including arterial hypertension, pulmonary hypertension, atherosclerosis, heart failure, liver cirrhosis, renal fibrosis, and erectile dysfunction (O. Evgenov et al., Nature Reviews, 2006, 5, 755-768 and Y. Wang-Rosenke et al., Curr. Med. Chem., 2008, 15, 1396-1406).

Under normal conditions, iron in rGC is in the divalent state, which is able to bind with NO and carbon monoxide (CO). However, under conditions of oxidative stress that can occur in various diseases, published reports indicate that heme iron is oxidized to a ferric state that cannot be activated by NO or CO. It was assumed that the inability of NO to signal through the oxidized heme iron sGC contributed to disease processes. Recently, two new classes of compounds have been described that enhance the action of sGC in a heme-dependent (rGC-stimulator) and heme-independent (rGC-activator) manner. The activity of sGC stimulators is synergistic with NO with increased cGMP production, while sGC activators only complement NO with increased cGMP levels (O. Evgenov et al., Nature Reviews, 2006, 5, 755-768). Both stimulants and activators of sGC have shown benefit in animal models of the disease. sGC activators provide the advantage that they can target predominantly diseased, non-functional forms of enzymes. sGC activators include BAY 58-2667 (cynaciguat) (JP Stasch et al., Brit J. Pharmacol., 2002, 136, 773783) and HMR-1766 (ataciguat) (U. Schindler et al., 2006, Mol. Pharmacol. , 69, 1260-1268).

NO plays an important role in maintaining the normal functioning of cells and tissues. However, sufficient signaling in the NO pathway can be compromised at several stages. NO signaling can be impaired by decreased levels of nitric oxide synthase (NOS) enzymes, NOS activity, NO bioavailability, sGC levels, and sGC activity. sGC activators have the ability to bypass the functional barriers caused by all these disorders. Since sGC activation occurs after NO synthesis or NO availability, these shortcomings do not affect the activity of sGC activators. As described above, sGC activity, whose function is impaired by heme iron oxidation, will be corrected by sGC activators. Thus, sGC activators have the ability to provide benefits in many diseases caused by impaired signaling in the NO pathway.

There is evidence that rHC activation may be beneficial in preventing tissue fibrosis, including the lungs, liver, skin, and kidneys. It is believed that the processes of epithelial-to-mesenchial transition (EMT) and the transformation of fibroblasts into myofibroblasts contribute to tissue fibrosis. When either zinc ciguat or BAY 41-2272 was combined with sildenafil, the conversion of lung fibroblasts to myofibroblasts was inhibited (T. Dunkern et al., Eur. J. Pharm., 2007, 572, 12-22). NO is able to inhibit EMT of alveolar epithelial cells (S. Vyas-Read et al., Am. J. Physiol. Lung Cell Mol. Physiol., 2007, 293, 1212-1221), suggesting that sGC activation is involved in this process . NO has also been shown to inhibit glomerular TGF-beta signaling (E. Dreieicher et al., J. Am. Soc. Nephrol., 2009, 20, 1963-1974), indicating that sGC activation may inhibit glomerular sclerosis. In a porcine serum model and a carbon tetrachloride model of liver fibrosis, rHC activator (BAY 60-2260) was effective in inhibiting fibrosis (A. Knorr et al., Arzneimittel-Forschung, 2008, 58, 71-80), suggesting that an increase in rHC activity can be used to treat non-alcoholic steatohepatitis (NASH). In bleomycin-induced mouse skin fibrosis and Tsk-1 mouse skin fibrosis, sGC stimulator BAY 41-2272 was able to inhibit skin thickening and myofibroblast differentiation (C. Beyer et al., Ann. Rheum. Dis., 2012, 71, 1019-1026), indicating that rHC activation may be beneficial in the treatment of systemic sclerosis.

Pharmacologically, sGC activity can be enhanced by sGC modulators, which include sGC stimulators and sRC activators. sGC stimulators bind to heme-containing rGCs and act heme-dependently, while sGC activators preferentially bind to oxidized

- 1 042973 sHC and act heme-independently (Sandner and Stasch, 2017). Both mechanisms of sGC stimulation lead to a significant increase in cGMP in environments with a low content of endogenous NO and a low content of cGMP. Riociguat (BAY 63-2521, Adempas®) is the first sHC modulator (stimulator) to successfully transition from animal experiments to patients for the treatment of pulmonary hypertension.

Since cGMP elevation is associated with antifibrotic, antiproliferative, and anti-inflammatory effects, sGC modulators may have therapeutic potential beyond vasorelaxation in fibrotic disorders (Sandner and Stasch, 2017). Two experimental studies investigated the effect of the sGC activator BAY 60-2770 on experimental cirrhosis: Knorr et. al. first demonstrated that BAY 60-2770 exhibits antifibrotic activity in rat models of CC14 fibrosis and porcine serum-induced liver damage (Knorr et al., 2008). Xie et al. confirmed these findings in a rat thioacetamide model and also observed an improvement in sinusoidal architecture after treatment with BAY 60-2770 (Xie et al., 2012). In a rat model of liver fibrosis with bile duct ligation (BDL), treatment with the sHC stimulator BAY 412272 caused a significant reduction in portal vein pressure and liver fibrosis, as measured by hydroxyproline content and Sirius-Red staining (Nowatzky et al., 2011 ).

Portal hypertension (PHT), one of the serious complications of liver cirrhosis, is determined by an increase in pressure in the portal vein system above 10 mm Hg. Art., and it is responsible for many complications such as esophageal varices, splenomegaly, hepatic encephalopathy and ascites (Garcia-Tsao, 2006). In most cases, patients with portal hypertension have increased intrahepatic resistance due to cirrhosis, as well as increased blood flow in the portal venous system via the hyperdynamic internal system (Fiorucci et al., 2004).

Non-selective beta-blockers (reducing liver flow; Reiberger et al., 2017) and nitrates (currently rarely used due to systemic side effects; Villanueva et al., 2001) are the only drugs available for the treatment of RHT. However, the ideal agent for portal hypertension should reduce portal venous pressure by reducing intrahepatic resistance and, if possible, maintain normal liver function by reducing or preventing hepatic fibrosis (Bosch et al., 2001).

Intrahepatic vascular resistance in cirrhosis is defined by both structural (i.e., fibrosis, vascular remodeling) and functional abnormalities (i.e., sinusoidal vasoconstriction, endothelial dysfunction; Fernandez, 2015). Endothelial dysfunction and sinusoidal vasoconstriction are caused by inflammation, oxidative stress, and an imbalance of vasodilators and vasoconstrictors. Nitric oxide (NO) is the most important biogenic vasodilator, while both NO production and response to NO are severely impaired in cirrhotic livers (Wiest & Groszmann, 2002). Downstream of the NO signaling pathway, target soluble guanylate cyclase (rGC) mediates vasodilation by catalyzing the reaction from GTP to cGMP (Zhao et al., 1999). Enzyme activity is predominantly regulated by the heme/Fe(II) group, which is susceptible to NO (Capece et al., 2015).

The above studies provide evidence for the use of rHC activators in patients with chronic liver disease, NASH, cirrhosis, and portal hypertension.

Brief description of the invention

The present invention provides methods for using the compounds of the invention that activate or enhance the action of sGC for the treatment of diseases and disorders that can be alleviated by activating or enhancing the action of sGC.

Compounds in accordance with the invention can be obtained using the methods and examples described in WO 2014/039434.

In a first embodiment, the invention relates to a method for the treatment of preventing or slowing the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension, which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of compounds No. 18, 27, 84 , 114, 133, 134, 136, 148, 154, 165 and 167:

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167, or its salts.

In a second embodiment (Embodiment 2), the invention relates to the method of Embodiment 1, wherein the disease or disorder is NASH.

In a third embodiment (embodiment 3), the invention relates to a method of any of embodiments 1 or 2, wherein the method is for treating, preventing or slowing the progression of portal hypertension in patients with cirrhosis of the liver when the cirrhosis is due to any etiology (cirrhosis of any cause) .

In the fourth embodiment (Embodiment 4), the invention relates to the method of any of Embodiments 1-3, wherein the compound is Compound 114.

In a fifth embodiment (embodiment 5), the invention relates to the use of a compound selected from the group consisting of compounds Nos. 18, 27, 84, 114, 133, 134, 136, 148, 154, 165 and 167:

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or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention or retardation of the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension.

In a sixth embodiment (Embodiment 6), the invention relates to the use of Embodiment 5, wherein the use is for treating, preventing or slowing the progression of portal hypertension in patients with cirrhosis of the liver when the cirrhosis is due to any etiology (cirrhosis from any cause) and the compound is connection 114.

In a seventh embodiment (embodiment 7), the invention relates to the use of a compound selected from the group consisting of compounds Nos. 18, 27, 84, 114, 133, 134, 136, 148, 154, 165 and 167:

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or a pharmaceutically acceptable salt thereof, for the treatment, prevention or retardation of the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension.

In an eighth embodiment (Embodiment 8), the invention relates to the use of Embodiment 7, wherein the use is for treating, preventing or slowing the progression of portal hypertension in patients with cirrhosis of the liver when the cirrhosis is due to any etiology (cirrhosis of any cause) and the compound is connection 114.

Detailed description of the invention

As stated above, the invention relates to a method for treating, preventing or slowing the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension, which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of compounds No. 18, 27, 84 , 114, 133, 134, 136, 148, 154, 165 and 167 listed in the table, and their pharmaceutically acceptable salts.

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Connection No. Structure Connection No. Structure 1 S ^οΑ ώ 2 O ^~he nD-o No. 9 0U\ L J ο'^γ ^οίγ F-tk^ F 3 όό\ 4 X ^OH % ^K o όν\ ° ίΓ ° ΊΓ F ^f ^x^Ou 5 Γ^ ^{0Η Ν} -Λ° όό\ 6 X ^{OH Ν} 'Λ°_ όν. °ίγ θ^ΊΓ F ov 7 Χ ^{ΟΗ Ν} -Λθ 8 X ^{he Ν} -Λθ όό\ about~7 ο'^γ ⁰¹ .Si ° ΊΓ ^νΟΟ^ 07

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9 h 10 ^° ^{Η Ν} 'Λ° όό\ \ / с*] νΟΟι OV AND G 12 mCh ⁿ Ν, Χ _η h? CCHI 13 l N. -^o A ° H? 14 O ^-on Ν^Α-0 Ν 0ύ\ ^jO 15 ^ ^he Ν. -^Ό ϊ 'h? 16 AyaCha b

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17 Do N. A _o A ' o Yu 18 b 19 O And he ΙΐΚθ A ° ΌΠ Cl C>J -^o 20 ^N 'n ^K ° 0ύ\ Cl O^Y 21 ^ ^he Ν, Α _η Ν ___-nO-y^ 22 bf^Y b 23 / -G V _o >/ uCo )=( ° vJ ^t 24 0 y ^N ' _N y όό\ ο^γ ^ctb

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25 I° ^Ν -Λ° 0ύ\ 26 I ^{he Ν} 'Λ° όό\ ° ίγ °'Yar 27 I ^{he Ν} 'Λ° όό\ I θ^ΊΓ 28 X ^he 'x tusa 29 X ^{he Ν} 'Λ° (S' Msa thirty 0 R ° ⁿ A ° .^oY'^; 31 La^b b 32 oh yaon N 0v\ o'Yar usxu

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33 ^ ^he όΐχχ he/I-^^ЯЯ 34 And ^he 0vx ηΑσ 35 AyaA^, b 336 AyaA^ b 37 And ^{he is} N. I- _o Ν 9 i _γ θ7 38 I ^he 0i \ ^AO _ύ οαΑ Ό 1 39 AyA^, 40 And ^{he n} ' ⁿ V 0<χ\ ^AO chax/

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41 b 42 Lyy^ 43 And ^{he is N} 'n 9 0S-H. _YoV ' ^: 44 A ^OH b ^K ° 1 °^T yOu ⁴ o 1 45 RA > >-s 46 b ^{OH N} n 9 Z-V M* 0χρ ηχσ 47 O JboH ftAo N 9 48 o %ΟΗ νΓΑ _ο Ν 9 II Ί oU'^; cr —ΛΛ b

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49 O 50 O ron ron Gk _o N 9 nO-o N R / / P'N L if L J ° ΊΓ ^Cl HN^kP T 51 O 52 ABOUT ron pOH N N^o A ° A'N to N L II II Ί Il T II J ° ΊΓ JI 1 ^hhch | ^{C| F} ^yN^kk _/ ^ ^NxkLk OK ok 53 O 54 o w /-He A° ^h N^k _o to ° ifk r^N ΗίΓ 11 Ί II 1 °^\ /\/p ^F /\X^k ^Cl /^yN^Xk o^J 55 O 56 Oh w ron A°H kk _o N klo ^N to (l ^N L if |l Ί T °^T ^{0 Cl Cl} Y/ ^Nxkk ^ ^h he ° J

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57 X / H - o O _Q J \=^ A 58 ''"O / 59 i/u ό 60 X / LA- O _o e t 61 b 62 O- 63 Aya^^ b 64 bb ⁿ -n ^K o^ Ar-OU' ^:

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65 X ^{n N} ' Xq 66 Χ° ^Η dx χχ Λ J °^τ ΤΊ O X^N^ XX χχ- ^Ν χ 4 67 Υ ^Ν Ύ°^ 68 0 ,/-01-1 χΧο όΧ-χ 0ϊχ Χ-χ ^χθ ο'^γ ^χθ -χ.Ν _χ q ο-. χχ- ^Ν χ ΧΧτ About _h 69 X ⁿ Ν, Ν 9 70 ο drn Ν^Χρ ^Ν X At όΐ^χ Il J Ογ^ ^χθ ^ο Χγ χ___,Ν^ Χχ u'O Ο Μχ^ b 71 X ^oh 72 ο ^-ΟΗ A ° o^· χθ X J Χτ F F Χφ

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73 O 74 O ^-he JAoh %l° Gk _o N °\ F II J ,Mil o C 11 T _x 'b^ ^N xA> Oh.M O 75 O 76 0 JAoh ^OH nO-o N nXo ^N \ I > / ιι ί °”^l J J °l^ ^o f oh i /° 77 O 78 O %OH JAoh nO-o N \ nD-o ^N A Il Ί o'M*^ х^/ХуШ^ХгУ °x/ 79 ABOUT 80 0 ^-he JAoh N^lo N 9 J < M οΎ ΛJ 1 1mil o'D /^zW 1 ¹ T T o.___J

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81 (Y-o \__/ \ 82 A Z 83 AnCh^ Kommersant 84 o Jy-OH SH~K _O A 85 Z about 86 O )ΑθΗ nA-ο l ° 87 4th ^Ν 'Λ° όόχ 88 o CH~ON Ν^Κ _Ο L ° OA? oA

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89 An^b b 90 b O / 91 Kommersant O / 92 And ^{he Ν} Ά° 0Aw ^AO Ya-oA 93 ό 94 A ^Ν -Λ<^ .yoY' ^: 95 Aa^^ O—( > ⁷ *—o 96 And ^{he Ν} -ν ^Κ ° _< 0Aw ^aO ° ΊΓ ΆνΟΑ

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97 /=\ > r° ϊ 98 I ^{he Ν} 'γΛ° 0Aa. > ^ΑίΑ about t \ J 1 yyyyyyyyyyyyyyyyy °-I 99 ABOUT 100 O \\ _I~OH ^on N^K _O N \ νΆ _ο l ° Yam |1 ΐ T 1 ^nA1 ο^γ / Η ίΓ G n / G \ II 1 N-^ ⁴ ^ / \ °~I o-z 101 0 102 O I° ⁿ >-he ιί~Α ₀ νΆο l ° ^v % I^s 0A-x 1II Ag N ^yal °^T ογ^ G ]| AaAHA^ O 103 O \\ 104 O A ^on uk-ON ml _about A ° Ν^Κ 1V I^Y 1 if L/L A ^ya ° ^AO 1 s*] ^χγ,ΑΑΑ A V-ο o___J

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105 y RA Г if _f оУ ^: 106 Kommersant 107 X ^OH Νχ m _O X ⁴ L if 1 /RJ ^CF 3 ^„..nCU o-^ 108 Kommersant 109 at G if ^jO 1 ^Ou O-^ 110 at R Ho Ν \___ G if °^1 o-^ 111 b 112 b

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FROM yay^ b 114 La^ya b 115 A" 1 A G if ^jO °^ΊΓ _οσ ο 116 °ya^ya b 117 b 118 LAYA ό 119 ό 120 i^i b

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121 b 122 b ^he I A _O Λ A L Ji I _П „.-Ои o-^ 123 b 124 δ o- W /=\ °^\ G/LA _La b 125 An ^ '-z 126 Λα^Ϊκ b 127 b ri^N Γ if schsst 128 b ^Ν 'Λ°^ (Λ^Ν Γ if ^jO i θ^ΊΓ ^.Oj o I *

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129 I ^{he N} x X ₀ Ν \___ Г if i θ^ΊΓ ^Ου ο 130 b ^0H Г if оУ ^: 'CZ/^ 131 I ⁿ Ν ₄ Χο Ν __ ri^N Γ if Co' ^: ' CZ^ 132 b 133 b 134 °bbSb b 135 b 136 b

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137 b ^0H An AL L Jf 1 o''] ^Cu o 138 1z 139 '—z O\__o 140 b 141 b 142 b ^{oH n} >A° _x Г if сх-оУ ^: 143 Α;Κ?χ ό 144 b

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145 δ 146 A a x _o N A_ G if ya 147 A N _x A- _O N Д__ Γ if ΟφΟσ o 148 Kommersant 149 Kommersant 150 A™ ^ν Ά°^ (Y-N O-G if _r m ^: o-^ 151 A n ₄ A _o . N \ O - Г if ^ο χΖ 152 O

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153 P Z--1 Ab 154 A ^oh N ₄ Λ-Ο N Д__ Г if ^Cu 155 b ^OH N _x Xo N Д__ Г if 1 ^ "аУ 156 •Abb '—z < O o ^t t 157 b 158 b 159 b 160 °</;ω °^ ^Ζ Α ba-

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161 Q Z--1 162 AchChya ό 163 I A _O N \___ G if 164 A z—< by 165 ^N XX _O N \___ L if CF ₃ Ci'y 166 b ^{he n} jA° _x Г if ^CF 3 v'''] /^^esy °AA 167 \/°b 168 b ^oH Г if 1 /OH ,^/U t _o ^W

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169 b 170 Q E C Z--4 xa 171 172 У ^N x Xo N \___ L ί Z-w XZ) R '-O }=* aoir 173 b" ^N x Xo N D_ XY G if ^jO ο^γ ^cX 174 \R r»^N G if o-X 1 175 176 Y ^N - Xo X ⁴ Г if 1 °^l °" bx ^z: A ABOUT °^>—N jA χΓ

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177 h 178 z--1 Plague 179 X ^he Γ if 180 δ ο- Μ οΧΧ /=\ °^\ U/~w Χχ b 181 5 o/ Η oAD / ^ζ= \ °^\ b 182 b 183 b 184 X ^{he Ν} χ Α-Ο X ⁴ Γ if xoV

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185 AyaU '—z __o 186 b" ⁿ >A<\ i<A^n Г if ^jO ^cxY oJ 1 187 b 188 b ^{oH N} x A _o X ^x Г if ^Q ^\ °c^ocY 189 b ^H ΛΑ Г if соа 190 b ^he 4 ^K <v ri^N Г if w 191 b ^{H N} XA _o X ⁴ r<A _N Г if ^AO cvoa 192 b ^{he N} x Ao X ⁴ Г if O-^nOO^ ¹

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193 I ^{n Ν} χ Ho Ν ___ Г if Х,оУ ¹ 194 ^Ν χ L-O N ^u \___ G if 1 c*! ^nQu ° 195 I ⁿ RA Г if ο^γ ^,Ου ο γ y 196 I ^{n N} 4 Xo N \___ rX^N Г ii i ^oX |^ bXjLJJ / 197 b ^OH Г if ^Ou о у γ^ 198 R ^N 4 Xo X ^x X 199 b” xn G ΙΪ -P X 200 b ^{he N} ^N ^X O^ γ<Χν Γ ΙΪ ^l3 °xC(p

- 33 042973

201 b 202 A ^ν Ά° _χ Г If СшО/ F 203 X /° g 204 y?r 205 G If <>oh 206 A rA^N G If O-O1U 207 A N ₄ W _O X ⁴ (Ά^ν Г if i θ^ΊΓ o—\ ' ΙΐΊ L^>.....ν II J 208 A ⁿ >a<v Г If а,аУ ^: F

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209 b 210 /bpv 211 k™ ^N χ X _o N D__ ι<Ρή ^oY ¹ 212 Y ^Ν 'Λ°^ r<A^N Г ii Xj Q <νΜ ^Ύ \ xy 213 b“ N ₄ A _O N \___ A^n Г if aОУ 214 r ⁴ ^ bfXr 215 AXX 216 k ^{OH N} x Ao N \___ Г if o^ b ^N XXX^

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217 AhJ^b 218 Ar^k b 219 Ar^h '—z O\__ O 220 X N ₄ Ao N ^u \___ rA^N Г if Α 221 Ts Aya 222 AnLe J X-O 223 A“ ⁿ tA° _x Г if ^jO /\ I o—( r^rArA XX 224 ArFrb

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225 L G if oh-oh 226 GU™ A^v D ii ^AO A AJ ’ ZA 227 I” % ^κ <ν I^L Г if i θ^ΊΓ ol / 71Ug Lu.....ν II Ί 228 l L L-o N D__ |I^Y Г if аЯ 229 I^L G if ο^γ AS ABOUT F 230 L ^N 4 Ho A ^x A ^ N G if ^ AO a-A F 231 ^Ν χ Ho A ^x AA G ΙΪ LO %oU 232 L l X _o Ν γ_ [I ^ s G if o ..A''

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233 ^Ν χ Xo N D__ Г if Z\ 1 ^oX |^ O—/ '^n 234 0 \e < _ζ ^/ν 235 XX _o N D__ 236 X Ho Ν D__ G if CJL mu ^: αζχ 237 v\ MA G if ^Gu o X ^x 238 luu b 239 ^N 'n\ G If GO cxx/ 240 Oh \uh Ζ-%M¥

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241 X ^Ν χ Ho N D__ Г if ° ϊ 1 242 '—zb 243 X N ₄ No N \___ Г if ^xO cACi/' 244 Αχ^-χ '—z h o / 245 X N ₄ Xo N Д__ Г if ο' ^χ ^χ Olj N-— 246 fZ^^ ⁰ z 247 X ^h N ₄ X _o X ⁴ x<x° 248 Χχβχ^ b

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249 b 250 Y Ns. Z^O X ^x Yn Г if O^Yp °Y ll N 251 A™ N ₄ X _O X ⁴ G if F ο 252 0 253 X" Γ if of T \__' F 254 N ₄ X ⁴ Yn Г if ο^γ OV o | \__' F 255 ό 256 Aby ό 257 N ₄ z^O Г if i 258 Ϋz

Unless specifically stated otherwise in the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometric isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and their racemates, as well as mixtures thereof in various proportions of individual enantiomers, mixtures of diastereomers, or mixtures of any of the above forms, where such isomers and enantiomers exist, as well as their salts, including their pharmaceutically acceptable salts and their solvates, such as, for example, hydrates, including solvates of the free compounds; or solvates of the salt of the compound.

Some of the compounds of the invention may exist in more than one tautomeric form. The invention includes methods for using all such tautomers.

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The invention includes pharmaceutically acceptable derivatives of the compounds of the invention. The term pharmaceutically acceptable derivative refers to any pharmaceutically acceptable salt or ester, or any other compound, which, when administered to a patient, is capable of providing (directly or indirectly) a compound useful in the invention, or its pharmacologically active metabolite or pharmacologically active residue. A pharmacologically active metabolite is to be understood as any compound according to the invention capable of being metabolized enzymatically or chemically. This includes, for example, a hydroxylated or oxidized derivative of a compound of the invention.

As used herein, the term pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound has been modified by obtaining its acidic or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acid residues such as carboxylic acids; and so on. For example, such salts include acetates, ascorbates, benzenesulfonates, benzates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates, esylates, fumarates, gluceptates, gluconates, glutamates. , glycolates, glycolylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, methyl bromides, methyl nitrates, methyl sulfates, mucates, napsilates, nitrates, oxalates, pamoates, pantothenates, phenyl acetates, phosphates /diphosphates, polygalacturonates, propionates, salicylates, stearates, subacetates, succinates, sulfamides, sulfates, tannates, tartrates, theoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. In addition, pharmaceutically acceptable salts can be formed with metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. (See also Pharmaceutical salts, Birge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acid moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a sufficient amount of a suitable base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, or a mixture thereof.

Salts of acids other than those mentioned above which are suitable, for example, for purifying or isolating the compounds of the present invention (eg, trifluoroacetate salts), also form part of this invention.

In addition, prodrugs of the compounds of the invention are used within the scope of this invention. Prodrugs include those compounds which, after a simple chemical transformation, are modified to give compounds according to the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. In particular, when a prodrug is administered to a patient, the prodrug can be converted to the compound described above, thereby providing the desired pharmacological effect.

Compounds in accordance with the invention are only those compounds that are considered chemically stable, which will be understood by experts in this field. For example, compounds that will have a free valency or carbanion are not compounds contemplated in the methods of the invention disclosed herein.

For all compounds disclosed above in this application, in case the nomenclature conflicts with the structure, it should be understood that the connection is determined by the structure.

All terms used in this description, unless otherwise indicated, should be understood in their usual meaning, known in the art. For example, C1. ₄ -alkyl is a saturated aliphatic hydrocarbon monovalent radical which contains 1-4 carbon atoms, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl or tert-butyl; _C1 . ₄ -alkoxy is C ₁ . ₄ -alkyl with a terminal oxygen atom, such as methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groups are to be understood as branched or unbranched, cyclized or uncyclized, if structurally possible and unless otherwise indicated. Other more specific definitions are given below:

Term C ₁ . _n -alkyl, where n is an integer from 2 to n, either alone or in combination with another radical, denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1-n carbon atoms. For example, the term C ₁ . ₅ -alkyl encompasses the radicals H ₃ C-, 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-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)- CH2-, HcC-CH(CHc)CH2-CH2-, HcC-CH2-C(CHc)2-, HcC-C(CHc)2-CH2-, HcC-CH(CHc)-CH(CHc)- and H ₃ C-CH2-CH(CH2CH ₃ )-.

Term C ₁ . _n -alkylene where n is an integer from 1 to n, either alone or in combination with another radical, denotes an acyclic, divalent alkyl radical with a linear

- 41 042973 or branched chain, which contains from 1 to n carbon atoms. For example, the term C1-4-alkylene includes -(CH ₂ )-, -(CH ₂ -CH ₂ )-, -(CH(CH ₃ ))-, -(CH ₂ -CH ₂ -CH ₂ )-, - (SSVD-, -(CH(CH2CHz))-, -(CH(CH3)CH2)-, -(CH2-CH(CH3))-, -(CH ₂ -CH ₂ -CH ₂ -CH ₂ )-, -(CH2-CH2-CHCH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C (CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH ₂ -CH(CH ₂ CH3))-,

-(CH (CH ₂ CH3) -CH ₂ )-, -(CH(CH ₂ CH ₂ CH3))-, -(CHCH(CH3) ₂ )- and -C(CH3)( _CH2 CH3)-.

The term C _3-n -cycloalkyl, where n is an integer from 4 to n, either alone or in combination with another radical, denotes a cyclic, saturated, linear hydrocarbon radical with 3-n carbon atoms. For example, the term C _3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term heteroatom in the context of this document should be understood to mean atoms other than carbon, such as O, N, S and P.

In all alkyl groups or carbon chains, one or more carbon atoms may optionally be replaced by heteroatoms: O, S or N, it should be understood that if N is not substituted, then this is NH, it should also be understood that heteroatoms can replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain. Such groups may be substituted as described above with groups such as oxo to give definitions such as, but not limited to, alkoxycarbonyl, acyl, amido, and thioxo.

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

The term heterocyclyl means a stable non-aromatic 4-8 membered monocyclic heterocyclic radical or a stable non-aromatic 6-11 membered fused bicyclic bridged bicyclic or spirocyclic heterocyclic radical. The 5-11 membered heterocycle is composed of carbon atoms and one or more, preferably one to four, heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle may be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo- ^1λ6 -thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of non-aromatic 6-11 membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of non-aromatic 6-11-membered bridged bicyclic radicals 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 6-11 membered spirocyclic heterocyclic radicals 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.

The term halogen as used herein should be understood to mean bromine, chlorine, fluorine or iodine. Definitions halogenated, partially or fully halogenated; partially or fully fluorinated; substituted with one or more halogen atoms, include, for example, mono, di - or trihalogen derivatives on one or more carbon atoms. For alkyl, a non-limiting example would be -CH2CHF2, _-CF3 , etc.

It is to be understood that each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl or analog thereof described herein is optionally 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, for -S-C1-6 alkyl radical, unless otherwise indicated, it should be understood that it includes -S (O) -C _l-6 alkyl and -S (O) ₂ -C _1-6 alkyl, similarly, -S-Ra can be represented as phenyl-S(O) _m - when Ra is phenyl and where m is 0, 1 or 2.

Methods of therapeutic use.

The compounds disclosed herein effectively activate soluble guanylate cyclase. Activation or enhancement of the action of soluble guanylate cyclase is a promising tool for the prevention and treatment of several diseases and disorders.

According to an embodiment of this aspect, the invention relates to a method for treating, preventing, slowing the progression of non-alcoholic steatohepatitis (NASH) in a patient in need, which is characterized in that the patient is administered a pharmaceutical composition or pharmaceutical dosage form, as defined below.

In one embodiment, the compounds according to the invention can be used to treat NASH with fibrosis, eg F1-F4.

In another embodiment, the compounds of the invention may be used to treat cirrhosis with and without clinically significant portal hypertension.

In another embodiment, the invention relates to the treatment of NASH compensated cirrhosis patients with clinically significant portal hypertension (CSPH). Portal venous pressure is the blood pressure in the portal vein of the liver, which is usually 5-10 mm Hg. Art. Increased pressure in the portal venous system is called portal hypertension and has numerous consequences such as ascites and hepatic encephalopathy. In one embodiment of the invention, CSPH is defined as a hepatic venous pressure gradient (HVPG) >10 mm/Hg. Accordingly, another embodiment of the invention relates to the treatment of patients with compensated NASH cirrhosis with a venous pressure gradient (HVPG) >10 mm/Hg.

In another embodiment, the invention relates to the treatment of portal hypertension in patients with cirrhosis of the liver, when the cirrhosis is due to any etiology (cirrhosis from any cause). The etiology includes, but is not limited to, NASH, alcoholic liver disease (ALD), hepatitis C, hepatitis B, chronic primary biliary liver diseases (primary sclerosing cholangitis, primary biliary cirrhosis).

According to another aspect, the present invention relates to a method for the treatment of non-alcoholic steatohepatitis (NASH, NAS>4), in particular NASH with liver fibrosis, for example, NASH with liver fibrosis stages 2 and 3, in a patient in need thereof, which is characterized in that the patient is administered a pharmaceutical composition containing a compound of the invention or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API), preferably a pharmaceutical composition of the invention.

In one embodiment, the invention relates to the use of a compound according to the invention for the manufacture of a medicament for the treatment, prevention, or retardation of the progression of non-alcoholic steatohepatitis (NASH).

In one embodiment, the invention relates to a compound according to the invention for use in the treatment, prevention, or retardation of the progression of non-alcoholic steatohepatitis (NASH).

The effect of administering a certain pharmaceutical composition to a patient with NASH and/or hepatic fibrosis can be observed by a change, in particular a decrease in relevant biomarkers of liver inflammation and/or liver function, such as ALT (alanine aminotransferase), ACT (e.g., aspartate aminotransferase), AR (alkaline phosphatase), gamma-GT (gamma-glutamyltransferase), fragments of CK-18 (cytokeratin 18) or HVPG (hepatic vein pressure gradient).

In addition, the effect of administering said pharmaceutical composition to a patient with NASH and/or liver fibrosis can be seen to improve, for example, the degree or stage of steatosis, fibrosis, liver stiffness, or health-related quality of life.

These disorders are well characterized in humans but also exist with a similar etiology in other mammals and can be treated with the pharmaceutical compositions of the present invention.

For therapeutic use, the compounds of the invention may be administered via a pharmaceutical composition in any conventional pharmaceutical dosage form by any conventional route. Conventional dosage forms typically include a pharmaceutically acceptable carrier suitable for the particular dosage form chosen. Routes of administration include, without limitation, intravenous, intramuscular, subcutaneous, intrasynovial, infusion, sublingual, transdermal, oral, topical, or inhalation. Preferred routes of administration are oral and intravenous.

Preferred doses of the compound according to the invention for oral administration once a day are from 0.1 to 100 mg; or 1 to 25 mg; or 1 to 10 mg; or 2 to 5 mg. In another embodiment, the preferred doses of API for once daily oral administration are selected from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 mg.

The compounds of the present invention may be administered alone or in combination with adjuvants that enhance the stability of inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide additional therapy

- 43 042973 pyu and the like, including other active ingredients.

As indicated above, dosage forms according to the present invention may include pharmaceutically acceptable carriers and adjuvants known to the person skilled in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, buffer substances, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenge, syrup, reconstituted powder, granule, suppository, and transdermal patch. 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)). Dosage levels and requirements for the compounds of the present invention may be selected by those skilled in the art from the available methods and techniques appropriate for a particular patient. In some embodiments, dosage levels are in the range of about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be administered. For oral doses, up to 2000 mg/day may be required. One of skill in the art will appreciate that lower or higher doses may be required depending on specific factors. For example, specific dosage and treatment regimens will depend on such factors as the general health profile of the patient, the severity and course of the patient's disorder or predisposition to it, and the judgment of the attending physician.

In one embodiment, for example, multiple compounds of the present invention may be administered. Advantageously, these combination therapies use lower dosages of conventional therapeutic agents, thus avoiding the potential toxicity and adverse side effects associated with using these agents as monotherapy. The compounds according to the invention can be physically combined with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. The compounds can then preferably be administered together in the same dosage form. In some embodiments, pharmaceutical compositions containing such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula of the invention (w/w), or a combination thereof. The optimal percentage (w/w) of the compound according to the invention may vary and is within the skill of the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants may be administered separately (either sequentially or in parallel). Separate dosing provides more flexibility in the dosing regimen.

Compounds of the present invention may be administered in combination with compounds to improve the metabolic (eg, obesity, diabetes, inflammation) condition of a patient. Non-limiting examples of such compounds include, for example, SGLT2 inhibitors (eg, empagliflozin, dapagliflozin, and canagliflozin), DPP-IV inhibitors (eg, linagliptin, sitagliptin, saxagliptin, vildagliptin, and alogliptin), and glitazones/thiazolidinediones (eg, pioglitazone and rosiglitazone).

The compounds of the present invention may also be administered in combination with compounds useful in the treatment of NASH, including metabolic modulators, RAAS inhibitors, lipid modulators, antifibrotic agents, anti-inflammatory agents, and immunomodulatory agents. Non-limiting examples of such NASH combination partner partners include:

- 44 042973

PF-05221304 (Pfizer), obeticholic acid (Intercept), GS-0976 (Gilead),

GS-9674 (Gilead), LJN452 (Novartis), LMB763 (Novartis), MSDC0602K/metabolic solutions (Octeca), EDP-305 (Enanta), INT-767 (Intercept),

0304 (Betagenon), PF-06835919 (Pfizer), semaglutide (Novo Nordisk), BMS-986036 (BMS), NGM282 (NGM), BMS-986171 (BMS), PF-06865571 (Pfizer), LIK066 (Novartis), ORMD 0801 (Oramed), CER-209 (Cerenis), TVB-2640 (3-V Bioscience),

DS102 (Afimmune), MGL-3196 (Madrigal, Roche), VK2809 (Viking), volixibate (Sanofi, Shire), IONIS-DGAT2Rx (lonis), AKCEA-ANGPTL3-LRx (Akcea), gemcaben (Gemphire), MT-3995 (Mitsubishi Tanabe), DUR-928 (Durect),

CORTI 18335 (Corcept), amacizumab (BirdRock/Janssen), elafibranor (Genfit),

GRI-0621 (GRI Bio), Seloncertib (Gilead), Cenicriviroc (Takeda, Allergan), JKB

121 (Taiwan), saroglitazar (Zydus), IMM-124E (Immuron), lanifibranor (IA337) (Inventiva), GR-MD-02 (Galectin), emrikasan (VAY785) (Novartis), tipelukast (Kyorin, MediciNova), BMS986263 (ND-L02-s201) (BMS), P F-06667272 (Pfizer), foralumab (Tiziana), and DRX-065 (DeuteRx).

In another embodiment, the component partners of the NASH treatment combinations are selected from the following:

acetyl-CoA carboxylase (ACC) inhibitors (eg, GS-0976);

copper 3 (AOC3) amine oxidase inhibitors (eg BI 1467335 (formerly known as PXS-4728A));

farnesoid X receptor (FXR) agonists (eg, obeticholic acid);

apoptosis signal-regulating kinase 1 (ASK1) inhibitors (eg, seloncertib); antagonists of C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) (for example, ceniriviroc); caspase inhibitors (eg emrikasan);

peroxisome proliferator-activated receptor (PPAR) gamma agonists (eg, elafibranor);

stearoyl-CoA desaturase-1 inhibitors (eg, aramchol);

vascular adhesion protein-1 (VAP-1) inhibitors (eg, PXS4728A); and pioglitazone/vitamin.

Assessment of biological activity.

Cirrhotic portal hypertension.

Compounds according to the invention can be tested in a rat model of cirrhosis of portal hypertension (PHT) with bile duct ligation (BDL) to show their utility in the treatment of diseases with portal hypertension or liver fibrosis/cirrhosis such as non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), or any other etiology. The compound according to the invention (3 and 10 mg/kg) or vehicle (VEH) is administered via gavage twice daily for 2-4 weeks (BDL). Mean arterial pressure (MAP), heart rate (HR), pressure in the portal vein system (PP) are measured. Liver fibrosis is quantified by hydroxyprol (HP) content and chromaniline blue (CAB) staining. Hepatic transaminases (ALT and ACT) and the target biomarker, hepatic cGMP, can also be measured.

Changes in hydroxyproline concentration, fibrosis area (chromaniline stain), portal venous pressure, and/or liver transaminases demonstrate that the compounds of the invention can be used to treat diseases with portal hypertension or liver fibrosis/cirrhosis, such as non-alcoholic steatohepatitis ( NASH), alcoholic steatohepatitis (ASH) and chronic liver disease of any other etiology.

Claims (8)

1. A method of treating, preventing or slowing the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension, which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from the group consisting of compounds No. 18, 27, 84, 114, 133, 134, 136, 148, 154, 165 and 167: - 45 042973 - 46 042973 167, or its salts. 2. The method of claim 1 for treating, preventing, or slowing the progression of NASH. 3. The method according to claim 1 for treating, preventing or slowing the progression of portal hypertension in patients with cirrhosis of the liver, when cirrhosis is due to any etiology (cirrhosis from any cause). 4. The method of claim 2 or 3, wherein the compound is compound 114. 5. Use of a compound selected from the group consisting of compounds No. 18, 27, 84, 114, 133, 134, 136, 148, 154, 165 and 167: - 47 042973 - 48 042973 167, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention, or retardation of the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension. 6. The use according to claim 5 for the treatment, prevention or slowing of the progression of portal hypertension in patients with cirrhosis of the liver, when cirrhosis is due to any etiology (cirrhosis from any cause) and the compound is compound 114. 7. Use of a compound selected from the group consisting of compounds No. 18, 27, 84, 114, 133, 134, 136, 148, 154, 165 and 167: - 49 042973 167, - 50 042973 or a pharmaceutically acceptable salt thereof, for the treatment, prevention or slowing of the progression of non-alcoholic steatohepatitis (NASH) or portal hypertension. 8. The use according to claim 7 for the treatment, prevention or slowing of the progression of portal hypertension in patients with cirrhosis of the liver, when cirrhosis is due to any etiology (cirrhosis from any cause) and the compound is compound 114.