WO2021245192A1 - Nouveaux activateurs de la guanylate cyclase soluble à double mode d'action et inhibiteurs de phosphodiestérase et leurs utilisations - Google Patents

Nouveaux activateurs de la guanylate cyclase soluble à double mode d'action et inhibiteurs de phosphodiestérase et leurs utilisations Download PDF

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WO2021245192A1
WO2021245192A1 PCT/EP2021/064917 EP2021064917W WO2021245192A1 WO 2021245192 A1 WO2021245192 A1 WO 2021245192A1 EP 2021064917 W EP2021064917 W EP 2021064917W WO 2021245192 A1 WO2021245192 A1 WO 2021245192A1
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ono
independently
formula
compound
dioxo
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Reto Naef
Hermann Tenor
Guido Koch
Christian Ludin
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Topadur Pharma Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutically useful compounds, in particular to compounds which are activators of the enzyme soluble guanylate cyclase (sGC) and at the same time inhibit cyclic guanosine 3 ',5 '-monophosphate phosphodiesterases (cGMP PDEs), in particular type 5 cyclic guanosine 3 ',5 '-monophosphate phosphodiesterase (cGMP PDE5).
  • sGC enzyme soluble guanylate cyclase
  • cGMP PDEs cyclic guanosine 3 ',5 '-monophosphate phosphodiesterases
  • cGMP PDE5 type 5 cyclic guanosine 3 ',5 '-monophosphate phosphodiesterase
  • the compounds of the present invention have utility in a variety of therapeutic areas, including male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes, wound healing, in particular chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer, and particularly for ophthalmic diseases like gla
  • Phosphodiesterases are enzymes that catalyzes the hydrolysis and thus the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and thereby regulates intracellular levels of second messengers. Inhibition of PDEs leads to increasing intracellular concentrations of endogenous cAMP/cGMP. Therefore, inhibition of PDE can mediate a variety of physiological mechanisms at different cell and organ levels.
  • Phosphodiesterase type 5 hydrolyses cyclic guanylate monophosphate (cGMP) specifically to 5' GMP.
  • cGMP cyclic guanylate monophosphate
  • the selective inhibition of PDE5 has been validated as a relevant approach and strategies directed to promote inhibition of PDE5 activity have been applied and suggested as therapeutic tools, in particular, in neuronal and cardiovascular conditions and cancer such as breast and gastrointestinal cancers, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and head and neck squamous cell carcinoma, colon and rectal cancers such as colorectal cancer, and prostate and pancreatic cancers, and colorectal cancer.
  • neuronal and cardiovascular conditions and cancer such as breast and gastrointestinal cancers, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and head and neck squamous cell carcinoma, colon and rectal cancers such as colorectal cancer, and
  • PDE5 inhibitors have revolutionized the treatment of male erectile dysfunction (MED) (Dobhal T, Kaur S, Prakash Sharma O, Hari Kumar SL, Critical Review in Pharmaceutical Sciences (2012) 1(3): 13-27).
  • MED male erectile dysfunction
  • PDE5 inhibitors are on the market and are characterized particularly for MED or pulmonary hypertension (PH), in particular pulmonary artery hypertension (PAH) (Papapetropoulos A, Hobbs AJ, Topouzis S, British Journal of Pharmacology (2015) 172:1397-1414; Monica FZ, Murad F, Bian K, OA Biochemistry (2014) Mar 11; 2(1):3; Beedimani RS, Kalmath B, Int J Pharm Bio Sci (2014) 5(2): 530-539; Wronski S, Cent European J Urol (2014) 67: 314-318; Barone I et al.
  • PDE5 inhibitors are Sildenafil, Tadalafil, Vardenafil and Mirodenafil which have been described among others, for example, in WO 99/24433, WO 01/60825, EP 995’751 and WO 2011/075655. Recently, a novel class of very potent PDE5 inhibitors has been described (WO 2017/085056 Al).
  • Endothelial dysfunction leads to an imbalance of vasodilator and vasoconstrictor mediators shifted towards the latter.
  • One key mechanism remains impaired endothelial NO generation and associated, reduced activation of soluble guanylyl cyclase (sGC) in adjacent smooth muscle cells.
  • sGC soluble guanylyl cyclase
  • Strategies to increase disturbed cGMP levels by enhancing cGMP in vascular smooth muscle by improving cGMP synthesis and inhibiting its degradation have been described. Examples are combinations of sGC stimulators or activators in combination with PDE5 inhibitors, for example WO 2010/081647 or US2002/0182162.
  • dual-pharmacology compounds of the present invention designed as NO-releasing PDE5 inhibitors believed to release NO in addition to its PDE5 inhibition modulate cGMP levels in a more than additive, thus, synergistic fashion.
  • the synergistic increase of cGMP results in highly potent vasodilatation, angiogenesis, enhanced microcirculation and inhibition of endothelial dysfunction (see Fig. 1).
  • the dual pharmacology NO-releasing PDE5 inhibitors of the present invention are expected to be especially beneficial in treating disorders where NO production is diminished such as in conditions of endothelial dysfunction.
  • the inventive dual-pharmacology NO- releasing PDE5 inhibitors are further believed to be highly beneficial for the treatment of diabetic patients.
  • the compounds of the present invention show even a significantly higher efficacy to elevate intracellular cGMP as compared to known PDE5 inhibitors such as tadalafil.
  • PDE5 inhibitors such as tadalafil.
  • the compounds of the present invention are useful in the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance.
  • cGMP levels are elevated, which in turn can give rise to beneficial vasodilatory, anti-vasospastic, anti-platelet, natriuretic and diuretic activities.
  • the dual-pharmacology NO-releasing PDE5 inhibitors allows the release of nitric oxide for activating the soluble guanylate cyclase as well as the PDE5 inhibition in a more than additive fashion.
  • the compounds of the present innovation increase intracellular cGMP levels in human trabaecular meshwork cells (HTMC) even much more compared to tadalafil as depicted in FIG. 2.
  • inventive compounds particularly contain least one covalently bound ONO 2 or ONO moiety and at most four, preferably at most three covalently bound ONCE or ONO moieties.
  • inventive compounds of the present invention function as prodrugs since inside the cell, the nitrate moiety is believed to be metabolically activated to the respective alcohol (PDE antagonist) and nitric oxide (sGC activation) representing the active entites.
  • the compounds of the present invention have utility in a variety of therapeutic areas, including male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes, wound healing, in particular chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer, and particularly for ophthalmic diseases like gla
  • the present invention provides for a compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula I comprises at least one covalently bound ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties, and wherein AR represents benzene or pyridine, each optionally substituted by 1 to 4 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 - C 3 alkyl, C 1 -C 3 alkoxy;
  • R 1 is selected from hydrogen; halogen; C 1- 8 alkyl, C 1- 8 alkenyl, C 1- 8 alkynyl, C 1- 8 alkoxy, C 1 - 8 haloalkyl, C 1- 8 haloalkenyl, C 1- 8 haloalkynyl, each optionally substituted by 1 to 4 R 6 ; aryl; heteroaryl; aryl or heteroaryl, each independently substituted by halogen; C 1- 8 alkyl, C 1- 8 alkenyl, C 1- 8 alkynyl, C 1- 8 haloalkyl, C 1- 8 haloalkenyl, C 1- 8 haloalkynyl, each optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; or wherein R 1 represents Zl-Cycle-P, wherein Z1 is selected from a bond; C 1-4 alkylene, C 1 - 4 alkenylene, C
  • X represents CHR 2 or a bond; wherein R 2 is selected from hydrogen; halogen; C 1- 8 alkyl, C 1 - 8 alkenyl, C 1- 8 alkynyl, C 1- 8 alkoxy, C 1- 8 haloalkyl, C 1- 8 haloalkenyl, C 1- 8 haloalkynyl, each optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ;
  • R 3 is selected from the group consisting of a monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan, and pyridine, each optionally substituted by 1 to 2 R 7 , and a bicyclic ring of the formula wherein the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen, each optionally substituted by 1 to 2 R 7 , wherein said R 7 is independently at each occurrence selected from halogen, OH, C 1-4 alkyl and C 1-4 alkoxy; and wherein said bicyclic ring is attached to the rest of the compound of formula I by a phenyl ring carbon atom; and R 4 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy.
  • the present invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the inventive compounds of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient, adjuvant, or carrier.
  • the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use as a medical treatment.
  • the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal, preferably in a human, wherein preferably said disease is selected from male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular vascular end
  • the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or in a non-human mammal, preferably in a human, wherein said disease is selected from male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud
  • FIG. 1 PDE5 inhibition and activation of soluble guanylate cyclase from one molecule.
  • FIG. 2 Action of compounds of the present invention on total cGMP levels in Human trabecular meshwork cells (HTMC) compared to Tadalafil.
  • HTMC Human trabecular meshwork cells
  • the compounds of the present invention are dualpharmacology NO-releasing PDE5 inhibitors believed to release NO in addition to its PDE5 inhibition resulting in a more than additive stimulation of intracellular cGMP elevation. Moreover, the compounds of the present invention show even a significantly higher efficacy to stimulate cGMP as compared to known single pharmacology PDE5 inhibitors such as tadalafil.
  • the present invention provides for a compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula I comprises at least one covalently bound ONO 2 or ONO moiety, and preferably at most four, further preferably at most three covalently bound ONO 2 or ONO moieties, and wherein AR represents benzene or pyridine, each optionally substituted by 1 to 4 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 - C 3 alkyl, C 1 -C 3 alkoxy; R 1 is selected from hydrogen; halogen; C 1- 8 alkyl, C 1- 8 alkenyl, C 1- 8 alkynyl, C 1- 8 alkoxy, C 1 - «haloalkyl, C 1- 8 haloalkenyl, C 1- 8 haloalkynyl, each optionally substituted by 1 to 4 R 6
  • X represents CHR 2 or a bond; wherein R 2 is selected from hydrogen; halogen; C 1- 8 alkyl, C 1 - xalkenyl, C 1 -xalkynyl, C 1 -xalkoxy, C 1- 8 haloalkyl, C 1- 8 haloalkenyl, C 1- 8 haloalkynyl, each optionally substituted by 1 to 4 R 6 ; wherein said R6 is independently at each occurrence selected from OH, ONO, ONO 2 ; R 3 is selected from the group consisting of a monocyclic aromatic ring selected from the group consisting of benzene, thiophene, furan, and pyridine, each optionally substituted by 1 to 2 R 7 , and a bicyclic ring of the formula wherein the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen, each
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having typically and preferably from one to eight carbon atoms ( e.g ., (C 1- 8 alkyl), and which typically is attached to the rest of the molecule by a single bond. Whenever it appears herein, a numerical range such as “1 to 8” refers to each integer in the given range.
  • alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are not limited to methyl, ethyl, «-propyl, prop-2-yl, «-butyl, but-2-yl, 2-methyl-prop- 1-yl or 2-methyl-prop-2-yl.
  • alkoxy refers to a "substituted hydroxyl" of the formula (-OR), wherein R is an “alkyl”, as defined herein, and the oxygen moiety is directly attached to the parent molecule, and thus the term “C 1- 8 alkoxy”, as used herein, refers to straight chain or branched C 1- 8 alkoxy which may be, for example, methoxy, ethoxy, propoxy, ipropoxy, n- butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neo-pentoxy, //-hexoxy. As described herein, alkoxy may include further substitutents such as halogen atoms leading to haloalkoxy moieties.
  • alkylene refers to a straight or branched hydrocarbon chain biradical derived from alkyl, as defined herein, wherein one hydrogen of said alkyl is cleaved off generating the second radical of said alkylene.
  • alkylene are, by way of illustration, - CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, or -CH(CH 2 CH 3 )-.
  • Each alkenyl moiety either alone or as part of a larger moiety such as alkenyloxy or alkenylene is a straight or branched chain and is preferably C 2 -C 6 alkenyl, more preferably C 2 - C4alkenyl.
  • Each moiety can be of either the (E)- or (Z)-configuration. Examples include vinyl and allyl.
  • a compound of the present invention comprising an alkenyl moiety thus may include, if applicable, either said compound with said alkenyl moiety in its (A)-configuration, said compound with said alkenyl moiety in its ( ⁇ -configuration and mixtures thereof in any ratio.
  • Alkenyl groups thus, contain at least one, typically one, carbon-carbon double bond.
  • alkynyl are defined identically as “alkyl,” except for containing at least one, typically one, carbon-carbon triple bond, respectively.
  • ONO 2 refers to the nitrate moiety *-0-N0 2 as described herein, wherein the * indicates the attachment to the parent structure and rest of the molecule.
  • said ONO 2 is a terminal ONO 2 substituent.
  • ONO refers to the nitrite moiety *-0-N0 as described herein, wherein the * indicates the attachment to the parent structure and rest of the molecule.
  • said ONO is a terminal ONO substituent.
  • halo or halogen is defined herein to include fluorine, bromine, chlorine, and iodine.
  • haloalkyl is defined herein as an alkyl group substituted with one or more halo substituents, either fluoro, chloro, bromo, or iodo.
  • haloalkyl moiety either alone or as part of a larger moiety such as haloalkoxy is an alkyl moiety substituted by one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.
  • haloalkenyl and “haloalkynyl” are defined identically as “haloalkyl,” except for containing at least one, typically one, carbon- carbon double bond or carbon-carbon triple bond, respectively.
  • carbocyclic ring refers to a saturated or partially unsaturated mono-cyclic ring formed by 3 to 8 carbon atoms, more preferably 3 to 7 carbon atoms.
  • saturated carbocyclic rings include cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • heterocyclic ring refers to a saturated or partially unsaturated carbocyclic ring containing one to four heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring.
  • Preferred examples are aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, tetrahydrofurane, dioxane, 2,5- diazabicyclo[2,2,l]heptane and 3,7-diazabicyclo[3,3,0]octane, and further preferred are aziridine, azetidine, pyrollidine, piperidine, morpholine, piperazine, homopiperazine, 2,5- diazabicyclo[2,2,l]heptane and 3,7-diazabicyclo[3,3,0]octane.
  • aryl alone or in combination, is defined herein as a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl.
  • an "aryl” group can be unsubstituted or substituted, for example, with one or more, and in particular one to three, halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, cyano, nitro, amino, alkylamino, acylamino, alkylthio, alkyl sulfinyl, and alkyl sulfonyl.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2 -methylphenyl, 4- methoxyphenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, and the like.
  • aryl C 1-3 alkyl and “heteroarylC 1 -3alkyl” are defined as an aryl or heteroaryl group having a C 1-3 alkyl substituent.
  • heteroaryl is defined herein as a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino,.
  • heteroaryl groups include thienyl, furyl, pyridyl, oxazolyl, quinolyl, isoquinolyl, indolyl, triazolyl, isothiazolyl, isoxazolyl, imidizolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • hydroxy is defined as -OH.
  • trifluoromethyl is defined as -CF 3.
  • a moiety is said to be substituted or optionally substituted, preferably there are 1-5 substituents or optionally 1-5 substituents, more preferably 1-4 substituents or optionally 1-4 substituents, or alternatively or preferably 1-3 substituents or optionally 1-3 substituents, again alternatively or preferably 1 or 2 substituents or optionally 1 or 2 substituents, unless it is specifically indicated a different preferred number of substitutions or optional substitutions.
  • a moiety is said to be substituted or optionally substituted, and where there are more than one substituent for said substitution or said optional substitution of said moiety, said more than one substituents can either be the same or different.
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
  • the term “chiral” refers to molecules which have the property of non- superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.
  • Enantiomers are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic” mixture. The term is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • Certain compounds of formula I of the present invention may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio.
  • the compounds of the invention also include all tautomeric forms of the compounds of formula I.
  • the compounds of formula I may also be solvated, especially hydrated, which are also included in the compounds of formula I. Solvation and hydration may take place during the preparation process.
  • the compounds of the present invention and, thus, the compounds of formula I include stereoisomers, geometric isomers and tautomers. Furthermore, the compounds of the present invention and, thus, the compounds of formula I include solvates or hydrates, pharmaceutically acceptable salts, and solvates or hydrates of the salts thereof.
  • compositions of formula I of the present invention include pharmaceutically acceptable salts of said compounds.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of the present invention, in particular acid addition salts.
  • Exemplary salts include, but are not limited to, salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or salts of organic acids, such as methane-sulfonic acid, / oluenesulfonic acid, lactic acid, malic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid
  • organic acids such as methane-sulfonic acid, / oluenesulfonic acid, lactic acid, malic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • pharmacologically acceptable salts of the compounds of formula I are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
  • alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
  • compositions of formula I include the hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogen phosphate, nitrate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, benzenesulphonate, p-toluenesulphonate or the like.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine.
  • DMSO dimethyl sulfoxide
  • hydrate refers to the complex where the solvent molecule is water.
  • said compound of formula I comprises at least one covalently bound ONCE or ONO moiety and at most four covalently bound ONO 2 or ONO moieties. In a further preferred embodiment, said compound of formula I comprises at least at least two covalently bound ONO 2 or ONO moiety and at most four covalently bound ONO 2 or ONO moieties. In a preferred embodiment, said compound of formula I comprises at least at least one covalently bound ONO 2 or ONO moiety and at most three covalently bound ONO 2 and ONO moieties. In a preferred embodiment, said compound of formula I comprises at least at least two covalently bound ONO 2 or ONO moiety and at most three covalently bound ONO 2 and ONO moieties. In another preferred embodiment, said compound of formula I comprises at most four covalently bound ONO 2 or ONO moieties. In another preferred embodiment, said compound of formula I comprises at most three covalently bound ONO 2 and ONO moieties.
  • said of compound of formula I comprises exactly one covalently bound ONO 2 moiety. In another preferred embodiment, said compound of formula I comprises exactly one covalently bound ONO moiety. In another preferred embodiment, said compound of formula I comprises exactly two covalently bound ONO 2 or two covalently bound ONO moieties. In another preferred embodiment, said compound of formula I comprises exactly two covalently bound ONO 2 moieties. In another preferred embodiment, said compound of formula I comprises exactly two covalently bound ONO moieties. In another preferred embodiment, said compound of formula I comprises exactly one covalently bound ONO 2 moiety and one covalently bound ONO moiety. In another preferred embodiment, said compound of formula I comprises exactly three covalently bound ONO 2 or three covalently bound ONO moieties.
  • said compound of formula I comprises exactly three covalently bound moieties selected from ONO 2 and ONO moieties. In another preferred embodiment, said compound of formula I comprises exactly four covalently bound ONO 2 or four ONO moieties. In another preferred embodiment, said compound of formula I comprises exactly four covalently bound moieties selected from ONO 2 and ONO moieties.
  • said compound of formula I comprises at least at least one covalently bound ONO 2 and at most four covalently bound ONO 2 moieties. In a further preferred embodiment, said compound of formula I comprises at least at least two covalently bound ONO 2 moiety and at most four covalently bound ONO 2 moieties. In a preferred embodiment, said compound of formula I comprises at least at least one covalently bound ONO 2 moiety and at most three covalently bound ONO 2 moieties. In a preferred embodiment, said compound of formula I comprises at least at least two covalently bound ONO 2 moiety and at most three covalently bound ONO 2 moieties. In another preferred embodiment, said compound of formula I comprises at most four covalently bound ONO 2 moieties. In another preferred embodiment, said compound of formula I comprises at most three covalently bound ONO 2 moieties.
  • At least one of said R1 or R2 independently of each other comprises at least at least one covalently bound ONO 2 or ONO moiety and at most four covalently bound ONO 2 or ONO moieties. In a further preferred embodiment, at least one of said R1 or R2 independently of each other comprises at least at least two covalently bound ONO 2 or ONO moiety and at most four covalently bound ONO 2 or ONO moieties. In a preferred embodiment, at least one of said R1 or R2 independently of each other comprises at least at least one covalently bound ONO 2 or ONO moiety and at most three covalently bound ONO 2 and ONO moieties.
  • At least one of said R1 or R2 independently of each other comprises at least at least two covalently bound ONO 2 or ONO moiety and at most three covalently bound ONO 2 and ONO moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises at most four covalently bound ONO 2 or ONO moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises at most three covalently bound ONO 2 and ONO moieties.
  • At least one of said R1 or R2 independently of each other comprises at least at least one covalently bound ONO 2 and at most four covalently bound ONO 2 moieties. In a further preferred embodiment, at least one of said R1 or R2 independently of each other comprises at least at least two covalently bound ONO 2 moiety and at most four covalently bound ONO 2 moieties. In a preferred embodiment, at least one of said R1 or R2 independently of each other comprises at least at least one covalently bound ONO 2 moiety and at most three covalently bound ONO 2 moieties.
  • At least one of said R1 or R2 independently of each other comprises at least at least two covalently bound ONO 2 moiety and at most three covalently bound ONO 2 moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises at most four covalently bound ONO 2 moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises at most three covalently bound ONO 2 moieties.
  • At least one of said R1 or R2 independently of each other comprises exactly one covalently bound ONO 2 moiety. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly one covalently bound ONO moiety. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly two covalently bound ONO 2 or two covalently bound ONO moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly two covalently bound ONO 2 moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly two covalently bound ONO moieties.
  • At least one of said R1 or R2 independently of each other comprises exactly one covalently bound ONO 2 moiety and one covalently bound ONO moiety. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly three covalently bound ONO 2 or three covalently bound ONO moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly three covalently bound moieties selected from ONO 2 and ONO moieties. In another preferred embodiment, at least one of said R1 or R2 independently of each other comprises exactly four covalently bound ONO 2 or four ONO moieties.
  • At least one of said R1 or R2 independently of each other comprises exactly four covalently bound moieties selected from ONO 2 and ONO moieties.
  • said X is CHR 2.
  • said compound of formula l is a compound of formula II
  • said X is CHR 2 and said compound of formula I is a compound of formula II*
  • said X is CHR 2. and said R 2 is R 21 , and said compound of formula l is a compound of formula III wherein said R 21 is hydrogen or methyl. In another preferred embodiment, said R 21 is hydrogen.
  • said X is CHR 2. and said R 2 is R 21 , and said compound of formula l is a compound of formula III* wherein said R 21 is hydrogen or methyl. In another preferred embodiment, said R 21 is hydrogen.
  • said X is CHR 2 .and said R 1 is Rn, and said compound of formula l is a compound of formula IV wherein said Rn is hydrogen or methyl. In another preferred embodiment, said Rn is hydrogen. In another preferred embodiment, said Rn is methyl.
  • said X is CHR 2 .and said R 1 is Rn, and said compound of formula l is a compound of formula IV* wherein said Rn is hydrogen or methyl. In another preferred embodiment, said Rn is hydrogen. In another preferred embodiment, said Rn is methyl.
  • said X is a bond and said compound of formula I is a compound of formula V
  • said X is a bond and said compound of formula I is a compound of formula V*
  • said AR is selected from the following structures wherein the * denotes the atoms common with the pyrrol moiety of formula I. In a preferred embodiment, said AR is selected from the following structures wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is benzene or pyridine, each optionally substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 - Cihaloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is benzene or pyridine, each optionally substituted with 1 to 3 R 5 , wherein said R 3 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is benzene or pyridine, each optionally substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is benzene or pyridine, each optionally substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from F and methyl.
  • said pyridine is wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is benzene or pyridine, each optionally substituted with 1 or 2 R 5 , wherein said R 3 is independently at each occurrence selected from halogen, C 1 - C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is benzene or pyridine, each optionally substituted with 1 or 2 R 5 , wherein said R 3 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is benzene or pyridine, each optionally substituted with 1 or 2 R 5 , wherein said R 5 is independently at each occurrence selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is benzene or pyridine, each optionally substituted with 1 or 2 R 5 , wherein said R 5 is independently at each occurrence selected from F and methyl.
  • said pyridine is wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is benzene or pyridine, each optionally substituted with one R 5 , wherein said R 5 is selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 - C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is benzene or pyridine, each optionally substituted with one R 5 , wherein said R 3 is selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is benzene or pyridine, each optionally substituted with one R 5 , wherein said R 5 is selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is benzene or pyridine, each optionally substituted with one R 5 , wherein said R 5 is independently at each occurrence selected from F and methyl.
  • said pyridine is wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is benzene or benzene substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is benzene or benzene substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is benzene or benzene substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from F, Cl, Br, methyl, ethyl, methoxy. In a preferred embodiment, said AR is benzene or benzene substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from F and methyl.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from F and methyl.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 3 is F.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 3 is independently at each occurrence selected from F, Cl and methyl.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from F and Cl.
  • said AR is benzene or benzene substituted with 1 to 2 R 5 , wherein said R 5 is Cl.
  • said AR is benzene , wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is benzene or benzene substituted with one R 5 , wherein said R 5 is selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -
  • said AR is benzene or benzene substituted with one R 5 , wherein said R 5 is selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is benzene or benzene substituted with one R 5 , wherein said R 5 is selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is benzene or benzene substituted with one R 5 , wherein said R 5 is independently at each occurrence selected from F and methyl.
  • said AR is pyridine or pyridine substituted with 1 to 3 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is pyridine or pyridine substituted with 1 to 3 R 5 , wherein said R 3 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is pyridine or pyridine substituted with 1 to 3 R 5 , wherein said R 3 is independently at each occurrence selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is pyridine or pyridine substituted with 1 to 3 R 5 , wherein said R 3 is independently at each occurrence selected from F and methyl.
  • said pyridine is wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is pyridine or pyridine substituted with 1 or 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • said AR is pyridine or pyridine substituted with 1 or 2 R 5 , wherein said R 3 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is pyridine or pyridine substituted with 1 or 2 R 5 , wherein said R 3 is independently at each occurrence selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is pyridine or pyridine substituted with 1 or 2 R 5 , wherein said R 3 is independently at each occurrence selected from F and methyl.
  • said pyridine is wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said AR is pyridine or pyridine substituted with one R 5 , wherein said R 5 is selected from halogen, C 1 -C 2 haloalkyl, preferably CF 3 , C 1 -C 3 alkyl, C 1 - C 3 alkoxy.
  • said AR is pyridine or pyridine substituted with one R 5 , wherein said R 5 is selected from halogen, CF 3 , C 1 -C 2 alkyl, C 1 -C 2 alkoxy.
  • said AR is pyridine or pyridine substituted with one R 5 , wherein said R 3 is selected from F, Cl, Br, methyl, ethyl, methoxy.
  • said AR is pyridine or pyridine substituted with one R 5 , wherein said R 3 is independently at each occurrence selected from F and methyl.
  • said pyridine is wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R2 is selected from hydrogen; halogen; C 1- 8 alkyl, C 1- 8 alkenyl, C 1- 8 alkynyl, C 1- 8 alkoxy, C 1 -xhaloalkyl, C 1 -xhaloalkenyl, C 1 -xhaloalkynyl, each optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said X is CHR2 and said R2 is selected from hydrogen; halogen; C 1 -xalkyl, C 1 -xalkenyl, C 1 -xalkynyl, C
  • said R2 is selected from hydrogen; C 1 -xalkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said X is CHR 2 and said R 2 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 2 is selected from hydrogen; C 1-6 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 2 is selected from hydrogen; C 1-4 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said X is CHR 2 and said compound of formula I is a compound of formula II* and said R 2 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO,
  • said X is CHR 2 and said compound of formula I is a compound of formula IV* and said R 2 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said compound of formula I is a compound of formula II, a compound of formula III, a compound of formula IV or a compound of formula V, and wherein said R 1 or said R 2 comprises at least one ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula II*, a compound of formula III*, a compound of formula IV* or a compound of formula V*, and wherein said R 1 or said R 2 comprises at least one ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula III, a compound of formula IV or a compound of formula V, and wherein said R 1 or said R 2 comprises at least one ONO 2 or ONO moiety and at most three, preferably at most two, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula III*, a compound of formula IV* or a compound of formula V*, and wherein said R 1 or said R 2 comprises at least one ONO 2 or ONO moiety and at most three, preferably at most two, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula IV, and wherein said R 2 comprises at least one ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula IV*, and wherein said R 2 comprises at least one ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula III or a compound of formula V, and wherein said R 1 comprises at least one ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties.
  • said compound of formula I is a compound of formula III* or a compound of formula V*, and wherein said R 1 comprises at least one ONO 2 or ONO moiety and at most four, preferably at most three, covalently bound ONO 2 or ONO moieties.
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is selected from a bond; C 1 - 4 alkylene, C 1-4 alkenylene, C 1-4 alkynylene, C 1-4 haloalkylene, C 1-4 haloalkenylene, C 1 - 4 haloalkynylene, each optionally substituted by 1 to 2 R 6 ; wherein Cycle-P is a saturated 3- to 8- membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, aziridine, oxirane, azetidine, oxet
  • said R 1 is selected from hydrogen; C 1 -xalkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is selected from a bond; C 1 - 2 alkylene, C 1-2 alkenylene, C 1-2 alkynylene, C 1-2 haloalkylene, C 1-2 haloalkenylene, C 1 - 2 haloalkynylene, each optionally substituted by 1 to 2 R 6 ; wherein Cycle-P is a saturated 3- to 8- membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, aziridine, oxirane, azetidine, ox
  • said R 1 is selected from hydrogen; C 1 -xalkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is selected from a bond; C 1 - 2alkylene optionally substituted by 1 to 2 R 6 ; wherein Cycle-P is a saturated 3- to 8-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, pipe
  • R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1 -xalkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is selected from a bond; C 1 - 2alkylene optionally substituted by 1 to 2 R 6 ; wherein Cycle-P is a saturated 3- to 6-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine,
  • R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1 -xalkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is selected from a bond; C 1 - 2alkylene; wherein Cycle-P is a saturated 3- to 6-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane,
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is selected from a bond or - CH 2 -; wherein Cycle-P is a saturated 3- to 6-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is preferably selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is selected from a bond or - CH 2 -; wherein Cycle-P is a saturated 3- to 6-membered carbocyclic ring or heterocyclic ring containing 1 or 2 heteroatoms independently selected from N and O, wherein said carbocyclic or said heterocyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carb
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 3- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 4 R (
  • said R 1 is selected from hydrogen; C 1 -xalkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence
  • said R 1 is selected from hydrogen; C 1- 8 al kyl , optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1- 8 al kyl or C 1- 8 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substitute
  • said R 1 is selected from hydrogen; Ci ⁇ alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl- Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 2 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO CH 2 CH 2 CH
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO.
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl, C 1-6 alkyene-OH, C 1-6 alkyene-ONO, C 1-6 alkyene-ONO 2.
  • said R 1 is selected from C 1-6 alkyl substituted by 1 to 3 R 5 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-4 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, O
  • said R 1 is selected from C 1-6 alkyl substituted by 1 to 3 R 5 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cycl
  • said R 1 is selected from C 1-4 alkyl substituted by 1 to 2 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane,
  • said R 1 is selected from CH 2 ONO 2 , CH 2 ONO, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO, (CH 2 ) 4 ONO 2 , (CH 2 ) 4 ONO, (CH 2 ) 5 ONO 2 , (CH 2 ) 5 ONO, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 3 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2.
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, te
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydr
  • said R 1 is -Cycle-P, wherein Cycle-P is selected from
  • R6i is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 6 ; wherein said R6 is independently at each occurrence selected from OH, ONO, ONO 2 , and wherein preferably said R6i is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • said R 3 is selected from the group consisting of a monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, each optionally substituted by 1 to 2 R 7 , and a bicyclic ring selected from naphthalene, indene, benzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline, indole, benzothiophene, benzofuran, and a bicyclic ring structure of the formula wherein n is an integer 1 or 2, and G 1 , G 2 is independently selected from CH 2 , CHR 8 , O, S, NH and NR9, wherein said R 8 and R 9 is independently selected from C 1-3 alkyl and C 1-3 alkoxy, and wherein said bicyclic ring structure is attached to the rest of the compound of formula I by a phenyl ring carbon atom, and wherein each bicyclic ring is optionally substituted by
  • said R 3 is phenyl or a bicyclic ring of the formula wherein Gi, G2 is independently selected from CH 2 and O, wherein said bicyclic ring is attached to the rest of the compound of formula I by a phenyl ring carbon atom, and wherein said phenyl and bicyclic ring are optionally independently substituted by 1 to 2 R 7 , wherein said R 7 is independently at each occurrence selected from halogen, OH, C 1-2 alky 1 and C 1-2 alkoxy.
  • said R 3 is phenyl or a bicyclic ring selected from the formulas and , wherein the line denotes that said bicyclic ring is attached to the rest of the compound of formula I by a phenyl ring carbon atom, and wherein said phenyl and said bicyclic ring are optionally independently substituted by 1 to 2 R 7 , wherein said R 7 is independently at each occurrence selected from halogen, OH, C 1-2 alkyl and C 1-2 alkoxy.
  • said R 3 is phenyl or a bicyclic ring selected from the formulas and , wherein the line denotes that said bicyclic ring is attached to the rest of the compound of formula I by a phenyl ring carbon atom, and wherein said phenyl and said bicyclic ring are optionally independently substituted by 1 to 2 R 7 , wherein said R 7 is independently at each occurrence selected from F, methyl and methoxy.
  • said R 3 is phenyl; phenyl substituted by 1 to 2 R 7 , wherein said R 7 is independently at each occurrence selected from halogen, OH, C 1-2 alky 1 and C 1 -2alkoxy; or a bicyclic ring selected from the formulas
  • said R 3 is phenyl; phenyl substituted by methoxy, preferably phenyl substituted by methoxy at the /3 ⁇ 4/ra-position to the attachment to the rest of the compound of formula I, and a bicyclic ring selected from the formulas ,
  • said R4 is selected from hydrogen or methyl or ethyl. In another preferred embodiment, said R4 is selected from hydrogen or methyl. In another preferred embodiment, said R4 is methyl. In another preferred embodiment, said R4 is hydrogen.
  • said compound of formula I is a compound of formula wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, carbocyclic ring, or a fused 5- or 6-membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1 - 2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said compound of formula I is a compound of formula VII, a compound of formula VIII, a compound of formula IX or a compound of formula X wherein said Rn is hydrogen or methyl, wherein said R 21 is hydrogen or methyl, and wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 1 , R 2 and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said compound of formula I is a compound of formula
  • said compound of formula I is a compound of formula
  • said compound of formula I is a compound of formula
  • said compound of formula l is a compound of formula X.
  • said compound of formula I is a compound of formula VII*, a compound of formula VIII*, a compound of formula IX* or a compound of formula X* wherein said Rn is hydrogen or methyl, wherein said R21 is hydrogen or methyl, and wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 1 , R 2 and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said compound of formula I is a compound of formula VII*. In another preferred embodiment, said compound of formula I is a compound of formula VIII*. In another preferred embodiment, said compound of formula I is a compound of formula IX*. In another preferred embodiment, said compound of formula I is a compound of formula X*.
  • said compound of formula I is a compound of formula
  • R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1 - 2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, carbocyclic ring, or a fused 5- or 6-membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1 - 2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring
  • AR, R 1 , R 2 and R4 are as defined herein including any preferred embodiments.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R2 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 4 R 5 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6- membered carbocyclic ring or heterocyclic ring selected from, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine, dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 8 alkyl or C 1- 8
  • said compound of formula I is a compound of formula wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, carbocyclic ring, or a fused 5- or 6-membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1 - 2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring
  • AR, R 1 , R 2 and R 4 are as defined herein including any preferred embodiments.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 2 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6- membered carbocyclic ring or heterocyclic ring selected from, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine, dioxane, wherein said carbocyclic or said heterocyclic ring is independently optionally substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - «alkyl or C 1- 8
  • said X is CHR 2. and said R 2 is R 21 , and said compound of formula l is a compound of formula VIII, wherein said R21 is hydrogen or methyl and wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 1 , and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, carbocyclic ring, or a fused 5- or 6- membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said R21 is hydrogen.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle- P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 3- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl- Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine, dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - «alkyl or C 1- 8 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 -6alkyl or C 1-6 alkyl substituted by 1
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 6alkyl or C 1-6 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 2 R 5 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R6i, wherein said R6i is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 R 6 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO CH 2 CH 2 CH 2 O
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2
  • R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl, C 1-6 alkyene-OH, C 1-6 alkyene-ONO, C 1-6 alkyene-ONO 2.
  • said R 4 is selected from hydrogen or methyl.
  • said R 4 is methyl
  • said X is CHR 2. and said R 2 is R 21 , and said compound of formula l is a compound of formula VIII*, wherein said R21 is hydrogen or methyl and wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 1 , and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, carbocyclic ring, or a fused 5- or 6- membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said R 21 is hydrogen.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle- P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 3- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl- Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine, dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1
  • said R 1 is selected from hydrogen; C 1 -xalkyl, optionally substituted by 1 to 3 R 5 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - xalkyl or C 1. «al kyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 1 is selected from hydrogen; C 1. «al kyl, optionally substituted by 1 to 3 R 5 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 -6alkyl or C 1 -6alkyl substituted
  • said R 1 is selected from hydrogen; C 1. «al kyl , optionally substituted by 1 to 3 R 5 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 6alkyl or C 1 -6alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 2 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO CH 2 CH 2 CH 2
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl, C 1 - 6 alkyene-OH, C 1 - 6 alkyene-ONO, C 1 - 6 alkyene-ONO 2.
  • said R 4 is selected from hydrogen or methyl.
  • said R 4 is selected from hydrogen or methyl.
  • said R 4 is selected from hydrogen or methyl.
  • said R 4 is
  • said X is CHR 2. and said R 1 is Rn, and said compound of formula l is a compound of formula IX wherein said Rn is hydrogen or methyl, and wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 2 , and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, carbocyclic ring, or a fused 5- or 6- membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said R 11 is hydrogen.
  • said Rn is methyl.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 2 is selected from hydrogen; Ci ⁇ alkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from hydrogen; C 1-6 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from hydrogen; C 1-4 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from C 1-4 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from alkyl, optionally substituted by 1 R 6 ; wherein said R 6 is selected from OH, ONO, ONO 2 , wherein preferably said R 6 is ONO 2 .
  • said R 4 is selected from hydrogen or methyl. In another preferred embodiment, said R 4 is methyl. In another preferred embodiment, said R 4 is hydrogen.
  • said X is CHR 2 .and said R 1 is Rn, and said compound of formula l is a compound of formula IX* wherein said Rn is hydrogen or methyl, and wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1 - 3 alkyl and C 1 - 3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 2 , and R 4 are as defined herein including any preferred embodiments.
  • said R 3I , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 3I , R 32 represent a fused 5- or 6-membered saturated, carbocyclic ring, or a fused 5- or 6- membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 33 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 33 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 33 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 33 , R 3 ⁇ 4 represent a fused dioxolane ring.
  • said R 33 is methoxy
  • R 32 is hydrogen or wherein said R 33 , R 3 ⁇ 4 represent a fused dioxolane ring.
  • said Rn is hydrogen. In another preferred embodiment, said Rn is methyl.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 2 is selected from hydrogen; C 1-6 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from hydrogen; C 1-4 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from C 1-4 alkyl, optionally substituted by 1 to 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 2 is selected from C 1-4 alkyl, optionally substituted by 1 R 6 ; wherein said R 6 is selected from OH, ONO, ONO 2 , wherein preferably said R 6 is ONO 2 .
  • said R 2 is selected from hydrogen; Cnsalkyl, optionally substituted by 1 to 4 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 4 is selected from hydrogen or methyl. In another preferred embodiment, said R 4 is methyl. In another preferred embodiment, said R 4 is hydrogen.
  • said X is a bond and said compound of formula I is a compound of formula X wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 1 , and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alkyl and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, carbocyclic ring, or a fused 5- or 6-membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1 - 2alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said Rn is hydrogen.
  • said R 11 is methyl.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle- P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 3- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl- Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine, dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - «alkyl or C 1- 8 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 -6alkyl or C 1 -6alkyl substituted by
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 6alkyl or C 1-6 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 2 R 5 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO, C(OH)(CH 2 ONO 2 )CH 2 ONO,
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl, C 1-6 alkyene-OH, C 1-6 alkyene-ONO, C 1-6 alkyene-ONO 2.
  • said R 4 is selected from hydrogen or methyl.
  • said R 4 is methyl
  • said X is a bond and said compound of formula I is a compound of formula X* wherein said R 31 , R 32 are independently selected from hydrogen, OH, C 1-3 alkyl and C 1-3 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated carbocyclic ring, or a fused 5- or 6-membered saturated, partially unsaturated or fully unsaturated heterocyclic ring comprising one or two heteroatoms selected from sulfur, oxygen or nitrogen, and wherein AR, R 1 , and R 4 are as defined herein including any preferred embodiments.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alkyl and C 1-2 alkoxy or wherein said R 31 , R 32 represent a fused 5- or 6- membered saturated, carbocyclic ring, or a fused 5- or 6-membered saturated heterocyclic ring comprising one or two heteroatoms selected from oxygen or nitrogen.
  • said R 31 , R 32 are independently selected from hydrogen, OH, C 1-2 alky 1 and C 1 - 2 alkoxy or wherein said R 31 , R 32 represent a fused 5-membered saturated, carbocyclic ring, or a fused 5-membered saturated heterocyclic ring comprising one or two oxygen.
  • said R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring.
  • said R 31 is methoxy
  • R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring.
  • said Rn is hydrogen. In another preferred embodiment, said Rn is methyl.
  • said wherein said AR is selected from the following structures wherein each optionally substituted by 1 to 2 R 5 , wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and wherein the * denotes the atoms common with the pyrrol moiety of formula I.
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl-Cycle- P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 3- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, aziridine, oxirane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 4 R 6 ; or R 1 represents Zl- Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine, dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl optionally substituted by 1 to 4 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 4 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond or -CH 2 -, preferably Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - «alkyl or C 1- 8 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-6 alkyl or C 1-6 alkyl substituted by 1 to
  • said R 1 is selected from hydrogen; C 1- 8 alkyl, optionally substituted by 1 to 3 R 6 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 6alkyl or C 1-6 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen; C 1- 8 alkyl , optionally substituted by 1 to 2 R 5 ; or R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R6i, wherein said R6i is independently at each occurrence selected from C 1 -6alkyl or C 1 -6alkyl substituted by 1 to 3 R 6 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO .
  • CH 2 CH 2 CH 2 ONO 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO,
  • R 1 represents Zl-Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO CH 2 CH 2 CH 2 O
  • said R 1 is selected from hydrogen, CH 2 ONO 2 , CH 2 ONO, CH 2 OH, CH 2 CH 2 ONO 2 , CH 2 CH 2 ONO, CH 2 CH 2 OH, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 OH, CH 2 CH 2 CH 2 CH 2 ONO 2 , CH 2 CH 2 CH 2 ONO, CH 2 CH 2 CH 2 CH 2 OH, CH(ONO 2 )CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2 )CH 2 ONO, CH(ONO 2
  • R 1 represents Z1 -Cycle-P, wherein Z1 is a bond; wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R6i is independently at each occurrence selected from C 1-6 alkyl, C 1-6 alkyene-OH, C 1-6 alkyene-ONO, C 1-6 alkyene-ONO 2 .
  • said R4 is selected from hydrogen or methyl.
  • said R4 is selected from hydrogen or methyl.
  • said compound of formula I is a compound of formula VIII, a compound of formula IX or a compound of formula X wherein said compound of formula I comprises at least one covalently bound ONO 2 or ONO moiety and at most three, covalently bound ONO 2 or ONO moieties, wherein preferably said compound of formula I comprises one or two covalently bound ONO 2 moiety; and wherein AR is selected from wherein each optionally substituted by 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , methyl, methoxy, and wherein preferably AR is benzene and wherein said benzene is optionally substituted by 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from
  • R11 is hydrogen or methyl, wherein preferably R 11 is methyl;
  • R2 is selected from C 1 - 3 alkyl substituted by 1 or 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; preferably said R2 is selected from C 1-2 alkyl substituted by 1 or 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; further preferably said R2 is selected from C 1.2 alkyl substituted by 1 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; again further preferably said R2 is selected from C 1-2 alkyl substituted by 1 R 6 ; wherein said R 6 is ONO 2 ;
  • R21 is hydrogen or methyl, wherein preferably R21 is hydrogen;
  • R 3 I , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 3I , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 33 , R 32 represent a fused dioxolane ring; again more preferably said R 3 I is methoxy, R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring;
  • R4 is hydrogen or methyl, wherein preferably R4 is hydrogen; R 1 is selected from C 1-6 alkyl substituted by 1 to 3 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said R 6
  • said R 1 is selected from C 1-6 alkyl substituted by 1 to 3 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cycl
  • said R 1 is selected from C 1-4 alkyl substituted by 1 to 2 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane,
  • said R 1 is selected from CH 2 ONO 2 , CH 2 ONO, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO, (CH 2 ) 4 ONO 2 , (CH 2 ) 4 ONO, (CH 2 ) 5 ONO 2 , (CH 2 ) 5 ONO, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydr
  • said R 1 is -Cycle-P, wherein Cycle-P is selected from wherein the arrow denotes the binding to the ring nitrogen atom of formula I, and wherein said R 61 is independently at each occurrence selected from C 1 - 3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 , and wherein preferably said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • said compound of formula I is a compound of formula VIII*, a compound of formula IX* or a compound of formula X* wherein said compound of formula I comprises at least one covalently bound ONO 2 or ONO moiety and at most three, covalently bound ONO 2 or ONO moieties, wherein preferably said compound of formula I comprises one or two covalently bound ONO 2 moiety; and wherein AR is selected from wherein each optionally substituted by 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , methyl, methoxy, and wherein preferably AR is benzene and wherein said benzene is optionally substituted by 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence
  • R11 is hydrogen or methyl, wherein preferably Rn is methyl
  • R2 is selected from Ci. 3 alkyl substituted by 1 or 2 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; preferably said R2 is selected from C 1-2 alkyl substituted by 1 or 2 l ⁇ ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; further preferably said R2 is selected from C 1.2 alkyl substituted by 1 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 ; again further preferably said R2 is selected from C 1-2 alkyl substituted by 1 R 6 ; wherein said R 6 is ONO 2 ;
  • R21 is hydrogen or methyl, wherein preferably R21 is hydrogen;
  • R 3 I , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 3I , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 33 , R 32 represent a fused dioxolane ring; again more preferably said R 3 I is methoxy, R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring;
  • R4 is hydrogen or methyl, wherein preferably R4 is hydrogen; R 1 is selected from C 1 - 6 alkyl substituted by 1 to 3 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said
  • said R 1 is selected from C 1 - 6 alkyl substituted by 1 to 3 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 1 is selected from C 1-4 alkyl substituted by 1 to 2 R 5 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 1 is selected from CH 2 ONO 2 , CH 2 ONO, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO, (CH 2 ) 4 ONO 2 , (CH 2 ) 4 ONO, (CH 2 ) 5 ONO 2 , (CH 2 ) 5 ONO, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, te
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydr
  • said R 1 is -Cycle-P, wherein Cycle-P is selected from and wherein the arrow denotes the binding to the ring nitrogen atom of formula I, and wherein said R 61 is independently at each occurrence selected from C 1 - 3 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 , and wherein preferably said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • said compound of formula I is a compound of formula
  • said compound of formula I comprises at least one covalently bound ONO 2 or ONO moiety and at most three, covalently bound ONO 2 or ONO moieties, wherein preferably said compound of formula I comprises one or two covalently bound ONO 2 moiety; and wherein AR is selected from wherein each optionally substituted by 1-3, preferably by 1 or 2, R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , methyl, methoxy, and wherein preferably AR is benzene and wherein said benzene is optionally substituted 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , methyl and methoxy, preferably wherein said R 5 is independently at each occurrence selected from F and
  • R21 is hydrogen or methyl, wherein preferably R21 is hydrogen;
  • R 31 , R 32 are independently selected from hydrogen, methyl and methoxy, or wherein said R 31 , R 32 represent a fused 5-membered saturated heterocyclic ring comprising one or two oxygen, wherein preferably said R 31 , R 32 represent a fused dioxolane ring; again more preferably said R 31 is methoxy, R 32 is hydrogen or wherein said R 31 , R 32 represent a fused dioxolane ring;
  • R t is hydrogen or methyl, wherein preferably R4 is hydrogen; R 1 is selected from C 1 -6alkyl substituted by 1 to 3 R; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-4 alkyl substituted by 1 to 3 R 5 ; wherein said R 5
  • said R 1 is selected from C 1 -6alkyl substituted by 1 to 3 R 5 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected C 1-4 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane,
  • said R 1 is selected from C 1-4 alkyl substituted by 1 to 2 R 5 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 5 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane,
  • said R 1 is selected from CH 2 ONO 2 , CH 2 ONO, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO, (CH 2 ) 4 ONO 2 , (CH 2 ) 4 ONO, (CH 2 ) 5 ONO 2 , (CH 2 ) 5 ONO, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1 - 3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 .
  • Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine,
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydr
  • said R 1 is -Cycle-P, wherein Cycle-P is selected from wherein the arrow denotes the binding to the ring nitrogen atom of formula I, and wherein said R 61 is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2 , and wherein preferably said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 ,
  • said compound of formula I is a compound of formula X* wherein said compound of formula I comprises at least one covalently bound ONO 2 or ONO moiety and at most three, covalently bound ONO 2 or ONO moieties, wherein preferably said compound of formula I comprises one or two covalently bound ONO 2 moiety; and wherein AR is selected from wherein each optionally substituted by 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , methyl, methoxy, and wherein preferably AR is benzene and wherein said benzene is optionally substituted by 1-3, preferably by 1 or 2 R 5 , wherein the * denotes the atoms common with the pyrrol moiety of formula I; and wherein said R 5 is independently at each occurrence selected from halogen, CF 3 , methyl, methoxy, and wherein
  • R4 is hydrogen or methyl, wherein preferably R4 is hydrogen; R 1 is selected from C 1-6 alkyl substituted by 1 to 3 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, pyrrolidine, tetrahedrofuran, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, dioxalane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said R 6
  • said R 1 is selected from C 1 - 6 alkyl substituted by 1 to 3 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected C 1-4 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 1 is selected from C 1-4 alkyl substituted by 1 to 2 R 6 ; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- to 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclopentane, cyclohexane, pyrrolidine, tetrahedrofuran, pyrazolidine, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 6 ; wherein said R 6 is independently at each occurrence selected from OH, ONO, ONO 2.
  • said R 1 is selected from CH 2 ONO 2 , CH 2 ONO, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO, (CH 2 ) 4 ONO 2 , (CH 2 ) 4 ONO, (CH 2 ) 5 ONO 2 , (CH 2 ) 5 ONO, CH(ONO 2 )CH 2 OH, CH(ONO)CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , CH(ONO)CH 2 ONO 2 , CH(ONO 2 )CH 2 ONO; or R 1 represents -Cycle-P, wherein Cycle-P is a saturated 4- or 6-membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic
  • said R 1 is -Cycle-P, wherein Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydropyrane, piperazine, morpholine and dioxane, wherein said carbocyclic or said heterocyclic ring is independently substituted by 1 to 3 R 61 , wherein said R 61 is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • Cycle-P is a saturated 4- or 6- membered carbocyclic ring or heterocyclic ring selected from cyclobutane, cyclohexane, piperidine, tetrahydr
  • said R 1 is -Cycle-P, wherein Cycle-P is selected from wherein the arrow denotes the binding to the ring nitrogen atom of formula I, and wherein said R6i is independently at each occurrence selected from C 1-3 alkyl substituted by 1 to 3 R 6 ; wherein said R 5 is independently at each occurrence selected from OH, ONO, ONO 2 , and wherein preferably said R6i is independently at each occurrence selected from CH 2 ONO 2 , CH 2 ONO, CH 2 OH, (CH 2 ) 2 ONO 2 , (CH 2 ) 2 ONO, (CH 2 ) 2 OH, (CH 2 ) 3 ONO 2 , (CH 2 ) 3 ONO and (CH 2 ) 3 OH.
  • said compound of formula I is selected from the formula
  • said compound is a compound of formula I, and wherein said compound is selected from
  • the present invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the inventive compounds of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient, adjuvant, or carrier.
  • the present invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising exactly one inventive compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable excipient, adjuvant, or carrier.
  • Pharmaceutically acceptable excipient, adjuvant, or carrier are known to the skilled person.
  • the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use as a medicament.
  • the present invention provides for a compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use as a pharmaceutical.
  • the present invention provides for a compound of formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use as an animal medicament.
  • the compounds as well as the pharmaceutical compositions of the present invention are dual-pharmacology NO-releasing PDE5 inhibitors believed to release NO in addition to its PDE5 inhibition in a more than additive fashion.
  • the novel compounds of the present invention are useful in the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance.
  • the compounds of the present invention are activators of soluble guanylyl cyclase (sGC) potent and at the same time selective inhibitors of cyclic guanosine 3’ -5’ -monophosphate specific phosphodiesterase 5 (cGMP specific PDE5) and thus have utility in variety of therapeutic areas where such inhibition is beneficial.
  • sGC soluble guanylyl cyclase
  • Some of the preferred therapeutic areas are wound healing, in particular glaucoma, diabetic retinopathy, age dependent macular degeneration, male erectile dysfunction, female sexual dysfunction, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud’s, diabetes, hair loss, skin aging, vascular aging, pulmonary artery hypertension and livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis.
  • wound healing in particular glaucoma, diabetic retinopathy, age dependent macular degeneration, male erectile dysfunction, female sexual dysfunction, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud’s, diabetes, hair loss, skin aging, vascular aging, pulmonary artery hypertension and livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis.
  • cGMP levels are expected to be elevated, which in turn can give rise to beneficial anti-platelet, anti-vasospastic, vasodilatory, natriuretic and diuretic activities as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF) nitric oxide (NO), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and endothelium-dependent relaxing agents such as bradykinin, acetylcholine and 5-HTi.
  • EDRF endothelium-derived relaxing factor
  • NO nitric oxide
  • NAF atrial natriuretic factor
  • BNP brain natriuretic peptide
  • CNP C-type natriuretic peptide
  • endothelium-dependent relaxing agents such as bradykinin, acetylcholine
  • the compounds of formula I therefore have utility in the treatment of a number of disorders, including male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes, wound healing, in particular chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer, and particularly for ophthalmic diseases like
  • the present invention provides for a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal, preferably in a human.
  • said disease is selected from male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes, wound healing, in particular chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer, and particularly for ophthalmic diseases like glaucoma, diabetic retinopathy
  • the present invention provides for the inventive compound of formula I or II, or the inventive pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or in a non-human mammal, preferably in a human, wherein said disease is selected male erectile dysfunction (MED), priapism, Alzheimer’s disease, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, endothelial dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss (enhancing hair growth or diminishing hair loss), cystic fibrosis, peripheral vascular disease, vascular disorders such as Rayn
  • the present invention provides for the inventive compound of formula I or II, or the inventive pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or in a nonhuman mammal, preferably in a human, wherein said disease is selected glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, Raynaud’s disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary artery hypertension; livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, stable, unstable and variant (Prinzmetal) angina; hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atheros
  • the present invention provides for the inventive compound of formula I or the inventive pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or in a non-human mammal, preferably in a human, wherein said disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer (Chen Y.-J. et al. Molecular Pharmaceutics 2019 16:10 (4241-4251; Salcido R.S, Advances in skin & wound care 2008 21:3(106, 108-109; Isenberg J.S., et al.
  • Cancer Drug Resist 2019; 2:933-947. non-small cell lung cancer, skin cancers such as melanoma, myeloma and head and neck squamous cell carcinoma ((Tuttle TR, Mierzwa ML, Wells SI, Fox SR, Ben-Jonathan N. Cancer Lett. 2016;370(2):279-285.)), colon and rectal cancers such as colorectal cancer, and prostate and pancreatic cancers, and in particular colorectal cancer (Islam BN, Sharman SK, Hou Y, et al. Cancer Prev Res (Phila). 2017;10(7):377-388; Huang W, Sundquist J, Sundquist K, Ji J. Gastroenterology.
  • skin cancers such as melanoma, myeloma and head and neck squamous cell carcinoma ((Tuttle TR, Mierzwa ML, Wells SI, Fox SR, Ben-Jonathan N. Cancer Lett
  • the present invention provides for a method of treating or preventing a disease by activation of soluble guanylyl cyclase (sGC) and/or inhibition of PDE5 in a human or in a non-human mammal, preferably in a human, comprising administering to said human or said non-human mammal, preferably to said human an effective amount of a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • sGC soluble guanylyl cyclase
  • the present invention provides for a method of treating or preventing a disease alleviated by activation of soluble guanylyl cyclase (sGC) and/or inhibition of PDE5 in a human or in a non-human mammal, preferably in a human, comprising administering to said human or said non-human mammal, preferably to said human an effective amount of a compound of formula I or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • sGC soluble guanylyl cyclase
  • the present invention provides for a method of treating a medical condition in a human or in a non-human mammal, preferably in a human, wherein for said medical condition activation of soluble guanylyl cyclase (sGC) and/or inhibition of PDE5 is desired, comprising administering to said human or said non-human mammal, preferably to said human an effective amount of a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • sGC soluble guanylyl cyclase
  • the present invention provides for a method of treating or preventing a disease in a human or in a non-human mammal, preferably in a human, comprising administering to said human or said non-human mammal, preferably to said human, an effective amount of a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • said disease or said a medical condition is selected from glaucoma, diabetic retinopathy, age dependent macular degeneration, Retinopathia pigmentosa, pulmonary artery hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedoid vasculopathy, thromboangitis obliterans, chronic anal fissure, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcer, leg ulcer, diabetic neuropathy and pressure ulcer.
  • the terms “treatment”, “treat”, “treated” or “treating” refer to prophylaxis and/or therapy.
  • treatment refers to a therapeutic treatment.
  • treatment refers to a prophylactic treatment.
  • beneficial or desired clinical results of said treatment include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or medical condition, stabilized (i.e., not worsening) state of disease or medical condition, delay or slowing of disease or medical condition progression, amelioration or palliation of the disease or medical condition state.
  • the term “effective amount” refers to an amount necessary or sufficient to realize a desired biologic effect.
  • the term “effective amount” refers to an amount of a compound of formula I of the present invention that (i) treats or prevents the particular disease, medical condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, medical condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, medical condition, or disorder described herein.
  • An effective amount of the inventive compound of formula I, or said pharmaceutical composition would be the amount that achieves this selected result, and such an amount could be determined as a matter of routine by a person skilled in the art.
  • the term “effective amount”, as used herein, refers to an amount necessary or sufficient to be effective to activation of soluble guanylyl cyclase (sGC) and/or increase the inhibition of PDE5.
  • the effective amount can vary depending on the particular composition being administered and the size of the subject.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular composition of the present invention without necessitating undue experimentation.
  • mammal includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
  • mammal as used herein, preferably refers to humans.
  • the compounds of formula I and the pharmaceutical compositions of the present invention may be administered by any suitable route, for example by oral, buccal, sublingual, rectal, vaginal, intranasal, nasal, topical, intradermal, transdermal, subcutaneous, intraocular injection, transcutaneous, enteral, local, intravenous, intraperitoneal or parenteral administration, which forms another aspect of the present invention.
  • Other routes are known in the art that could also be employed such as by way of chirurgical inlets.
  • a device may be used for administration, such as conventional needles and syringes, micro needles, patches (e.g. as in WO 98/20734), needle free injection systems (e.g. as in WO 1999027961 Al), spray devices and the like, depending on the dose form and administration route.
  • the device may be pre-filled or coated with the inventive compound or pharmaceutical composition.
  • topical administration is used in its broadest sense to include administration to a surface on the body that is generally open to the surroundings. This includes not only the skin but also the nasal and oral passages and the genitalia. Thus, topical administration can include application to the skin, application to the nasal passages, application to the oral cavity (including the upper throat), and application to the genitalia. Topical formulations have been available in a variety of forms, including creams, ointments, solutions, lotions, suspensions, pastes, emulsions, foams and the like.
  • Water miscible creams have generally been employed for moist or weeping lesions, whereas ointments have been generally chosen for dry, lichenified or scaly lesions or where a more occlusive effect has been required. Lotions have generally been useful when minimal application to a large or hair-bearing area has been required or for the treatment of exudative lesions.
  • local administration is used herein to refer to topical administration as well as administration to the eyes.
  • Combination therapies may involve co-administration or sequential administration, and in particular of the inventive compound of formula I or the pharmaceutical composition and the at least one sGC stimulator.
  • Soluble guanylyl cyclase (sGC) stimulators are known in the art and have been described (E S. Buys et al, Nitric Oxide 78 (2016) 72-80; P. Sandner et al, Nitric Oxide 77 (2016) 88-95; P. Sandner et al, Gerontology 63 (2017) 216-227).
  • sGC stimulators are typically small molecule drugs that synergistically increase sGC enzyme activity with NO by binding to sGC and potentiate NO-mediated cGMP signaling. Further sGC stimulators have also been described in W02009032249, W02009094242, WO 2 010099054, WO 2 010065275, WO 2 011119518,
  • said sGC stimulator is selected from the group consisting Riociguat, Vericiguat, Praliciguat, Olinciguat, IW-64630, A-330619, A-344905, A-778935, BAY 41-2272, BAY 41-8543, CFM-1571, GSK2181236 A, IWP-051, IWP-550, IWP-854, IWP-953, etriciguat, nelociguat and YC-1, and wherein further preferably said sGC stimulator is selected from the group consisting Riociguat, Vericiguat, Praliciguat and Olinciguat.
  • inventive compounds of formula I pharmaceutical compositions or combination products can be administered to any subject, preferably human, that can experience the beneficial effects of the inventive compounds, compositions or products, as described herein.
  • inventive compounds of formula I pharmaceutical compositions or combination products as described herein can be administered by any means that achieve their intended purpose.
  • administration can be by oral, buccal, sublingual, rectal, vaginal, intranasal, nasal, topical, intradermal, transdermal, subcutaneous, intraocular injection, transcutaneous, enteral, local, intravenous, intraperitoneal or parenteral administration.
  • the co-administration or sequential administration is effected by the same type of administration, even though different type of administrations such as a local application for the compounds of formula I or the pharmaceutical compositions and an oral administration of the at least one sGC stimulator is also envisaged and encompassed within the present invention.
  • Scheme 1 shows the alkylation of the inventive compounds to introduce, in particular, R 2
  • Scheme 2 exemplifies the synthesis for the introduction, in particular, of R 1 in accordance with the present invention.
  • compounds of the present invention represented by formula [P] can be obtained from intermediates represented by formula [N], previously described by Daugan A. et al. J Med. Chem. 2003, 46, 4525-4532 by reacting with primary amines of the general formula H2N-R 1 with the meaning of R 1 as defined in accordance with the present invention and an appropriate cyclization agent.
  • Scheme 3 illustrates the synthesis of hydantoins.
  • Boc tert Butoxy carbonyl
  • Boc20 Di-tert butyl decarbonate
  • DMAP 4- Dimethylamino pyridine
  • DMF N,N-Dimethyl formamide
  • DMSO Dimethylsulfoxide
  • MeOH Methanol
  • PG Protecting Group
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofurane.
  • Scheme 4 shows the synthesis of methyl (lR,3R)-l-(benzo[d][l,3]dioxol-5-yl)-2-(2- chloroacetyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole-3-carboxylate (5) which corresponds to specific preferred intermediates of formula [K] (see Scheme 2).
  • Step A methyl -l-(benzordiri.31dioxol-5-yl)-2.3.4.9-tetrahvdro-lH-pyridor3.4-b1indole- 3-carboxylate (3A) and methyl ( ⁇ S.3R)- 1 -tbenzordiri .31dioxol-5-yl)-2.3A9-tetrahydro- l H- pyridor3.4-b1indole-3-carboxylate (3)
  • Step B methyl ( ⁇ R.3R)- 1 -tbenzordiri .31dioxol-5-yl)-2-(2-chloroacetyl )-2.3A9-tetrahydro-l H- pyridor3.4-blindole-3-carboxylate (5)
  • Scheme 5 shows the synthesis of (4-aminocyclohexane-l,l-diyl)dimethanol hydrochloride, which corresponds to specific preferred intermediates for introducing substituents R 1 within the inventive compounds of formula I (see Scheme 3).
  • Step A diethyl 4-(Ytert-butylsulfmyl )amino)cvclohexane-l . 1 -di carboxyl ate (8)
  • the reaction mixture was stirred at room temperature for 3h.
  • the reaction was quenched with water and stirred at room temperature for lh.
  • the heterogeneous mixture was filtered and washed with dichloromethane.
  • the organic layer was separated from the filtrate and the aqueous layer extracted with 10% methanol with dichloromethane.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford the title compound (4.3 g, 99%).
  • Step B N-(4.4-bis(hvdroxymethyl level ohexyl )-2-methylpropane-2-sulfinamide (9)
  • Step C (4-aminocvclohexane-Ll-divOdimethanol (10) To a stirred solution of N-(4,4-bis(hydroxymethyl)cyclohexyl)-2-methylpropane-2- sulfmamide (2.8 g, 10.63 mmol) in methanol (28 mL) was added 4M HC1 in dioxane at 10°C and stirred at room temperature for 2h. After completion, the reaction was concentrated under reduced pressure to afford crude title compound as its hydrochloride salt (2.8 g).
  • Scheme 6 shows the synthesis of 2-[4-amino-l -(2-hydroxy ethyl)cyclohexyl]ethanol 17, which corresponds to specific preferred intermediates for introducing substituents R 1 within the inventive compounds of formula I (see Scheme 3).
  • Step A N. N-dibenzyl-L 4-dioxaspiro G4, 51 decan-8-amine (11)
  • 4-dioxaspiro [4. 5] decan-8-one (11) (5 g, 31.05 mmol) in DCE (129 mL and AcOH 1.8 mL ) was added dibenzylamine (6.3 mL, 31.05 mmol) at room temperature and the reaction mixture was stirred for 15 min.
  • sodium triacetoxyborohydride (STAB) was added in many portions slowly at rt and the reaction mixture was allowed to stir at room temperature for 16h.
  • the reaction mixture was washed with saturated aq. NaHCCh solution and extracted in DCM.
  • Step B 4-(dibenzylamino)cvclohexan-l-one (13):
  • Step C 9-(dibenzylamino)-2.4-dioxo-3-azaspiror5.51undecane-F5-dicarbonitrile (14)
  • Step D 2.2'-(4-(dibenzylamino)cvclohexane-Ll-divDdiacetic acid (15)
  • Step E 2.2'-(4-(dibenzylamino)cvclohexane-Ll-divDbis(ethan-l-ol) (16) To a stirred solution of compound 2,2'-(4-(dibenzylamino)cyclohexane-l,l-diyl)diacetic acid (15) (1.0 g, 2.16 mmol) in THF (30 mL) was slowly added L1AIH 4 (2.0 M in THF, 7.2 mL) at 0°C. The reaction mixture was allowed to stir at 65°C for 16h.
  • Scheme 7 shows the synthesis of [4-amino-6-(hydroxymethyl)tetrahydropyran-2- yljmethanol (24), which corresponds to specific preferred intermediates for introducing substituents R 1 within the inventive compounds of formula I (see Scheme 3).
  • Step B diethyl 4-hvdroxytetrahvdro-2H-pyran-2.6-dicarboxylate (20)
  • Step C diethyl 4-oxotetrahvdro-2H-pyran-2.6-di carboxyl ate (21)
  • Step D diethyl 4-(benzylamino)tetrahvdro-2H-pyran-2.6-dicarboxylate (22)
  • Step E (4-(benzyl ami no )tetrahydro-2H-pyran-2.6-diyl)di methanol (23)
  • Scheme 8 shows the synthesis of 3,3-bis[[tert-butyl(dimethyl)silyl]oxymethyl]cyclo- butanamine, which corresponds to specific preferred intermediates for introducing substituents R 1 within the inventive compounds of formula I (see Scheme 3).
  • Step A (3.3-dimethoxycvclobutane- l . 1 -diyl idimethanol (26)
  • Step B 3.3-bis(Tivdroxymethyl )cvclobutan- l -one (27)
  • acetone 100 mL
  • 6N HCL 70 mL
  • the pH was adjusted to 8 with NaHCCri followed by extraction with 10% methanol in ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 27 (6.5 g, 88%).
  • MS 130.12 m/z (M+H) + .
  • Step C 3.3-bis(((tert-butyldimethylsilyl)oxy)methyl )cvclobutan- l -one (28)
  • Step D N-benzyl-3.3-bis(((tert-butyldimethylsilyl )oxy)methyl )cvclobutan- l -amine (29)
  • benzylamine 5.94 mL, 54 mmol
  • NaCNBH 3 1.84 g, 29 mmol
  • acetic acid 10 mL
  • Step E 3.3-bis(((tert-butyldimethylsilyl)oxy)methyl level obutan-1 -amine (30) To a solution of benzylamine 29 (5.5 g, 12 mmol) in methanol (150 mL) was added 10%
  • Step A tert-butyl (6R.12aR)-6-(benzordirL31dioxol-5-vn-2-methyl-L4-dioxo-L3.4.6.12.12a- hexahvdropyrazinorr.2':L61pyridor3.4-blindole-7(2H)-carboxylate
  • 6R,12aR 6-(benzo[d][l,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a- hexahydropyrazino[r,2':l,6]pyrido[3,4-b]indole-l,4-dione
  • Tadalafil 2.0 g, 5.14 mmol
  • CH 2 CI2 60 mL
  • DMAP 314 mg, 2.57 mmol
  • Boc-anhydride 2.4 mL, 10.28 mmol
  • Step B tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-3-(2-ethoxy-2-oxoethyl)-2-methyl- L4-dioxo-L3A6.12.12a-hexahvdropyrazino
  • Step C (6R.12aR)-6-(benzordirL31dioxol-5-vn-3-(2-hvdroxyethvn-2-methyl-2.3.6.7.12.12a- hexahydropyrazinor G.2' : L61pyridor3 ,4-blindole- 1 ,4-dione
  • Step D tert-butyl (6RJ 2aR)-6-( ' benzordH 1.31dioxol-5-yl)-2-methyl-3-(2-(nitrooxy)ethyl)-l
  • Step E 2-((6R.12aR)-6-(benzordirL31dioxol-5-vn-2-methyl-L4-dioxo-L2.3.4.6.7.12.12a- octahvdropyrazinorr.2': E61pyridor3.4-b1indol-3-vDethyl nitrate
  • Step F 2-r(2R.5R.8R)-2-(E3-benzodioxol-5-v0-6-methyl-4.7-dioxo-3.6.17-triazatetracvclo
  • Step A (6R.12aRV6-(benzordiri.31dioxol-5-vD-3-(hvdroxymethvD-2-methyl-1.4-dioxo-
  • Step B (6R.12aR)-6-(benzordirE31dioxol-5-vD-3-(hvdroxymethvD-2-methyl-2.3.6.7.12.12a- hexahydro pyrazinor G.2' : 1,61rnp ⁇ oG3.4-blindole- 1 Adi one
  • the reaction mixture was warmed to room temperature and stirred for 15 min. After completion of the reaction, acetone was added, and the reaction was stirred for 10 min. The heterogeneous mixture was filtered, and the obtained filtrate was concentrated under reduced pressure.
  • the obtained crude was purified by reverse phase column chromatography. The pure fractions were concentrated and extracted with ethyl acetate. The combined organic layer was dried over anhydrous NaiSCR and concentrated under reduced pressure. The product was triturated with pentane, filtered and dried under reduced pressure to afford the title compound (15.2 mg, 8%).
  • Step C tert-butyl (6R. 12aR)-6-(benzordiri .31dioxol-5-yl )-3 -(hydroxymethyl )-2-methyl- l
  • tert-butyl (6R. 12aR)-6-(benzordiri .31dioxol-5-yl )-3 -(hydroxymethyl )-2-methyl- l A dioxo-E3A6.12.12a-hexahvdropyrazino
  • Step D tert-butyl (6R. 12aR)-6-(benzordir i .31dioxol-5-yl )-2-methyl-3-(Ynitrc>oxy)methyl )- 1
  • tert-butyl (6R,12aR)-6-(benzo[d][l,3]dioxol-5-yl)-3-(hydroxymethyl)-2- methyl-l,4-dioxo-l,3,4,6,12,12a-hexahydropyrazino[r,2':l,6]pyrido[3,4-b]indole-7(2H)- carboxylate 150 mg, 0.29 mmol
  • CH 2 CI2 6.0 mL
  • Step E ((6R.12aR)-6-(benzordirE31dioxol-5-vn-2-methyl-E4-dioxo-E2.3.4.6.7.12.12a-octa- hvdropyrazinorr.2': E61pyridor3.4-blindol-3-vnmethyl nitrate
  • Step A (6R. 12aR)-6-(benzordir i Jldioxol-5-yl )-2-(4.4-bis(hydroxymethyl )cvclohexyl )-
  • reaction mixture was heated to 90°C and stirred for 15h in a sealed tube. After 15h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the residue, which was diluted with water and extracted with 5% methanol in dichloromethane. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Two identical batches were combined for purification by reverse phase column chromatography. Pure fractions were lyophilized to afford the title compound (110 mg; 7% yield).
  • Step B tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-2-(4.4-bis(hvdroxymethyl icvclohexyl )
  • Step C tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-2-(4.4-bis(Tnitrooxy)methyl icvclo- hexyD-1.4-dioxo-1.3A6.12.12a-hexahvdropyrazino
  • Step D (4-((6R.12aR)-6-(benzordirE31dioxol-5-vn-E4-dioxo-3.4.6.7.12.12a-hexahydro- pyrazinor G.2' : E61pyrido G 3.4-b1indol-2(TH)-vDcvclohexane- 1.1 -divDbisrin ethylene) dinitrate
  • Step B (6R.12aRy6-(benzordiri.31dioxol-5-vD-2-((lr.4R)-4-(hvdrc)xymethvDcvclohexyD-1.4- dioxo-1.3.4.6.12.12a-hexahvdropyrazinorr.2':1.61pyridor3.4-blindole-7(2H)-carboxylate
  • Step C tert-butyl (6RJ 2aR)-6-(benzordiri .31dioxol-5-yl)-2-(Yl r.4R)-4-(Ynitrooxy)methyl icvclo- hexyD-L4-dioxo-L3A6.12.12a-hexahvdropyrazino
  • Step D ((lR.4r)-4-((6R.12aR)-6-(benzordirL31dioxol-5-vn-L4-dioxo-3.4.6.7.12.12a-hexahydro pyrazino IT.2': L61pyridor3.4-blindol-2(TH)-vDcvclohexyDmethyl nitrate
  • Step A (6R.12aR)-6-(benzordirE31dioxol-5-vn-2-n-(3-hvdroxypropynpiperidin-4-vn-2.3.6.7. 12.12a-hexahvdropyrazinorr.2':E61pyridor3.4-blindole-E4-dione
  • the reaction mixture was heated to 85°C and stirred for 20h. After completion of reaction, the mixture was concentrated under reduced pressure and the obtained residue was diluted with water and then extracted with 10% methanol with dichloromethane. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC. Pure fractions were lyophilized to afford the title compound (28 mg; 18%).
  • Step B tert-butyl (6R.12aR)-6-(benzordirE31dioxol-5-vD-2-n-(3-hvdrc)xyprc)pyDpiperidin-4- vD- 1.4-dioxo- E3.4.6.12.12a-hexahydropyrazinor G.2' : 1 ,61rnp ⁇ oG3.4-blindole-7(2H)-carboxylate To a stirred solution of (6R,12aR)-6-(benzo[d][l,3]dioxol-5-yl)-2-(l-(3- hydroxypropyl)piperidin-4-yl)-2,3,6,7,12,12a-hexahydropyrazino[r,2':l,6]pyrido[3,4-b]indole- 1,4-dione (230 mg, 0.44 mmol) in DMF (9 mL) were added
  • reaction mixture was heated to 50°C and stirred for 3h. After completion, the reaction mixture was cooled to room temperature, quenched with ice-water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to afford the title compound (110 mg; 30%).
  • Step C tert-butyl (6R.12aR)-6-(benzordirE31dioxol-5-vn-2-n-(3-(nitrooxy)propyl)piperidin-4- vD- 1.4-dioxo- E3.4.6.12.12a-hexahydropyrazinor G.2' : 1.61pyridor3.4-blindole-7(2H)-carboxylate
  • tert-butyl (6R,12aR)-6-(benzo[d][l,3]dioxol-5-yl)-2-(l-(3- hydroxypropyl)piperidin-4-yl)- 1 4-dioxo- 1,3,4,6,12,12a-hexahydropyrazino[ T,2' : 1 ,6]pyrido[3 ,4- b]indole-7(2H)-carboxylate (90 mg, 0.09
  • Step D 3-(4-((6R.12aR)-6-(benzordirE31dioxol-5-vD-E4-dioxo-3.4.6.7.12.12a-hexahvdro- pyrazino
  • Step A 3-(Ytert-butyldimethylsilv0oxy)propan-l-amine
  • Step B (6R.12aR)-6-(benzordiri.31dioxol-5-vn-2-(3-((tert-butyldimethylsilvnoxy)-propyn- 2.3.6.7.12.12a-hexahvdropyrazino
  • Step C tert-butyl (6RJ 2aR)-6-(benzordiri .31dioxol-5-yl)-2-(3-((tert-butyldimethylsilyl )-oxy) propyl)- 1.4-dioxo- 1.3.4.6.12.12a-hexahvdropyrazino
  • Step D tert-butyl (6R.12aR)-6-(benzordiri.31dioxol-5-yl)-2-(3-hvdroxypropyl)-1.4-dioxo- 1.3.4.6.12.12a-hexahvdropyrazino
  • Step E tert-butyl (6R.12aR)-6-(benzordirE31dioxol-5-vn-2-(3-(nitrooxy)propyl)-E4-dioxo- E3A6.12.12a-hexahvdropyrazinorr.2':E61pyridor3.4-b1indole-7(2H)-carboxylate
  • Acetyl nitrate preparation Fuming nitric acid (1 mL) was added drop wise at -15°C to acetic anhydride (5.4 mL) and the resulting mixture was stirred for 20 min.
  • Step F 3-((6R.12aR)-6-(benzordirL31dioxol-5-vn-L4-dioxo-3.4.6.7.12.12a-hexahydro- pyrazinorr.2': L6]pyridor3.4-b1indol-2(TH)-v0propyl nitrate
  • Step B (6RJ 2aR)-6-(benzordin .3 ldioxol-5-yl )-2-(3-((tert-butyldi methyl silyl )oxy)-butyl)-
  • Step C tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-2-(4-((tert-butyldimethylsilyl )-oxy) butyl)-E4-dioxo-E3A6.12.12a-hexahvdropyrazino
  • Step D tert-butyl (6RJ 2aR)-6-( ' benzordH 1.31dioxol-5-yl)-2-(4-hvdroxybutyl)- l .4-dioxo-
  • Step E tert-butyl (6R. 12aR)-6-(benzordin .31dioxol-5-yl)-2-(4-(nitrooxy)butyl )- 1.4-dioxo- L3A6.12.12a-hexahvdropyrazino
  • Acetyl nitrate preparation Fuming nitric acid (1 mL) was added drop wise at -15°C to acetic anhydride (5.4 mL) and the resulting mixture was stirred for 20 min.
  • Step F 4-((6R.12aR)-6-(benzordirE31dioxol-5-vD-E4-dioxo-3 A6.7.12.12a-hexahvdro-pyrazino rr.2':E61pyridor3.4-blindol-2nH)-yl)butyl nitrate
  • amine 30 (2.52 g, 7 mmol) in toluene (40 mL) and DMF (2 mL) was added methyl (lR,3R)-l-(benzo[d][l,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-lH- pyrido-[3,4-b]indole-3-carboxylate (5) (2 g, 4 mmol) and K2CO3 (971 mg, 7
  • Step B tert-butyl (6RJ 2aR)-6-(benzordiri .31dioxol-5-yl)-2-(3.3-bis(((tert-butyldimethylsilyl ) oxyimethyl level obutyl )- 1 ,4-dioxo- 1.3.4.6.12.12a-hexahydropyrazino G G.2' : 1 ,61rnp ⁇ oG3 ,4-bl- indole-7(2H)-carboxylate
  • reaction mixture was stirred at RT for 4 h.
  • the reaction mixture was diluted with chloroform (50 mL) and washed with water and brine solution.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified over silica gel chromatography to afford the title compound (1.7 g, 78%).
  • Step C tert-butyl (6R.12aR)-6-(benzordin .31dioxol-5-yl )-2-(3.3-bis(Tivdroxymethyl ) cvclo- butvf)-L4-dioxo-L3 A6.12.12a-hexahvdropyrazino
  • Step D tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-2-(3.3-bis(Ynitrooxy)methyl ) cvclobutyr)-L4-dioxo-L3A6.12.12a-hexahvdropyrazino
  • Step E (3-((6R.12aR)-6-(benzordin.31dioxol-5-vn-1.4-dioxo-3.4.6.7.12.12a-hexahvdro- pyrazinofl '.2': 1.61pyridol3.4-blindol-2n H)-yl)cvclobutane- l . 1 -diyl ibisimethylene) dinitrate
  • Step B r3-r(2R.8R)-2-(T.3-benzodioxol-5-yr)-4.7-dioxo-3.6.17-triazatetracvclor8,7.0,03.8,011.
  • Step A 9-(tert-butyl) 3-methyl (lR.3R)-l-(benzordiri.31 dioxol-5-vO-2-(2-chloroacetvO-l.2.3.4- tetrahydro-9H-pyridor3.4-b1 indole-3.9-di carboxyl ate
  • Step B tert-butyl (6R.12aR)-6-(benzordin.31 dioxol-5-vO-2-(4.4-bis(TivdroxylmethvO- cvclohexyD-1.4-dioxo-1.3.4.6.12.12a-hexahvdropyrazinorr.2':1.61pyridor3.4-b1indole-7(2H)- carboxyl ate
  • Step D (4-((6R.12aR)-6-(benzordirL31dioxol-5-vn-L4-dioxo-3.4.6.7.12.12a-hexahydro- pyrazinorr.2':L61pyridor3.4-b1indol-2(TH)-yr)cvclohexane-Ll-divDbis(ethane-2.1-divD dinitrate
  • Step B 2-(4-((6R.12aR)-6-(benzordirL31dioxol-5-yl)-L4-dioxo-3.4.6.7.12.12a-hexahvdro- pyrazinorr.2': L61pyridor3.4-b1indol-2nH)-yl)-l-(2-hvdroxyethyl)cvclohexyl)ethyl nitrate (cis- / trans-isomers)
  • Step A tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-2-(2-(((tert-butoxycarbonyl) oxy)methvD-6-(Ynitrooxy)methyl)tetrahvdro-2H-pyran-4-vD- 1 ,4-dioxo- 1.3A6J2J 2a-hexa- hvdropyrazinorr.2': E61pyridor3.4-blindole-7(2H)-carboxylate To a stirred solution of tert-butyl (6R,12aR)-6-(benzo[d][l,3]dioxol-5-yl)-2-(2-(((tert- butoxycarbonyl)oxy)methyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-l,4-dioxo-
  • Step B (4-((6R.12aR)-6-(benzordirL31dioxol-5-vn-L4-dioxo-3.4.6.7.12.12a-hexahydro- pyrazinon '.2': 1.61pyridor3.4-blindol-2n H)-yl)-6-(Tivdroxymethyl )tetrahydro-2H-pyran-2- vQmethyl nitrate
  • Step A (6RJ 2aR)-6-(benzordir i .31dioxol-5-yl)-2-(2.6-bis(hvdroxymethyl )tetrahydro-2H-pyran-
  • Step B tert-butyl (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-2-(2.6-bis(Tivdroxymethyl itetrahydro-
  • reaction mixture was heated at 50°C for 1.5h. After completion of the reaction, the mixture was cooled to room temperature, diluted with cold water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. This reaction was repeated in three batches.
  • Step C tert-butyl (6R.12aR)-6-(benzordirL31dioxol-5-vn-2-(4.4-bis((nitrooxy)methvncvclo- hexyD-L4-dioxo-L3 A6.12.12a-hexahvdropyrazino
  • Step D (4-((6R.12aR)-6-(benzordin.31dioxol-5-vn-1.4-dioxo-3.4.6.7.12.12a-hexahvdro- pyrazinon ',2': 1.61pyridor3.4-blindol-2n H)-yl )tetrahydro-2H-pyran-2.6-diyl ibisimethylene) dinitrate
  • Step A (6R.12aR)-6-(benzordirE31dioxol-5-vn-2-(2-(2-(benzyloxy)ethvn-E3-dioxan-5-vn- 2.3.6.7.12.12a-hexahvdropyrazinorr.2':E61pyridor3.4-blindole-E4-dione
  • Step B 6R.12aR)-6-(benzordirE31dioxol-5-vn-2-(2-(2-(benzyloxy)ethvn-E3-dioxan-5-vn-
  • Step C tert-butyl (6R. 12aR)-6-(benzordiri .31dioxol-5-yl )-2-(2-(2-hydroxyethyl )- 1 ,3-dioxan-5- vD- 1.4-dioxo- E3.4.6.12.12a-hexahydropyrazinor G.2' : 1 ,61rnp ⁇ oG3.4-blindole-7(2H)-carboxylate
  • reaction mixture was heated at 50°C for 30 min. After completion the reaction mixture was cooled to room temperature, diluted with cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. This reaction was repeated in another batch (1 x 200 mg) as describe above. The combined crude product was purified by chromatography to afford the title compound (0.21 g, 44%).
  • Step D tert-butyl (6R.12aR)-6-(benzordiri.31dioxol-5-vD-2-(2-(2-(nitrooxy)ethvD-1.3-dioxan-5- vD- 1.4-dioxo- 1.3.4.6.12.12a-hexahydropyrazinor G.2' : 1.61pyridor3.4-blindole-7 -carboxylate
  • tert-butyl (6R,12aR)-6-(benzo[d][l,3]dioxol-5-yl)-2-(4,4- bis(hydroxymethyl)cyclohexyl)- 1 4-dioxo- 1,3,4,6,12,12a-hexahydropyrazino[ T,2' : 1 ,6]pyrido- [3,4-b]indole-7(2H)-carboxylate (130 mg, 0.214 mmol)
  • Step E 2-(5-(Y6R.12aR)-6-( ' benzordiri.31dioxol-5-yr)-1.4-dioxo-3.4.6.7.12.12a-hexahydro- pyrazino
  • Step A Methyl P R.3R)- 1 -(4-methoxyphenyl )-2.3A9-tetrahydro-l H-pyridor3.4-blindole-3- carboxylate
  • Step B (5R.11 aR)-2-(2-(benzyloxy)ethyl )-5-(4-methoxyphenyl )-5.6.11.11 a-tetrahydro- 1H- imidazor
  • G.5' 1.61pyridor3 ,4-blindole- L3 (2H)-dione
  • Step C tert-butyl (5S J 1 aR)-2-(2-(benzyloxy)ethyl )-5-(4-methoxyphenyl )- 1 ,3-dioxo-
  • Step D tert-butyl (5SJ laR)-2-(2-hvdroxyethyl)-5-(4-methoxyphenyl)- 1.3-dioxo- 1.2.3.5J 1 J 1 a- hexahydro-6H-imidazor 1 5' : 1 ,61rnp ⁇ oG3.4-blindole-6-carboxylate
  • Step E tert-butyl (5SJ 1 aR)-5-(4-methoxyphenyl )-2-(2-(nitrooxy)ethyl)- l ,3-dioxo-
  • Step F 2-(Y5S.l laR)-5-(4-methoxyphenvO-L3-dioxo-5.6.11.1 la-tetrahydro-lH-imidazo rr.5':1.61pyridor3.4-b1indol-2(3H)-vDethyl nitrate
  • Step A 1 -(6-fluoro- 1 H-indol-3-yl )-N.N-dimethylmethanamine
  • Step B 1 -(6-fluoro- 1 H-indol-3-yl )-N. N. N-tri ethyl ethanaminium. iodide
  • Step C methyl 2-(Ydiphenylmethylene)amino)-3-(6-fluoro-lH-indol-3-vDpropanoate
  • Step D methyl 2-amino-3-(6-fluoro-lH-indol-3-vDpropanoate
  • Step E methyl flR3E)-l-fbenzo[d][1.3]dioxol-5-yD-7-fluoro-2.3.4.9-tetrahydro-lH- pyrido[3.4-b]indole-3-carboxylate fcis-isomer) and methyl flS.3R)-l-fbenzo[d][1.3]dioxol- 5-yD-7-fluoro-2.3.4.9-tetrahydro-lH-pyrido[3.4-b]indole-3-carboxylate f trans-isomer)
  • Step F methyl nR.3R)-l-(benzordiri.31dioxol-5-vD-2-(2-chlorc)acetvD-7-fluorc)-2.3A9- tetrahydro- 1 H-pyridc>r3.4-bl indole-3 -carboxyl ate
  • Step G (6RJ 2aR)-6-(benzordin .31dioxol-5-yl)-9-fluoro-2-(4-(hvdroxymethyl)-cvclohexyl )-
  • Step H tert-butyl (6RJ 2aR)-6-(benzordiri .31dioxol-5-yl)-9-fluoro-2-(4-(Tivdroxymethyl)- cvclohexyD-L4-dioxo-L3A6.12.12a-hexahvdropyrazinorr.2':L61pyridor3.4-b1indole-7(2H)- carboxyl ate
  • Step I tert-butyl (6RJ 2aR)-6-(benzordiri .31dioxol-5-yl)-9-fluoro-2-(4-(Ynitrooxy)methyl)- cvclohexyD-E4-dioxo-E3A6.12.12a-hexahvdropyrazinorr.2':E61p y ridor3.4-b1indole-7(2H)- carboxyl ate
  • Step _ T _ (4-(Y6R.12aR)-6-(benzor d] G 1.31dioxol-5-vn-9-fluoro- 1 ,4-dioxo-3 A6.7.12.12a- hexahvdropyrazinorr.2': L61pyridor3.4-b1indol-2(TH)-v0cvclohexy0methyl nitrate
  • Step A N.N-dimethyl- 1 -P H-pyrrolor2.3-blpyridin-3-yl)methanamine
  • Step B N. N. N-trimethyl- 1 -P H-pyrrolo[2.3-blpyridin-3-yl imethanaminium iodide
  • N, N-dimethyl-l-(lH-pyrrolo[2,3-b] pyridin-3-yl)methanamine (11.5 g, 22.24 mmol) in THF (110 mL) was added Mel (5.11 mL, 24.54 mmol) at 0° C and the reaction mixture was warmed up to RT and stirred for 2h. After completion, the reaction mixture was evaporated under reduced pressure to afford the crude product which was triturated with MTBE.
  • Step C methyl 2-(Ydiphenyl methyl eneiami no )-3-( ⁇ H-pyrrolor2.3-blpyridin-3-yl ipropanoate
  • Step D methyl 2-amino-3-( l H-pyrrolo[2.3-blpyridin-3-yl ipropanoate
  • Step E methyl 2-ami no-3 -P H-pyrrolo[2.3-blpyridin-3-yl ipropanoate hydrochloride
  • Step F methyl (6R.8R)-8-(benzordiri.31dioxol-5-vn-6.7.8.9-tetrahvdro-5H-pyrrolor2.3-b:5.4- c'ldipyridine-6-carboxylate
  • methyl 2-amino-3-(lH-pyrrolo[2,3-b]pyridin-3-yl)propanoate hydrochloride 5.5 g, 21.56 mmol
  • piperonal 3.6 g, 23.72 mmol
  • Step G methyl (6R.8R)-8-(benzordin .31dioxol-5-yl)-7-(2-chloroacetyl )-6.7.8.9-tetrahydro-5H- pyrrolor 2.3 -b : 5.4-c'ldipyridine-6-carboxylate
  • Step H (5aR.l lR)-l l-(benzordirL31dioxol-5-yl)-7-(nr.4R)-4-(hvdroxymethvncvclohexyn- 5.5a.7.8.1 L12-hexahvdropyridor3".2":4'.5'lpyrrolor3'.2':4.51pyridorL2-alpyrazine-6.9-dione
  • Step I tert-butyl (5aR. 1 1 R)- 1 l-(benzordiri.31dioxol-5-yl)-7-((l r.4R)-4-(Tivdroxymethyl) cvclohexyn-6.9-dioxo-5.6.7.8.9.1 l-hexahvdropyridor3".2":4'.5'lpyrrolor3'.2':4.51pyridorE2-al pyrazine- 12(5aH)-carboxylate
  • reaction mixture was heated at 50°C for 30 min. After completion of the reaction, the mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The reaction was repeated on 150 mg scale.
  • Step J tert-butyl (5aR. 1 1 R)- 1 l-(benzordin.31dioxol-5-yl)-7-tn r.4R)-4-(Ynitrooxy)methyl) cvclohexyD-6.9-dioxo-5.6.7.8.9.1 l-hexahvdropyridor3".2":4'.5'lpyrrolor3'.2':4.51pyridorE2- alpyrazine-12(5aH)-carboxylate
  • Step K ((lR.4r)-4-((5aR.l 1R)-1 l-(benzordiri.31dioxol-5-vn-6.9-dioxo-5a.6.8.9.11.12-hexa hvdropyridor3".2":4'.5'lpyrrolor3'.2':4.51pyridori.2-alpyrazin-7(5H)-vncvclohexynmethyl nitrate
  • Step A tert-butyl (5SJ 1 aR)-5-(benzordiri .31dioxol-5-yl)-2-(4-(hvdroxymethyl)-4-((nitrooxy)- methvDcvclohexyr)-L3-dioxo-L2.3.5.1 LI la-hexahvdro-6H-imidazo
  • Step B (4-(Y5S.l laR)-5-(benzordirL31dioxol-5-vn-L3-dioxo-5.6.1 LI la-tetrahydro-lH-imidazo
  • Step B tert-butyl (5S.l laR)-5-(benzordirL31dioxol-5-vn-2-(4.4-bis(((tert-butyl dimethylsilvD oxyImethvDcvclohexyD- 1.3 -dioxo- 1.2.3.5.1
  • L 11 a-hexahydro-6H-imidazor G.5' L61 pyridor 3.4- blindole-6-carboxylate:
  • Step C tert-butyl (5S.l laR)-5-(benzordirL31dioxol-5-vn-2-(4.4-bis(hvdroxymethvn- cvclohexyO-L3-dioxo- 1.2.3.5.1 LI la-hexahvdro-6H-imidazo
  • Step D tert-butyl (5S.llaR)-5-(benzordirE31dioxol-5-vn-2-(4.4-bis((nitrooxy)methvn- cvclohexyD-E3-dioxo-E2.3.5.1 El la-hexahvdro-6H-imidazo
  • Step E (4-(Y5S.l laR)-5-(benzordirL31dioxol-5-vn-L3-dioxo-5.6.1 El la-tetrahydro-lH- imidazor G.5' : 1.61pyridor3.4-b1indol-2(3H)-vDcvclohexane- 1.1 -divDbisrin ethylene) dinitrate:
  • STEP B 1 -(4-11 uoro- 1 H-indol-3-yl )-N.N.N-trimethylmethanaminium iodide
  • STEP E methyl P R.3R1-1 -(benzordin .31dioxol-5-yl)-5-fluoro-2.3 A9-tetrahydro-l H- pyridor3.4-blindole-3-carboxylate (Cis Isomer) and methyl (lS.3R)-l-(benzordHT.31dioxol-5- yl)-5-fluoro-2J A9-tetrahydro- 1 H-pyridor3.4-blindole-3 -carboxyl ate (Trans isomer)
  • STEP G 9-(tert-butvD 3-methyl nR,3R)-l-(benzordirL31dioxol-5-yl)-2-(2-chloroacetvD-5- fluoro- 1.2.3.4-tetrahydro-9H-pyridor3.4-blindole-3.9-di carboxyl ate
  • reaction mixture was diluted with chloroform (50 mL), washed with water and brine solution.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (600 mg, 75.2%) as a light brown solid.
  • reaction mixture was heated at 100 °C for 36 h. The progress of the reaction was monitored by TLC and indicates the completion of the reaction.
  • the reaction mixture was filtered and concentrated under reduced pressure to give crude compound. It was purified over silica gel (60-120 mesh) column chromatography by eluting with 2% methanol in chloroform to give the title compound (400 mg, 60%) as a pale yellow solid.
  • the reaction mixture was stirred for 20 min. The progress of the reaction was monitored by TLC and indicated the completion of the reaction.
  • the reaction mixture was quenched with saturated aq. NaHCCL at -15 °C and extracted with chloroform (30 mL). The organic layer was separated, washed with water (10 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. It was purified over silica gel (60-120 mesh) column chromatography by eluting with 3% ethyl acetate in chloroform to give the title compound (130 mg, 40.3%) as a brown solid.
  • STEP E methyl (1 R.3R)- 1 -(benzordin .31dioxol-5-yl)-6-fluoro-2.3 A9-tetrahydro- l H- pyridor3.4-blindole-3-carboxylate and methyl (lS.3R)-l-(benzordiri.31dioxol-5-vD-6-fluoro- 2.3 A9-tetrahydro- l H-pyridor3.4-bl indole-3 -carboxyl ate
  • STEP H tert-butyl (6R.12aR)-6-(benzordirL31dioxol-5-vn-10-fluoro-2-((lr.4R)-4- (hydroxym ethyl level ohexyl )- 1.4-dioxo-l .3 A6J 2. 12a-hexahvdropyrazinon ',2': 1 ,61rnp ⁇ oG3,4- blindole-7(2H)-carboxylate
  • the progress of the reaction was monitored by TLC and indicated the completion of the reaction.
  • the reaction mixture was quenched with saturated aq. NaHCCri at -15 °C and extracted with chloroform (30 mL). The organic layer was separated, washed with water (10 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. It was purified over silica gel (100-200 mesh) column chromatography by eluting with 3% ethyl acetate in chloroform to afford the title compound (220 mg, 34%) as a pale yellow solid.
  • the reaction mixture was stirred at 70 °C for lh. The progress of the reaction was monitored by TLC.
  • the reaction mixture was concentrated under reduced pressure to give the crude compound.
  • the crude material pH was increased up to 8 by the addition of saturated aq. NaHCO 3 and extracted with DCM (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. It was purified over silica gel (100-200 mesh) column chromatography by eluting with 10% ethyl acetate in chloroform to give the title compound (20 mg, 40%) as a dark brown solid.
  • STEP B 1 -(7-fluoro- 1 H-indol-3-yl )-N.N.N-trimethylmethanaminium iodide
  • reaction mixture was washed with cold water (50 mL) and saturated NaHCCri solution (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.1 g, 83%) as a light brown solid.
  • STEP G 9-(tert-butv0 3-methyl ( ⁇ R.3R)- 1 - .31dioxol-5-yl )-2-(2-chloroacetyl )-8- fluoro- 1.2.3.4-tetrahydro-9H-pyridor3.4-blindole-3.9-di carboxyl ate
  • reaction mixture was diluted with chloroform (50 mL), washed with water and brine solution.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.1 g, 82%) as a light brown solid.
  • STEP H Tert-butyl (6R.12aR)-6-(benzordiri.31dioxol-5-vn-8-fluoro-2-((lr.4R)-4- (hydroxym ethyl icvclohexyl )- 1.4-dioxo- l .3 A6J 2. 12a-hexahydropyrazinon '.2': 1 ,61rnp ⁇ oG3,4- blindole-7(2H)-carboxylate
  • reaction mixture was heated at 100 °C for 36 h. The progress of the reaction was monitored by TLC and indicates the completion of the reaction.
  • the reaction mixture was filtered and concentrated under reduced pressure to give crude compound. It was purified over silica gel (60-120 mesh) column chromatography by eluting with 2% methanol in chloroform to give title compound (500 mg, 41%) as an off- white solid.
  • the progress of the reaction was monitored by TLC and indicated the completion of the reaction.
  • the reaction mixture was quenched with saturated aq. NaHCCri at -15 °C and extracted with chloroform (30 mL). The organic layer was separated, washed with water (10 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. It was purified over silica gel (60-120 mesh) column chromatography by eluting with 3% ethyl acetate in chloroform to give the title compound (130 mg, 40.3%) as a light brown solid.
  • STEP J ((lR.4r)-4-((6R.12aR)-6-(benzordirL31dioxol-5-vn-8-fluoro-L4-dioxo-3.4.6.7.12.12a- hexahydropyrazinorr.2': L61pyridor3.4-blindol-2(TIT)-v0cvclohexy0methyl nitrate
  • the reaction mixture was stirred at 70 °C for lh. The progress of the reaction was monitored by TLC.
  • the reaction mixture was concentrated under reduced pressure to give the crude compound.
  • the pH was increased up to 8 by the addition of saturated aq. NaHCCh and extracted with DCM (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound. It was purified over silica gel (100-200 mesh) column chromatography by eluting with 10% ethyl acetate in chloroform to afford the title compound (60 mg, 54.4%) as a pale yellow solid.
  • reaction was poured into ice water (100 mL) and adjusted the pH ⁇ 11 with 2N NaOH solution (200 mL) to obtain gummy solid.
  • the reaction mixture was extracted with EtOAc (3 x 100 mL), the combined organic layers dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude product was purified by flash column chromatography (Column size: 40 g) using 5-10% [20% MeOH-DCM in DCM] to give the title compound (3.5 g, 51%), as a brown color solid.
  • the crude mixture was purified by flash column (Column size: 24 g) chromatography using 15-30% EtOAc in petrol ether to give (0.4 g, 26%; first eluted compound) the cis isomer as a pale yellow solid and (0.48 g, 28%; second eluted compound) the trans isomer as a white solid.
  • Cis isomer 'E NMR (400 MHz, DMSO-i/e) d ppm 10.49 (s, 1H), 7.46 - 7.42 (m, 1H), 7.16 - 7.11 (m, 1H), 6.92 - 6.82 (m, 3H), 6.01 (s, 2H), 5.11 (d, J 5.6 Hz, 1H), 3.85 - 3.82 (m, 1H), 3.70 (s, 3H), 2.81 - 2.77 (m, 1H), 2.75 - 2.71 (m, 2H); LCMS (ESI): m/z 387.07 ([M+H] + ).
  • reaction was quenched with saturated NaHCCh solution (30 mL) at 0°C and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous Na2S04 and concentrate under reduced pressure to give the title compound (0.45 g) as a pale yellow solid, which was used to next step without purification.
  • reaction mixture was quenched with chilled saturated NaHCCh solution (30 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. [Note: The reaction was repeated with 2 x 400 mg scale].
  • the crude product was purified by flash column (Column size: 40 g) chromatography using 40-50% EtOAc in petrol ether to give the title compound (520 mg, -42%); LCMS (ESI): m/z 669.28 ([M+H] + ).
  • reaction mixture was then stirred at same temperature for 30 min. After completion (monitored by TLC), the reaction mixture was quenched with saturated NaHCCri solution (50 mL), extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The obtained crude product was purified by flash column (Column size: 12 g) chromatography using 70-80% EtOAc in pet ether to give the title compound (0.25 g, 46%) as an off-white solid.
  • reaction was added to ice cool water (10 mL) and adjusted the pH ⁇ 12 with 2N NaOH solution (10 mL) at 0°C and stirred for 4h.
  • the reaction mixture was extracted with 10% MeOH in DCM (2 x 100 mL).
  • the combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • the crude was purified with flash column (column size: 80 g) chromatography using 10-15% [20% MeOH-DCM in DCM + 10% TEA] to give the title compound (2.6 g, 47%) as a pale yellow solid.
  • STEP B 1 -('4.6-difluoro-l//-indol-3-yl)-A f .A f .A f -trimethylmethanaminium iodide
  • reaction mixture was slowly warmed up to RT and stirred for 3h. After completion (monitored by TLC), the reaction mixture was quenched with chilled saturated NH 4 C1 solution (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaiSCf and concentrated under reduced pressure to give the title compound (crude 5.6 g) as pale yellow liquid, which was used as such in next step without any purification.

Abstract

La présente invention concerne des composés de formule (I), ou un sel pharmaceutiquement acceptable, un solvate ou un hydrate de ceux-ci, ledit composé de formule (I) comprenant au moins une fraction -ONO2 ou -ONO liée de manière covalente et au plus quatre fractions -ONO2 ou -ONO liées de manière covalente, et AR, R1, X, R3 et R4 étant tels que définis dans la revendication 1 ; ainsi que des compositions pharmaceutiques de ceux-ci, et leur utilisation dans des méthodes de traitement ou de prévention d'une maladie atténuée par l'inhibition de PDE5 chez un être humain ou chez un mammifère non humain.
PCT/EP2021/064917 2020-06-04 2021-06-03 Nouveaux activateurs de la guanylate cyclase soluble à double mode d'action et inhibiteurs de phosphodiestérase et leurs utilisations WO2021245192A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4233867A1 (fr) 2022-02-24 2023-08-30 Nicox SA Inhibiteur de pde5 pour utilisation dans le traitement de la neuropathie optique ischémique antérieure

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4233867A1 (fr) 2022-02-24 2023-08-30 Nicox SA Inhibiteur de pde5 pour utilisation dans le traitement de la neuropathie optique ischémique antérieure
WO2023161314A1 (fr) 2022-02-24 2023-08-31 Nicox Sa Inhibiteur de la pde5 destiné à être utilisé dans le traitement d'une neuropathie optique ischémique antérieure

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