Novel dual-acting soluble guanylate cyclase activators and phosphodiesterase inhibitors and methods of use thereof

Abstract

The present invention provides a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein said compound of formula (I) and said compound of formula II each contain at least one ONO or ONO moiety; R1 is C1-C3 alkyl; R2 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C2 alkoxy, or C2-C4 alkenyl; R3 is C1-C4 alkyl optionally substituted with C1-C2 alkoxy, C3-C4 cycloalkyl, or C2-C4 alkenyl; R4 and R5 are each independently H, or F, OH, ONO, ONO, COOH, C1-C3 alkenyl, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. or C1-C6 alkyl optionally substituted with alkoxy, C3-C6 cycloalkyl, or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane, and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is optionally substituted with one or more R6 independently, wherein R6 is one or more of halogen, OH, ONO, ONO2, C1-C3 alkoxy, C1-C3 haloalkoxy, COOR7, NR8R9, C=NR 10 R7 is H or C1-C4 alkyl optionally substituted with F, OH, ONO, ONO2, NR8R9, R8 and R9 are independently H or C1-C4 alkyl optionally substituted with ONO, ONO2, R 10 is C1-C4 alkyl, C3-C6 cycloalkyl optionally substituted with F, ONO, ONO2), pharmaceutical compositions thereof, and their use in methods for treating or preventing diseases alleviated by the inhibition of PDE5 in humans or non-human mammals.

Description

[Technical field]

[0001] The present invention relates to pharma- ceutically useful compounds, in particular compounds which are activators of the enzyme soluble guanylate cyclase (sGC) and which at the same time inhibit cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE), in particular type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE5). The compounds of the invention are useful in treating conditions such as male erectile dysfunction (MED), priapism, female sexual dysfunction, Alzheimer's disease and neurodegenerative diseases, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, skin aging, glaucoma, diabetic retinopathy, age-related macular degeneration, pigmentary retinopathy, endotheliopathy (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), hair loss, cystic fibrosis, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, diabetes, wound healing, in particular They are useful in a variety of therapeutic areas including chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bed sores, particularly pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction, scleroderma, skin aging, glaucoma, diabetic retinopathy, age-related macular degeneration, pigmentary retinopathy, wound healing, particularly chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bed sores, and cancer such as breast cancer, gastrointestinal cancer, lung cancer, skin cancer, prostate cancer, pancreatic cancer, colon cancer and rectal cancer, particularly colorectal cancer. [Background technology]

[0002] Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis, and thus the degradation, of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby regulating the intracellular levels of second messengers. Inhibition of PDEs leads to an increase in the intracellular concentration of endogenous cAMP / cGMP. Thus, inhibition of PDEs can mediate various physiological mechanisms at different cellular and organ levels.

[0003] Phosphodiesterase type 5 (PDE5) specifically hydrolyzes cyclic guanylate monophosphate (cGMP) to 5'GMP. Selective inhibition of PDE5 has been validated as a relevant approach, and strategies aimed at promoting inhibition of PDE5 activity have been applied and suggested as therapeutic tools, especially for neurological and cardiovascular diseases as well as cancer. Moreover, the introduction of PDE5 inhibitors has 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). Several PDE5 inhibitors are on the market and have been characterized for MED or pulmonary hypertension (PH), especially pulmonary arterial 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) March 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., Oncotarget (2017) 8(58):99179-99202; Vighini et al., Oncotarget (2017) 8(58):99179-99202; E et al., Oncotarget (2018) 9(4): 5301-5320; Huang W et al., Gastroenterology 2019; 157: 672-681; and references cited therein). The most prominent examples of PDE5 inhibitors are sildenafil, tadalafil, vardenafil and mirodenafil, which are described, inter alia, in, for example, WO 99 / 24433, WO 01 / 60825, EP 995'751 and WO 2011 / 075655. Recently, a new class of highly potent PDE5 inhibitors has been described (WO 2017 / 085056A1).

[0004] In addition to the success of known PDE5 inhibitors, there is still a need for further more effective drugs and their pharmaceutical compositions for use in the therapeutic treatment or prevention of diseases related to disturbed cGMP balance.Furthermore, there is still a need for compounds and their pharmaceutical compositions that are useful for use in the therapeutic treatment or prevention of diseases related to cGMP imbalance in general.

[0005] Endothelial dysfunction leads to an imbalance between vasodilator and vasoconstrictor mediators, shifting towards the latter. One important mechanism is that endothelial NO production remains impaired, with the concomitant decrease in the activation of soluble guanylyl cyclase (sGC) in adjacent smooth muscle cells. Strategies have been described to increase the disturbed cGMP level by improving cGMP synthesis and enhancing cGMP in vascular smooth muscle by inhibiting its degradation. An example is the combination of sGC stimulators or activators in combination with PDE5 inhibitors, for example WO2010 / 081647 or US2002 / 0182162. Summary of the Invention

[0006] The inventors have surprisingly found that the dual pharmacological compounds of the present invention, designed as NO-releasing PDE5 inhibitors, which are believed to release NO in addition to PDE5 inhibition, modulate cGMP levels in a more than additive manner, and therefore in a synergistic manner. The inventors have further surprisingly found that the compounds of the present invention are highly bound to plasma proteins when they reach the blood circulation. High protein binding capacity results in very little free exposure to the whole body, making the compounds described in the present invention particularly amenable to local application and local action. The synergistic increase in cGMP results in very strong vasodilation, angiogenesis, enhanced microcirculation and inhibition of endothelial dysfunction (see FIG. 1). Thus, the dual pharmacological NO-releasing PDE5 inhibitors of the present invention are expected to be particularly beneficial in the treatment of disorders in which NO production is reduced, such as in conditions of endothelial dysfunction. Moreover, the dual pharmacological NO-releasing PDE5 inhibitors of the present invention are further believed to be highly beneficial in the treatment of diabetic patients.

[0007] Moreover, the present inventors have surprisingly found that the compounds of the present invention even show significantly higher efficacy in raising intracellular cGMP compared with known PDE5 inhibitors such as sildenafil or vardenafil.In addition, the present inventors have found that some compounds of the present invention have very high binding with plasma protein, making them particularly suitable for local application and local action.As a result, the novel pyrazolopyrimidone and imidazotriazinone compounds of the present invention are useful for treating and preventing diseases related to disturbed cGMP balance.

[0008] Due to the potent and selective PDE5 inhibition combined with the stimulation of soluble guanylate cyclase shown by the compounds of the present invention, cGMP level is increased, which can then produce beneficial vasodilatory activity, antivasoconstrictive activity, antiplatelet activity, natriuretic activity and diuretic activity.In addition, the dual pharmacological NO-releasing PDE5 inhibitor allows the release of nitric oxide to activate soluble guanylate cyclase and PDE5 inhibition in a more than additive manner.Surprisingly, the compounds of the present invention further increase intracellular cGMP level in comparison with the equimolar effect of the combination of organic nitrate and PDE5 inhibitor shown in Figure 3A and Figure 3B.

[0009] Thus, the compounds of the present invention have utility in a variety of therapeutic areas where a disturbed cGMP balance has occurred and / or where PDE5 inhibition is believed to be beneficial. The compounds of the present invention are particularly suitable for topical drug application as shown in FIG. Some of the preferred treatment areas are glaucoma, diabetic retinopathy, age-related macular degeneration, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction, wound healing, especially chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, Alzheimer's disease, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, diabetes, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, chronic heart failure, cancer, breast cancer, gastrointestinal cancer, non-small cell lung cancer, skin cancer such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate cancer and pancreatic cancer, especially colorectal cancer.

[0010] Thus, in a first aspect, the present invention provides a compound of formula I or formula II: [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: The compounds of formula I and II each comprise at least one covalently bound ONO 2 or an ONO moiety, and preferably, the compounds of formula I and the compounds of formula II each contain at least one covalently bound ONO 2 or an ONO moiety and up to four covalently bound ONO 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocyclic ring, preferably the heterocyclic ring is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocyclic ring is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 is alkyl, R7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 is cycloalkyl, Preferably, the compound of formula I is [ka] isn't it.

[0011] In a further aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds of the present invention of formula I or formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant, or carrier.

[0012] In another aspect, the present invention provides a compound of Formula I or Formula II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use as a medical treatment.

[0013] In another aspect, the present invention provides a compound of Formula I or Formula II or a pharmaceutical composition or a pharma- ceutically acceptable salt, solvate or hydrate thereof for use in a method of treating or preventing in a human or non-human mammal, preferably a human, a disease that is alleviated by the inhibition of PDE5, preferably the disease is selected from the group consisting of glaucoma, diabetic retinopathy, age-related macular degeneration, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, stable angina, unstable angina and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, and / or chronic myocardial infarction. The cancer is selected from embolism, pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, achalasia, sickle cell disease (SCD), diabetic nephropathy, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, diseases characterized by intestinal motility disorders such as irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, and cancers that are breast and gastrointestinal cancers, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancers such as colorectal cancer, and prostate and pancreatic cancers, in particular colorectal cancer.

[0014] In another aspect, the present invention provides a compound of formula I or formula II or a pharmaceutical composition or a pharma- ceutically acceptable salt, solvate or hydrate thereof for use in a method of treating or preventing a disease in a human or non-human mammal, preferably a human, comprising administering to said mammal a therapeutically effective amount of the compound of formula I or formula II or a pharmaceutical composition or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or non-human mammal, preferably a human, the disease being selected from the group consisting of glaucoma, diabetic retinopathy, age-related macular degeneration, 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 arterial hypertension, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, stable angina, unstable angina and variant (Prinzmetal) angina, high blood pressure, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, The disease is selected from achalasia, sickle cell disease (SCD), inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, gastrointestinal motility disorders such as irritable bowel syndrome, hepatic fibrosis, Alzheimer's disease and chronic heart failure, and preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and The cancer is selected from female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and pressure ulcers, as well as breast and gastrointestinal cancers, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancers such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer.

[0015] Further aspects and embodiments of the invention will become apparent as this description continues. [Brief description of the drawings]

[0016] [Figure 1] PDE5 inhibition and activation of soluble guanylate cyclase from a single molecule. [Diagram 2]Dual pharmacological NO releasing PDE5 inhibitors to address disturbed cGMP balance in diseases with disturbed cGMP balance. [Figure 3A] Concentration-dependent measurement of cyclic guanosine 3'-5'-monophosphate (cGMP) in 10 μM riociguat-stimulated human trabecular meshwork cells (HTMC) incubated in the presence of the compound of the invention, 2a. [Figure 3B] Measurement of cyclic guanosine 3'-5'-monophosphate (cGMP) in human trabecular meshwork cells (HTMC) stimulated with 10 μM riociguat incubated in the presence of 1 μM sildenafil or 1 μM vardenafil and 0, 1, 10 1 μM isosorbide 2-nitrate. [Figure 4] Human pulmonary artery smooth muscle cells (hPASMC) incubated in the presence of compounds of the invention 2a and 1c or the reference PDE5 inhibitor vardenafil. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. The embodiments, preferred and highly preferred embodiments described and disclosed herein should be applied to all aspects and other embodiments, preferred and highly preferred embodiments, whether or not specifically mentioned again, and whether or not their repetition is avoided for brevity.

[0018] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. The term "or" as used herein should be understood to mean "and / or" unless the context clearly indicates otherwise.

[0019] The inventors have surprisingly found that the compound of the present invention is a dual pharmacological NO-releasing PDE5 inhibitor, which, in addition to its PDE5 inhibition, releases NO, and is believed to lead to further stimulation of intracellular cGMP elevation.In addition, the compound of the present invention even shows significantly higher efficacy of stimulating cGMP compared with known single pharmacological PDE5 inhibitors such as sildenafil or vardenafil.In addition, when the compound of the present invention reaches blood circulation, it is highly bound to plasma protein, which makes it particularly easy to apply locally and act locally.

[0020] Thus, in a first aspect, the present invention provides a compound of formula I or formula II: [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: The compounds of formula I and II each comprise at least one covalently bound ONO 2 or ONO moiety, and preferably, the compounds of formula I and the compounds of formula II each contain at least one ONO moiety. 2 Or ONO part and up to 4 ONOs 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 is alkyl, R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9are independently H, or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 is cycloalkyl, The compound of formula I is [ka] isn't it.

[0021] Thus, in a first aspect, the present invention provides a compound of formula I or formula II: [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: The compounds of formula I and II each contain at least one ONO 2 or ONO moiety, and preferably, the compounds of formula I and the compounds of formula II each contain at least one ONO moiety. 2 Or ONO part and up to 4 ONOs 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 is alkyl, R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with1 ~C 4 is alkyl, R 8 and R 9 are independently H, or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 It is cycloalkyl.

[0022] Typically and preferably, the compound of formula I is [ka] isn't it.

[0023] Thus, in a further aspect, the present invention provides a compound of formula I or formula II: [ka] or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: R 4 and R 5 At least one of the 2 or an ONO moiety, preferably R 4 and R 5 At least one of the 2 or an ONO moiety, and up to four, typically and preferably covalently linked ONO 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 alkyl, preferably R 6 At least one, typically and preferably covalently bound ONO 2 or ONO moieties, more preferably up to four, typically and preferably covalently linked ONO 2 or containing an ONO moiety, R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H, or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 is cycloalkyl, The compound of formula I is [ka] isn't it.

[0024] In a further aspect, the present invention provides a compound of formula I or formula II, [ka] wherein said compound of formula I and said compound of formula II each comprise at least one, typically and preferably covalently bound ONO 2or ONO moiety, preferably the compounds of formula I and the compounds of formula II each contain at least one, typically and preferably covalently bound ONO 2 or an ONO moiety and up to four, typically and preferably covalently linked ONO 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 alkyl, preferably R 6 At least one ONO 2 or an ONO moiety, more preferably up to four ONO 2 or containing an ONO moiety. R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 is cycloalkyl, The compound of formula I is [ka] isn't it.

[0025] In a further aspect, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: [ka] The compounds of formula I contain at least one covalently bound ONO 2 or an ONO moiety, preferably the compound of formula I comprises at least one covalently bound ONO 2 or an ONO moiety and up to four covalently bound ONO 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 alkyl, preferably R 6 At least one ONO 2 or an ONO moiety, more preferably up to four ONO 2 or containing an ONO moiety. R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with1 ~C 4 Alkyl, C 3 ~C 6 is cycloalkyl, The compound of formula I is [ka] isn't it.

[0026] In a further aspect, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: [ka] The compounds of formula I include at least one ONO 2 or ONO moiety, preferably the compound of formula I comprises at least one ONO 2 Or ONO part and up to 4 ONOs 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2, COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 alkyl, preferably R 6 At least one ONO 2 or an ONO moiety, more preferably up to four ONO 2 or containing an ONO moiety. R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H or ONO, ONO 2C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 It is cycloalkyl.

[0027] Typically and preferably, the compound of formula I is [ka] isn't it.

[0028] In a preferred embodiment of the invention, the compound of formula II comprises at least one ONO 2 Or ONO part and up to 4 ONOs 2 or ONO moieties. In a preferred embodiment of the invention, the compound of formula II comprises at least two ONO 2 Or ONO part and up to 4 ONOs 2 or ONO moiety. In a preferred embodiment of the invention, the compound of formula II comprises at least one ONO 2 Or ONO part and up to 4 ONOs 2 and ONO moieties. In a preferred embodiment of the invention, the compound of formula II comprises at least two ONO 2 Or ONO part and up to 4 ONOs 2 and ONO moieties. In another preferred embodiment of the invention, the compound of formula II comprises up to four ONO 2 or ONO moieties. In another preferred embodiment of the invention, the compound of formula II contains up to four ONO 2 and ONO moiety.

[0029] In a preferred embodiment of the invention, the compound of formula I comprises at least one covalently bound ONO 2 or an ONO moiety and up to four covalently bound ONO 2or ONO moieties. In a preferred embodiment of the invention, the compound of formula I comprises at least two covalently linked ONO moieties. 2 or an ONO moiety and up to four covalently bound ONO 2 or ONO moiety. In a preferred embodiment of the invention, the compound of formula I comprises at least one covalently bound ONO 2 or an ONO moiety as well as up to four covalently bound ONO 2 and ONO moieties. In a preferred embodiment of the invention, the compound of formula I comprises at least two covalently linked ONO 2 or an ONO moiety as well as up to four covalently bound ONO 2 and ONO moieties. In another preferred embodiment of the invention, the compound of formula I comprises up to four covalently linked ONO 2 or ONO moieties. In another preferred embodiment of the invention, the compound of formula I comprises up to four covalently linked ONO moieties. 2 and ONO moiety.

[0030] In a further aspect, the present invention provides a compound of formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: [ka] The compounds of formula II contain at least one covalently bound ONO 2 or an ONO moiety, preferably the compound of formula II contains at least one covalently bound ONO 2 or an ONO moiety and up to four covalently bound ONO 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 alkyl, preferably R 6At least one ONO 2 or an ONO moiety, more preferably up to four ONO 2 or containing an ONO moiety. R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 is cycloalkyl, The compound of formula I is [ka] isn't it.

[0031] In a further aspect, the present invention provides a compound of formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: [ka] The compound of formula II comprises at least one ONO 2 or ONO moiety, preferably the compound of formula II contains at least one ONO 2 Or ONO part and up to 4 ONOs 2 or containing an ONO moiety, R 1 is C 1 ~C 3 is alkyl, R 2 , H, C1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 and preferably the heterocycle is independently substituted with one, two, three or four R 6 and more preferably, the heterocycle is independently substituted with one or two R 6 and R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R.8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 alkyl, preferably R 6 At least one ONO 2 or an ONO moiety, more preferably up to four ONO 2 or containing an ONO moiety. R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 It is cycloalkyl.

[0032] Typically and preferably, the compound of formula I is [ka] isn't it.

[0033] In a preferred embodiment of the invention, the compound of formula II comprises at least one ONO 2 Or ONO part and up to 4 ONOs 2 or ONO moieties. In a preferred embodiment of the invention, the compound of formula II comprises at least two ONO 2 Or ONO part and up to 4 ONOs 2or ONO moiety. In a preferred embodiment of the invention, the compound of formula II comprises at least one ONO 2 Or ONO part and up to 4 ONOs 2 and ONO moieties. In a preferred embodiment of the invention, the compound of formula II comprises at least two ONO 2 Or ONO part and up to 4 ONOs 2 and ONO moieties. In another preferred embodiment of the invention, the compound of formula II comprises up to four ONO 2 or ONO moieties. In another preferred embodiment of the invention, the compound of formula II contains up to four ONO 2 and ONO moiety.

[0034] In a preferred embodiment of the invention, the compound of formula II comprises at least one covalently bound ONO 2 or an ONO moiety and up to four covalently bound ONO 2 or ONO moieties. In a preferred embodiment of the invention, the compound of formula II comprises at least two covalently linked ONO moieties. 2 or an ONO moiety and up to four covalently bound ONO 2 or ONO moiety. In a preferred embodiment of the invention, the compound of formula II comprises at least one covalently bound ONO 2 or an ONO moiety as well as up to four covalently bound ONO 2 and ONO moieties. In a preferred embodiment of the invention, the compound of formula II comprises at least two covalently linked ONO moieties. 2 or an ONO moiety as well as up to four covalently bound ONO 2 and ONO moieties. In another preferred embodiment of the invention, the compound of formula II comprises up to four covalently linked ONO moieties. 2 or ONO moieties. In another preferred embodiment of the invention, the compound of formula II comprises up to four covalently linked ONO moieties. 2 and ONO moiety.

[0035] The term "alkyl," as used herein, consists solely of carbon and hydrogen atoms, contains no unsaturation, and typically and preferably has 1 to 6 carbon atoms (e.g., C 1 ~ 6 Alkyl) refers to a straight or branched hydrocarbon chain radical, typically attached to the rest of the molecule by a single bond. Whenever it appears herein, a numerical range such as "1-6" refers to each integer within the given range. For example, "1-6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to 6 carbon atoms, but the definition is also intended to cover occurrences of the term "alkyl" where no numerical range is specifically specified. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl.

[0036] The term "alkoxy" as used herein refers to a "substituted hydroxyl" of the formula (-OR'), where R' is an "alkyl", as defined herein, and the oxygen moiety is directly attached to the parent molecule, thus "C 1 ~C 6 The term "-alkoxy" as used herein refers to a straight or branched C alkyl group which may be, for example, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neo-pentoxy, n-hexoxy. 1 ~C 6 As described herein, alkoxy may include further substituents such as halogen atoms, resulting in a haloalkoxy moiety.

[0037] The term "alkylene," as used herein, refers to a biradical of a straight or branched hydrocarbon chain derived from an alkyl, as defined herein, in which one hydrogen of the alkyl is broken to produce a second radical of the alkylene. Examples of alkylenes include, by way of illustration, -CH 2 -, -CH2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 - or -CH(CH 2 CH 3 )-.

[0038] Each cycloalkyl moiety may be in mono- or bicyclic form, typically and preferably in monocyclic form, and preferably contains from 3 to 8 carbon atoms, more preferably from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyl moieties include cyclopropyl, cyclobutyl and cyclohexyl.

[0039] Each alkenyl moiety, either alone or as part of a larger moiety such as alkenyloxy or alkenylene, may be straight or branched chain and is preferably C 2 ~C 6 Alkenyl, more preferably C 2 ~C 4 alkenyl. Each moiety may be in either the (E)- or (Z)-configuration. Examples include vinyl and allyl. Thus, compounds of the invention that contain an alkenyl moiety may include, where applicable, those compounds having the alkenyl moiety in its (E)-configuration, those compounds having the alkenyl moiety in its (Z)-configuration, and mixtures thereof, in any ratio.

[0040] The term "ONO2" refers to a nitrate moiety as described herein. * -O-NO 2 Refers to, * indicates the bond to the parent structure and the remainder of the molecule. Preferably, the ONO2 is a terminal ONO substituent.

[0041] The term "ONO" refers to the nitrite moiety described herein. * -O-NO, *indicates the bond to the parent structure and the remainder of the molecule. Preferably, the ONO2 is a terminal ONO2 substituent.

[0042] The term "cycloalkoxy" refers to an -O-cycloalkyl group, where "cycloalkyl" is defined herein as being attached to an oxygen directly attached to the parent molecule. Examples include, but are not limited to, cyclopropyloxy and cyclohexyloxy. As described herein, cycloalkoxy may include further substituents such as halogen atoms.

[0043] Halogen is fluorine, chlorine, bromine or iodine.

[0044] Each haloalkyl moiety, either alone or as part of a larger moiety such as haloalkoxy, is an alkyl moiety substituted with one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoroethyl.

[0045] The term "heterocycle" 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, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, tetrahydrofuran, dioxane, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, more preferred are aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane.

[0046] When a moiety is said to be substituted or optionally substituted, preferably there are 1 to 5 substituents or optionally 1 to 5 substituents, more preferably 1 to 4 substituents or optionally 1 to 4 substituents, more preferably 1 to 3 substituents or optionally 1 to 3 substituents, and even more preferably 1 or 2 substituents or optionally 1 or 2 substituents, unless a different preferred number of substitutions or optional substitutions is specifically indicated. When a moiety is said to be substituted or optionally substituted and there is more than one substituent for that substitution or optional substitution of the moiety, the one or more substituents may be the same or different.

[0047] Certain compounds of formula I or II of the present invention may contain one or more chirality centers, and such compounds may be provided as pure enantiomers or pure diastereoisomers, as well as mixtures thereof in any ratio. Compounds of the present invention also include all tautomeric forms of compounds of formula I or II. Compounds of formula I or II may also be solvated, particularly hydrated, which also includes compounds of formula I or II. Solvation and hydration may occur during the preparation process.

[0048] As a result, the compounds of the invention, and thus the compounds of formula I or II, include stereoisomers, geometric isomers and tautomers.Furthermore, the compounds of the invention, and thus the compounds of formula I or II, include solvates or hydrates thereof, pharma-ceutically acceptable salts, and solvates or hydrates of those salts.

[0049] The compounds of formula I or II of the present invention include pharmaceutically acceptable salts of said compounds.In particular, the term "pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention, particularly 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 methanesulfonic acid, p-toluenesulfonic acid, lactic acid, malic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.Further examples of pharmacologically acceptable salts of compounds of formula I or II are, for example, alkali metal and alkaline earth metal salts such as sodium, potassium, lithium, calcium or magnesium salts, ammonium salts such as methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts, or salts of organic bases. Further examples of pharma- ceutically acceptable salts of the compounds of formula I or II include hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogen phosphate, nitrate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, benzenesulfonate, p-toluenesulfonate, and the like.

[0050] "Solvate" refers to an association or complex of one or more solvent molecules with the compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0051] Typically and preferably, at least one ONO is used herein. 2 or containing an ONO moiety, such as those of formula I, I * or formula II, II * When referring to a compound of formula I, I * or formula II, II * The compound of the present invention has at least one covalently bound ONO2 or at least one ONO as the ONO moiety 2 or ONO moiety. Thus, in a preferred embodiment, the compound of formula I or formula II, respectively, comprises at least one ONO 2 Or ONO part and up to 4 ONOs 2 or ONO moieties. In a preferred embodiment, the compound of formula I or formula II, respectively, contains at least two ONO 2 Or ONO part and up to 4 ONOs 2 or ONO moiety. In a preferred embodiment, the compound of formula I or formula II, respectively, comprises at least one ONO moiety. 2 Or ONO part and up to 4 ONOs 2 and ONO moieties. In a preferred embodiment, the compounds of formula I or formula II each contain at least two ONO 2 Or ONO part and up to 4 ONOs 2 and ONO moieties. In another preferred embodiment, the compound of formula I or formula II each contains up to four ONO moieties. 2 or ONO moieties. In another preferred embodiment, the compound of formula I or formula II, respectively, contains up to four ONO moieties. 2 and ONO moieties. In another preferred embodiment, the compound of formula I or formula II, respectively, comprises at least one ONO moiety. 2 Partial and up to 4 ONOs 2 In a preferred embodiment, the compound of formula I or formula II each comprises at least two ONO moieties. 2 Partial and up to 4 ONOs 2 In a preferred embodiment, the compound of formula I or formula II each comprises at least one ONO moiety. 2 Partial and up to 4 ONOs 2 In a preferred embodiment, the compound of formula I or formula II each comprises at least two ONO moieties. 2 Partial and up to 4 ONOs 2 In another preferred embodiment, the compound of formula I or formula II each comprises up to four ONO moieties.2 In another preferred embodiment, the compound of formula I or formula II each comprises up to four ONO moieties. 2 Includes parts.

[0052] In a preferred embodiment of the invention, the compound of formula I or formula II each contains exactly one ONO 2 In another preferred embodiment, the compound of formula I or formula II, respectively, contains exactly one ONO moiety. In a preferred embodiment, the compound of formula I or formula II, respectively, contains exactly one ONO moiety. 2 In another preferred embodiment, the compound of formula I or formula II each comprises exactly two ONO moieties. 2 or two ONO moieties. In another preferred embodiment, the compound of formula I or formula II, respectively, contains exactly two ONO moieties. 2 In another preferred embodiment, the compound of formula I or formula II, respectively, contains exactly two ONO moieties. In another preferred embodiment, the compound of formula I or formula II, respectively, contains exactly one ONO moiety. 2 In another preferred embodiment, the compound of formula I or formula II, respectively, comprises an ONO moiety. 2 and at least three moieties selected from the group consisting of ONO and ONO moieties, and up to four ONO moieties. 2 or ONO moieties. In another preferred embodiment, the compound of formula I or formula II, respectively, contains exactly three ONO moieties. 2 In another preferred embodiment, the compound of formula I or formula II, respectively, contains an ONO moiety. 2 In another preferred embodiment, the compound of formula I or formula II each contains exactly three moieties selected from the group consisting of ONO, OH ... 2 or 4 ONO moieties. In another preferred embodiment, the compound of formula I or formula II, respectively, contains ONO 2 and ONO moieties.

[0053] In a preferred embodiment of the invention, the compound is a compound of formula I, wherein the compound of formula I is a compound having exactly one ONO 2 In another preferred embodiment, the compound of formula I contains exactly one ONO moiety. In a preferred embodiment, the compound of formula I contains an ONO 2 or ONO moieties. In another preferred embodiment, the compound of formula I comprises exactly two ONO 2 or two ONO moieties. In another preferred embodiment, the compound of formula I contains exactly two ONO moieties. 2 In another preferred embodiment, the compound of formula I contains exactly two ONO moieties. In another preferred embodiment, the compound of formula I contains exactly one ONO moiety. 2 In another preferred embodiment, the compound of formula I comprises an ONO moiety. 2 and at least three moieties selected from the group consisting of ONO and ONO moieties, and up to four ONO moieties. 2 or ONO moieties. In another preferred embodiment, the compound of formula I contains exactly three ONO 2 or 3 ONO moieties. In another preferred embodiment, the compound of formula I contains an ONO 2 In another preferred embodiment, the compound of formula I contains exactly three moieties selected from the group consisting of ONO, OH ... 2 or 4 ONO moieties. In another preferred embodiment, the compound of formula I contains an ONO 2 In another preferred embodiment of the invention, the compound is a compound of formula I, which comprises at least two ONO moieties. 2 Partial and up to 4 ONOs 2 In another preferred embodiment, the compound of formula I comprises at least three ONO moieties. 2 Partial and up to 4 ONOs 2 In another preferred embodiment, the compound of formula I comprises exactly three ONO moieties. 2 In another preferred embodiment, the compound of formula I comprises exactly three moieties ONO2 In another preferred embodiment, the compound of formula I comprises exactly four ONO moieties. 2 Contains an ONO moiety.

[0054] In a preferred embodiment, the compound is a compound of formula II, wherein the compound of formula II is a compound having exactly one ONO 2 In another preferred embodiment, the compound of formula II contains exactly one ONO moiety. In a preferred embodiment, the compound of formula II contains an ONO 2 or ONO moieties. In another preferred embodiment, the compound of formula II comprises exactly two ONO moieties. 2 or two ONO moieties. In another preferred embodiment, the compound of formula II contains exactly two ONO moieties. 2 In another preferred embodiment, the compound of formula II contains exactly two ONO moieties. In another preferred embodiment, the compound of formula II contains exactly one ONO moiety. 2 and one ONO moiety. In another preferred embodiment, the compound of formula II comprises an ONO moiety. 2 and at least three moieties selected from the group consisting of ONO and ONO moieties, and up to four ONO moieties. 2 or ONO moieties. In another preferred embodiment, the compound of formula II contains exactly three ONO 2 or 3 ONO moieties. In another preferred embodiment, the compound of formula II contains an ONO 2 In another preferred embodiment, the compound of formula II contains exactly three moieties selected from the group consisting of ONO, OH ... 2 or 4 ONO moieties. In another preferred embodiment, the compound of formula II contains ONO 2 and ONO moieties. In another preferred embodiment of the invention, the compound is a compound of formula II, wherein the compound of formula II comprises at least two ONO moieties. 2 Partial and up to 4 ONOs 2 In another preferred embodiment, the compound of formula II comprises at least three ONO moieties.2 Partial and up to 4 ONOs 2 In another preferred embodiment, the compound of formula II comprises exactly three ONO moieties. 2 In another preferred embodiment, the compound of formula II comprises exactly three moieties ONO 2 In another preferred embodiment, the compound of formula II comprises exactly four ONO moieties. 2 Contains an ONO moiety.

[0055] In a preferred embodiment of the present invention, R 1 is C 1 ~C 3 In a further preferred embodiment, R 1 is CH 3 or C 2 H 5 In a further highly preferred embodiment, R 1 is CH 3 It is.

[0056] In a preferred embodiment of the present invention, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 In a preferred embodiment of the present invention, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 4 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 In a further preferred embodiment, the R 2 , H, C 1 ~C 6 Alkyl or C 3 ~C 4 In a further preferred embodiment, R 2 is C 1 ~C6 Alkyl or C 3 ~C 4 In a further preferred embodiment, R 2 is C 1 ~C 3 Alkyl or C 3 ~C 6 In a further preferred embodiment, R 2 is C 1 ~C 6 In a further preferred embodiment, R 2 is C 1 ~C 3 In a further preferred embodiment, R 2 is C 3 ~C 6 Cycloalkyl, preferably C 3 ~C 4 In a highly preferred embodiment of the present invention, R 2 is C 2 ~C 3 In a highly preferred embodiment, R 2 is n-propyl.

[0057] In another preferred embodiment, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 In a further preferred embodiment, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Optionally substituted with cycloalkyl 1 ~C 4 In a further preferred embodiment, R 3 is C 1 ~C 4 In a further highly preferred embodiment, R 3is ethyl or n-propyl. In a further highly preferred embodiment, R 3 is ethyl. In a further highly preferred embodiment, R 3 is n-propyl.

[0058] In another preferred embodiment, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 In another preferred embodiment, R 6 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 In another preferred embodiment, R 7 is H or F, OH, ONO, ONO 2 , N.R. 8 R 9 C which may be substituted with 1 ~C 4 In another preferred embodiment, R 8 and R 9are each independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 In another preferred embodiment, R 10 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 6 It is cycloalkyl.

[0059] In another preferred embodiment, R 4 and R 5 are each independently H or F, OH, ONO, ONO 2 , COOH, C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 It is an alkyl.

[0060] In a further preferred embodiment, R 4 and R 5 are each independently H or C 1 ~C 3 Alkoxy, C 3 ~C 6 Optionally substituted with cycloalkyl 1 ~C 6 or together with the nitrogen atom to which they are attached form a heterocycle, preferably the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is preferably selected from one or more R 6 may be independently substituted with

[0061] In another preferred embodiment, R 4 and R 5together with the nitrogen atom to which they are attached form a heterocycle, which is formed by one or more R 6 In another preferred embodiment, R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocycle, which heterocycle is 6 In another preferred embodiment, R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocycle, which is 6 In another preferred embodiment, R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocycle, which heterocycle is 6 In another preferred embodiment, R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocycle, which is 6 In another preferred embodiment, the heterocycle is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane, and 3,7-diazabicyclo[3,3,0]octane. 4 and R 5 the heterocycle formed together with the nitrogen atom to which they are attached is selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane, and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is selected from one or more R 6 and preferably each independently has one or two R 6 may be independently substituted with

[0062] In another preferred embodiment, the R6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 is alkyl, R 7 is H or OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 8 and R 9 are each independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 , ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 4 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, COOR 7 C may be independently substituted with 1 ~C 6 alkyl, preferably, 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 is alkyl, R 7 is H or OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 It is an alkyl.

[0063] In another preferred embodiment, R4 and R 5 together with the nitrogen atom to which they are attached form a heterocycle selected from piperidine, piperazine and homopiperazine, and the heterocycle is selected from one or more R 6 In another preferred embodiment, the heterocycle is optionally substituted independently with one, two or three R 6 In another preferred embodiment, the heterocycle is optionally substituted independently with one or two R 6 In another preferred embodiment, the heterocycle is optionally substituted independently with one, two or three R 6 In another preferred embodiment, the heterocycle is independently substituted with one or two R 6 In another highly preferred embodiment, the heterocycle is piperidine or piperazine. In another highly preferred embodiment, the heterocycle is piperidine. In another highly preferred embodiment, the heterocycle is piperazine. In another highly preferred embodiment, the heterocycle is piperidine or piperazine. In another highly preferred embodiment, the heterocycle is independently substituted with one or two R 6 In another highly preferred embodiment, the heterocycle is a piperidine optionally independently substituted with one or two R 6 and R 1 is an optionally substituted piperazine.

[0064] In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, COOR 7 , N.R. 8 R 9 , C=NR 10 C may be independently substituted with 1 ~C 6 is alkyl, R 7 is H or OH, ONO, ONO 2 C which may be substituted with 1 ~C 4is alkyl, R 8 and R 9 are each independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 10 , ONO, ONO 2 C which may be substituted with 1 ~C 4 Alkyl, C 3 ~C 4 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, COOR 7 C may be independently substituted with 1 ~C 6 alkyl, preferably, 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, COOR 7 C independently substituted with 1 ~C 6 alkyl, preferably, 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, COOR 7 C may be independently substituted with1 ~C 6 alkyl, preferably, 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 is alkyl, R 7 is H or OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C independently substituted with haloalkoxy 1 ~C 6 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 C may be independently substituted with 1 ~C 6 In another preferred embodiment, the R 6 is one or more OH, ONO, ONO 2 C independently substituted with 1 ~C 6 It is an alkyl.

[0065] In a further highly preferred embodiment, the compound of formula I has formula I * and the compound of formula II is a compound of formula II * or the compound of I* and II * and for each independently, a pharma- ceutically acceptable salt, solvate, or hydrate thereof; [ka] In the formula, R 1 , R 2 and R 3 is as defined herein, preferably R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 alkyl, wherein X is CR 16 or N, R 11 , R 12 , R 13 , R 14 and R 15 are independently H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C6 With alkyl, R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 17 is H or F, OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 18 and R 19 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 20 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, The R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, preferably 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R15 and R 16 Each other, ONO 2 and an ONO moiety.

[0066] Typically and preferably, the compound of formula I * The compound of [ka] isn't it.

[0067] In a further highly preferred embodiment, the compound of formula I has formula I * and the compound of formula II is a compound of formula II * or the compound of I * and II * and for each independently, a pharma- ceutically acceptable salt, solvate, or hydrate thereof; [ka] [ka] In the formula, R 1 , R 2 and R 3 is as defined herein, preferably R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 alkyl, wherein X is CR 16 or N, R 11 , R 12 , R 13 , R 14 and R 15 are independently H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 17 is H or F, OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 18 and R 19 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 20 F, ONO, ONO2 C which may be substituted with 1 ~C 4 is alkyl, The R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, preferably 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and up to four moieties selected from the group consisting of an ONO moiety, Formula I * The compound of [ka] isn't it.

[0068] In a preferred embodiment of the present invention, the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and ONO moieties. In a preferred embodiment of the invention, the R11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the ONOs is independently selected from at least two ONOs. 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and an ONO moiety.

[0069] In a preferred embodiment of the present invention, the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 part, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each of them can use up to four ONOs. 2 In a preferred embodiment of the invention, the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the ONOs is independently selected from at least two ONOs. 2 part, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each of them can use up to four ONOs. 2 Includes parts.

[0070] In a further highly preferred embodiment, the compound of formula I has formula I *or a pharma- ceutically acceptable salt, solvate or hydrate thereof; [ka] In the formula, R 1 , R 2 and R 3 is as defined herein, preferably R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 alkyl, wherein X is CR 16 or N, R 11 , R 12 , R 13 , R 14 and R 15 are independently H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 17 is H or F, OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 18 and R 19 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 20 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, The R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, preferably 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO2 and up to four moieties selected from the group consisting of an ONO moiety, Formula I * The compound of [ka] isn't it.

[0071] In a further highly preferred embodiment, the compound of formula I has formula I * or a pharma- ceutically acceptable salt, solvate or hydrate thereof; [ka] In the formula, R 1 , R 2 and R 3 is as defined herein, preferably R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C 1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 is alkyl, X is CR 16 or N, R 11 , R 12 , R 13 , R 14 and R 15are independently H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 17 is H or F, OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 18 and R 19 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 20 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, The R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2or an ONO moiety, preferably 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and an ONO moiety.

[0072] Typically and preferably, the compound of formula I is [ka] isn't it.

[0073] In a further highly preferred embodiment, the compound of formula II is * or a pharma- ceutically acceptable salt, solvate or hydrate thereof; [ka] In the formula, R 1 , R 2 and R 3 is as defined herein, preferably R 1 is C 1 ~C 3 is alkyl, R 2 , H, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 2 Alkoxy, C 2 ~C 4 alkenyl, R 3 is C1 ~C 2 Alkoxy, C 3 ~C 4 Cycloalkyl, C 2 ~C 4 C optionally substituted with alkenyl 1 ~C 4 alkyl, wherein X is CR 16 or N, R 11 , R 12 , R 13 , R 14 and R 15 are independently H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 With alkyl, R 17 is H or F, OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, R 18 and R 19 are independently H or ONO, ONO 2 C which may be substituted with 1 ~C4 is alkyl, R 20 F, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, The R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, preferably 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and an ONO moiety.

[0074] As indicated, the embodiments, preferred and highly preferred embodiments described and disclosed herein shall apply to all aspects and other embodiments, preferred and highly preferred embodiments, whether specifically mentioned again or not, and whether the repetition is avoided for brevity. Thus, in a further highly preferred embodiment, the X is CH or N. In another highly preferred embodiment, the X is CR 16 In another highly preferred embodiment, X is N. In another highly preferred embodiment, X is CR 16 and the R 16 is H.

[0075] Furthermore, in a further highly preferred embodiment, the R 11and R 12 One of the R 11 and R 12 The other is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 11 and R 12 One of the R 11 and R 12 The other is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 It is an alkyl.

[0076] In a further highly preferred embodiment, the R 11 and R 12 One of the R 11 and R 12 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R11 and R 12 One of the R 11 and R 12 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 It is an alkyl.

[0077] In a further highly preferred embodiment, the R 11 and R 12 One of the R 11 and R 12 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 11 and R 12 One of the R 11 and R 12 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C independently substituted with haloalkoxy 1 ~C 6 It is an alkyl.

[0078] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14The other is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 The other is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 It is an alkyl.

[0079] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 It is an alkyl.

[0080] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C independently substituted with haloalkoxy 1 ~C 6 It is an alkyl.

[0081] In a further highly preferred embodiment, the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 16 is H.

[0082] In a further highly preferred embodiment, the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 15 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 In a further highly preferred embodiment, the R 15 is one or more OH, ONO, ONO 2 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 16 is H.

[0083] In a further highly preferred embodiment, the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C independently substituted with haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 15 are halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C substituted with at least two substituents independently selected from haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 15 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C independently substituted with alkoxy 1 ~C 6 In a further highly preferred embodiment, the R 15 are halogens, OH, ONO, ONO 2 , C 1 ~C 3 C substituted with at least two substituents independently selected from alkoxy 1 ~C 6 In a further highly preferred embodiment, the R 15 is one or more OH, ONO, ONO 2 C independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 16 is H.

[0084] In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with at least one and up to four substituents independently selected from1 ~C 6 In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with at least two and up to four substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with one substituent independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with two substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with three substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with at least two substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with at least three substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 16 is H.

[0085] In a further highly preferred embodiment, the R 15 OH and ONO 2 C substituted with at least one and up to four substituents independently selected from 1 ~C 6In a further highly preferred embodiment, the R 15 OH and ONO 2 C substituted with at least two and up to four substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH and ONO 2 C substituted with one substituent independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH and ONO 2 C substituted with two substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 15 OH and ONO 2 C substituted with three substituents independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 16 is H.

[0086] In a further highly preferred embodiment, the R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 16 is H.

[0087] In a further highly preferred embodiment, R 17 is H or OH, ONO, ONO 2 C which may be substituted with1 ~C 4 It is an alkyl.

[0088] In a further highly preferred embodiment, the R 18 and R 19 are each independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 It is an alkyl.

[0089] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 The other is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 The other is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 is alkyl, and the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 is alkyl, and the R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 is alkyl, and the R 17 is H or OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, and the R 18 and R 19 are each independently H or ONO, ONO 2 C which may be substituted with 1 ~C 4 It is an alkyl.

[0090] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 In a further highly preferred embodiment, the R13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C independently substituted with 1 ~C 6 is alkyl, and the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 is alkyl, and the R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, COOR 17 , N.R. 18 R 19 , C=NR 20 C may be independently substituted with 1 ~C 6 is alkyl, and the R 17 is H or OH, ONO, ONO 2 C which may be substituted with 1 ~C 4 is alkyl, and the R 18 and R 19 are each independently H or ONO, ONO 2 C which may be substituted with 1 ~C4 It is an alkyl.

[0091] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C independently substituted with haloalkoxy 1 ~C 6 is alkyl, and the R 15 is one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 is alkyl, and the R 16 is H or one or more halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C, which is optionally substituted independently with haloalkoxy 1 ~C 6 It is an alkyl.

[0092] In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more of OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 In a further highly preferred embodiment, the R 13 and R 14 One of the R 13 and R 14 the other is H or one or more of OH, ONO, ONO 2 , C 1 ~C 3 C independently substituted with alkoxy 1 ~C 6 is alkyl, and the R 15 is one or more OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 is alkyl, and the R 16 is H or one or more of OH, ONO, ONO 2 , C 1 ~C 3 C, optionally independently substituted with alkoxy 1 ~C 6 It is an alkyl.

[0093] In a further highly preferred embodiment, the R 11 and R 12 One of the R 13 and R 14 One of the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and an ONO moiety.

[0094] In a further highly preferred embodiment, the R 11 and R 12 One of the R 13 and R 14 One of the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the 2 part, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each of them can use up to four ONOs. 2 Includes parts.

[0095] In a further highly preferred embodiment of the present invention, 11 and R 12 One of the R 13 and R 14 One of the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the ONOs is independently selected from at least two ONOs. 2 or an ONO moiety, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each other, ONO 2 and an ONO moiety.

[0096] In a further highly preferred embodiment of the present invention, 11 and R 12 One of the R 13 and R 14 One of the R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of the ONOs is independently selected from at least two ONOs. 2 part, 11 , R 12 , R 13 , R 14 , R 15 and R 16 Each of them can use up to four ONOs. 2 Includes parts.

[0097] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H. In a further highly preferred embodiment, the R 15 OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 In a further highly preferred embodiment of the present invention, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 16 is H or OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6In a further highly preferred embodiment, the R 16 is H. In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 is alkyl, and the R 16 is H or OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, and therefore said X is N or CH. In a further highly preferred embodiment, said R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one and up to four substituents independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, and thus X is N or CH. In another highly preferred embodiment, X is CR 16 and the R 16 is H, therefore, said X is CH.

[0098] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 are halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C substituted with at least two substituents independently selected from haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 are the halogens, OH, ONO and ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C substituted with at least two, preferably up to four, substituents independently selected from haloalkoxy 1 ~C 6 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 , C 1 ~C 3 C substituted with at least two, preferably up to four, substituents independently selected from alkoxy 1 ~C 6 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C is substituted with at least two, preferably up to four, substituents independently selected from 1 ~C 6In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2 C is substituted with at least two, preferably up to four, substituents independently selected from 1 ~C 6 It is an alkyl.

[0099] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 are halogens, OH, ONO, ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C substituted with at least two substituents independently selected from haloalkoxy 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, so that X is N or CH, preferably, X is CH. In a further highly preferred embodiment, R 11 , R 12 , R 13 , R 14 is H, and the R 15 are the halogens, OH, ONO and ONO 2 , C 1 ~C 3 Alkoxy, C 1 ~C 3 C substituted with at least two, preferably up to four, substituents independently selected from haloalkoxy 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, so that X is N or CH, preferably, X is CH. In a further highly preferred embodiment, R11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 , C 1 ~C 3 C substituted with at least two, preferably up to four, substituents independently selected from alkoxy 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, so that X is N or CH, preferably, X is CH. In a further highly preferred embodiment, R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C is substituted with at least two, preferably up to four, substituents independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, so that X is N or CH, preferably, X is CH. In a further highly preferred embodiment, R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2 C is substituted with at least two, preferably up to four, substituents independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, therefore, said X is N or CH, preferably, said X is CH.

[0100] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 alkyl, and X is CR 16 and the R 16 is H. In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one and up to four substituents independently selected from 1 ~C 6 alkyl, and X is CR 16 and the R 16 is H. In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 is alkyl, and the R 16 is H or OH, ONO and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 is alkyl, and the R 15 and the R 16 Each other, ONO 2 and an ONO moiety, and each other, at least two moieties independently selected from an ONO moiety. 2 and ONO moieties. In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2C substituted with at least one substituent independently selected from 1 ~C 6 is alkyl, and the R 16 is H or OH and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 is alkyl, and the R 15 and the R 16 Each has at least two ONOs. 2 Parts, and each other, up to 4 ONO 2 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, therefore, the X is N or CH, preferably, the X is CH, and the R 15 At least two ONOs 2 Parts, and each other, up to 4 ONO 2 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, therefore, the X is N or CH, preferably, the X is CH, and the R 15 At least one ONO 2 Parts, and each other, up to 4 ONO 2 Includes parts.

[0101] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 alkyl, and X is CR 16 and the R 16 is H, preferably, X is CH and R 15 At least two ONOs 2 Parts, and each other, up to 4 ONO 2 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH and ONO 2 C substituted with at least one substituent independently selected from 1 ~C 6 alkyl, and X is CR 16 and the R 16 is H, preferably, X is CH and R 15 At least one ONO 2 Parts, and each other, up to 4 ONO 2 Includes parts.

[0102] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with 1, 2 or 3 substituents independently selected from 1 ~C 6 is alkyl, and the R 16 is H or OH, ONO and ONO 2C substituted with 1, 2 or 3 substituents independently selected from 1 ~C 6 is alkyl, and the R 15 and the R 16 Each other, ONO 2 and ONO moieties, and each other, ONO 2 and an ONO moiety.

[0103] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with 1, 2 or 3 substituents independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, therefore, the X is N or CH, preferably, the X is CH, and the R 15 is ONO 2 and ONO moieties, and each other, ONO 2 and ONO moieties. In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with 1, 2 or 3 substituents independently selected from 1 ~C 6 alkyl, and X is N or CR 16 and the R 16 is H, therefore, the X is N or CH, preferably, the X is CH, and the R 15 At least one ONO 2 Partial and up to 4 ONOs2 Includes parts.

[0104] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with 1, 2 or 3 substituents independently selected from 1 ~C 6 alkyl, and X is CR 16 and the R 16 is H, preferably, X is CH and R 15 is ONO 2 and ONO moieties, and each other, ONO 2 and ONO moieties. In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 OH, ONO and ONO 2 C substituted with 1, 2 or 3 substituents independently selected from 1 ~C 6 alkyl, and X is CR 16 and the R 16 is H, preferably, X is CH and R 15 At least one ONO 2 Partial and up to 4 ONOs 2 Includes parts.

[0105] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H.2 CH 2 ONO 2 、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(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、C(OH)(CH 2 ONO)CH 2 ONO 2 、C(OH)(CH 2 ONO 2 )CH 2 ONO 2 、C(OH)(CH 2 CH 2 ONO)CH 2 CH 2 ONO 2 、C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO、C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 、 preferably, the R 15 is CH 2 ONO 2 、CH 2 CH 2 ONO 2 、CH(OH)CH 2 ONO2 , C.H. 2 CH 2 CH 2 ONO 2 , CH(ONO 2 )CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 is selected from.

[0106] In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H. 2 CH 2 ONO 2 , CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO, C.H. 2 CH 2 CH 2 ONO 2 , C.H. 2 CH 2 CH 2 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, C(OH)(CH 2IT 2 )CH 2 ON、C(OH)(CH 2 ON)CH 2 IT 2 、C(OH)(CH 2 IT 2 )CH 2 IT 2 、C(OH)(CH 2 CH 2 ON)CH 2 CH 2 IT 2 、C(OH)(CH 2 CH 2 IT 2 )CH 2 CH 2 ON、C(OH)(CH 2 CH 2 IT 2 )CH 2 CH 2 IT 2 、CH 2 CH(CH 2 IT) 2 、CH 2 CH(CH 2 IT 2 ) 2 、CH 2 CH(CH 2 IT 2 )(CH 2 IT)、CH 2 CH(CH 2 IT 2 )(CH 2 OH)、CH 2 CH(CH 2 IT)(CH 2 OH)、 CH 2 C(CH 3 )(CH 2 IT) 2 、CH 2 C(CH 3 )(CH 2 IT) 2 、CH 2 C(CH 3 )(CH 2 IT 2 )(CH 2 IT)、CH 2C(CH 3 )(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO)(CH 2 OH), preferably, 15 is CH 2 ONO 2 , C.H. 2 CH 2 ONO 2 , CH(OH)CH 2 ONO 2 , C.H. 2 CH 2 CH 2 ONO 2 , CH(ONO 2 )CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 , C.H. 2 CH(CH 2 ONO 2 ) 2 , C.H. 2 CH(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH).

[0107] In a further highly preferred embodiment, the R11 , R 12 , R 13 , R 14 is H, and the said R 15 is CH 2 ONO 2 , CH 2 ONO, CH 2 CH 2 ONO, 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(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, C(OH)(CH 2 ONO)CH 2 ONO 2 , C(OH)(CH 2 ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 CH 2 ONO)CH 2 CH 2 ONO 2 , C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO, C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 , CH2 CH(CH 2 ONO) 2 、CH 2 CH(CH 2 ONO 2 ) 2 、CH 2 CH(CH 2 ONO 2 )(CH 2 ONO)、CH 2 CH(CH 2 ONO 2 )(CH 2 OH)、CH 2 CH(CH 2 ONO)(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO) 2 、CH 2 C(CH 3 )(CH 2 ONO) 2 、CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 ONO)、CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH)、CH 2 C(CH 3 )(CH 2 ONO)(CH 2 OH) in the R 15 は、CH 2 ONO 2 、CH(OH)CH 2 ONO 2 、CH 2 CH 2 CH 2 ONO 2 、CH(ONO 2 )CH 2 OH、CH(ONO 2 )CH 2 ONO 2 、C(OH)(CH 2 ONO 2 )CH2 ONO 2 , C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 , C.H. 2 CH(CH 2 ONO 2 ) 2 , C.H. 2 CH(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH).

[0108] Formula I * In the compound of formula I, R 1 is C 1 ~C 2 is alkyl, R 2 is C 1 ~C 3 Alkyl or C 3 ~C 6 cycloalkyl, R 3 is C 1 ~C 4 is alkyl, R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H. 2 CH 2 ONO 2 , CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO, C.H.2 CH 2 CH 2 ONO 2 、CH 2 CH 2 CH 2 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、C(OH)(CH 2 ONO 2 )CH 2 ONO、C(OH)(CH 2 ONO)CH 2 ONO 2 、C(OH)(CH 2 ONO 2 )CH 2 ONO 2 、C(OH)(CH 2 CH 2 ONO)CH 2 CH 2 ONO 2 、C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO、C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 selected from, preferably R 15 is CH 2 ONO 2 、CH 2 CH 2 ONO 2 、CH(OH)CH 2 ONO 2 、CH 2 CH 2 CH 2 ONO 2 、CH(ONO 2 )CH 2OH, CH(ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 Preferably, R 16 is H.

[0109] Formula I * In the compound of formula I, R 1 is C 1 ~C 2 is alkyl, R 2 is C 1 ~C 3 Alkyl or C 3 ~C 6 cycloalkyl, R 3 is C 1 ~C 4 is alkyl, R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H. 2 CH 2 ONO 2 , CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO, C.H. 2 CH 2 CH 2 ONO 2 , C.H. 2 CH 2 CH 2 ONO, CH(ONO 2 )CH 2 OH,CH(ONO)CH 2 OH, CH(ONO 2)CH 2 IT 2 、CH(ONO)CH 2 IT 2 、CH(ONO 2 )CH 2 ON、C(OH)(CH 2 IT 2 )CH 2 ON、C(OH)(CH 2 ON)CH 2 IT 2 、C(OH)(CH 2 IT 2 )CH 2 IT 2 、C(OH)(CH 2 CH 2 ON)CH 2 CH 2 IT 2 、C(OH)(CH 2 CH 2 IT 2 )CH 2 CH 2 ON、C(OH)(CH 2 CH 2 IT 2 )CH 2 CH 2 IT 2 、CH 2 CH(CH 2 IT) 2 、CH 2 CH(CH 2 IT 2 ) 2 、CH 2 CH(CH 2 IT 2 )(CH 2 IT)、CH 2 CH(CH 2 IT 2 )(CH 2 OH)、CH 2 CH(CH 2 IT)(CH 2 OH)、 CH 2 C(CH 3 )(CH 2 IT) 2 、CH 2 C(CH 3 )(CH2 ONO) 2 、CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 ONO)、CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH)、CH 2 C(CH 3 )(CH 2 ONO)(CH 2 OH) R 15 は、CH 2 ONO 2 、CH 2 CH 2 ONO 2 、CH(OH)CH 2 ONO 2 、CH 2 CH 2 CH 2 ONO 2 、CH(ONO 2 )CH 2 OH、CH(ONO 2 )CH 2 ONO 2 、C(OH)(CH 2 ONO 2 )CH 2 ONO 2 、C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 、CH 2 CH(CH 2 ONO 2 ) 2 、CH 2 CH(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 、CH 2 C(CH 3)(CH 2 ONO 2 )(CH 2 OH), preferably R 16 is H.

[0110] Formula I * In the compound of formula I, R 1 is C 1 ~C 2 is alkyl, R 2 is C 1 ~C 3 Alkyl or C 3 ~C 6 cycloalkyl, R 3 is C 1 ~C 4 is alkyl, R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, CH(OH)CH 2 ONO 2 , CH(OH)CH 2 ONO, C.H. 2 CH 2 CH 2 ONO 2 , C.H. 2 CH 2 CH 2 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, C(OH)(CH 2 ONO 2 )CH 2 ONO, C(OH)(CH 2 ONO)CH 2 ONO2 、C(OH)(CH 2 IT 2 )CH 2 IT 2 、C(OH)(CH 2 CH 2 ON)CH 2 CH 2 IT 2 、C(OH)(CH 2 CH 2 IT 2 )CH 2 CH 2 ON、C(OH)(CH 2 CH 2 IT 2 )CH 2 CH 2 IT 2 、CH 2 CH(CH 2 IT) 2 、CH 2 CH(CH 2 IT 2 ) 2 、CH 2 CH(CH 2 IT 2 )(CH 2 IT)、CH 2 CH(CH 2 IT 2 )(CH 2 OH)、CH 2 CH(CH 2 IT)(CH 2 OH)、 CH 2 C(CH 3 )(CH 2 IT) 2 、CH 2 C(CH 3 )(CH 2 IT) 2 、CH 2 C(CH 3 )(CH 2 IT 2 )(CH 2 IT)、CH 2 C(CH 3 )(CH 2 IT 2 )(CH 2 OH)、CH2 C(CH 3 )(CH 2 ONO)(CH 2 OH), preferably R 15 is CH 2 ONO 2 , CH(OH)CH 2 ONO 2 , C.H. 2 CH 2 CH 2 ONO 2 , CH(ONO 2 )CH 2 OH, CH(ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 ONO 2 )CH 2 ONO 2 , C(OH)(CH 2 CH 2 ONO 2 )CH 2 CH 2 ONO 2 , C.H. 2 CH(CH 2 ONO 2 ) 2 , C.H. 2 CH(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH), preferably R 16 is H.

[0111] In a further highly preferred embodiment, the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H.2 CH 2 ONO 2 Preferably, R 15 is CH 2 ONO 2 or CH 2 CH 2 ONO 2 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H. 2 CH 2 ONO 2 Preferably, R 15 is CH 2 ONO 2 or CH 2 CH 2 ONO 2 In a further highly preferred embodiment, the R 16 is CH 2 ONO 2 , C.H. 2 ONO, C.H. 2 CH 2 ONO, C.H. 2 CH 2 ONO 2 Preferably, R 16 is CH 2 ONO 2 or CH 2 CH 2 ONO 2 In a further preferred embodiment, the R 15 OH or ONO 2 C replaced with 2 ~C 3 Alkyl, preferably one, two or three OH or ONO 2 C replaced with 2 ~C 3 Alkyl, more preferably one OH or one or two ONO2 C replaced with 2 ~C 3 It is an alkyl.

[0112] In a further highly preferred embodiment, the R 15 is CH 2 C(CH 3 )(CH 2 ONO) 2 , C.H. 2 C(CH 3 )(CH 2 ONO) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 ONO), CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO)(CH 2 OH), preferably R 15 is CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 In a further highly preferred embodiment, the R 11 , R 12 , R 13 , R 14 is H, and the R 15 is CH 2 C(CH 3 )(CH 2 ONO) 2 , C.H. 2 C(CH 3 )(CH 2 ONO) 2 , C.H. 2 C(CH 3 )(CH 2 ONO2 )(CH 2 ONO), CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO)(CH 2 OH), preferably R 15 is CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 In a further highly preferred embodiment, the R 16 is CH 2 C(CH 3 )(CH 2 ONO) 2 , C.H. 2 C(CH 3 )(CH 2 ONO) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 ONO), CH 2 C(CH 3 )(CH 2 ONO 2 )(CH 2 OH), CH 2 C(CH 3 )(CH 2 ONO)(CH 2 OH), preferably R 16 is CH 2 C(CH 3 )(CH 2 ONO 2 ) 2 , C.H. 2 C(CH 3 )(CH 2 ONO 2 )(CH 2In a further preferred embodiment, the R 15 OH or ONO 2 C replaced with 3 ~C 6 Alkyl, preferably one, two or three OH or ONO 2 C replaced with 3 ~C 6 Alkyl, more preferably one OH or one or two ONO 2 C replaced with 3 ~C 6 In a further preferred embodiment, the R 15 OH or ONO 2 C replaced with 4 ~C 5 Alkyl, preferably one, two or three OH or ONO 2 C replaced with 4 ~C 5 Alkyl, more preferably one OH or one or two ONO 2 C replaced with 3 ~C 6 It is an alkyl.

[0113] Further highly preferred embodiments of the present invention are represented by the individual compounds of Formula I or II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0114] Thus, in another highly preferred embodiment, the compound of formula I or II is selected from: (R)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate [ka] (S)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyldinitrate [ka] (R)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate [ka] (S)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate [ka] 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer A [ka] 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer B [ka] 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate [ka] 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyldinitrate [ka] 2-((1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (racemic) [ka] 1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer A [ka] 1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer B [ka] (R)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate [ka] (S)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate [ka] (R)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate [ka] (S)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate [ka] 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer A [ka] 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer B [ka] 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate [ka] 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate [ka] 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate [ka] 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer A [ka] 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer B [ka] 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)propane-1,3-diyl dinitrate [ka] 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)propyl nitrate [ka] 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylpropane-1,3-diyl dinitrate [ka] 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)-2-methylpropyl nitrate [ka]

[0115] In a further highly preferred embodiment, the compound is a compound of formula I, and the compound is selected from: (R)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1a), (S)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1b), (R)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (1c), (S)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (1d), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer A (1e), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer B (1f), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate (1g), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (1h), and 2-((1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (1i), 1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer A (1k), and 1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer B (1l).

[0116] In a further highly preferred embodiment, the compound is a compound of formula I, and the compound is selected from: (R)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (2a), (S)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (2b), (R)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (2c), (S)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (2d), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer A (2e), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer B (2f), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate (2g), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (2h), 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (2i), 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer A (2k), 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer B(2l) 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)propane-1,3-diyl dinitrate (2m), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)propyl nitrate (2n), 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylpropane-1,3-diyl dinitrate (2o), and 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)-2-methylpropyl nitrate (2p).

[0117] The compounds of the present invention have been shown to be potent and selective inhibitors of cGMP-specific PDE.Furthermore, the compounds of the present invention have been found to be dual pharmacological NO-releasing PDE5 inhibitors that, in addition to their PDE5 inhibition, release NO in a more than additive manner.Therefore, the compounds of formula I or II are intended for use in treatment, particularly in the treatment of various conditions in which the inhibition of cGMP-specific PDE is considered beneficial.In view of the discovery of strong plasma protein binding, the compounds of the present invention are particularly suitable for local action after topical application (see Figure 2).

[0118] Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds of the present invention of formula I or formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant, or carrier.

[0119] Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds of the invention of formula I, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant, or carrier.

[0120] Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds of the present invention of formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant, or carrier.

[0121] In another aspect, the present invention provides a pharmaceutical composition comprising exactly one compound of the present invention of formula I or II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant or carrier. Pharmaceutically acceptable excipients, adjuvants or carriers are known to those skilled in the art.

[0122] In another aspect, the present invention provides a pharmaceutical composition comprising exactly one compound of the present invention of formula I, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant, or carrier. Pharmaceutically acceptable excipients, adjuvants, or carriers are known to those skilled in the art.

[0123] In another aspect, the present invention provides a pharmaceutical composition comprising exactly one compound of the present invention of formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant or carrier. Pharmaceutically acceptable excipients, adjuvants or carriers are known to those skilled in the art.

[0124] In another aspect, the present invention provides a compound of Formula I or Formula II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use as a medicament.

[0125] In another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use as a medicament.

[0126] In another aspect, the present invention provides a compound of formula II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use as a medicament.

[0127] In another aspect, the present invention provides a compound of formula I or formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use as a medicament.In yet another aspect, the present invention provides a compound of formula I or formula II, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use as a veterinary medicine.

[0128] As shown in Figures 3A and 3B, compounds of the invention had a superadditive effect when compared with the organic nitrate ITN and the PDE5 inhibitors sildenafil or vardenafil in increasing cGMP in HTMC in the presence of the soluble guanylate cyclase (sGC) stimulator riociguat.

[0129] Thus, in another aspect and preferred embodiment of the invention, the pharmaceutical composition of the invention further comprises at least one sGC stimulant, preferably the sGC stimulant is selected from the group consisting of riociguat, vericiguat, praliciguat and olinciguat.

[0130] Soluble guanylyl cyclase (sGC) stimulators are known and described in the art (E S. Buys et al., Nitric Oxide 78 (2018) 72-80; P. Sandner et al., Nitric Oxide 77 (2018) 88-95; P. Sandner et al., Gerontology, 63 (2017) 216-227). sGC stimulators are typically small molecule drugs that synergistically increase sGC enzyme activity by NO by binding to sGC, enhancing NO-mediated cGMP signaling. Soluble guanylyl cyclase (sGC) stimulators are typically administered orally.In addition to the sGC stimulants already approved by the FDA (riociguat) or tested in clinical trials (vericiguat, praliciguat, olinciguat), further sGC stimulants are currently in the development stage or have been approved for use in clinical trials, e.g. IW-64630 (E S. Buys et al., Nitric Oxide, 78 (2018) 72-80), A-330619, A-344905 and A-778935 (LN Miller et al., Life Sci., 72 (9) (2003) 1015-1025), BAY 41-2272 (A. Straub et al., Bioorg. Med. Chem. Lett., 11 (6) (2001) 781-784; DE 19834047; DE 19942809), BAY 41-8543 (JP Stasch et al., Br. J. Pharmacol., 135(2)(2002)333-343; JP Stasch et al., Br. J. Pharmacol., 135(2)(2002)344-35; N. Wilck et al., JCI Insight, 3(4)(2018); German Patent No. 19834044), CFM-1571 (DL Selwood et al., J. Med. Chem., 44(1)(2001)78-93; International Publication No. 2000027394), GSK2181236A (MH Costell et al., Front. Pharmacol., 3(2012)128), IWP-051 (T. Nakai et al., ACS Med. Chem. Lett., 7(5)(2016)465-46), IWP-550 (G. Liu et al., In Experimental Biology(2018)(San Diego)), IWP-854 (JA Wales et al., J. Biol. Chem., 293(5)(2018)1850-1864), IWP-953 (P. Ge et al., Invest. Ophthalmol. Vis. Sci., 57(3)(2016)1317-1326), etoriciguat (WO 2003086407), nerociguat (BAY 60-4552, International Publication No. 2003095451) and YC-1 (FN Ko et al., Blood, 84(12)(1994)4226-4233; A. Mulsch et al., Br. J. Pharmacol., 120(4)(1997)681-689, EP667345). [ka]

[0131] These and further sGC stimulators are also described in WO2009032249, WO2009094242, WO2010099054, WO2010065275, WO2011119518, WO2011149921, WO2012058132 and Tetrahedron Letters (2003), 44(48):8661-8663.

[0132] Thus, in a preferred embodiment, the sGC stimulant is selected from the group consisting of riociguat, vericiguat, praliciguat, olinciguat, IW-64630, A-330619, A-344905, A-778935, BAY41-2272, BAY41-8543, CFM-1571, GSK2181236A, IWP-051, IWP-550, IWP-854, IWP-953, etoriciguat, nerociguat and YC-1, more preferably, the sGC stimulant is selected from the group consisting of riociguat, vericiguat, praliciguat and olinciguat.

[0133] Riociguat is a known stimulator of soluble guanylate cyclase (sGC) and is 20 H 19 FN 8 O 2 -carbamic acid, N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl-N-methyl-, methyl ester (J. Mittendorf et al., Chem Med Chem, 4(5)(2009) 853-865, German Patent No. 19834044). [ka]

[0134] Vericiguat is a further known stimulator of soluble guanylate cyclase (sGC) and is 19 H 16 F 2 N 8 O 2 -carbamic acid, N-[4,6-diamino-2-[5-fluoro-1-[2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-, methyl ester (JP Stasch, OVEvgenov, Handb. Exp. Pharmacol. 218 (2013) 279-313; M. Follmann et al., J. Med. Chem. 60(12) (2017) 5146-5161). [ka]

[0135] Praliciguat is a further known stimulator of soluble guanylate cyclase (sGC) and is 21 H 14 F 8 N 6 O 2 -2-Propanol, 1,1,1,3,3,3,-Hexafluoro-2-[[[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(3-isoxazolyl)-1H-pyrazol-3-yl]-4-pyrimidinyl]amino]methyl]- (R. Flores-Costa et al., Br. J. Pharmacol. 175(6)(2018)953-967). [ka]

[0136] Olinciguat is a further known stimulator of soluble guanylate cyclase (sGC) and is 21 H 16 F 5 N 7 O 3-propanamide, 3,3,3,-trifluoro-2-[[[5-fluoro-2-[1-[(2-fluorophenyl)methyl]-5-(3-isoxazolyl)-1H-pyrazol-3-yl]-4-pyrimidinyl]amino]methyl]-2-hydroxy-, (2R)- (E S. Buys et al., Nitric Oxide 78 (2018) 72-80). [ka]

[0137] Moreover, as shown, it has been surprisingly found that the compounds and pharmaceutical compositions of the present invention are dual pharmacological NO-releasing PDE5 inhibitors, which, in addition to their PDE5 inhibition, release NO in a more than additive manner.As a result, the novel compounds of the present invention are useful for treating and preventing diseases related to disturbed cGMP balance.In particular, the compounds of the present invention are activators of soluble guanylyl cyclase (sGC) and potent yet selective inhibitors of cyclic guanosine 3'-5'-monophosphate-specific phosphodiesterase 5 (cGMP-specific PDE5), and therefore have utility in various therapeutic areas where such inhibition is beneficial.

[0138] Some of the preferred treatment areas are wound healing, especially chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, glaucoma, diabetic retinopathy, age-related macular degeneration, male erectile dysfunction, female sexual dysfunction, diabetes, hair loss, skin aging, vascular aging, pulmonary arterial hypertension and livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis.

[0139] As a result of the selective PDE5 inhibition exhibited by the compounds of the present invention, cGMP levels are expected to increase, which in turn results in beneficial antiplatelet, antivasospastic, vasodilatory, natriuretic and diuretic activity, as well as increased levels of endothelium-derived relaxing factor (EDRF), nitric oxide (NO), nitrovasodilators, atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), as well as bradykinin, acetylcholine and 5-HT 1 Thus, the compounds of formula I or II can be used to treat stable angina, unstable angina and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions with reduced vascular patency (e.g., after percutaneous transluminal coronary angioplasty), peripheral vascular disease, vascular disorders such as Raynaud's disease, diabetic retinopathy, age-related macular degeneration, male erectile dysfunction, female sexual dysfunction, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetes, glaucoma, and diseases characterized by impaired intestinal motility such as irritable bowel syndrome, wound healing, particularly chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Alzheimer's disease, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, chronic heart failure, cancers including breast cancer and gastrointestinal cancer, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancers such as colorectal cancer, and prostate and pancreatic cancers, particularly colorectal cancer.

[0140] Therefore, in another aspect, the present invention provides a compound of formula I or II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing a disease that is alleviated by the inhibition of PDE5 in a human or non-human mammal, preferably a human.Therefore, in another aspect, the present invention provides a compound of formula I, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing a disease that is alleviated by the inhibition of PDE5 in a human or non-human mammal, preferably a human.Therefore, in another aspect, the present invention provides a compound of formula II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing a disease that is alleviated by the inhibition of PDE5 in a human or non-human mammal, preferably a human.Preferably, the disease is 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 arterial hypertension, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, stable angina, unstable angina and variant (Prinzmetal) angina, high blood pressure, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, reduced vascular patency. conditions, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, achalasia, sickle cell disease (SCD), inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration or diseases characterized by gastrointestinal motility disorders such as irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, breast and gastrointestinal cancers, non-small cell lung cancer , skin cancer such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, and preferably the disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedo vasculopathy, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension, Preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0141] In yet another aspect, the present invention provides a compound of the invention of formula I or II, or a pharmaceutical composition of the invention, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method of treating or preventing a disease in a human or non-human mammal, preferably a human, the disease being wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, livedo vasculopathy, thromboangiitis obliterans, chronic anal fissures, Dermatofibrosis, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, states of compromised vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, achalasia, sickle cell disease (SCD), inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration or hypersensitivity. and preferably the disease is selected from cancers characterized by gastrointestinal motility disorders such as bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, breast cancer and gastrointestinal cancer, non-small cell lung cancer, skin cancer such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, and preferably the disease is wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedovascular disease, thromboangiitis obliterans, chronic anal fissures. The disease is selected from wounds, skin fibrosis, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bed sores.

[0142] In yet another aspect, the present invention provides a compound of the invention of formula I, or a pharmaceutical composition of the invention, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing a disease in a human or non-human mammal, preferably a human, the disease being wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, livedo vasculopathy, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, angina, stable angina, unstable angina and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, states of compromised vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, achalasia, sickle cell disease (SCD), inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration or irritable bowel syndrome group, liver fibrosis, Alzheimer's disease, chronic heart failure, breast cancer and gastrointestinal cancer, non-small cell lung cancer, skin cancer such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, and preferably the disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedo vasculopathy, thromboangiitis obliterans, chronic anal fissures. , skin fibrosis, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0143] In yet another aspect, the present invention provides a compound of the invention of formula II, or a pharmaceutical composition of the invention, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing a disease in a human or non-human mammal, preferably a human, the disease being wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, livedo vasculopathy, thromboangiitis obliterans, chronic anal fissures, skin follicles, inflammatory bowel disease, chronic myelopathy, chronic ... Fibrosis, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, states of compromised vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, achalasia, sickle cell disease (SCD), inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration or irritable bowel disease and preferably the disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, chronic rectal fissures, chronic vascular diseases such as bronchitis, ... , skin fibrosis, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0144] In another aspect, the present invention provides a compound of formula I or II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing disease in a human or non-human mammal, preferably a human, by activating soluble guanylyl cyclase (sGC) and inhibiting PDE5.In another aspect, the present invention provides a compound of formula I or II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating or preventing disease in a human or non-human mammal, preferably a human, by activating soluble guanylyl cyclase (sGC) or inhibiting PDE5.In another aspect, the present invention provides a compound of formula I or II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method for treating a medical condition in a human or non-human mammal, preferably a human, for which inhibition of PDE5 and / or activation of soluble guanylyl cyclase (sGC) is desirable. Very preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and pressure ulcers.

[0145] In yet another aspect, the present invention provides the use of a compound of formula I or II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for the treatment or prevention of a disease caused by the activation of soluble guanylyl cyclase (sGC) and / or the inhibition of PDE5 in a human or non-human mammal, preferably a human. In yet another aspect, the present invention provides the use of a compound of formula I or II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for the treatment or prevention of a disease caused by the activation of soluble guanylyl cyclase (sGC) and / or the inhibition of PDE5 in a human or non-human mammal, preferably a human. In yet another aspect, the invention provides the use of a compound of formula I or II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for the treatment of a medical condition, in a human or non-human mammal, preferably a human, for which activation of soluble guanylyl cyclase (sGC) and / or inhibition of PDE5 is desirable.In yet another aspect, the present invention provides the use of a compound of formula I or II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for treating or preventing a disease, the disease being 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 arterial hypertension, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, stable angina, unstable vasculitis, chronic ... Angina and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, states of compromised vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration or diseases characterized by intestinal motility disorders such as irritable bowel syndrome, hepatic fibrosis, Alzheimer's disease, chronic heart failure, breast and gastrointestinal cancer, non-small cell lung cancer, skin cancer such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, and more preferably the disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedoangiopathy, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, systemic Preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0146] In yet another aspect, the present invention provides a method for treating or preventing a disease in a human or non-human mammal, preferably a human, by activating soluble guanylyl cyclase (sGC) and / or inhibiting PDE5, comprising administering to said human or non-human mammal, preferably said human, an effective amount of a compound of formula I or II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof.In yet another aspect, the present invention provides a method for treating or preventing a disease in a human or non-human mammal, preferably a human, by activating soluble guanylyl cyclase (sGC) and / or inhibiting PDE5, comprising administering to said human or non-human mammal, preferably said human, an effective amount of a compound of formula I or II, or a pharmaceutical composition, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In yet another aspect, the present invention provides a method for treating a medical condition in a human or non-human mammal, preferably a human, for which activation of soluble guanylyl cyclase (sGC) and / or inhibition of PDE5 is desirable, comprising administering to said human or non-human mammal, preferably said human, an effective amount of a compound of formula I or II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.In yet another aspect, the present invention provides a method of treating or preventing a disease in a human or a non-human mammal, preferably a human, comprising administering to said human or said non-human mammal, preferably said human, an effective amount of a compound of formula I or II, or a pharmaceutical composition, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein the disease is wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, priapism, female sexual dysfunction, hair loss, skin aging, vascular aging, pulmonary arterial hyperplasia, pulmonary fibrosis ... Hypertension, Livedovasculopathy, Thromboangiitis Obliterans, Chronic Anal Fissure, Skin Fibrosis, Stable Angina, Unstable Angina and Variant (Prinzmetal) Angina, High Blood Pressure, Pulmonary Hypertension, Chronic Obstructive Pulmonary Disease, Congestive Heart Failure, Renal Failure, Atherosclerosis, States of Reduced Vascular Patency, Peripheral Vascular Disease, Vascular Disorders, Systemic Sclerosis (SSc), Scleroderma, Morphea, Inflammatory Diseases, Stroke, Bronchitis, Chronic Asthma, Allergic Asthma, Allergic Rhinitis, Diabetic Neuropathy, Idiopathic Pulmonary Fibrosis (IPF), Peyronie's Disease, Glaucoma, Diabetic Retinopathy, Age-Related Macular Degeneration or diseases characterized by gastrointestinal motility disorders such as irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, breast cancer and gastrointestinal cancer, non-small cell lung cancer, skin cancer such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, more preferably the disease is selected from wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, livedo vasculopathy, thromboangiitis obliterans, The disease is selected from chronic anal fissures, skin fibrosis, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0147] In a preferred embodiment of the invention, the disease or medical condition is a disease selected from the group consisting of livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, female sexual dysfunction, diabetes, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, stable angina, unstable angina and variant (Prinzmetal) angina, high blood pressure, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, pulmonary fibrosis, chronic pulmonary disease, chronic pulmonary arterial disease, chronic pulmonary ... romatic arteriosclerosis, conditions with reduced vascular patency, peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, diseases characterized by age-related macular degeneration or gastrointestinal motility disorders such as irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, breast and gastrointestinal cancers, non-small cell lung cancer, black-eye disease, and other conditions. Preferably, the disease is selected from skin cancer such as bronchial carcinoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, and preferably the disease is selected from cancers including livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension, Preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, diabetes mellitus, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0148] Thus, in further aspects of the invention, the present invention is directed to the treatment of wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, female sexual dysfunction, diabetes, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, stable angina, unstable angina and variant (Prinzmetal) angina, high blood pressure, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease. Diseases characterized by gastrointestinal motility disorders such as vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration or irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, breast and gastrointestinal cancers, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and and head and neck squamous cell carcinoma, colon and rectal cancer such as colorectal cancer, and prostate and pancreatic cancer, particularly colorectal cancer, preferably the disease is wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic hematologic malignancies such as rheumatoid arthritis (rheumatoid arthritis), rheumatoid arthritis (rheumatoid arthritis), rheumatoid arthritis (rheumatoid arthritis), rheumatoid arthritis (rheumatoid arthritis), rheumatoid arthritis, ... Preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0149] According to another aspect of the invention, the present invention is directed to the treatment of wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, female sexual dysfunction, diabetes, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, stable angina, unstable angina and variant (Prinzmetal) angina, high blood pressure, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, vascular disorders, Systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, diseases characterized by gastrointestinal motility disorders such as age-related macular degeneration or irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, 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. The present invention provides the use of a compound of formula I or II for the manufacture of a medicament for the treatment of cancer, which is epithelial cancer, colon and rectal cancer, such as colorectal cancer, and prostate and pancreatic cancer, in particular colorectal cancer, preferably the disease is wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic hematologic malignancies, and / or chronic myocardial infarction (CHI). Preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer, more preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

[0150] In a further aspect, the present invention provides a method for treating a range of conditions, including but not limited to wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, Raynaud's disease, male erectile dysfunction, female sexual dysfunction, diabetes, hair loss, skin aging, vascular aging, pulmonary arterial hypertension, stable angina, unstable angina and variant (Prinzmetal) angina, high blood pressure, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, osteoporosis ... Peripheral vascular disease, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, diseases characterized by gastrointestinal motility disorders such as age-related macular degeneration or irritable bowel syndrome, liver fibrosis, Alzheimer's disease, chronic heart failure, breast and gastrointestinal cancers, non-small cell lung cancer, skin cancers such as melanoma, head and neck cancer, myeloma and squamous cell carcinoma of the head and neck, The present invention provides a method for treating cancer, preferably cancers including colon and rectal cancer, such as colorectal cancer, as well as prostate and pancreatic cancer, particularly colorectal cancer, and preferably the disease is selected from the group consisting of wound healing, preferably chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy, peripheral vascular disease, vascular disorders such as Raynaud's disease, systemic sclerosis (SSc), scleroderma, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, diabetes, male erectile dysfunction, priapism, female sexual dysfunction and colorectal cancer. Selected, and more preferably, the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and pressure ulcers, and the method comprises administering an effective amount of a compound of formula I or II to said human or said non-human mammal, preferably said human.

[0151] In highly preferred embodiments of the invention, the disease or medical condition is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, skin aging, glaucoma, diabetic retinopathy, age-related macular degeneration, pigmentary retinopathy, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and pressure ulcers.

[0152] In highly preferred embodiments of the invention, the disease or medical condition is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, male erectile dysfunction, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and pressure ulcers.

[0153] In highly preferred embodiments of the invention, the disease or medical condition is selected from wound healing, preferably chronic wound healing, diabetic foot, diabetic foot and leg ulcers, pulmonary arterial hypertension and male erectile dysfunction and livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis.

[0154] Chronic non-healing skin wounds, such as those in diabetes mellitus, are governed by complex disease mechanisms including impaired angiogenesis, microcirculatory dysfunction, and endothelial dysfunction. Diabetic foot ulcers and chronic wounds are a major cause of morbidity and the leading cause of hospitalization in diabetic patients. They affect 15% (275 Mio) of diabetic patients and represent a significant burden to patients and payers ($12 billion / year). 3-4% of all diabetic patients undergo lower limb amputation annually. Ultra-potent PDE5 inhibitors or compounds incorporating highly potent activation of soluble guanylyl cyclase (sGC) and / or inhibition of PDE5 as well as activation of nitric oxide-dependent soluble guanylate cyclase as in the present invention can be expected to promote wound healing.

[0155] As used herein, the terms "treatment", "treat", "treated" or "treating" refer to prophylaxis and / or therapy. In one embodiment, the terms "treatment", "treat", "treated" or "treating" refer to therapeutic treatment. In another embodiment, the terms "treatment", "treat", "treated" or "treating" refer to prophylactic treatment. Preferably, beneficial or desired clinical results of the treatment include, but are not limited to, alleviation of symptoms, reduction in the severity of a disease or medical condition, stabilization (i.e., not worsening) of the state of a disease or medical condition, delay or slowing of the progression of a disease or medical condition, improvement or palliative care of the state of a disease or medical condition.

[0156] As used herein, the term "effective amount" refers to an amount necessary or sufficient to achieve a desired biological effect. Preferably, the term "effective amount" refers to an amount of the compound of formula I or II of the present invention that (i) treats or prevents a particular disease, medical condition, or disorder, (ii) attenuates, improves, or eliminates one or more symptoms of a particular disease, medical condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, medical condition, or disorder, as described herein. An effective amount of the compound of formula I or II of the present invention or its pharmaceutical composition is an amount that achieves this selected result, and such an amount can be routinely determined by a person skilled in the art. More preferably, as used herein, the term "effective amount" refers to an amount necessary or sufficient to be effective in activating soluble guanylyl cyclase (sGC) and / or to increase the inhibition of PDE5, typically and preferably as determined in Example 53, or to increase the formation of cGMP, typically and preferably as determined in Example 55. The effective amount may vary depending on the particular composition 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 invention without necessitating undue experimentation.

[0157] As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. As used herein, the term "mammal" preferably refers to humans.

[0158] The compounds of formula I and pharmaceutical compositions of the present invention can be administered by any suitable route, for example, 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 and can also be used, for example, by surgical portal. Thus, depending on the dosage form and route of administration, devices such as conventional needles and syringes, microneedles, patches (for example, as in WO 98 / 20734), needle-free injection systems (for example, as in WO 1999027961A1), spray devices, etc. can be used for administration. The devices may be pre-filled or coated with the compounds or pharmaceutical compositions of the present invention.

[0159] The term "topical administration" is used in its broadest sense and generally includes administration to surfaces of the body that are open to the environment. This includes not only the skin, but also the nasal and oral passages and 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 are available in a variety of forms, including creams, ointments, solutions, lotions, suspensions, pastes, emulsions, foams, and the like. Water-miscible creams have generally been used for moist or vesicular lesions, while ointments have generally been selected for dry, lichenified or scaly lesions, or when a more occlusive effect is required. Lotions have generally been useful when minimal application to large or hair-containing areas is required, or for the treatment of exudative lesions. The term "local administration" is used herein to refer to topical administration as well as administration to the eye.

[0160] As described herein, combination therapy, i.e. the use of at least two compounds or pharmaceutical compositions of the present invention, in particular the use of a compound of the present invention and an sGC stimulant according to the present invention, can in particular include simultaneous or sequential administration of a compound of formula I or formula II or a pharmaceutical composition of the present invention and at least one sGC stimulant.

[0161] The compounds of the present invention of formula I or formula II, pharmaceutical compositions or combination products, preferably those containing the compounds of the present invention of formula I or formula II or pharmaceutical compositions and at least one sGC stimulant, can be administered to any subject, preferably human, that can experience the beneficial effects of the compounds of the present invention, compositions or products described herein. Thus, the compounds of the present invention of formula I or formula II, pharmaceutical compositions or combination products described herein can be administered by any means that achieve their intended purpose. For example, administration may be by oral, buccal, sublingual, rectal, vaginal, intranasal, nasal, topical, intradermal, transdermal, subcutaneous, intraocular injection, transdermal, enteral, topical, intravenous, intraperitoneal or parenteral administration. Typically, simultaneous or sequential administration is performed by the same type of administration, but different types of administration, such as topical application of the compounds of formula I or formula II or pharmaceutical compositions and oral administration of at least one sGC stimulant, are also envisioned and are encompassed by the present invention.

[0162] The compounds of the invention of formula I or II can be prepared according to Reaction Scheme 1 and Scheme 2. These schemes represent the synthesis of general compounds of formula I or II and form part of the invention.

[0163] Compounds of formula I can be easily obtained starting from commercially available sildenafil or pyrazolo[4,3-d]pyrimidin-7-one by acidic sulfonamide hydrolysis leading to hydrolysis to intermediate sulfonic acid as outlined in scheme 1. Acidic hydrolysis leads to intermediate sulfonic acid IV. Alternatively, the sulfonic acid can be obtained as described in the literature (European Patent Application Publication No. 463756A1 / 19920102, see also Dunn PJ Organic Process Research & Development (2005), 9(1), 88-97). Formation of chlorosulfonic acid derivative V and treatment with amine VI leads to sulfonamide VII. Nitration using acetyl nitrate leads to compound I.

[0164] Similarly, compounds of formula II can be easily obtained starting from commercially available vardenafil or 2-phenylimidazotriazinone by acidic sulfonamide hydrolysis leading to hydrolysis to intermediate sulfonic acid VIII as outlined in scheme 2. Acidic hydrolysis leads to intermediate sulfonic acid VIII. Alternatively, sulfonic acid can be obtained as described in the literature (WO2002089808 / 20021114). Formation of chlorosulfonic acid derivative IX and treatment with amine VI leads to sulfonamide X. Nitration using acetyl nitrate leads to compound II.

[0165] Scheme 1: [ka]

[0166] Scheme 2: [ka]

[0167] example The synthesis of preferred compounds of formula I and II is illustrated below and typically preceded by a reaction scheme. The following examples further illustrate the invention but should not be construed as in any way limiting its scope.

[0168] Scheme 3 [ka]

[0169] Example 1 4-Ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonic acid (1) To a stirred solution of 5-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil) (1.0 g, 2.10 mmol) in water (21 mL) was added concentrated sulfuric acid (16 mL) dropwise at room temperature for 1 h. After addition, the reaction was heated to 100 °C for 40 h. The reaction was monitored by TLC and LCMS analysis. After completion, the reaction mixture was cooled to 0 °C and neutralized with 25% aqueous NaOH (90 mL) (pH approx. 7-8). The resulting heterogeneous mixture was concentrated under reduced pressure until the water was completely removed. The resulting residue was treated with 10% methanol in dichloromethane (3 x 300 mL) and filtered. The combined organic filtrate was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (C-18 column, Grace system) eluting with a 5-10% gradient of acetonitrile in water to give the title compound 1 (410 mg, 50% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 11.90(br s,1 H;D 2 O exchangeable)7.76-7.52(m,2 H)7.02-6.99(m,1 H),4.11(s,3 H),4.10-4.06(m,2 H),2.76-2.72(m,2 H),1.75-1.67(m,2 H),1.29-1.26(m,3 H),0.91(t,J=7.5 Hz,3 H);LCMS(ESI):m / z 393.3 [M+H] + ;Purity ~99.8%.

[0170] Example 2 (R)-5-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4) CH 2 Cl 2To a stirred solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonic acid 1 (230 mg, 0.6 mmol) in DMF (14 mL) and DMF (0.23 mL) was added dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 5 h. After the reaction was completed (monitored by TLC), the reaction solution was concentrated under reduced pressure below 20° C. and filled with argon atmosphere. The crude liquid was eluted with CH 2 Cl 2 (2×6 mL) to give the crude product 2 as a pale yellow liquid.

[0171] Meanwhile, (R)-1-(piperidin-4-yl)ethane-1,2-diol hydrochloride 3 (prepared according to the procedure set out in WO2005026145A1) (220 mg, 1.2 mmol) in ethanol (14 mL) was treated with Amberlyst A-21 ion exchange resin (1.1 g, 5 wt / wt) at room temperature for 2 h and filtered. Triethylamine (1.3 mL, 9.0 mmol) was added dropwise to the filtrate at 0° C., followed by elution with CH at 0° C. under an inert atmosphere. 2 Cl 2 A solution of crude product 2 in (5 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was directly purified by reverse phase column chromatography (C-18 column, Grace system) eluting with 25% acetonitrile in water to give the title compound 4 (23.8 mg) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.24(br s,1 H;D 2 O exchangeable),7.85(d,J=2.4 Hz,1 H),7.82(dd,J=8.8,2.4 Hz,1 H),7.36(d,J=8.8 Hz,1 H),4.45-4.38(m,2 H;D 2O exchangeable),4.20(q,J=6.9 Hz,2 H),4.16(s,3 H),3.67-3.64(m,2 H),3.33-3.25(m,2 H),3.22-3.16(m,1 H),2.79-2.75(m,2 H),2.21-2.14(m,2 LCMS(ESI):m / z 520.5 [M+H] + ;Purity ~99.7%.

[0172] Scheme 4 [ka]

[0173] Example 3 (R)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1a) and (R)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (1c). CH 2 Cl 2 To a stirred solution of (R)-5-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,4-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (4) (140 mg, 0.27 mmol) in (2.8 mL) was added freshly prepared acetyl nitrate (0.24 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.04 mL, 6.0 equiv.) in acetic anhydride (0.20 mL, 1:5 HNO 3A solution of (prepared separately) was added dropwise at -10°C under argon atmosphere slowly to 100 ml of ethyl acetate (Note: Do not allow temperature to rise above 0°C)) at -10°C under argon atmosphere. The reaction mixture was stirred at 0°C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to 0°C with saturated NaHCO 3 The reaction was quenched with a solution (approximately 15 mL, pH approximately 7-8). The resulting solution was then diluted with CH 2 Cl 2 (3×10 mL). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18 column) using a 40-100% gradient of acetonitrile. The appropriate fractions were lyophilized to give 1a (33.6 mg) as a white solid and 1c (46.3 mg) as a white solid.

[0174] 1a Analysis data: 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.17(br s,1 H;D 2 O exchangeable),7.86(d,J=2.4 Hz,1 H),7.82(dd,J=8.8,2.4 Hz,1 H),7.36(d,J=8.8 Hz,1 H),5.33-5.30(m,1 H),4.94(dd,J=12.7,2.4 Hz,1 H),4.71(dd,J=12.7,5.8 Hz,1 H),4.20(q,J=7.1 Hz,2 H),4.16(s,3 H),3.71-3.68(m,2 H),2.79-2.75(m,2 H),2.27-2.20(m,2 H),1.82-1.70(m,5 H),1.49-1.36(m,2 H),1.33(t,J=7.1 Hz,3 H),0.94(t,J=7.6 Hz,3 H);LCMS(ESI):m / z 610.0 [M+H + ];Purity ~98.7%.

[0175] 1c Analysis data: 1 H NMR (400 MHz, DMSO-d 6) δ ppm 12.18(br s,1 H;D 2 O exchangeable),7.86(d,J=2.4 Hz,1 H),7.82(dd,J=8.8,2.4 Hz,1 H),7.36(d,J=8.8 Hz,1 H),5.22(d,J=5.4 Hz,1 H;D 2 O exchangeable),4.52(dd,J=11.2,2.9 Hz,1 H),4.37(dd,J=11.2,7.3 Hz,1 H),4.21(d,J=6.9 Hz,2 H),4.16(s,3 H),3.70-3.66(m,2 H),3.54-3.51(m,1 H),2.79-2.75(m,2 H),2.24-2.17(m,2 H),1.82-1.70(m,3 H),1.65-1.62(m,1 H),1.40-1.30(m,6 H),0.94(t,J=7.3 Hz,3 H);LCMS(ESI):m / z 564.9 [M+H + ];Purity ~99.5%.

[0176] Scheme 5 [ka]

[0177] Example 4 (S)-5-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (6) CH 2 Cl 2 To a stirred solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonic acid 1 (150 mg, 0.38 mmol) in DMF (9 mL) and DMF (0.15 mL) was added dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 4 h. After the reaction was completed (monitored by TLC), the reaction solution was concentrated under reduced pressure below 20° C. and filled with argon atmosphere. The crude liquid was eluted with CH 2 Cl2 (5 mL) to give 150 mg of crude product 2 as a pale yellow liquid.

[0178] Meanwhile, (S)-1-(piperidin-4-yl)ethane-1,2-diol hydrochloride (5, prepared according to the procedure set out in WO2005026145A1) (133 mg, 0.73 mmol) in ethanol (9 mL) was treated with Amberlyst A-21 ion exchange resin (665 mg, 5 w / w) at room temperature for 2 h and filtered. Triethylamine (0.76 mL, 5.48 mmol) was added dropwise to the filtrate at 0° C., followed by elution with CH at 0° C. under an inert atmosphere. 2 Cl 2 A solution of crude product 2 in (3 mL) was added. The reaction mixture was warmed to room temperature and stirred for 12 h. After completion of the reaction (monitored by LCMS), the reaction mixture was directly purified by reverse phase column chromatography (C-18 column, Grace system) eluting with a 25-35% gradient of acetonitrile with water to give the title compound 6 (48 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.24(br s,1 H;D 2 O exchangeable),7.85(d,J=2.4 Hz,1 H),7.82(dd,J=8.8,2.4 Hz,1 H),7.36(d,J=8.8 Hz,1 H),4.45-4.38(m,2 H;D 2 O exchangeable),4.20(q,J=6.9 Hz,2 H),4.16(s,3 H),3.67-3.64(m,2 H),3.33-3.25(m,2 H),3.22-3.16(m,1 H),2.79-2.75(m,2 H),2.21-2.14(m,2 LCMS(ESI):m / z 520.2 [M+H] + ;Purity ~99.6%.

[0179] Scheme 6 [ka]

[0180] Example 5 (S)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1b) and (S)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (1d). CH 2 Cl 2 To a stirred solution of (S)-5-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,4-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (6) (120 mg, 0.23 mmol) in (1.8 mL) was added freshly prepared acetyl nitrate (0.18 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.03 mL, 6.0 equiv.) in acetic anhydride (0.15 mL, 1:5 HNO 3 A solution of (prepared separately) was added dropwise at -10°C under argon atmosphere slowly to a solution of (Note: Do not allow temperature to rise above 0°C)) at -10°C under argon atmosphere. The reaction mixture was stirred at 0°C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to 0°C with saturated NaHCO 3 The reaction was quenched with a solution (approximately 10 mL, pH approximately 7-8). The resulting solution was then diluted with CH 2 Cl 2 (3×10 mL). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18 column) using a 40-100% gradient of acetonitrile. The appropriate fractions were lyophilized to give 1b (31 mg) as a white solid and 1d (10.2 mg) as a white solid.

[0181] 1b Analytical data: 1 H NMR(400 MHz, DMSO-d 6 ) δ ppm 12.17(br s, 1 H; D 2 O exchangeable), 7.86(d, J = 2.4 Hz, 1 H), 7.82(dd, J = 8.8, 2.4 Hz, 1 H), 7.36(d, J = 8.8 Hz, 1 H), 5.33 - 5.30(m, 1 H), 4.94(dd, J = 12.7, 2.4 Hz, 1 H), 4.71(dd, J = 12.7, 5.8 Hz, 1 H), 4.20(q, J = 7.1 Hz, 2 H), 4.16(s, 3 H), 3.71 - 3.68(m, 2 H), 2.79 - 2.75(m, 2 H), 2.27 - 2.20(m, 2 H), 1.82 - 1.70(m, 5 H), 1.49 - 1.36(m, 2 H), 1.33(t, J = 7.1 Hz, 3 H), 0.94(t, J = 7.6 Hz, 3 H); LCMS(ESI): m / z 610.0 [M + H + ; Purity ~99.5%.

[0182] 1d Analytical data: 1 H NMR(400 MHz, DMSO-d 6 ) δ ppm 12.18(br s, 1 H; D 2 O exchangeable), 7.86(d, J = 2.4 Hz, 1 H), 7.82(dd, J = 8.8, 2.4 Hz, 1 H), 7.36(d, J = 8.8 Hz, 1 H), 5.22(d, J = 5.4 Hz, 1 H; D 2 O exchangeable), 4.52(dd, J = 11.2, 2.9 Hz, 1 H), 4.37(dd, J = 11.2, 7.3 Hz, 1 H), 4.21(d, J = 6.9 Hz, 2 H), 4.16(s, 3 H), 3.70 - 3.66(m, 2 H), 3.54 - 3.51(m, 1 H), 2.79 - 2.75(m, 2 H), 2.24 - 2.17(m, 2 H), 1.82 - 1.70(m, 3 H), 1.65 - 1.62(m, 1 H), 1.40 - 1.30(m, 6 H), 0.94(t, J = 7.3 Hz, 3 H); LCMS(ESI): m / z 565.3 [M + H +];Purity ~97.1%.

[0183] Scheme 7 [ka]

[0184] Example 6 tert-Butyl 4-(3-(tert-butoxy)-3-oxopropanoyl)piperidine-1-carboxylate (9) and di-tert-butyl 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-hydroxypentanedioate (10) To a stirred solution of tert-butyl acetate 8 (214.8 g, 1.85 mol) in THF (300 mL) was added 2.0 M lithium diisopropylamide solution in THF (462 mL, 0.924 mol) at −78° C. and stirred for 1 h. To the reaction mixture was added tert-butyl 4-formylpiperidine-1-carboxylate 7 (7.5 g, 0.0308 mol) at −78° C. and stirred at the same temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 10% aqueous ammonium chloride solution (150 mL) at −78° C. The solution was warmed to room temperature and extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with brine (400 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. Note: The reaction was carried out in two lots (2 x 7.5 g scale). The crude mixture obtained from both batches was combined and purified by silica gel column chromatography (eluted with 30% ethyl acetate with petroleum ether) to give 37.5 g of the title compounds 9 and 10 as a mixture (57% 9 and 42% 10 by LCMS analysis) as a brown liquid. The concentrated mixture was purified by reverse phase preparative HPLC (column: Kromosil (25 * 150 mm), 10 μm; Mobile phase: (A): 100% water (B): 100% acetonitrile, Flow rate: 19 mL / min, Gradient - (T / %B): 0 / 65, 1 / 65, 12 / 85, 14 / 85, 16 / 99, 18 / 99, 18.05 / 65, 20 / 65, Solubility: ACN+H 2The pure fractions were purified by lyophilization to give tert-butyl 4-(3-(tert-butoxy)-3-oxopropanoyl)piperidine-1-carboxylate 9 (6.2 g, 30% yield, early eluting compound) as a pale yellow liquid and di-tert-butyl 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-hydroxypentanedioate 10 (7.0 g, 25% yield, late eluting compound) as a colorless liquid.

[0185] Data for tert-butyl 4-(3-(tert-butoxy)-3-oxopropanoyl)piperidine-1-carboxylate (9): 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.14-4.09(m,2 H),3.40(s,2 H),2.82-2.74(m,2 H),2.64-2.58(m,1 H),1.87-1.81(m,2 H),1.57-1.47(m,2 H),1.49(s,9 H),1.46(s,9 H);LCMS(ELSD):m / z 328.26 [M+H + ];Purity ~99%.

[0186] Data for di-tert-butyl 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-hydroxypentanedioate (10): 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.31(s,1 H),4.26-4.10(br m,2 H),2.64-2.50(m,6 H),1.76-1.61(m,3 H),1.46-1.39(m,27 H),1.32-1.25(m,2 H);LCMS(ELSD):m / z 444.36 [M+H + ];Purity ~99%.

[0187] Scheme 8 [ka]

[0188] Example 7 tert-Butyl 4-(1,3-dihydroxypropyl)piperidine-1-carboxylate (11) To a stirred solution of tert-butyl 4-(3-(tert-butoxy)-3-oxopropanoyl)piperidine-1-carboxylate 9 (4.5 g, 13.75 mmol) in methanol (45 mL) was added sodium borohydride (4.04 g, 106.8 mmol) portionwise at 0° C. for 20 min and the reaction was allowed to reach room temperature. The reaction mixture was slowly heated to reflux temperature and stirred for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., quenched with ice water (50 mL) and extracted into dichloromethane (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 11 (3.2 g, 90%) as a colorless liquid. 1 H NMR (300 MHz, DMSO-d 6 )δ ppm 4.39(br s,1 H),3.99-3.92(m,2 H),3.53-3.38(m,4 H),2.66-2.53(m,2 H),1.67-1.61(m,1 H),1.56-1.23(m,12 H),1.23-0.98(m,3 H);LCMS(ELSD;ESI):m / z Actual value 260.32 [M+H + ];Purity ~93.68%.

[0189] Example 8 1-(Piperidin-4-yl)propane-1,3-diol hydrochloride (12) To a stirred solution of tert-butyl 4-(1,3-dihydroxypropyl)piperidine-1-carboxylate 11 (3.0 g, 11.57 mmol) in methanol (30 mL) was added 4N HCl solution in 1,4-dioxane (30 mL) at 0° C. and stirred at room temperature for 3 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The resulting residue was lyophilized to give the title compound 12 (2.1 g, 92%) as a semi-solid, which was collected as such for the next step. 1 H NMR (300 MHz, DMSO-d 6)δ ppm 9.04(br s 1H),8.64(br s,1 H),4.52(br s,2 H),3.53-3.50(m,2 H),3.46-3.41(m,1 H),3.27-3.17(m,2 H),2.83-2.71(m,2 H),1.81-1.72(m,1 H),1.61-1.43(m,6 H).

[0190] Scheme 9 [ka]

[0191] Example 9 5-(5-((4-(1,3-dihydroxypropyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (13): To a stirred solution of 1-(piperidin-4-yl)propane-1,3-diol hydrochloride (12) (314 mg, 1.60 mmol) in ethanol (18 mL) was added Amberlyst A-21 basic resin (1.5 g) and stirred at room temperature. After stirring for 3 hours, the ethanol solution was filtered (removing the resin beads). To the filtrate was added triethylamine (1.01 mL, 7.31 mmol) dropwise at 0° C. and stirred for 15 minutes. To this was added a solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride 2 (300 mg, 0.73 mmol) in dichloromethane (18 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure. NOTE: The reaction was repeated with sulfonyl chloride 2 on a 300 mg scale. The residues obtained from both batches were combined and purified (without workup) by reversed-phase column chromatography (C18-40g column; Grace system; eluted with 45-50% gradient of acetonitrile with water) to give 120 mg of the title compound with 84% purity, which was purified by reversed-phase preparative HPLC (column used: YMC TRIAT(25*150)mm, 10μm); mobile phase: (A): 100% water, (B): acetonitrile; flow rate: 19mL / min; gradient-(T / %B): 0 / 30, 1 / 30, 11 / 70, 11.1 / 99, 13 / 99, 13.1 / 30, 15 / 30; solubility: ACN+H 2 3H+THF). The pure fractions were lyophilized to give the title compound 13 (80 mg, 10% yield) as a white solid. LCMS (ESI): m / z Found 534.12 [M+H + ];Purity ~98.8%. 80 mg of 13 was subjected to chiral preparative SFC purification to give 34 mg of enantiomer 14-1 and 35 mg of enantiomer 14-2 as white solids.

[0192] Analysis SFC conditions Column / dimensions: Chiralpak AD-H (4.6 x 250 mm), 5μ %CO2:70.0% % Co-solvent: 30.0% (0.5% IP amine in isopropanol) Total flow rate: 3.0g / min Back pressure: 100.0bar Temperature: 30.0℃ UV: 214.0 nm

[0193] Preparative SFC conditions Column / dimensions: Chiralpak AD-H (30 x 250 mm), 5μ % CO2: 85.0% % Co-solvent: 15.0% (0.5% IP amine in isopropanol) Total flow rate: 60.0g / min Back pressure: 90.0bar UV: 214.0 nm Stack time: 10.0 minutes Filling / Injection: 6.5mg Solubility: 14ml of methanol Number of injections: 16 Equipment Details: Make / Model: SFC-080

[0194] 14Peak-1 Analytical Data: White solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 12.19(br s,1 H),7.84(d,J=2.3 Hz,1 H),7.80(dd,J=8.8,2.3 Hz,1 H),7.34(d,J=8.8 Hz,1 H),4.35(d,J=5.9 Hz,1 H),4.31(br s,1 H),4.19(q,J=7.1 Hz,2 H),4.15(s,3 H),3.71-3.66(m,2 H),3.51-3.43(m,2 H),3.33-3.29(m,1 H),2.78-2.74(m,2 H),2.21-2.11(m,2 H),1.78-1.69(m,3 H),1.62-1.58(m,1 H),1.52-1.43(m,1 H),1.40-1.14(m,7 H),0.94(t,J=7.4 Hz,3 H);LCMS(ESI):m / z Actual value 534.65 [M+H +; Purity ~98.85%; UPLC: Purity ~96.48%; Chiral SFC: 98.56% ee; 99.283% with RT: 8.92 min; (Column: Chiralpak AD-H (4.6*250) mm, 5 μm, co-solvent name: 0.5% IPAmine in isopropanol, % co-solvent: 30%, flow rate: 3.0 ml / min, outlet pressure: 100 bar; Temp: 30°C, UV: 214 nm).

[0195] 14 Peak-2 analysis data: White solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.19 (br s, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 7.80 (dd, J = 8.8, 2.3 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 4.35 (d, J = 5.9 Hz, 1 H), 4.31 (br s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.15 (s, 3 H), 3.71 - 3.66 (m, 2 H), 3.51 - 3.43 (m, 2 H), 3.33 - 3.29 (m, 1 H), 2.78 - 2.74 (m, 2 H), 2.21 - 2.11 (m, 2 H), 1.78 - 1.69 (m, 3 H), 1.62 - 1.58 (m, 1 H), 1.52 - 1.43 (m, 1 H), 1.40 - 1.14 (m, 7 H), 0.94 (t, J = 7.4 Hz, 3 H); LCMS (ESI): Measured value m / z 534.65 [M+H + ; Purity ~99.94%; UPLC: Purity ~98.90%; Chiral SFC: 90.98% ee; 95.494% with RT: 10.24 min; (Column: Chiralpak AD-H (4.6*250) mm, 5 μm, co-solvent name: 0.5% IPAmine in isopropanol, % co-solvent: 30%, flow rate: 3.0 ml / min, outlet pressure: 100 bar; Temp: 30°C, UV: 214 nm).

[0196] Scheme 10 [Chemical Structure]

[0197] Dichloromethane (8.5 Example 10 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate (1ef) To a stirred solution of 5-(5-((4-(1,3-dihydroxypropyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (13) (170 mg, 0.318 mmol) in 1 mL of freshly prepared acetyl nitrate (0.2 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.03 mL, 2.23 mmol) in acetic anhydride (0.17 mL, 1:5 fuming HNO 3 A solution of (prepared separately) was added dropwise at -10 °C under argon atmosphere (Note: Do not allow temperature to rise above 0 °C)) to a solution of (prepared separately) at -5 °C under argon atmosphere. The reaction was stirred at -5 to 0 °C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Grace system, C18-12g column, eluted with a 50-55% gradient of acetonitrile with water). The pure fractions were lyophilized to give the title compound 1ef (47 mg, 25%) as a white solid. LCMS (ESI): m / z 579.45 [M+H + ];Purity ~88.71%. 47 mg of 1ef was subjected to chiral preparative SFC purification to give 10.1 mg of 1e as a white solid and 11.5 mg of 1f as a white solid.

[0198] Analysis SFC conditions Column / dimensions: Chiralpak AD-H (4.6 x 250 mm), 5μ %CO 2 :70.0% % Co-solvent: 30.0% (30mm methanolic ammonia in isopropanol) Total flow rate: 3.0g / min Back pressure: 100.0bar Temperature: 30.0℃ UV: 214.0 nm

[0199] Preparative SFC conditions Column / dimensions: Chiralpak AD-H (30 x 250 mm), 5μ %CO 2 :85.0% % Co-solvent: 15.0% (30 mm methanolic ammonia in isopropanol) Total flow rate: 70.0g / min Back pressure: 90.0bar UV: 214.0 nm Stack time: 9.0 minutes Filling / Injection: 2.2mg Solubility: 20ml of methanol Number of injections: 18 Equipment Details: Make / Model: SFC-80

[0200] 1e Analytical data: White solid. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 12.17 (broad singlet, 1H), 7.85 (doublet, J = 2.3 Hz, 1H), 7.82 (doublet of doublets, J = 8.8, 2.3 Hz, 1H), 7.36 (doublet, J = 8.8 Hz, 1H), 4.78 (doublet, J = 5.9 Hz, 1H), 4.61 - 4.54 (multiplet, 2H), 4.20 (quartet, J = 7.3 Hz, 2H), 4.15 (singlet, 3H), 3.71 - 3.66 (multiplet, 2H), 3.40 - 3.37 (multiplet, 1H), 2.79 - 2.75 (multiplet, 2H), 2.20 - 2.13 (multiplet, 2H), 1.80 - 1.70 (multiplet, 3H), 1.64 - 1.57 (multiplet, 2H), 1.38 - 1.15 (multiplet, 7H), 0.94 (triplet, J = 7.3 Hz, 3H); LCMS (ESI): m / z measured value 579.23 [M + H + ; Purity ~95.09%; UPLC: Purity ~95.14%; Chiral SFC: 98.38% ee; 99.19% with RT: 2.64 min; (Column: Chiralpak AD - 3 (4.6 * 150) mm, 3μm, co - solvent name: 0.5% IPAmine in isopropanol, % co - solvent: 30%, flow rate: 3.0 ml / min, outlet pressure: 1500 psi; Temp: 30°C, UV: 220 nm).

[0201] 1f analysis data: White solid. 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 12.17 (broad singlet, 1H), 7.85 (doublet, J = 2.3 Hz, 1H), 7.82 (doublet of doublets, J = 8.8, 2.3 Hz, 1H), 7.36 (doublet, J = 8.8 Hz, 1H), 4.78 (doublet, J = 5.9 Hz, 1H), 4.61 - 4.54 (multiplet, 2H), 4.20 (quartet, J = 7.3 Hz, 2H), 4.15 (singlet, 3H), 3.71 - 3.66 (multiplet, 2H), 3.40 - 3.37 (multiplet, 1H), 2.79 - 2.75 (multiplet, 2H), 2.20 - 2.13 (multiplet, 2H), 1.80 - 1.70 (multiplet, 3H), 1.64 - 1.57 (multiplet, 2H), 1.38 - 1.15 (multiplet, 7H), 0.94 (triplet, J = 7.3 Hz, 3H); LCMS (ESI): m / z measured value 579.19 [M + H +]; Purity ~ 99.20%; UPLC: Purity ~ 98.46%; Chiral SFC: 95.22% ee; 97.61% with RT: 3.60 min; (Column: Chiralpak AD-3 (4.6*150) mm, 3 μm, Co-solvent name: 0.5% IPAmine in isopropanol, % co-solvent: 30%, Flow rate: 3.0 ml / min, Outlet pressure: 1500 psi; Temp: 30°C, UV: 220 nm).

[0202] Scheme 11 [ka]

[0203] Example 11 tert-Butyl 4-(1,3,5-trihydroxypentan-3-yl)piperidine-1-carboxylate (14) To a stirred solution of di-tert-butyl 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-hydroxypentanedioate 10 (250 mg, 0.563 mmol) in THF (5 mL) was added 2.0 M lithium aluminum hydride solution in THF (1.68 mL, 3.38 mmol) at 0 °C and stirred at cold temperature (0-10 °C) for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with wet sodium sulfate (0.6 g) at 0 °C. The solution was stirred at room temperature for 3 h and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase preparative HPLC (column used: XBRIDGE C18 (19*250mm) 5μm, mobile phase: (A): water, (B): acetonitrile; flow rate: 19mL / min; gradient-(T / %B): 0 / 20, 11 / 30, 11.1 / 100, 13 / 100, 13.1 / 20, 15 / 20; solubility: DMSO). The pure fractions were lyophilized to give analytically pure title compound 14 (18mg, 10% yield) as a brown liquid. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 4.40(br s,2 H),4.15(br s,1 H),4.04-3.93(m,2 H),3.52-3.48(m,4 H),2.61-2.53(m,2 H),1.62-1.43(m,7 H),1.39(s,9 H),1.17-1.08(m,2 H);LCMS(ELSD):m / z 304.30 [M+H + ];Purity ~99%. NOTE: The reaction was repeated at different scales ranging from 0.25 to 3 g scale. The crude product was directly recovered for the next reaction without purification.

[0204] Example 12 3-(Piperidin-4-yl)pentane-1,3,5-triol hydrochloride (15): To a stirred solution of tert-butyl 4-(1,3,5-trihydroxypentan-3-yl)piperidine-1-carboxylate 14 (1.3 g, 4.29 mmol) in methanol (13 mL) was added 4 M hydrogen chloride solution in 1,4-dioxane (13 mL) at 0° C. and stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and lyophilized to afford title 15 (800 mg, 77%) as a pale yellow semi-solid, which was directly collected for the next reaction. LCMS (ELSD): m / z found 204.27 [M+H + ];Purity ~99.7%.

[0205] Scheme 12 [ka]

[0206] Example 13 5-(2-ethoxy-5-((4-(1,3,5-trihydroxypentan-3-yl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (15) To a stirred solution of 3-(piperidin-4-yl)pentane-1,3,5-triol hydrochloride (14) (153 mg, 0.69 mmol) in ethanol (14.4 mL) was added triethylamine (0.6 mL, 4.38 mmol) dropwise at 0° C. and stirred at room temperature for 30 min. To this, a solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride 2 (120 mg, 0.29 mmol) in dichloromethane (7.2 mL) was added at 0° C. under inert atmosphere. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 20 ml of ice-cold water and extracted with dichloromethane (30 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and evaporated under reduced pressure. The crude product was purified by reverse phase column chromatography (C18-12g column, Grace system, eluted with a 30-35% gradient of acetonitrile with water). The pure fractions were lyophilized to give the title compound 15 (70 mg, 37% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 12.17(br s,1 H),7.85(d,J=2.3 Hz,1 H),7.81(dd,J=8.8,2.3 Hz,1 H),7.36(d,J=8.8 Hz,1 H),4.36(t,J=4.9 Hz,2 H),4.23-4.15(m,6 H),3.73-3.69(m,2 H),3.49-3.41(m,4 H),2.80-2.75(m,2 H),2.16-2.09(m,2 H),1.78-1.69(m,4 H),1.58-1.47(m,4 H),1.36-1.17(m,6 H),0.94(t,J=7.3 Hz,3 H);LCMS(ESI):m / z Actual value 578.48 [M+H] + ;Purity ~97.6%;UPLC: Purity ~95.7%.

[0207] Scheme 13 [ka]

[0208] Example 14 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate (1g) CH 2 Cl 2 To a stirred solution of 5-(2-ethoxy-5-((4-(1,3,5-trihydroxypentan-3-yl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 15 (100 mg, 0.173 mmol) in 1 mL of freshly prepared acetyl nitrate (0.06 mL) [(acetyl nitrate is dissolved in fuming HNO 3. NO 2 (0.01 mL, 3.0 equiv.) in acetic anhydride (0.05 mL, 1:5 HNO 3. NO 2 A solution of (prepared separately) was added dropwise at -15°C under argon atmosphere slowly to 100 ml of ethyl acetate (Note: Do not allow temperature to rise above 0°C)) at -15°C under argon atmosphere. The reaction mixture was stirred at the same temperature for 30 min. After completion of the reaction (monitored by TLC), the reaction was cooled to 0°C with saturated NaHCO 3 The resulting solution was quenched with CH 2 Cl 2 (2×5 mL). The combined organic layers were washed with brine (5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 4° C. and concentrated under reduced pressure. The crude product (41% of the desired mononitrate and 16% of the dinitrate based on LCMS analysis) was purified by reverse-phase column chromatography (Grace system, C18-12g column, eluting with a 50-55% gradient of acetonitrile with water). The pure fractions were lyophilized to give the title compound 1g (21.7 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 12.19(br s,1 H),7.86(d,J=2.3 Hz,1 H),7.82(dd,J=8.8,2.3 Hz,1 H),7.37(d,J=8.8 Hz,1 H),4.57-4.53(m,2 H),4.49-4.45(m,2 H),4.20(q,J=7.3 Hz,2 H),4.16(s,3 H),3.73-3.69(m,2 H),3.50-3.44(m,2 H),2.79-2.75(m,2 H),2.18-2.11(m,2 H),1.79-1.68(m,6 H),1.58-1.52(m,2 H),1.46-1.24(m,6 H),0.94(t,J=7.3 Hz,3 H);LCMS(ESI):m / z 623.24 [M+H + ];Purity ~96.4%;UPLC: Purity ~95.5%.

[0209] Scheme 14 [ka]

[0210] Example 15 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (1h) CH 2 Cl 2 To a stirred solution of 5-(2-ethoxy-5-((4-(1,3,5-trihydroxypentan-3-yl)piperidin-1-yl)sulfonyl)phenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 15 (50 mg, 0.086 mmol) in 1.5 mL of freshly prepared acetyl nitrate (0.056 mL) [(acetyl nitrate is dissolved in fuming HNO 3. NO 2 (0.009 mL, 5.0 equiv.) in acetic anhydride (0.047 mL, 1:5 HNO 3. NO 2A solution of (prepared separately) was added dropwise at -10°C under argon atmosphere (Note: Do not allow temperature to rise above 0°C)) to 100 ml of ethyl acetate at -5 to 0°C under argon atmosphere. The reaction mixture was stirred at -5 to 0°C for 1 h. After the reaction was complete (monitored by TLC), the reaction was cooled to 0°C with saturated NaHCO 3 The resulting solution was quenched with CH 2 Cl 2 (2×5 mL). The combined organic layers were washed with brine (5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (Grace system, C18-12g column, eluted with a 70-75% gradient of acetonitrile with water). The pure fractions were lyophilized to give the title compound 1h (21 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 12.17(br s,1 H),7.87(d,J=2.3 Hz,1 H),7.83(dd,J=8.8,2.3 Hz,1 H),7.37(d,J=8.8 Hz,1 H),4.77(s,1 H),4.58-4.54(m,4 H),4.20(q,J=7.3 Hz,2 H),4.15(s,3 H),3.75-3.70(m,2 H),2.79-2.75(m,2 H),2.21-2.16(m,2 H),1.82-1.60(m,8 H),1.36-1.29(m,6 H),0.94(t,J=7.3 Hz,3 H);LCMS(ESI):m / z Actual value 668.48 [M+H + ];Purity ~95.1%;UPLC: Purity ~95.1%

[0211] Scheme 14 [ka]

[0212] Example 16 Di-tert-butyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)(hydroxy)methyl)malonate (18) To a stirred solution of di-tert-butyl malonate 17 (52.5 mL, 234.43 mmol) in THF (200 mL), lithium diisopropylamide solution (2.0 M in THF, 94 mL, 188 mmol) was added dropwise at −78° C. for 20 min under inert atmosphere and stirred at the same temperature for 1 h. To this, a solution of tert-butyl 4-formylpiperidine-1-carboxylate 16 (10.0 g, 46.89 mmol) in THF (40 mL) was added dropwise at −78° C. for 15 min and stirred at the same temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was washed with saturated NH 4 The mixture was quenched with aqueous Cl (70 mL), warmed to room temperature and stirred for 10 min. The resulting solution was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (2×50 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with a gradient of 10–15% ethyl acetate in petroleum ether) to give 18 (6.0 g, 29% yield) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.22-4.14(m,2 H),3.87-3.83(m,1 H),3.45(br d,J=6.1 Hz,1 H),3.38(d,J=5.3 Hz,1 H),2.70-2.58(m,2 H),1.92-1.87(m,1 H),1.54-1.50(m,2 H),1.49-1.47(m,27 H),1.39-1.31(m,2 H);LCMS(ELSD,ESI):m / z Actual value 430.39 [M+H] + ;Purity ~99.5%.

[0213] Example 17 Di-tert-butyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)((trimethylsilyl)oxy)methyl)malonate (19) CH 2 Cl 2To a stirred solution of di-tert-butyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)(hydroxy)methyl)malonate 18 (5.0 g, 11.64 mmol) in 10 mL of ethyl acetate was added triethylamine (5.0 mL, 34.92 mmol) followed by 4-dimethylaminopyridine (1.42 g, 11.64 mmol) under inert atmosphere at room temperature and stirred for 10 min. The reaction mixture was cooled to 0° C. and trimethylsilyl chloride (2.22 mL, 17.5 mmol) was added dropwise and stirred at the same temperature for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with CH 2 Cl 2 (100 mL) and dilute with saturated NaHCO 3 solution (100 mL), washed with brine (100 mL), and then with Na 2 SO 4 The mixture was dried at 4°C for 10 min and concentrated under reduced pressure. NOTE: The reaction was performed in two lots (1 x 5.0 g, 1 x 3.5 g). The crude products from both batches were combined and purified by column chromatography (neutral alumina, eluted with a 0-5% gradient of ethyl acetate in petroleum ether) to give 19 (7.0 g, 70%) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.17-4.09(m,3 H),3.38(d,J=7.2 Hz,1 H),2.65-2.59(m,2 H),1.71-1.67(m,1 H),1.56-1.52(m,2 H),1.47-1.45(m,27 H),1.36-1.27(m,2 H),0.11(s,9 H).LCMS(ELSD,ESI):m / z Actual value 502.43 [M+H] + ;Purity ~99.3%.

[0214] Example 18 tert-Butyl 4-(1,3-dihydroxy-2-(hydroxymethyl)propyl)piperidine-1-carboxylate (20) To a stirred solution of di-tert-butyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)((trimethylsilyl)oxy)methyl)malonate 19 (7.0 g, 13.95 mmol) in THF (210 mL) was added lithium aluminum hydride (2.0 M solution in THF, 28.0 mL, 56.0 mmol) dropwise under inert atmosphere at 0° C. and stirred at 0-10° C. for 1 h under inert atmosphere. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with saturated Na 2 SO 4 The solution (approximately 6.0 mL) was added dropwise at 0° C. for 30 min. The reaction mixture was allowed to reach room temperature and stirred for 2 h. The resulting heterogeneous mixture was diluted with ethyl acetate (200 mL), filtered, and washed thoroughly with methanol (2×100 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (neutral alumina, eluted with 0-10% methanolic ammonia in dichloromethane) to give the title compound 20 (1.75 g, 43%) as a gummy liquid. 1 H NMR (300 MHz, DMSO-d 6 )δ ppm 4.38-4.24(m,3 H),4.01-3.92(m,2 H),3.67-3.32(m,5 H),2.62-2.53(m,2 H),1.78-1.51(m,4 H),1.49(s,9 H),1.18-1.04(m,2 H).

[0215] Example 19 2-(Hydroxymethyl)-1-(piperidin-4-yl)propane-1,3-diol hydrochloride (21) To a stirred solution of tert-butyl 4-(1,3-dihydroxy-2-(hydroxymethyl)propyl)piperidine-1-carboxylate 20 (1.75 g, 6.05 mmol) in methanol (17.5 mL) was added dropwise 4.0 M hydrogen chloride solution in 1,4-dioxane (17.5 mL) at 0° C. under inert atmosphere. The reaction mixture was allowed to reach room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction solution was concentrated under reduced pressure and lyophilized to give the crude title compound (1.4 g) as a gummy liquid, which was used directly in the next step. 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.80(br s,2 H), 3.63-3.58(m,1 H), 3.50-3.39(m,3 H), 3.33-3.31(m,1 H), 3.27-3.24(m,2 H), 2.86-2.74(m,2 H), 1.91-1.87(m,1 H), 1.74-1.36(m,5 H)(-OH protons not observed; exchanged with water); LCMS(ELSD,ESI): m / z 190.21 [M+H] + ;Purity ~99%.

[0216] Scheme 15 [ka]

[0217] Example 20 5-(5-((4-(1,3-dihydroxy-2-(hydroxymethyl)propyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (22) To a stirred solution of 2-(hydroxymethyl)-1-(piperidin-4-yl)propane-1,3-diol hydrochloride (21) (200 mg, 0.88 mmol) in ethanol (18 mL) was added triethylamine (0.8 mL, 5.48 mmol) dropwise at 0° C. and stirred at room temperature for 30 min. To this was added a solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride 2 (150 mg, crude product) in dichloromethane (9 mL) under inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by LCMS), the reaction solution was concentrated under reduced pressure to give a residue. Note: The reaction was carried out in two lots (1×150 mg, 1×100 mg). The reaction residues from both batches were combined (without workup) and purified by reverse-phase column chromatography (Grace system, C18-12g column, eluted with a gradient of 25-35% acetonitrile in water). The pure fractions were lyophilized to afford the title compound 22 (23 mg, 6% overall yield for two steps) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 12.18(br s,1 H),7.85(d,J=2.3 Hz,1 H),7.82(dd,J=8.8,2.3 Hz,1 H),7.36(d,J=8.8 Hz,1 H),4.37(d,J=5.9 Hz,1 H),4.32(t,J=4.9 Hz,1 H),4.28(t,J=4.9 Hz,1 H),4.24-4.18(m,2 H),4.16(s,3 H),3.68-3.64(m,2 H),3.59-3.52(m,1 H),3.44-3.33(m,3 H),3.31-3.27(m,1 H),2.79-2.75(m,2 H),2.20-2.11(m,2 H),1.86-1.83(m,1 H),1.78-1.70(m,2 H),1.62-1.53(m,2 H),1.40-1.11(m,6 H),0.94(t,J=7.3 Hz,3 H);LCMS(ESI):m / z Actual value 564.51 [M+H + ];Purity ~99.6%;UPLC: Purity ~99.1%.

[0218] Scheme 16 [ka]

[0219] Example 21 2-((1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (1i) To a stirred solution of 5-(5-((4-(1,3-dihydroxy-2-(hydroxymethyl)propyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one 22 (55 mg, 0.098 mmol) in dichloromethane (4 mL) was added freshly prepared acetyl nitrate (0.42 mL; acetyl nitrate is dissolved in fuming HNO 3 (0.07 mL, 3.21 mmol) in acetic anhydride (0.35 mL, 1:5 volume of fuming HNO 3 ) was added dropwise under inert atmosphere at -10 °C (Note: Do not allow temperature to rise above 0 °C) to 0 °C and stirred for 10 min. After the reaction was complete (monitored by TLC), the reaction was cooled to 0 °C with saturated NaHCO 3 The mixture was quenched with dichloromethane (10 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (Grace system, C18-12g column, eluted with a 45-55% gradient of acetonitrile in water). The pure fractions were lyophilized to give the title compound 1i (12.3 mg, 19%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 12.17(br s,1 H),7.87(d,J=2.3 Hz,1 H),7.83(dd,J=8.8,2.3 Hz,1 H),7.37(d,J=8.8 Hz,1 H),5.19(d,J=6.4 Hz,1 H),4.70-4.66(m,1 H),4.59-4.44(m,3 H),4.21(q,J=7.3 Hz,2 H),4.16(s,3 H),3.72-3.67(m,2 H),3.40-3.38(m,1 H),2.79-2.75(m,2 H),2.32-2.28(m,1 H),2.21-2.15(m,2 H),1.91-1.87(m,1 H),1.78-1.71(m,2 H),1.63-1.59(m,1 H),1.39-1.20(m,6 H),0.94(t,J=7.34 Hz,3 H);LCMS(ESI):m / z Actual value 654.20 [M+H + ];Purity ~98.0%;UPLC: Purity ~97.3%.

[0220] Scheme 17 [ka]

[0221] Example 22 4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonic acid (23) To a stirred solution of 2-(2-ethoxy-5-((4-ethylpiperazin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (vardenafil) (500 mg, 1.02 mmol) in water (10.5 mL) was added concentrated sulfuric acid (8.0 mL) dropwise at room temperature. After the addition, the reaction was heated to 100° C. for 60 h. After the reaction was completed (monitored by TLC and LCMS), the reaction mixture was cooled to about 10° C. and neutralized with 25% aqueous NaOH (about 40 mL). The resulting heterogeneous mixture was concentrated under reduced pressure until the water was completely removed. The resulting residue was treated with 20% methanol in dichloromethane (5×100 mL) and filtered. The combined organic filtrate was diluted with anhydrous Na2 SO 4 The crude product was co-distilled with toluene (2×50 mL), triturated with diethyl ether (20 mL), filtered and dried under vacuum to give the title compound 23 (500 mg) as an off-white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.63(br s,1 H),7.62(d,J=2.4 Hz,1 H),7.49(dd,J=8.8,2.4 Hz,1 H),6.91(d,J=8.8 Hz,1 H),4.01(q,J=6.8 Hz,2 H),2.74-2.70(m,2 LCMS(ESI):m / z 393.3 [M+H + ];Purity ~85.1%.

[0222] Example 23 (R)-2-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (25) CH 2 Cl 2 To a stirred solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonic acid 23 (100 mg, 0.26 mmol) in DMF (6 mL) and DMF (0.1 mL) was added dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 5 h. After completion of the reaction (monitored by TLC), the reaction was concentrated under reduced pressure below 20° C. and the vacuum was returned under argon atmosphere. The resulting residue was purified by CH 2 Cl 2 (2×6 mL) to give the crude product 24 as a pale yellow liquid.

[0223] Meanwhile, (R)-1-(piperidin-4-yl)ethane-1,2-diol hydrochloride (3, prepared according to the procedure set out in WO2005026145A1) (95 mg, 0.52 mmol) in ethanol (6 mL) solution was treated with Amberlyst A-21 ion exchange resin (5 wt / wt) at room temperature for 2 h and filtered. To the filtrate, triethylamine (0.5 mL, 3.9 mmol) was added dropwise at 0 °C, followed by CH 2 Cl 2 A solution of the above crude product 24 in (3 mL) was added at 0° C. under inert atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was directly purified by reverse phase column chromatography (C-18 column, Grace system) eluting with 30% acetonitrile in water. Note: The reaction was carried out in two lots (2×100 mg) and purified as above to give the title compound 25 (23.2 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.65(br s,1 H;D 2 O exchangeable),7.87-7.83(m,2 H),7.37(d,J=8.3 Hz,1 H),4.44-4.38(m,2 H;D 2 O exchangeable),4.21(q,J=7.2 Hz,2 H),3.68-3.64(m,2 H),3.31-3.25(m,2 H),3.22-3.16(m,1 H),2.84-2.81(m,2 H),2.48(s,3 H),2.21-2.13(m,2 LCMS(ESI):m / z 520.5 [M+H] + ;Purity ~99.5%.

[0224] Scheme 18 [ka]

[0225] Example 24 (R)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (2a) and (R)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (2c). CH 2 Cl 2 To a stirred solution of (R)-2-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (25) (110 mg, 0.21 mmol) in (2.0 mL) was added freshly prepared acetyl nitrate (0.18 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.03 mL, 6.0 equiv.) in acetic anhydride (0.15 mL, 1:5 HNO 3 A solution of (prepared separately) was added dropwise at -10°C under argon atmosphere slowly to 100 ml of ethyl acetate (Note: Do not allow temperature to rise above 0°C)) at -10°C under argon atmosphere. The reaction mixture was stirred at 0°C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to 0°C with saturated NaHCO 3 The resulting solution was quenched with CH 2 Cl 2 (2×10 mL). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18 column) using a 40-100% gradient of acetonitrile. The appropriate fractions were lyophilized to give 2a (38.4 mg) as a white solid and 2c (18.8 mg) as a white solid.

[0226] 2a Analysis data: 1 H NMR (400 MHz, DMSO-d6 ) δ ppm 11.66 (br s, 1 H; D 2 O exchangeable), 7.89 - 7.84 (m, 2 H), 7.38 (d, J = 9.2 Hz, 1 H), 5.35 - 5.31 (m, 1 H), 4.95 (dd, J = 12.7, 2.4 Hz, 1 H), 4.71 (dd, J = 12.7, 6.1 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3.72 - 3.68 (m, 2 H), 2.84 - 2.80 (m, 2 H), 2.48 (s, 3 H), 2.26 - 2.21 (m, 2 H), 1.82 - 1.69 (m, 5 H), 1.51 - 1.37 (m, 2 H), 1.33 (t, J = 7.1 Hz, 3 H), 0.92 (t, J = 7.3 Hz, 3 H); LCMS(ESI): m / z 610 [M + H + ; Purity ~99%.

[0227] 2c analysis data: 1 H NMR (400 MHz, DMSO - d 6 ) δ ppm 11.66 (br s, 1 H; D 2 O exchangeable), 7.87 - 7.83 (m, 2 H), 7.37 (d, J = 9.2 Hz, 1 H), 5.23 (d, J = 5.8 Hz, 1 H; D 2 O exchangeable), 4.53 (dd, J = 11.2, 3.4 Hz, 1 H), 4.38 (dd, J = 11.2, 7.3 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.70 - 3.65 (m, 2 H), 3.55 - 3.51 (m, 1 H), 2.84 - 2.80 (m, 2 H), 2.48 (s, 3 H), 2.24 - 2.17 (m, 2 H), 1.81 - 1.69 (m, 3 H), 1.68 - 1.61 (m, 1 H), 1.38 - 1.26 (m, 6 H), 0.92 (t, J = 7.3 Hz, 3 H); LCMS(ESI): m / z 565.05 [M + H + ; Purity ~99.7%.

[0228] Scheme 19

Chemical Structure

[0229] Example 25 (S)-2-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (26) CH 2 Cl 2 To a stirred solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonic acid 23 (300 mg, 0.76 mmol) in DMF (18 mL) and DMF (0.3 mL) was added dropwise at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 4 h. After completion of the reaction (monitored by TLC), the reaction was concentrated under reduced pressure below 20° C. and the vacuum was returned under argon atmosphere. The resulting residue was purified by CH 2 Cl 2 (9 mL) to give the crude product 24 as a pale yellow liquid.

[0230] Meanwhile, (S)-1-(piperidin-4-yl)ethane-1,2-diol hydrochloride (5) (270 mg, 1.53 mmol) in ethanol (18 mL) solution was treated with Amberlyst A-21 ion exchange resin (5 wt / wt) at room temperature for 2 h and filtered. Triethylamine (1.06 mL, 7.6 mmol) was added dropwise to the filtrate at 0 °C, followed by CH 2 Cl 2 A solution of the above crude product 24 in (3 mL) was added at 0° C. under inert atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was directly purified by reverse phase column chromatography (C-18 column, Grace system) eluting with 30% acetonitrile in water to give the title compound 26 (50 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.63(br s,1 H;D 2O exchangeable),7.87-7.83(m,2 H),7.37(d,J=8.3 Hz,1 H),4.44-4.38(m,2 H;D 2 O exchangeable),4.21(q,J=7.2 Hz,2 H),3.68-3.64(m,2 H),3.31-3.25(m,2 H),3.22-3.16(m,1 H),2.84-2.81(m,2 H),2.48(s,3 H),2.21-2.13(m,2 LCMS(ESI):m / z 520.5 [M+H] + ;Purity ~96.9%.

[0231] Scheme 20 [ka]

[0232] Example 26 (S)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (2b) and (S)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (2d). CH 2 Cl 2 To a stirred solution of (S)-2-(5-((4-(1,2-dihydroxyethyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (26) (150 mg, 0.29 mmol) in (2.5 mL) was added freshly prepared acetyl nitrate (0.22 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.037 mL, 6.0 equiv.) in acetic anhydride (0.18 mL, 1:5 HNO3 A solution of (prepared separately) was added dropwise at -10°C under argon atmosphere slowly to 100 ml of ethyl acetate (Note: Do not allow temperature to rise above 0°C)) at -10°C under argon atmosphere. The reaction mixture was stirred at 0°C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to 0°C with saturated NaHCO 3 The resulting solution was quenched with CH 2 Cl 2 (3×30 mL). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by preparative HPLC (XBridge C18 column) using a 40-100% gradient of acetonitrile. The appropriate fractions were lyophilized to give 2b (26 mg) as a white solid and 2d (19 mg) as a white solid.

[0233] 2b Analysis data: 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66(br s,1 H;D 2 O exchangeable),7.87-7.84(m,2 H),7.37(d,J=9.2 Hz,1 H),5.35-5.31(m,1 H),4.95(dd,J=12.7,2.4 Hz,1 H),4.71(dd,J=12.7,6.1 Hz,1 H),4.21(q,J=7.1 Hz,2 H),3.72-3.68(m,2 H),2.84-2.80(m,2 H),2.48(s,3 H),2.26-2.21(m,2 H),1.82-1.69(m,5 H),1.51-1.37(m,2 H),1.33(t,J=7.1 Hz,3 H),0.92(t,J=7.3 Hz,3 H); LCMS (ESI): m / z 610 [M+H + ];Purity ~99.2%.

[0234] 2D analysis data: 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66(br s,1 H;D 2O exchangeable),7.87-7.83(m,2 H),7.37(d,J=9.2 Hz,1 H),5.23(d,J=5.8 Hz,1 H;D 2 O exchangeable),4.53(dd,J=11.2,3.4 Hz,1 H),4.38(dd,J=11.2,7.3 Hz,1 H),4.20(q,J=7.1 Hz,2 H),3.70-3.65(m,2 H),3.55-3.51(m,1 H),2.84-2.80(m,2 H),2.48(s,3 H),2.24-2.17(m,2 H),1.81-1.69(m,3 H),1.68-1.61(m,1 H),1.38-1.26(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z 565.3 [M+H + ];Purity ~97%.

[0235] Scheme 21 [ka]

[0236] Example 27 2-(5-((4-(1,3-dihydroxypropyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (27) To a stirred solution of 1-(piperidin-4-yl)propane-1,3-diol hydrochloride (12) (373 mg, 1.91 mmol) in ethanol (18 mL) was added Amberlyst A-21 basic resin (1.5 g) and stirred at room temperature. After stirring for 3 hours, the ethanol solution was filtered (removing the resin beads). To the filtrate was added triethylamine (1.06 mL, 7.65 mmol) dropwise at 0° C. and stirred for 15 minutes. To this was added a solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride 24 (300 mg, 0.76 mmol) in dichloromethane (18 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to give the crude product. Note: The reaction was repeated in three batches as above (2 × 300 mg and 100 mg = 700 mg of sulfonyl chloride 4). The residues obtained from the three batches were combined and purified (without workup) by reverse phase column chromatography (C18-40 g column, Grace system, eluted with 45-50% gradient acetonitrile with water). The pure fractions were lyophilized to give the title compound 27 (racemic) (170 mg, 17% yield) as a white solid. LCMS (ESI): m / z Found 534.58 [M+H + ];Purity ~94%.

[0237] Example 28 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate (2e, 2f) To a stirred solution of 2-(5-((4-(1,3-dihydroxypropyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (27) (200 mg, 0.375 mmol) in dichloromethane (10 mL) was added freshly prepared acetyl nitrate (0.235 mL) [(acetyl nitrate is dissolved in fuming HNO3 (0.039 mL, 1.87 mmol) in acetic anhydride (0.196 mL, 1:5 fuming HNO 3 ) was added dropwise at -10 °C under argon atmosphere (Note: Do not allow temperature to rise above 0 °C)) at -5 °C under argon atmosphere. The reaction was stirred at -5 to 0 °C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Grace system, C18-12g column, eluted with a 50-55% gradient of acetonitrile with water). The pure fractions were lyophilized to give the title compounds 2e and 2f as racemates (70 mg, 31%) as white solids. LCMS (ESI): m / z 579.45 [M+H + ];Purity ~96.72%.

[0238] 70 mg of the racemate was subjected to chiral preparative SFC purification to give 21.2 mg of 2e as a white solid and 25.6 mg of 2f as a white solid.

[0239] Analysis SFC conditions Column / dimensions: Chiralpak AD-H (4.6 x 250 mm), 5μ %CO 2 :70.0% % Co-solvent: 30.0% (100% ethanol) Total flow rate: 3.0g / min Back pressure: 100.0bar Temperature: 30.0℃ UV: 214.0 nm

[0240] Preparative SFC conditions Column / dimensions: Chiralpak AD-H (30 x 250 mm), 5μ %CO 2 :80.0% % Co-solvent: 20.0% (100% ethanol) Total flow rate: 70.0 g / min Back pressure: 90.0 bar UV: 214.0 nm Stacking time: 6.7 min Filling / Injection: 4.2 mg Solubility: 20 ml of methanol Number of injections: 18 times Equipment details: Manufacture / Model: SFC-80

[0241] 2e analysis data: White solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.66 (br s, 1 H), 7.88 - 7.83 (m, 2 H), 7.37 (d, J = 8.2 Hz, 1 H), 4.79 (d, J = 5.8 Hz, 1 H), 4.61 - 4.52 (m, 2 H), 4.20 (q, J = 6.8 Hz, 2 H), 3.71 - 3.64 (m, 2 H), 3.33 - 3.28 (m, 1 H), 2.84 - 2.80 (m, 2 H), 2.48 (s, 3 H), 2.21 - 2.13 (m, 2 H), 1.81 - 1.59 (m, 4 H), 1.66 - 1.56 (m, 2 H), 1.39 - 1.12 (m, 6 H), 0.92 (t, J = 7.3 Hz, 3 H); LCMS (ESI): m / z measured value 579.23 [M+H + ; Purity ~96.07%; UPLC: Purity ~95.08%; Chiral SFC: 99.34% ee; 99.67% with RT: 2.17 min; (Column: Chiralpak AD-3 (4.6*150) mm, 3 μm, Co-solvent name: 0.5% DEA in Ethanol, % Co-solvent: 30%, Flow rate: 3.0 g / min, Outlet pressure: 1500 psi; Temp: 30°C, UV: 250 nm).

[0242] 2f: White solid. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 11.66(br s,1 H),7.88-7.83(m,2 H),7.37(d,J=8.2 Hz,1 H),4.79(d,J=5.8 Hz,1 H),4.61-4.52(m,2 H),4.20(q,J=6.8 Hz,2 H),3.71-3.64(m,2 H),3.33-3.28(m,1 H),2.84-2.80(m,2 H),2.48(s,3 H),2.21-2.13(m,2 H),1.81-1.59(m,4 H),1.66-1.56(m,2 H),1.39-1.12(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z Measured value 579.19 [M+H + ];Purity~99.96%;UPLC:Purity~99.65%;Chiral SFC:97.80% ee;98.90% with RT:3.08 min;(Column:Chiralpak AD-3(4.6*150)mm,3μm,Cosolvent name:0.5% DEA in ethanol,%Cosolvent:30%,Flow rate:3.0 g / min, outlet pressure: 1500 psi; Temp: 30°C, UV: 250 nm).

[0243] Scheme 22 [ka]

[0244] Example 29 2-(2-ethoxy-5-((4-(1,3,5-trihydroxypentan-3-yl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (28) To a stirred solution of 3-(piperidin-4-yl)pentane-1,3,5-triol hydrochloride (14) (243 mg, 1.02 mmol) in ethanol (12 mL) was added triethylamine (0.7 mL, 5.10 mmol) dropwise at 0° C. and stirred at room temperature for 30 min. To this was added a solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride 24 (200 mg, 0.510 mmol) in dichloromethane (12 mL) under inert atmosphere at 0° C. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure. Note: The reaction was repeated with 200 mg and 100 mg scales of sulfonyl chloride 4. The residues from the three batches were combined and purified (without workup) by reverse-phase column chromatography (C18-40g column, Grace system, eluted with a 45-50% gradient of acetonitrile in water). The pure fractions were lyophilized to give the title compound 28 (120 mg, 16%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.62(br s,1 H),7.87-7.83(m,2 H),7.37(d,J=8.8 Hz,1 H),4.37(t,J=4.8 Hz,2 H),4.24-4.17(m,2 H),4.16(s,1 H),3.73-3.67(m,2 H),3.49-3.34(m,4 H),2.84-2.80(m,2 H),2.48(s,3 H),2.16-2.09(m,2 H),1.78-1.68(m,4 H),1.59-1.47(m,4 H),1.36-1.15(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z 578.49 [M+H] + ;Purity ~98.41%.

[0245] Scheme 23 [ka]

[0246] Example 30 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate (2g) and 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (2h). To a stirred solution of 2-(2-ethoxy-5-((4-(1,3,5-trihydroxypentan-3-yl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (28) (100 mg, 0.173 mmol) in dichloromethane (5 mL) was added freshly prepared acetyl nitrate (0.06 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.01 mL, 0.519 mmol) in acetic anhydride (0.05 mL, 1:5 fuming HNO 3 ) was added dropwise at -10 °C under argon atmosphere (Note: Do not allow temperature to rise above 0 °C). The reaction was stirred at -5 to 0 °C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The resulting crude mixture was purified by reverse-phase column chromatography (Grace system, Revelis®, C18 column-40 g, eluted with 48-53% linear gradient acetonitrile with water). The pure fractions were lyophilized to give the title compounds 2g (8.4 mg, 8% yield, early eluting compound) as a white solid and 2h (35.6 mg, 31% yield, late eluting compound) as a white solid.

[0247] 2g analysis of データ: white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.66(br s,1 H),7.88-7.82(m,2 H),7.37(d,J=8.8 Hz,1 H),4.60-4.54(m,2 H),4.49-4.44(m,2 H),4.21(q,J=6.8 Hz,2 H),3.74-3.69(m,2 H),3.50-3.44(m,2 H),2.84-2.80(m,2 H),2.48(s,3 H),2.20-2.13(m,2 H),1.78-1.67(m,6 H),1.59-1.52(m,2 H),1.38-1.22(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z 623.24 [M+H + ]; Purity ~97.23%.

[0248] 2h analytical data: white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.62(br s,1 H),7.88-7.83(m,2 H),7.37(d,J=8.8 Hz,1 H),4.78(s,1 H),4.56(t,J=7.3 Hz,4 H),4.21(q,J=6.8 Hz,2 H),3.75-3.70(m,2 H),2.84-2.80(m,2 H),2.48(s,3 H),2.32-2.26(m,2 H),1.83-1.68(m,8 H),1.35-1.25(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ES):m / z 668.24 [M+H + ]; Purity ~98.31%.

[0249] スキーム24

change

[0250] Example 31 2-(5-((4-(1,3-dihydroxy-2-(hydroxymethyl)propyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (29) To a stirred solution of 2-(hydroxymethyl)-1-(piperidin-4-yl)propane-1,3-diol hydrochloride (21) (200 mg, 0.88 mmol) in ethanol (18 mL) was added Amberlyst A-21 basic resin (1.0 g) at room temperature and stirred for 2 h. The reaction solution was filtered through a Buchner funnel and washed with ethanol (6.0 mL). To the filtrate was added triethylamine (0.51 mL, 3.65 mmol) dropwise at 0° C. and stirred for 30 min. To this was added a solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride 24 (150 mg, 0.365 mmol) in dichloromethane (9 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed (monitored by LCMS), the reaction solution was concentrated under reduced pressure to give a residue. Note: The reaction was carried out in three lots (1 × 100 mg, 2 × 150 mg). The reaction residues from the three batches were combined and purified (without workup) by reverse phase column chromatography (Grace system, Reveleris®, C18 column-40 g, eluted with a 30-35% gradient acetonitrile in water). The pure fractions were lyophilized to give the title compound 29 (100 mg, 18% overall yield for two steps) as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 11.81(br s,1 H),7.88-7.83(m,2 H),7.37(d,J=8.8 Hz,1 H),4.38-4.25(m,3 H),4.21(q,J=6.8 Hz,2 H),3.72-3.62(m,2 H),3.58-3.52(m,1 H),3.46-3.38 m,4 H),2.84-2.80(m,2 H),2.48(s,3 H),2.21-2.12(m,2 H),1.87-1.82(m,1 H),1.78-1.69(m,2 H),1.63-1.52(m,2 H),1.41-1.20(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z Actual value 564.22 [M+H + ];Purity ~95.18%;UPLC: Purity ~95.12%.

[0251] Scheme 25 [ka]

[0252] Example 32 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (2i) To a stirred solution of 2-(5-((4-(1,3-dihydroxy-2-(hydroxymethyl)propyl)piperidin-1-yl)sulfonyl)-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one 29 (80 mg, 0.142 mmol) in dichloromethane (8 mL) was added freshly prepared acetyl nitrate (0.6 mL; acetyl nitrate is dissolved in fuming HNO 3 (0.1 mL, 4.59 mmol) in acetic anhydride (0.5 mL, 1:5 volume of fuming HNO 3) was added dropwise at -10°C under inert atmosphere (Note: Do not allow temperature to rise above 0°C) at 0°C and stirred for 15 min. After the reaction was complete (monitored by TLC), the reaction was diluted with saturated NaHCO 3 The mixture was quenched with dichloromethane (2×10 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography (Grace system, Reveleris®, C18 column-12 g column, eluted with a gradient of 45% acetonitrile in water). The pure fractions were lyophilized to give the title compound 2i (33.9 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.67(s,1 H),7.91-7.79(m,2 H),7.38(d,J=8.8 Hz,1 H),5.19(d,J=5.8 Hz,1 H),4.71-4.68(m,1 H),4.61-4.42(m,3 H),4.21(q,J=6.8 Hz,2 H),3.71-3.65(m,2 H),3.39-3.32(m,1 H),2.84-2.80(m,2 H),2.48(s,3 H),2.33-2.28(m,1 H),2.24-2.13(m,2 H),1.91-1.85(m,1 H),1.78-1.69(m,2 H),1.63-1.59(m,1 H),1.42-1.19(m,6 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z Actual value 654.54 [M+H + ];Purity ~98.64%;UPLC: Purity ~97.98%.

[0253] Scheme 26 [ka]

[0254] Example 33 Methyl 2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyacetate (31) CH 2 Cl 2 To a stirred solution of methyl 2-hydroxy-2-(piperidin-4-yl)acetate 30 (200 mg, 0.70 mmol) in 12 mL of ethyl acetate was added triethylamine (1.0 mL, 7.35 mmol) dropwise at 0° C. under an argon atmosphere and stirred for 30 min. The reaction mixture was diluted with CH 2 Cl 2 A solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)benzene-1-sulfonyl chloride 24 (200 mg, 0.49 mmol) in 10 mL of ethyl acetate was added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was diluted with CH 2 Cl 2 (20 mL) and washed with water (20 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 The resulting aqueous solution was dried over 1000 ml of ethyl acetate (2×75 mL) and concentrated under reduced pressure. Note: The reaction was carried out in three batches (1×100 mg, 2×200 mg). The resulting crude products of the three batches were combined and purified by reverse phase column chromatography (Grace system, Reveleris®, C18 column, eluting with a 35% gradient of acetonitrile with water). The pure fractions were concentrated until the acetonitrile solvent was completely removed. The resulting aqueous solution was extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound 31 (300 mg, approx. 42% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d 6)δ ppm 11.64(s,1 H),7.86-7.81(m,2 H),7.37(d,J=8.8 Hz,1 H),5.44(d,J=5.8 Hz,1 H),4.21(q,J=6.9 Hz,2 H),3.89-3.83(m,1 H),3.71-3.59(m,5 H),2.85-2.81(m,2 H),2.28-2.17(m,2 H),1.80-1.66(m,2 H),1.62-1.43(m,3 H),1.42-1.09(m,8 H),0.92(t,J=7.3 Hz,3 H);LCMS(ESI):m / z 548.20 [M+H + ];Purity ~93.19%.

[0255] Example 34 Methyl 2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(nitrooxy)acetate (32) To a stirred solution of methyl 2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyacetate 31 (150 mg, 0.27 mmol) in dichloromethane (7.5 mL) was added freshly prepared acetyl nitrate (1.0 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.17 mL, 7.8 mmol) in acetic anhydride (0.83 mL, 1:5 fuming HNO 3 A solution of (prepared separately) was added dropwise at -10°C under argon atmosphere (Note: Do not allow temperature to rise above 0°C)) to 0°C under argon atmosphere. The reaction was stirred at 0°C for 15 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (25 mL) and anhydrous Na 2 SO 4After drying at 40° C. and concentrating under reduced pressure, the title compound 32 (170 mg) was obtained as a semi-solid, which was used immediately in the next reaction without purification. LCMS (ESI): m / z 593.22 [M+H + ];Purity ~90.49%.

[0256] Example 35 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (33-racemic) To a stirred solution of methyl 2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(nitrooxy)acetate 32 (170 mg, crude) in THF (8.5 mL) was added 2 M LiAlH 4 The solution was added dropwise under argon atmosphere at 0° C. and stirred for 15 min at 0° C. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with saturated Na 2 SO 4 The mixture was quenched by dropwise addition of 1.0 mL of ethyl acetate at 0° C., brought to room temperature and stirred for 2 h. The resulting solution was filtered through a bed of celite and washed with ethyl acetate (25 mL). The filtrate was washed with brine (25 mL) and anhydrous Na 2 SO 4 The resulting aqueous solution was dried over 1000 ml of ethyl acetate (2×75 mL) and concentrated under reduced pressure. Note: The reaction was carried out in three batches (1×60 mg, 1×110 mg, 1×170 mg). The resulting crude products of the three batches were combined and purified by reverse phase column chromatography (Grace system, Revelis®, C18-40 g column, eluted with a 40% gradient of acetonitrile with water). The pure fractions were combined and concentrated until the acetonitrile solvent was completely removed. The resulting aqueous solution was extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with anhydrous Na 2 SO 4and concentrated under reduced pressure to give the title compound 33-racemate (128 mg) as an off-white solid. LCMS (ESI): m / z 565.23 [M+H + ]; Purity ~ 94.90%; Chiral SFC: Peak-1: 49.77% at RT = 9.97 min; Peak-2: 50.23% at RT 12.26 min (Column: Chiralpak AD-H (250 * 4.6) mm; 5um; Co-solvent: 25%, Co-solvent name: Isopropyl alcohol, Outlet pressure: 100 bar, Temperature: 30 °C; UV: 214 nm).

[0257] 128 mg of the 33-racemate was separated by chiral preparative SFC purification to give 26.0 mg of 2k-peak-1 as an off-white solid and 8.9 mg of 2i-peak-2 as an off-white solid.

[0258] Analysis SFC conditions: Column / dimensions: Chiralpak AD-H (250 x 4.6) mm, 5 μm %CO 2 :75% % Co-solvent: 25% (100% isopropyl alcohol) Flow rate: 3.0g / min Back pressure: 100.0bar Temperature: 30.0℃ Wavelength: 214nm

[0259] Preparative SFC conditions: Column / dimensions: Chiralpak AD-H (250 x 30) mm, 5 μm %CO 2 :85% % Co-solvent: 15% (0.5% isopropylamine in isopropyl alcohol) Flow rate: 60.0g / min Back pressure: 90.0bar Wavelength: 214nm Solubility: 20ml of methanol Fillability / Inj:2.8mg Total injections: 34 Equipment Details: Make / Model: SFC-080

[0260] 2k - 16 peak - 1 analysis data: 1 H NMR(300 MHz, DMSO - d 6 ) δ ppm 11.61(br s, 1H), 7.89 - 7.81(m, 2H), 7.37(d, J = 8.8 Hz, 1H), 5.08 - 4.91(m, 2H), 4.21(q, J = 6.9 Hz, 2H), 3.72 - 3.49(m, 4H), 2.85 - 2.80(m, 2H), 2.48(s, 3H), 2.28 - 2.19(m, 2H), 1.82 - 1.62(m, 5H), 1.41 - 1.24(m, 5H), 0.92(t, J = 7.3 Hz, 3H); LCMS(ESI): m / z 565.23 [M + H + ; Purity ~99.84%; UPLC: Purity ~98.44%; Chiral SFC: 96.99% ee; 98.49% at RT 8.65 min (Column: Chiralpak AD - H(250*4.6)mm; 5um; Co - solvent: 25%, Co - solvent name: Isopropyl alcohol, Outlet pressure: 100 bar, Temperature: 30 °C; UV: 214 nm).

[0261] 2i - peak - 2 analysis data: 1 H NMR(300 MHz, DMSO - d 6 ) δ ppm 11.61(br s, 1H), 7.89 - 7.81(m, 2H), 7.37(d, J = 8.8 Hz, 1H), 5.08 - 4.91(m, 2H), 4.21(q, J = 6.9 Hz, 2H), 3.72 - 3.49(m, 4H), 2.85 - 2.80(m, 2H), 2.48(s, 3H), 2.28 - 2.19(m, 2H), 1.82 - 1.62(m, 5H), 1.41 - 1.24(m, 5H), 0.92(t, J = 7.3 Hz, 3H); LCMS(ESI): m / z 565.23 [M + H +]; Purity ~ 99.60%; UPLC: Purity ~ 99.0%; Chiral SFC: 97.17%ee; 98.58% at RT 10.72 min (Column: Chiralpak AD-H (250*4.6) mm; 5um; Co-solvent: 25%, Co-solvent name: Isopropyl alcohol, Outlet pressure: 100 bar, Temperature: 30 °C; UV: 214 nm).

[0262] Scheme 27 [ka]

[0263] Example 36 Methyl 2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyacetate (35) CH 2 Cl 2 To a stirred solution of methyl 2-hydroxy-2-(piperidin-4-yl)acetate, 2,2,2-trifluoroacetate salt (34) (870 mg, 3.04 mmol) in 1,2-difluoropropanediol (50 mL) was added triethylamine (2.5 mL, 18.26 mmol) dropwise under argon atmosphere at 0° C. and stirred for 30 min. The reaction mixture was diluted with CH 2 Cl 2 A solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)benzene-1-sulfonyl chloride (2) (500 mg, 1.217 mmol) in 1,2-dimethylphenylsulfonyl chloride (2) (25 mL) was added dropwise at 0° C. and stirred for 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. Note: The reaction was carried out in two batches (2×500 mg). After the reaction was complete (monitored by TLC), both reaction mixtures were concentrated and the resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with anhydrous NaCl. 2 SO 4The resulting aqueous solution was dried over 1000 ml of ethyl acetate (2×150 mL) and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Reveleris® C-18 column, Grace System) eluting with a 35% gradient of acetonitrile with water. The pure fractions were concentrated until the acetonitrile solvent was completely removed. The resulting aqueous solution was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound 35 (400 mg, approx. 26% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.20(br s,1 H;D 2 O exchangeable),7.85-7.79(m,2 H),7.36(d,J=8.8 Hz,1 H),5.43(d,J=6.4 Hz,1 H;D 2 O exchangeable),4.21(q,J=6.8 Hz,2 H),4.16(s,3 H),3.88-3.85(m,1 H),3.68-3.64(m,2 H),3.60(s,3 H),2.79-2.75(m,2 H),2.22-2.17(m,2 LCMS(ESI):m / z 548.34 [M+H + ];Purity ~92.24%.

[0264] Example 37 Methyl 2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(nitrooxy)acetate (36) To a stirred solution of methyl 2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyacetate (35) (200 mg, 0.365 mmol) in dichloromethane (10 mL) was added freshly prepared acetyl nitrate (1.44 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.24 mL, 10.70 mmol) in acetic anhydride (1.2 mL, 1:5 fuming HNO 3 ) was added dropwise at -10°C under argon atmosphere (Note: Do not allow temperature to rise above 0°C)) at 0°C under argon atmosphere. The reaction was stirred at 0°C for 15 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (25 mL) and anhydrous Na 2 SO 4 After drying at 40° C. and concentrating under reduced pressure, the title compound 36 (250 mg) was obtained as a semi-solid, which was used immediately in the next reaction without purification. LCMS (ESI): m / z 593.08 [M+H + ];Purity ~81%.

[0265] Example 38 1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (37) To a stirred solution of methyl 2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(nitrooxy)acetate 36 (250 mg, 81% purity) in THF (12.5 mL) was added 2 M LiAlH 4The solution was added dropwise under argon atmosphere at 0° C. and stirred for 15 min at 0° C. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with saturated Na 2 SO 4 The solution was quenched by dropwise addition of 0.4 mL of ethyl acetate at 0° C., allowed to warm to room temperature and stirred for 2 h. The resulting solution was filtered through a bed of celite, washed with ethyl acetate (25 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. Note: The reaction was carried out in two batches (2 x 250 mg) as described above. The crude products obtained from both batches were combined and purified by reversed-phase column chromatography (Reveleris® C18-40 g column, Grace System) eluting with a 40-45% gradient of acetonitrile with water. The pure fractions were combined and concentrated until the acetonitrile solvent was completely removed. The resulting aqueous solution was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound 37 (240 mg, 58% overall yield for two steps) as a white solid. LCMS (ESI): m / z 565.34 [M+H + ];Purity~95.65%;Chiral SFC:Peak-1:~49.67% at RT=7.56 min;Peak-2:~49.81% at RT 8.63 min(Column:Chiralpak AD-H(250*4.6)mm;5um;Cosolvent:25%,Cosolvent name: Isopropanol,Outlet pressure:100 bar,Temperature:30 °C, UV:214 nm).

[0266] 215 mg of 37 was subjected to chiral preparative SFC purification to give 52.9 mg of 1k as a white solid and 45.5 mg of 1l as a white solid.

[0267] Analysis SFC conditions: Column / dimensions: Chiralpak AD-H (250 x 4.6) mm, 5 μm %CO 2 :75% % Co-solvent: 25% (100% isopropanol) Flow rate: 3.0g / min Back pressure:100.0bar Temperature: 30.0℃ Wavelength: 214nm

[0268] NP-HPLC conditions: カラム / inch method: Chiralpak AD-H (250×30)mm, 5μm %CO 2 :75% %Total solvent: 25% (100% イソプロパノール) Flow rate: 90.0g / min Back pressure:100.0bar Wavelength: 214nm Solubility: メタノール 30mL Filling capacity / Inj:5.5mg / Inj Number of injections: 40 times

[0269] 1k: 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 12.20(br s,1 H;D 2 O exchange possible), 7.86-7.80 (m, 2 H), 7.36 (d, J = 8.8 Hz, 1 H), 5.05 (d, J = 5.2 Hz, 1 H; D 2 O exchangeable), 4.98-4.93 (m, 1 H), 4.20 (q, J = 6.8 Hz, 2 H), 4.16 (s, 3 H), 3.70-3.61 (m, 3 H), 3.56-3.50 (m, 1 H), 2.79-2.75 (m, 2 H), 2.26-2.17 (m, 2 H), 1.78-1.68 (m, 5 H), 1.41-1.30 (m, 5 H), 0.94 (t, J = 7.2 Hz, 3 H); LCMS (ESI): m / z 565.26 [M+H] + ;Purity~96.73%;UPLC:98.84%;Chiral SFC:98.12%ee;99.06% at RT 7.68 min(カラム:Chiralpak AD-3 (150*4.6)mm; 3um; co-solvent: 35%, co-solvent name: メタノール, outlet pressure: 1500 psi, temperature: 30 °C, UV: 215 nm).

[0270] 1l:12.20(br s,1 H;D 2 O replaceable),7.86-7.80(m,2 H),7.36(d,J=8.8 Hz,1 H),5.05(d,J=5.2 Hz,1 H;D 2 O exchangeable),4.98-4.93(m,1 H),4.20(q,J=6.8 Hz,2 H),4.16(s,3 H),3.70-3.61(m,3 H),3.56-3.50(m,1 H),2.79-2.75(m,2 H),2.26-2.17(m,2 H),1.78-1.68(m,5 H),1.41-1.30(m,5 H),0.94(t,J=7.2 Hz,3 H);LCMS(ESI):m / z 565.26 [M+H] + ; Purity ~98.15%; UPLC: 99.17%; Chiral SFC: 91.84%ee; 95.92% at RT 8.92 min (Column: Chiralpak AD-3 (150*4.6) mm; 3um; Co-solvent: 35%, Co-solvent name: Methanol, Outlet pressure: 1500 psi, Temperature: 30 °C, UV: 215 nm).

[0271] Scheme 28 [ka]

[0272] Example 39 Diethyl 2-((1-(benzyloxycarbonyl)piperidin-4-yl)methylene)malonate (40): To a stirred solution of benzyl 4-formylpiperidine-1-carboxylate 38 (2.5 g, 10.10 mmol) and diethyl malonate 39 (2.16 mL, 14.14 mmol) in benzene (30 mL), piperidine (0.1 mL, 1.01 mmol) and acetic acid (0.12 mL, 2.02 mmol) were added in an azeotropic setting at room temperature. The reaction mixture was heated to reflux temperature and stirred for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The reaction solution was diluted with saturated NaHCO 3 Aqueous solution (50mL), saturated NH 4The organic layer was separated and washed with anhydrous NaCl (50 mL) and brine (50 mL). 2 SO 4 The extract was dried at 40° C., concentrated under reduced pressure, and purified by normal phase column chromatography (silica gel-40 g, Grace system) eluted with 10–15% ethyl acetate with petroleum ether to give the title compound 40 (2.5 g, approximately 59% yield) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl 3 )δ ppm 7.37-7.30(m,5 H),6.74(d,J=10.4 Hz,1H),5.13(s,2H),4.34-4.14(m,6H),2.89-2.74(m,2H),2.65-2.56(m,1 H),1.75-1.68(m,2H),1.46-1.35(m,2H),1.34-1.24(m,6H);LCMS(ESI):m / z 390.36 [M+H + ];Purity ~93.99%.

[0273] Example 40 Diethyl 2-(piperidin-4-ylmethyl)malonate (41) as the acetate salt To a stirred solution of diethyl 2-((1-(benzyloxycarbonyl)piperidin-4-yl)methylene)malonate 40 (900 mg, 2.31 mmol) in ethanol (18 mL) was added 10% palladium on carbon 50% wet (0.18 g, 0.2 w / w) at room temperature. The reaction mixture was stripped off with argon twice and purged with H via a balloon at room temperature. 2 Pressure (25 psi) was applied and stirred for 3 h. After the reaction was completed (monitored by 1H NMR), the reaction mixture was filtered through a bed of celite and washed with ethanol (10 mL). The filtrate was completely concentrated under reduced pressure to give title 41 (630 mg, 81% yield) as a colorless liquid, which was used directly in the next step. 1 H NMR (400 MHz, CDCl 3)δ ppm 4.22-4.16(m,4H),3.46-3.42(m,1H),3.08-3.03(m,2H),2.59-2.52(m,2H),1.96(s,3H),1.85-1.82 (m,2H),1.71-1.65(m,2H),1.43-1.32(m,1H),1.28-1.23(m,6H),1.18-1.07(m,2H);LCMS(ESI):m / z 258.36 [M+H + ];Purity ~99.82%.

[0274] Scheme 29 [ka]

[0275] Example 41 Diethyl 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)malonate (42) CH 2 Cl 2 To a stirred solution of diethyl 2-(piperidin-4-ylmethyl)malonate acetate 41 (627 mg, 1.97 mmol) in 1H2O (50 mL) was added triethylamine (2.6 mL, 18.3 mmol) dropwise at 0° C. under argon atmosphere and stirred for 30 min. The reaction mixture was diluted with CH 2 Cl 2 A solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)benzene-1-sulfonyl chloride 24 (500 mg, 1.22 mmol) in 10 mL of ethyl acetate was added dropwise at 0° C. and stirred for 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with CH 2 Cl 2 (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4The mixture was dried over 1000 ml of ethyl acetate (2×50 mL), concentrated under reduced pressure, and purified by reverse-phase column chromatography (Reveleris® C-18 column, Grace System) eluting with a 60% gradient of acetonitrile with water. The pure fractions were concentrated until the acetonitrile solvent was completely removed. The resulting aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound 42 (150 mg, 19% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ ppm 11.62(br s,1 H),7.87-7.83(m,2 H),7.36(d,J=8.4 Hz,1 H),4.20(q,J=7.2 Hz,2 H),4.12-4.04(m,4 H),3.63-3.58(m,2 H),3.52-3.47(m,1 H),2.84-2.80(m,2 H),2.48(s,3 H),2.23-2.16(m,2 H),1.76-1.67(m,6 H),1.32(t,J=7.2 Hz,3 H),1.20-1.09(m,9 H),0.92(d,J=7.2 Hz,3 H);LCMS(ESI):m / z 632.47 [M+H] + ;Purity ~82.06%.

[0276] Example 42 2-(2-ethoxy-5-(4-(3-hydroxy-2-(hydroxymethyl)propyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-7-propylimidazo[1,5-f][1,2,4]triazin-4(3H)-one (43) In a RB flask, sodium borohydride (110 mg, 2.91 mmol) and lithium chloride (3 mg, 0.073 mmol) were suspended in THF (2.0 mL) and ethanol (2.0 mL) under argon atmosphere at room temperature. To this, a solution of diethyl 2-((1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperidin-4-yl)methyl)malonate 42 (115 mg, 0.182 mmol) in THF (1.0 mL) and ethanol (1.0 mL) was added dropwise at room temperature and stirred for 16 h. Note: The reaction was carried out in three batches (1 x 10 mg, 1 x 25 mg, 1 x 115 mg). After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice water (4 mL) and extracted with ethyl acetate (5×25 mL). The organic layers were combined and concentrated. The crude products obtained from all batches were combined and purified by reverse phase preparative HPLC (column: X-BRIDGE C18 (250 * 19) Purified by: mm 5 μm, mobile phase A: 10 mM ammonium bicarbonate in water, B: 100% acetonitrile, flow rate: 19 ml / min; method T / %B=0 / 40, 11 / 40, 11.1 / 100, 13 / 100, 13.1 / 40, 15 / 4). Pure fractions were lyophilized to give the title compound 43 (45 mg, 34% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.65(br s,1 H;D 2 O exchangeable),7.87-7.83(m,2 H),7.37(br d,J=8.8 Hz,1 H),4.26(br t,J=5.52 Hz,2 H;D 2O exchangeable), 4.20(q,J=7.2 Hz,2 H),3.63-3.59(m,2 H),3.31-3.25(m,4 H),2.84-2.80(m,2 H),2.49(s,3 H),2.25-2.19(m,2 H),1.76-1.68(m,4 LCMS(ESI):m / z 548.14 [M+H] + ;Purity ~97.52%, UPLC: Purity ~96.72%.

[0277] Example 43 2-((1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperidin-4-yl)methyl)propane-1,3-diyl dinitrate (2m) To a stirred solution of 2-(2-ethoxy-5-(4-(3-hydroxy-2-(hydroxymethyl)propyl)piperidin-1-ylsulfonyl)phenyl)-5-methyl-7-propylimidazo[1,5-f][1,2,4]triazin-4(3H)-one 43 (105 mg, 0.192 mmol) in dichloromethane (4 mL) was added freshly prepared acetyl nitrate (1.32 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.22 mL, 10.09 mmol) in acetic anhydride (1.1 mL, 1:5 fuming HNO 3 A solution of ) was added dropwise at -10 °C under argon atmosphere (Note: Do not allow temperature to rise above 0 °C)) to 10 mL of ethyl acetate at 0 °C under argon atmosphere and stirred for 15 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (15 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4The mixture was dried at 4° C. and concentrated under reduced pressure. Note: The reaction was performed in two batches (1×25 mg, 1×105 mg). The resulting crude products were combined and purified by reverse-phase column chromatography (Reveleris® C-18 column, Grace system) eluting with a 60-65% gradient of acetonitrile with water. The pure fractions were lyophilized to give the title compound 2m (34.1 mg, 23% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.65(br s,1 H;D 2 O exchangeable),7.88-7.83(m,2 H),7.37(br d,J=8.4 Hz,1 H),4.52-4.42(m,4 H),4.20(q,J=7.2 Hz,2 H),3.66-3.60(m,2 H),2.84-2.80(m,2 LCMS(ESI):m / z 638.19 [M+H] + ;Purity ~98.06%, HPLC:98.25%.

[0278] Scheme 30 [ka]

[0279] Example 44 3-(1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperidin-4-yl)-2-(hydroxymethyl)propyl nitrate (2n) To a stirred solution of 2-((1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)phenylsulfonyl)piperidin-4-yl)methyl)propane-1,3-diyl dinitrate 2m (110 mg, 0.172 mmol) in ethanol (11 mL) was added 10% palladium on carbon 50% wet (22 mg, 0.2 w / w) at room temperature. The reaction mixture was stripped off with argon twice and purified with H via a balloon at room temperature. 2 Pressure (25 psi) was applied and stirred for 2 h. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through a bed of Celite and washed with ethanol (5 mL). The filtrate was completely concentrated under reduced pressure. The resulting crude mixture was purified by reverse phase preparative HPLC (column: Luna C18 (150 * 25) mm 10um; mobile phase A: 100% water, B: 100% ACN; method T / %B=0 / 50, 1 / 50, 10 / 80, 10.1 / 100, 13 / 100, 13.1 / 50, 15 / 50; flow rate: 19 ml / min) to give the title compound 2n (31.2 mg, 28% yield) as an off-white solid and 43 (28.6 mg, 26% yield) as a white solid.

[0280] TOP-V1-27 Analysis Data: 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.63(br s,1 H;D 2 O exchangeable),7.88-7.83(m,2 H),7.37(br d,J=8.8 Hz,1 H),4.66(t,J=5.2 Hz,1 H;D 2 O exchangeable),4.47-4.39(m,2 H),4.20(q,J=7.2 Hz,2 H),3.65-3.60(m,2 H),3.43-3.26(m,2 H),2.84-2.80(m,2 H),2.48(s,3 H),2.25-2.19(m,2 LCMS(ESI):m / z 593.16 [M+H] +;Purity ~96.69%, HPLC:98.45%.

[0281] Scheme 31 [ka]

[0282] Example 45 Diethyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2-methylmalonate (44) To a suspension of NaH (60% dispersion in oil, 503 mg, 12.57 mmol) in dry THF (20 mL) under argon atmosphere, a solution of diethyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)malonate 41 (3.0 g, 8.4 mmol) in THF (20 mL) was added dropwise at room temperature and stirred for 30 min. To this, a solution of methyl iodide (1.05 mL, 16.8 mmol) in THF (10 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with crushed ice (5.0 g) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The extract was dried at 40° C., concentrated under reduced pressure, and purified by silica gel column chromatography eluting with 10-15% ethyl acetate with petroleum ether to give the title compound 44 (1.3 g, 45% overall yield for two steps) as a thick liquid. 1 H NMR (400 MHz, CDCl 3 )δ ppm 4.20-4.13(m,4 H),4.06-3.95(m,2 H),2.70-2.61(m,2 H),1.87(d,J=6.0 Hz,2 H),1.60-1.54(m,2 H),1.49-1.41(m,13 H),1.27-1.21(m,6 H),1.19-1.10(m,2 H);LCMS(ESI):m / z 372.23 [M+H + ];Purity ~99.64%.

[0283] Example 46 Diethyl 2-methyl-2-(piperidin-4-ylmethyl)malonate hydrochloride (45) To a stirred solution of diethyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-2-methylmalonate 44 (1.2 g, 3.23 mmol) in methanol (12 mL) was added dropwise 4M hydrochloric acid in 1,4-dioxane (12 mL) at 0° C. under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed (monitored by TLC), the reaction solution was concentrated under reduced pressure, co-distilled with methanol (2×10 mL) and dried under vacuum to give crude title 45 (750 mg) as a thick liquid, which was directly recovered in the next reaction without purification. 1 H NMR (400 MHz, CDCl 3 )δ ppm 9.52(br s,1 H),9.22(br s,1 H),4.19-4.12(m,4 H),3.48-3.36(m,2 H),2.90-2.76(m,2 H),1.94-1.81(m,3 H),1.75-1.62(m,2 H),1.42(s,3 H),1.34-1.20(m,6 H),0.92-0.82(m,2 H).

[0284] Scheme 32 [ka]

[0285] Example 47 Diethyl 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylmalonate (46) CH 2 Cl 2To a stirred solution of diethyl 2-(piperidin-4-ylmethyl)malonate hydrochloride 45 (750 mg, 2.436 mmol) in 1,2-dichlorophenyl ether (50 mL) was added Amberlyst A-21 basic resin (3.75 g) at room temperature, stirred for 2 h, and then filtered. Triethylamine (2.5 mL, 18.26 mmol) was added dropwise to the filtrate under argon atmosphere at 0° C. and stirred for 30 min. The reaction mixture was diluted with CH 2 Cl 2 A solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)benzene-1-sulfonyl chloride 24 (500 mg, 1.22 mmol) in 10 mL of ethyl acetate was added dropwise at 0° C. and stirred for 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with CH 2 Cl 2 (75 mL) and washed with water (2×50 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 The crude product was purified by trituration with n-pentane (3×10 mL), decanted off the solvent, and dried under vacuum to give the title compound 46 (300 mg, approx. 30% yield) as a semi-solid, which was directly taken up in the next reaction. LCMS (ESI): m / z 646.29 [M+H + ];Purity ~84.28%.

[0286] Example 48 2-(2-ethoxy-5-((4-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (47) To a stirred solution of diethyl 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylmalonate 46 (215 mg, 0.33 mmol) in ethanol (10.75 mL) was added sodium borohydride (500 mg, 13.22 mmol) at room temperature under argon atmosphere. The reaction mixture was warmed to reflux temperature (80° C.) and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice water (5 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. NOTE: The reaction was performed in three batches (1 × 10 mg, 1 × 60 mg, 1 × 215 mg). The crude products obtained from the three batches were combined and purified by reverse-phase column chromatography (Reveleris® C-18 column, Grace system) eluting with a 30-35% gradient of acetonitrile with water. The pure fractions were lyophilized to afford the title compound 47 (80 mg, approximately 37% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.65(br s,1 H;D 2 O exchangeable),7.86-7.83(m,2 H),7.36(br d,J=8.8 Hz,1 H),4.26(br t,J=5.2 Hz,2 H;D 2 O exchangeable),4.20(q,J=7.2 Hz,2 H),3.55-3.51(m,2 H),3.12(d,J=5.2 Hz,4 H),2.84-2.80(m,2 H),2.48(s,3 H),2.27-2.22(m,2 H),1.76-1.70(m,4 LCMS(ESI):m / z 562.21 [M+H] + ;Purity ~99.36%, UPLC:98.70%.

[0287] Example 49 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylpropane-1,3-diyl dinitrate (2o) To a stirred solution of 2-(2-ethoxy-5-((4-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)piperidin-1-yl)sulfonyl)phenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one 47 (50 mg, 0.09 mmol) in dichloromethane (2 mL) was added freshly prepared acetyl nitrate (0.12 mL) [(acetyl nitrate is dissolved in fuming HNO 3 (0.02 mL, 0.917 mmol) in acetic anhydride (0.1 mL, 1:5 fuming HNO 3 A solution of ) was added dropwise at -10 °C under argon atmosphere (Note: Do not allow temperature to rise above 0 °C)) to 10 mL of ethyl acetate at 0 °C under argon atmosphere and stirred for 15 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with cold saturated NaHCO 3 The resulting solution was warmed to room temperature and extracted with dichloromethane (10 mL). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. Note: The reaction was carried out in two batches (1 × 25 mg, 1 × 50 mg). The crude products from both batches were combined and purified by reverse-phase column chromatography (Reveleris® C-18 column, Grace system) eluting with a 60-65% gradient of acetonitrile with water. The pure fractions were combined and concentrated until the acetonitrile solvent was completely removed. The resulting aqueous solution was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at rt and concentrated under reduced pressure to give the title compound 2o (32 mg, yield approx. 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.63(br s,1 H;D 2 O exchangeable),7.87-7.81(m,2 H),7.37(br d,J=8.8 Hz,1 H),4.38(s,4 H),4.20(q,J=7.2 Hz,2 H),3.59-3.54(m,2 H),2.84-2.79(m,2 H),2.47(s,3 LCMS(ESI):m / z 652.20 [M+H] + ;Purity ~97.87%, UPLC:97.04%.

[0288] Scheme 33 [ka]

[0289] Example 50 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)-2-methylpropyl nitrate (2p) To a stirred solution of 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylpropane-1,3-diyl dinitrate 2o (150 mg, 0.23 mmol) in ethanol (15 mL) was added 10% palladium on carbon 50% wet (30 mg, 0.2 w / w) at room temperature. The reaction mixture was stripped off with argon twice and purified with H via a balloon at room temperature. 2 Pressure (25 psi) was applied and stirred for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a bed of Celite and washed with ethanol (10 mL). The filtrate was concentrated under reduced pressure. The resulting crude mixture was purified by reverse phase preparative HPLC (column: Luna C18 (150 *The mixture was purified by HPLC using a HPLC-MS / MS chromatography- ...

[0290] 2p Analysis Data: 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.63(br s,1 H;D 2 O exchangeable),7.87-7.82(m,2 H),7.37(d,J=8.4 Hz,1 H),4.77(t,J=5.6 Hz,1 H;D 2 O exchangeable),4.29(s,2 H),4.20(q,J=7.2 Hz,2 H),3.58-3.53(m,2 H),3.20-3.13(m,2 H),2.84-2.80(m,2 H),2.48(s,3 H),2.30-2.23(m,2 LCMS(ESI):m / z 607.20 [M+H + ];Purity ~98.47%, UPLC(Area%):98.43%.

[0291] Example 51 Phosphodiesterase-5 activity assay As shown in Figure 1, the compounds of the present invention act synergistically by stimulating the production enzyme of cGMP (sGC) and inhibiting the main degradative enzyme (PDE5). Compounds 1a-2p are precursors of NO. In biological systems, the organic nitrate group is reduced to NO, which is believed to activate sGC. Both the nitrate-ester compounds and the resulting metabolites inhibit PDE5 with very high potency. The synergistic activity resulting from the modulation of both enzymes (activation of cGC and inhibition of PDE5) results in unprecedented potency and efficacy.

[0292] The inhibition of recombinant human (rh) PDE5A by test compounds is measured in a radioactive assay based on the Scintillation Proximity Assay (SPA) technique. The substrate [3H]cGMP / cGMP is hydrolyzed to [3H]5'GMP / 5'GMP upon the activity of rhPDE5A. The subsequent [3H]5'GMP / 5'GMP, but not [3H]cGMP / cGMP, is converted to Zn ++ In the presence of , it binds to SPA yttrium silicate beads and stimulates the scintillant within the beads to emit light, which is detected in a β-counter. The assay is performed in a 96-well format.

[0293] The assay consisted of adding rhPDE5A1 (GST-tagged, SIGMA E 9034) in an amount that did not exceed 20% cGMP hydrolysis within 20 min in Tris 20 mM pH 7.4 supplemented with 0.01% bovine serum albumin (BSA) in the presence of test compound or vehicle (0.1% DMSO), 20 mM Tris HCl pH 7.4, 5 mM MgCl 2 , 0.5 μM cGMP / [3H]cGMP (approximately 60000 dpm / well) substrate. The final assay volume is 100 μl and the reaction is carried out at 37° C. for 20 minutes.

[0294] Hydrolysis of [3H]cGMP / cGMP by rhPDE5A is terminated by adding 50 μl / well of SPA beads (PerkinElmer, RPNQ0024) prediluted in water according to the manufacturer's instructions and supplemented with 3-isobutyl-1-methylxanthine (1 mM). The beads are allowed to settle for at least 30 minutes before being measured on a Wallac Microbeta2 (PerkinElmer).

[0295] Typically, test compounds are added at seven different concentrations from 1 pM to 1 μM in logarithmic steps. Percent inhibition values ​​compared to vehicle control (0.1% DMSO) are calculated and IC50 values ​​are calculated using GraphPad Prism 7.03 software. Results (IC50) are given as the average from at least two independent experiments, each performed in triplicate. [Table 1-1] [Table 1-2]

[0296] Example 52 Measurement of human plasma protein binding An aliquot of 200 μL of human plasma containing the test compound was spiked into the donor well (red chamber) of the insert. 350 μL of PBS was added to the receiver well (white chamber) of the insert.

[0297] Samples were matrix-equilibrated with the opposite matrix (25 μL plasma / buffer samples were matched with 25 μL blank buffer / plasma). Matrix-matched samples were precipitated with 200 μL acetonitrile containing internal standards. Samples were vortexed at 1000 rpm for 5 min and centrifuged at 4000 rpm for 10 min. The supernatant was separated, diluted 2-fold with water, and analyzed by LC-MS / MS. (Table 2) [Table 2]

[0298] Example 53 Cellular cGMP assay Examples (test compounds) were characterized for their potency and efficacy in elevating cGMP in cell lines such as human trabecular meshwork cells (Table 3), human platelets (Table 5) and rat aortic smooth muscle cells (Table 4).

[0299] Human trabecular meshwork cells (ABC Biopply AG, Solothurn, Switzerland) or rat aortic smooth muscle cells (Sigma-Aldrich, Buchs, Switzerland) were seeded at 20.000 cells per well in 96-well plates precoated with collagen (type I collagen solution from rat tail, Sigma, diluted to 0.1 mg / ml) and grown in the corresponding trabecular meshwork (ABC Supply AG) or smooth muscle (Sigma) growth medium medium provided by the manufacturer. After 18 h, the medium was changed and fresh medium supplemented with 5 mM GSH was added. The next day, the medium was replaced with DMEM containing low glucose supplemented with 5 mM GSH. Cells were preincubated for 15 min with 10 μM riociguat (soluble guanylate cyclase stimulator, Lucerna-Chem AG, Lucerne, Switzerland) before the addition of test or reference compounds or vehicle to a final incubation volume of 100 μl per well. At the end of the incubation period (see below), the reaction was stopped by adding IBMX (isobutylmethylxanthine) (2 mM) in HCl (0.16 M), DMSO (2%) to the medium, final concentrations per well are indicated in brackets. After 20 s on a plate shaker (200 rpm), the plates were immediately frozen at -80°C.

[0300] cGMP was determined by a commercial ELISA kit as described in Example 39. As shown in Figure 3A and Figure 3B, the compound 2a of the present invention was used to obtain a superadditive effect from organic nitrate ITN and PDE5 inhibitors sildenafil or vardenafil to increase cGMP in HTMC. Extrapolation from nonlinear regression revealed that the concentration of 2.6nM / 12.4nM 2a or 10.6nM / 50.8nM 2a was equivalent to 1μM / 10μM ITN and 1μM vardenafil or 10μM ITN and 1μM sildenafil to increase cGMP in HTMC in this experiment under the current experimental conditions. [Table 3] [Table 4]

[0301] Example 54 The effects of test and reference compounds on total cGMP in human platelets were investigated as described by Dunkern and Hatzelmann (Cell Signal. 17:331-9, 2005) with modifications. Briefly, buffy coats (obtained from SRK Blutspende Zurich) were diluted 4-fold with 150 mM sodium chloride solution containing 0.9% sodium citrate and centrifuged at 200 g for 10 min. To the resulting platelet-rich plasma, 1 / 10 volume of ACD solution (85 mM sodium citrate, 111 mM D-glucose, 71 mM citric acid, pH 4.4) and apyrase (Sigma) were added to a final concentration of 2 U / ml. After another centrifugation (1400 g, 10 min), the cell pellet was resuspended in Ca2+ / Mg2+-free Hepes-Tyrode buffer (134 mM NaCl, 12 mM NaHCO3, 2.9 mM KCl, 0.36 mM NaH2PO4, 5 mM HEPES, 5 mM glucose, 0.5% (w / v) bovine serum albumin, pH 7.4) and platelets were counted.

[0302] Platelets were used at 9x107 cells in 100μl per well, and after addition of test and reference compounds, the incubation volume in Hepes-Tyrode was 200μl per well. Experiments with platelets were performed in the presence of 1μM riociguat and 100nM BAY 190954 (PDE2 inhibitor) (Lucerna Chem AG), and test / reference compounds were added after a preincubation period of 15 minutes. At the end of the incubation period (see below), the reaction was stopped by adding 20μl of 2N HCl per well. After 20 seconds on a plate shaker (300rpm), the plate was left for 15 minutes and then centrifuged at 1000xg for 5 minutes. The supernatant was stored at -80°C.

[0303] cGMP was determined by a commercial ELISA kit (Direct cGMP ELISA kit, Enzo Life Sciences, Lausen, Switzerland) using the acetylation protocol according to the manufacturer's instructions with a lower detection limit of 0.08 pmol / ml. Results are given as the mean from at least two independent experiments, each performed in triplicate.

[0304] To study the concentration dependence of total cGMP, test and reference compounds were tested from 0.1 nM to 1 μM in half-logarithmic steps with an incubation time of 2 h. To study the time course, incubation times were 10, 30, 60, 90, and 120 min with 1 μM test or reference compound.

[0305] Compounds were diluted from stock solutions in DMSO. The final concentration of DMSO in all wells, including vehicle controls, was 0.2% for human trabecular meshwork cells and rat aortic smooth muscle cells, and 0.3% for platelets.

[0306] Concentration or time-dependent effects on cGMP were analyzed by nonlinear regression using Graph Pad Software, which allows the concentration of test compound and reference compound to be extrapolated to obtain 2-fold and 3-fold increase in cGMP (ECx2, ECx3), maximum fold increase in cGMP over vehicle control (Emax, fold), and the concentration of test compound and reference compound to achieve half of the maximum cGMP increase (EC50). From time-course experiments, the time to half of the maximum cGMP increase by 1 μM test compound was extrapolated (t0.5max). [Table 5]

[0307] Example 55 Measurement of cGMP in human pulmonary artery smooth muscle cells (hPASMC) Human pulmonary artery smooth muscle cells (hPASMCs) were purchased from Clonetics™ Lonza (Lonza, ref. CC-2581) and cultured in Clonetics™ Smooth Muscle Growth Medium (Clonetics™ SmGM™-2 with BulletKit™ growth factor supplements (Lonza, ref. CC-3182) at 37° C., 5% CO 2 The medium was changed every 48 hours. The cells were cultured at 75 cm 2 were grown on culture plates.

[0308] 48 hours before the experiment, cells were trypsinized (Trypsin kit One ReagentPack™ (CC-5034), Lonza) and seeded at 10,000 cells per well in 96-well plates precoated with collagen I. 24 hours before the experiment, the medium was replaced with serum-reduced (0.5% FBS) medium. Just before the experiment, the medium was replaced and the compounds 1c, 2a and vardenafil (1×10 -11 M(0.1pM)~1×10 -6 hPASMCs were incubated in the presence of either 0.1% DMSO or vehicle (1 μM concentration) for 30 min.

[0309] Measurement of intracellular cGMP was performed using the Amersham cGMP EIA System (GE Healthcare, RPN226) according to the manufacturer's instructions. The assay has a sensitivity of 2 fmol of cGMP per well. Briefly, the incubation was terminated by adding Amersham's lysis buffer 1 and the cells were left under agitation for 10 min to allow complete lysis. cGMP in the samples was then acetylated using triethylamine and acetic anhydride and measured by competitive ELISA. The ELISA is based on the competition between acetylated cGMP in cell culture lysates and peroxidase-labeled cGMP conjugates for limited binding sites on cGMP-specific antiserum immobilized on pre-coated 96-well MTPs. cGMP was measured based on a standard curve. Results are presented as the mean + / - SE from three independent experiments performed in triplicate, with a 10% confidence interval.4 The cGMP levels were expressed as fmol of cGMP in cells (Figure 4). Surprisingly, the compounds 2a and 1c of the present invention show significantly higher efficacy in increasing cGMP levels than the reference inhibitor vardenafil (see Table 1), which is a more potent or even more potent PDE5 inhibitor than the compounds 2a and 1c of the present invention.

Claims

1. Compounds of Formula I or Formula II 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate or hydrate thereof, wherein: R １ is C １ ~C ３ is alkyl, R ２ is H, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ２ Alkoxy, C ２ ~C ４ alkenyl, R ３ is C １ ~C ２ Alkoxy, C ３ ~C ４ Cycloalkyl, C ２ ~C ４ C optionally substituted with alkenyl １ ~C ４ is alkyl, R ４ and R ５ together with the nitrogen atom to which they are attached form a heterocycle selected from aziridine, azetidine, pyrrolidine, piperidine, morpholine, piperazine, homopiperazine, 2,5-diazabicyclo[2,2,1]heptane, and 3,7-diazabicyclo[3,3,0]octane, and the heterocycle is selected from one or more R ６ is independently substituted with R ６ is one or more ONO or ONO ２ C substituted with １ ~C ６ alkyl, １ ~C ６ Alkyl is one or more halogens, OH, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR ７ , N.R. ８ R ９ , C=NR １０ and R ７ is H or F, OH, ONO, ONO ２ , N.R. ８ R ９ C optionally substituted with １ ~C ４ is alkyl, R ８ and R ９ are independently H or ONO, ONO ２ C optionally substituted with １ ~C ４ is alkyl, R １０ , F, ONO, ONO ２ C optionally substituted with １ ~C ４ Alkyl, C ３ ~C ６ is cycloalkyl, Provided that the compound of formula I 【Chemistry 2】 isn't it, compound.

2. R １ The compound of claim 1 , wherein is methyl or ethyl.

3. R １ The compound according to any one of claims 1 to 2, wherein is methyl.

4. R ２ But, C １ ~C ３ Alkyl or C ３ ~C ６ 4. The compound of claim 1 which is cycloalkyl.

5. R ３ But, C １ ~C ４ 5. The compound according to claim 1, wherein the aryl group is an alkyl group.

6. R ４ and R ５ together with the nitrogen atom to which they are attached form a heterocycle, said heterocycle being selected from piperidine, piperazine and homopiperazine, said heterocycle being selected from one or more R ６ 6. The compound of claim 1 , wherein each of the groups is independently substituted with:

7. The heterocycle is one or two R ６ 7. The compound of claim 6, independently substituted with:

8. R ６ One or more ONO, ONO ２ C substituted with １ ~C ６ is alkyl, having one or more OH, C １ ~C ３ 8. The compound of claim 1, which is optionally independently substituted with alkoxy.

9. The compound of formula I is ＊ wherein said compound of formula II is ＊ or, independently, a pharma- ceutically acceptable salt, solvate or hydrate thereof; 【Chemistry 3】 In the formula, R １ , R ２ and R ３ is as defined in any one of claims 1 to 5, X is CR １６ or N, R １１ , R １２ , R １３ , R １４ and R １５ are independently H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ is alkyl, R １６ is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ is alkyl, R １７ is H or F, OH, ONO, ONO ２ C optionally substituted with １ ~C ４ is alkyl, R １８ and R １９ are independently H or ONO, ONO ２ C optionally substituted with １ ~C ４ is alkyl, R ２０ , F, ONO, ONO ２ C optionally substituted with １ ~C ４ is alkyl, The R １１ , R １２ , R １３ , R １４ , R １５ and R １６ At least one of the ２ or containing an ONO moiety, With the proviso that said compound of formula I* is 【Chemistry 4】 isn't it, 9. A compound according to any one of claims 1 to 8.

10. The R １３ and R １４ is H, and １３ and R １４ the other is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ alkyl, and R １５ is one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ alkyl, and R １６ is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ The compound of claim 9 , which is alkyl.

11. The R １３ and R １４ is H, and １３ and R １４ the other is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ C, which may be independently substituted with haloalkoxy １ ~C ６ alkyl, and R １５ is one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ C, which is optionally substituted independently with haloalkoxy １ ~C ６ alkyl, and R １６ is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ C, which is optionally substituted independently with haloalkoxy １ ~C ６ 11. The compound of claim 9 or claim 10, which is alkyl.

12. The R １１ and R １２ is H, and １１ and R １２ the other is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C may be independently substituted with １ ~C ６ is alkyl, The R １３ and R １４ is H, and １３ and R １４ the other is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C may be independently substituted with １ ~C ６ is alkyl, R １５ is one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ It is an alkyl R １６ is H or one or more halogens, OH, ONO, ONO ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, COOR １７ , N.R. １８ R １９ , C=NR ２０ C, which may be independently substituted １ ~C ６ is alkyl, R １７ is H or OH, ONO, ONO ２ C optionally substituted with １ ~C ４ is alkyl, R １８ and R １９ are each independently H or ONO, ONO ２ C optionally substituted with １ ~C ４ 12. The compound of any one of claims 9 to 11, which is alkyl.

13. The compound is (R)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1a), (S)-1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (1b), (R)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (1c), (S)-2-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (1d), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer A (1e), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer B (1f), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl)nitrate (1g), 3-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (1h), 2-((1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (1i), 1-(1-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer A (1k), 1-(1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer B (1l), (R)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (2a), (S)-1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)ethane-1,2-diyl dinitrate (2b), (R)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (2c), (S)-2-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate (2d), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer A (2e), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypropyl nitrate enantiomer B (2f), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3,5-dihydroxypentyl nitrate (2g), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-3-hydroxypentane-1,5-diyl dinitrate (2h), 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)(hydroxy)methyl)propane-1,3-diyl dinitrate (2i), 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer A (2k), 1-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-hydroxyethyl nitrate enantiomer B (2l), 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)propane-1,3-diyl dinitrate (2m), 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)propyl)nitrate (2n), 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylpropane-1,3-diyl dinitrate (2o), 2. The compound of claim 1, selected from 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)-2-methylpropyl)nitrate (2p).

14. The compound is 2-((1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)methyl)-2-methylpropane-1,3-diyldinitrate (2o) 2. The compound of claim 1,

15. The compound is 3-(1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)sulfonyl)piperidin-4-yl)-2-(hydroxymethyl)-2-methylpropyl)nitrate (2p) 2. The compound of claim 1,

16. 16. A pharmaceutical composition comprising at least one compound of formula I or formula II as defined in any one of claims 1 to 15, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, and a pharma- ceutically acceptable excipient, adjuvant or carrier.

17. 17. The pharmaceutical composition of claim 16, further comprising at least one sGC stimulant.

18. 18. The pharmaceutical composition of claim 17, wherein the sGC stimulant is selected from the group consisting of riociguat, vericiguat, praliciguat and olinciguat.

19. 19. A pharmaceutical composition according to any one of claims 16 to 18 for treating or preventing a disease which is alleviated by the inhibition of PDE5 in a human or non-human mammal, comprising The pharmaceutical composition, wherein the disease is selected from wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, male erectile dysfunction, female sexual dysfunction, hair loss, skin aging, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, stable angina, unstable angina and variant (Prinzmetal) angina, chronic obstructive pulmonary disease, congestive heart failure, renal failure, vascular disorders, systemic sclerosis (SSc), scleroderma, morphea, achalasia, sickle cell disease (SCD), diabetic nephropathy, inflammatory diseases, diabetic neuropathy, idiopathic pulmonary fibrosis (IPF), Peyronie's disease, glaucoma, diabetic retinopathy, age-related macular degeneration, pigmentary retinopathy, diseases characterized by intestinal motility disorders, Alzheimer's disease, chronic heart failure, and cancer.

20. 20. The pharmaceutical composition of claim 19, wherein the wound healing is chronic wound healing.

21. 20. The pharmaceutical composition of claim 19, wherein the vascular disorder is selected from the group consisting of Raynaud's disease, hypertension, atherosclerosis, peripheral vascular disease, vascular aging, livedo vasculopathy, conditions of reduced vascular patency, and stroke.

22. 20. The pharmaceutical composition of claim 19, wherein the hypertension is pulmonary hypertension.

23. 20. The pharmaceutical composition of claim 19, wherein the inflammatory disease is selected from the group consisting of bronchitis, allergic rhinitis, chronic asthma, and allergic asthma.

24. 20. The pharmaceutical composition of claim 19, wherein the male erectile dysfunction is priapism.

25. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder of intestinal motility is selected from the group consisting of irritable bowel syndrome and liver fibrosis.

26. 20. The pharmaceutical composition of claim 19, wherein the cancer is selected from breast cancer, gastrointestinal cancer, lung cancer, skin cancer, prostate cancer, pancreatic cancer, colon cancer, and rectal cancer.

27. A pharmaceutical composition according to any one of claims 16 to 18 for treating or preventing a disease in a human or non-human mammal that is alleviated by inhibition of PDE5, comprising: The pharmaceutical composition, wherein the disease is selected from pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, diabetic retinopathy, pigmentary retinopathy, age-related macular degeneration, scleroderma, male erectile dysfunction, skin aging, priapism and female sexual dysfunction, livedovascular disease, thromboangiitis obliterans, chronic anal fissures, skin fibrosis, wound healing, chronic wound healing, diabetic foot, diabetic foot ulcers, leg ulcers, diabetic neuropathy and bedsores.

28. The pharmaceutical composition according to any one of claims 19 to 27, wherein said pharmaceutical composition is used in combination with at least one sGC stimulant.

29. 29. The pharmaceutical composition of claim 28, wherein the sGC stimulant is selected from the group consisting of riociguat, vericiguat, praliciguat and olinciguat.

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