RU2817643C2 - Pharmaceutically effective compounds selectively inhibiting myosin 2 isoforms - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to organic chemistry and includes a compound of formula (I) or (II), pharmaceutically acceptable salts and enantiomers thereof, individual compounds specified in the claim, as well as use of the compounds. In formula (I), R¹ is an H atom or a group of formula in which R⁶ and R¹⁰ are an H atom; R⁷, R⁸ and R⁹ are each independently H, saturated 6-member heterocyclic group containing two heteroatoms selected from N and O, C_1-12 straight or branched alkyl, C_1-12 dialkylamino , C_1-12 alkoxy, which can be substituted with one to three halogen atoms, or acetyl; R², R³ , R⁴ and R⁵ represent an H atom; each of one or more Q¹, Q², Q³ and Q⁴ is independently selected from a group consisting of an N atom, and others are CH. In formula (II), R¹ is an H atom or a group of formula in which R⁶ and R¹⁰ are an H atom; R⁷, R⁸ and R⁹ are each independently H, saturated 6-member heterocyclic group containing two heteroatoms, selected from N and O, NH₂, CN, C_1-12 straight or branched alkyl, C_1-12 alkoxy, which can be substituted with one to three halogen atoms, C_1-12 hydroxyalkyl , C_1-12 dialkylamino , C_1-12 alkylcyano or acetyl; R², R³, R⁴ and R⁵ represent an H atom; each of Q⁵, Q⁶ and Q⁷ is independently S or N.

EFFECT: disclosed are compounds of formulas (I) or (II), having inhibitory activity on sarcomeric myosin 2 isoforms.

25 cl, 1 dwg, 11 tbl, 11 ex

Description

The present invention relates to compounds of formula (I) or (II)

their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, and pharmaceutical uses of these compounds.

BACKGROUND ART

Myosin 2 isoforms and their prevalence in the human (animal) body

Myosins are motor proteins present in all eukaryotic cells that use free enthalpy from the hydrolysis of adenosine triphosphate (ATP) to move along the filaments of the actin cell scaffold. Myosins are composed of heavy and light chain subunits. The heavy chain consists of a motor domain responsible for ATP hydrolytic activity (ATPase) and force generation, containing actin and ATP binding sites; the neck region, which plays a role in transmitting and controlling force, and binding to the light chain; and the tail region, which includes polymerization and effector functions. The myosin superfamily has been classified into more than 30 classes based on phylogenetic analysis of heavy chain sequences [Sellers, J.R. (1999)). Myosins. John Wiley & Sons Ltd; Coluccio, L.M. (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media].

Members of myosin class 2 are found in all eukaryotic organisms except higher plants [Sellers, J.R. (1999). Myosins. John Wiley & Sons Ltd]. The heavy chains of these myosins form dimers, which can take the form of higher-level structures called fibers. Fiber size and dynamics within a given class show great variation between individual isoforms (protein variants encoded by different genes). Sarcomeric myosin 2 isoforms in striated muscles (skeletal muscle, myocardium) constitute the so-called thick filaments. Isoforms of nonsarcomeric myosin 2 include smooth muscle myosins and nonmuscle myosins (nonmuscle myosin 2, NM2). Nonsarcomeric myosins are fibers capable of reversible polymerization, and minifilaments in the case of NM2.

The mammalian and human genome contains 15 myosin heavy chain isoforms (see Table 1). Many isoforms of myosin 2 light chains are also known (the heavy chain binds to the so-called basic (ELC) and so-called regulatory (RLC) light chain); however, their distribution in the body and function are much less well understood than the distribution and function of heavy chains. The active substances that are the subject of the present application act through the myosin heavy chain, therefore, the authors of the present invention are limited to the discussion of the heavy chain isoforms.

Of the sarcomeric isoforms, MYH1, MYH2 and MYH4 are the major motor components for skeletal muscle [Coluccio, L.M. (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media]. MYH3 is expressed fetally, whereas MYH8 is perinatal. MYH7b is also found in the heart near skeletal muscle. MYH13 is found in the extraocular muscles, the function of MYH15 is less clear, while the masseter myosin gene MYH16 is inactivated in humans. Sarcomeric isoforms also include two human myocardial myosins: MYH6 (alpha myocardial myosin) is the major protein component of the myocardium in the atrium, while MYH7 (beta myocardial myosin) is the major protein component of the myocardium in the cardiac cavity. (In small-bodied mammals (eg, rodents), myocardial alpha-myosin is also the major isoform in the ventricular wall.

The single human smooth muscle myosin 2 isoform (MYH11) or the three NM2 (NM2A: MYH9, NM2B: MYH10, NM2C: MYH14) are phylogenetically close to each other; collectively they are called nonsarcomeric myosin 2 isoforms [Coluccio, L.M. (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media]. Each of these myosins is regulated by phosphorylation of the RLC or reversible polymerization of the filament associated with it. Smooth muscle myosin 2 is the main motor for the smooth muscles of hollow organs (except the heart). Several of its forms are known, resulting from splicing: in the SMA isoform, in the region of loop 1 of the ATP-binding site of the motor domain, there is an insertion of 7 amino acids, while SMB does not contain this peptide segment.

NM2 isoforms are highly abundant in the human body, even present in muscle cells. Several types of NM2 isoforms are found in most cell types. NM2 isoforms of individual organs and tissues also change during ontogeny. Platelets, a number of types of blood cells, lymph nodes, spleen and thymus cells are enriched in NM2A. NM2A and NM2C are expressed in the stomach and colon, whereas the 2A isoforms are not present in cardiomyocytes. Brain and testis are also enriched in NM2B [Coluccio, L.M. (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media].

The different spliced forms are expressed through alternative splicing of the NM2B and NM2C isoform genes: forms B1 or C1 in the loop-1 region, while forms B2 and C2 in the loop-2 region of the insertion containing the actin-binding site [Heissler, S.M. and Manstein, D.J. (2013). Nonmuscle myosin-2: mix and match. Cellular and molecular life sciences, 70(1), 1-21]. Any combination of the presence of these inserts appears in the body. The B1, B2 and C2 forms are found in the brain and spinal cord, while the C1 form is present in all tissues containing NM2C except the adult heart and skeletal muscle.

Each spliced form of NM2B is expressed in a different region of the adult mouse brain. B2 isoforms are present in low concentrations in the brains of fetal and neonatal mice, but are present in large quantities after birth in dendrites and during synaptogenesis of cerebellar Purkinje cells. The C0 (without insertion) and C1 forms are common, while the C2 form is found in nervous tissue, or the C1C2 form is found in neurites; the latter is the predominant form of NM2C during neuritogenesis.

In most adult mouse tissues, NM2C is present in the smallest amount of these three isoforms. However, immortalized cell lines (eg COS-7, HT29) contain significant amounts of NM2C. The increase in C1 shape was measured in tumor cell lines compared to non-tumor cell lines from the same tissue.

Physiological role of individual isoforms

Sarcomeric myosin 2 isoforms provide the driving force for skeletal muscle contraction, which is the basis of voluntary motor activities such as changing position, walking, chewing, fine movements and speech. The physiological properties of each muscle fiber type (e.g., speed and energy consumption of muscle contraction) are primarily determined by their myosin heavy chain 2 composition. The different mechanical properties of the atria and ventricles of the heart are also determined by the molecular function of the myocardial isoforms of the atrium with the faster mechanochemical cycle (alpha) and the ventricle with slower activity (beta). Myosin mutations in the myocardium cause a large proportion of hereditary hypertrophic cardiomyopathies or may also cause dilated cardiomyopathy.

Smooth muscle myosin 2 is responsible for the contraction or tone of the walls of most organs. The faster (having greater ATPase activity and the potential for faster motility) SMB isoform mainly drives so-called phasic, transient contraction (for example, in the walls of the bladder or portal vein and in the longitudinal layer of smooth muscle of the ileum), while the slower the active SMA isoform is primarily responsible for slow contraction and long-term force maintenance (eg, in large arteries and the tracheal wall).

In most cell types, NM2 isoforms have important or specific functions for cell movement, cell migration, cell adhesion, cytokinesis, morphogenetic movements (eg, gastrulation), tissue formation, wound healing, angiogenesis, immune control functions, epithelial renewal, cell growth and retraction. outgrowths (eg, neurites), membrane transport in cells, clathrin-mediated endocytosis, phagocytosis, exocytosis, fusion with the plasma membrane of secretory vesicles and exocytosis-dependent membrane repair induced by wounding [Newell-Litwa, K.A., Horwitz, R. and Lamers, M. .L. (2015). Non-muscle myosin II in disease: mechanisms and therapeutic opportunities. Disease models & mechanisms, 8(12), 1495-1515]. NM2 isoforms perform these functions in interactions with several cellular actin structures, which form stress fibers in the form of a contractile ring during cytokinesis and form a peripheral ring during cell adhesion.

As with other myosins, the diversity of molecular activities of the isoforms also serves as the basis for the physiological functions of the NM2 isoforms. Although all NM2 isoforms have a significantly slower rate of action compared to muscle myosins, the NM2A and NM2C isoforms are relatively faster and have a lower occupancy ratio (occupancy-steady-state actin binding ratio), whereas NM2B is slower and has a significantly larger function. employment relationship. Of the spliced variants, Form B1 exhibits increased ATPase activity and mobility. Similar to the B1 form, the C1 insertion also confers increased ATPase activity and provides myosin with the potential for faster motility, whereas the C1C2 variant has RLC phosphorylation-independent activity.

Of the above-mentioned cellular processes, a role for NM2A in clathrin-mediated endocytosis and exocytosis has been demonstrated. The NM2A isoform also plays a role in the formation of platelets from megakaryocytes.

During cell adhesion, NM2 isoforms play a key role in the dynamic reorganization of cell-cell contacts and in the formation of apical junction complexes between the apicolateral surfaces of epithelial cells [Vicente-Manzanares, M., Ma, X., Adelstein, R.S. and Horwitz, A.R. (2009). Non-muscle myosin II takes center stage in cell adhesion and migration. Nature reviews Molecular cell biology, 10(11), 778-790].

During cell migration, NM2 isoforms play a role in rear cell retraction and in driving retrograde actin flow in the lamella podium. These myosins exert their force on generated so-called focal complexes through stress fibers, play a central role in the perception of mechanical stress in the extracellular matrix, coordinate cellular protrusions and stabilize cell polarity. NM2B is an important component of force-sensing structures found at the rear of the cell, whereas the NM2A isoform is an important factor in the dynamic actin network at the front of the cell. NM2A also plays an important role in the dynamic crosstalk between actin fibers and microtubules.

The NM2A and NM2B isoforms cooperate in driving retrograde actin flow at the axon terminal [Kneussel, M. and Wagner, W. (2013). Myosin motors at neuronal synapses: drivers of membrane transport and actin dynamics. Nature Reviews Neuroscience, 14(4), 233–247] in both neurite outgrowth and retraction. Reduced expression of the NM2C1C2 isoform leads to shortening of neurites.

During cell division, NM2 isoforms generate force in the equatorial region of the dividing cell and play a role in the creation of the mitotic spindle [Wang, A., Ma, X., Conti, M.A. and Adelstein, R.S. (2011). Distinct and redundant roles of the non-muscle myosin II isoforms and functional domains]. The role of the NM2C1 isoform has also been demonstrated in abnormal cell proliferation. Alterations in NM2 function in tumor metastases may play a role in reducing cell adhesion, promoting tissue invasion, and promoting tumor-induced angiogenesis.

Mutations in the NM2A gene cause May-Hegglin abnormalities, characterized by a low platelet count, bleeding problems, nephritis, deafness, or the development of cataracts [Ma, X. and Adelstein, R.S. (2014). The role of vertebrate nonmuscle Myosin II in development and human disease. Bioarchitecture, 4(3), 88-102]. Lack of NM2A protein in the mouse causes embryonic lethality through defects in cell adhesion and gastrointestinal defects. Mutations in the mouse NM2B gene cause cardiac (cardiomyocyte multinuclease) and brain defects. Deletion of the NM2B1 form induces hydrocephalus, whereas knockout of the NM2B2 form causes cerebellar disorders. In humans, a point mutation in NM2C is known to activate deafness.

The role of megakaryocyte with myosin 2 (MK) in endomitosis was studied in international patent publication WO 2012113555 A1 and found that the addition of blebbastatin to MK cell cultures led to a significant increase in MK polyploidy.

Myosin 2 inhibitors

The two most recent reviews on myosin inhibitors and mechanisms of inhibition were created in 2013 and 2016. The following table summarizes the structure and effect of myosin 2 inhibitors:

N-benzyl-p-toluenesulfonamide (BTS)

Of the myosin 2 isoforms, BTS inhibits skeletal muscle fast myosin-2 100 times more strongly than skeletal muscle slow myosin-2, myocardial myosin-2, or non-muscle myosin 2 and does not inhibit platelet myosin 2-t.

2,3-Butanedione monoxime (BDM)

BDM inhibits skeletal muscle myosin 2 but binds weakly (IC50 (half-maximal inhibitory concentration) of the order of 5 mM), data on inhibition of other myosin isoforms is conflicting, and it has many other non-myosin targets.

Vanadate (Vi)

Vanadate is a phosphate analog that, in the nucleotide-binding pocket, in complex with ADP, maintains myosin in an ATP-bound state. It is a general ATP analogue that does not exclusively inhibit the myosin 2 isoform.

Blebbistatin

The best known and most widely used myosin-specific inhibitor is blebbistatin. Blebbistatin is an effective inhibitor of non-muscle myosin 2A and B, myocardial, skeletal muscle and smooth muscle forms of myosin, but it does not inhibit myosin 1, myosin 5 and myosin 10.

The blebbistatin rings are hereafter referred to as A, B, C and D, respectively.

For example, International Patent Application Publication No. WO 2009094718 A1 discloses the use of certain inhibitors in the treatment of thromboembolic disorders. The referenced document also describes, among other things, a study of the effect of myosin isoform 2A on the regulation of blood clot stability in vivo. In this context, blebbastatin is used to inhibit myosin.

In international patent publication document WO 2016180918 A1, non-muscle myosin 2 ATPase inhibitors are referred to as megakaryocyte modulating compounds. The document cited refers only to blebbistatin and azidoblebbistatin as examples of said inhibitors.

US Patent Publication Document US 2013071927 A1 also discloses only two small molecule myosin 2 inhibitors: N-benzyl-p-toluenesulfonamide and the best described and characterized myosin 2 inhibitor, blebbastatin.

European Patent Application Publication Number EP 2777703 A1 discloses non-muscle myosin 2 antagonists in connection with the treatment of certain diseases through stem cell therapy. The small molecule compounds mentioned as myosin 2 antagonists include 2,3-butanedione-2-monoxime, blebbistatin and their analogs, derivatives or variants, and pyrrolidone derivatives, but no structural information is provided herein for the analogs, derivatives or variants.

In the publication of international patent application No. WO 2016161192 A1, among the low molecular weight inhibitors of myosin 2, blebbistatin and its analogues, such as para-nitro-blebbistatin, (S)-nitro-blebbistatin and (S)-(-)-7-desmethyl-8, are disclosed -nitro-blebbistatin, as well as N-benzyl-p-toluenesulfonamide and 2,3-butanedione monoxime. These inhibitors from the cited document differ in structure from the small molecule inhibitors disclosed in the present invention.

International Patent Application Publication No. WO 2017129782 A1 discloses blebbistatin backbone compounds and their preparation that are useful for inhibiting myosin 2 isoforms, in particular for inhibiting the in vivo ATPase activity of neuronal non-muscle myosin 2 isoforms. This cited document also discloses the use disclosed compounds for the treatment or prevention of diseases mediated by myosin 2 (eg, schizophrenia, Alzheimer's disease, Parkinson's disease, cerebral ischemia). These disclosed compounds are distinguished by the substitution of ring A and ring D of the blebbistatin backbone with different substituents, i.e. the general formula of the disclosed compounds does not contain a heteroaromatic ring at ring position A.

US Patent Publication Document US 2017129886 A1 also discloses myosin 2 ATPase inhibitors. This document discloses that the disclosed compounds are useful for the treatment of overactive bladder. The compounds disclosed therein are also compounds with a blebbistatin backbone, wherein the blebbistatin backbone A at the ring nitrogen and at position 2, ring C and/or ring D is substituted with various substituents. The compounds described there do not contain a heteroaromatic ring in the A ring.

International Patent Application Publication No. WO 2012158942 A2 also relates to myosin ATPase 2 inhibitory compounds, methods for their preparation and their use in the treatment of overactive bladder. The disclosed compounds are blebbistatin derivatives which are substituted at positions 6 and 7 of the blebbistatin skeleton, i.e. on ring A, with different substituents. Also not disclosed herein are compounds that contain a heteroaromatic ring at the A ring position of the blebbistatin backbone.

International Patent Application Publication No. WO 2010120785 A2 mentions blebbastatin and a number of its analogs as myosin 2 inhibitors. These analogs are compounds in which the A ring of the blebbastatin backbone is replaced by various substituents, i.e. there is no heteroaromatic ring in place of the A ring.

PURPOSE OF THE INVENTION

There is a need for new compounds that, in addition to modulating selective/specific inhibition of myosin 2 isoforms, have additional beneficial properties, such as improved solubility and improved mutagenicity compared to the state of the art, which make these compounds suitable for use in medicine.

OPENING ACCORDING TO THE PRESENT INVENTION

The inventors of this invention have discovered that:

1. the structure of the compounds of the present invention has improved solubility and better mutagenicity properties compared to the blebbistatin backbone and can be used for specific medical indications based on its ability to inhibit myosin 2; And

2. By modifying the D ring, mutagenicity and specificity for different isoforms of myosin-2 (such as skeletal, cardiac, smooth muscle myosin-2, non-muscle myosin-2/NM2 A, B, C) can be further modulated.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Fig. 1: Measurement data regarding the mutagenicity assay of the compounds S(-)-blebbistatin (blue) and 188 (green) on strains TA98 (open circle) and TA100 (dark circle) without liver S9 fraction (open circle) or in the presence of liver S9 fraction (full disease).

BRIEF DESCRIPTION OF THE INVENTION

1. Compounds of formula (I) or (II):

in which in formula (I)

R ¹ represents a hydrogen atom or a group of the following formula,

,

wherein

R ⁶ and R ¹⁰ represent an H atom;

R ⁷ , R ⁸ and R ⁹ each independently represent an H atom, a halogen or a saturated, partially saturated, unsaturated or aromatic 5-, 6- or 7-membered heterocycle, each independently containing one or more N, O, S; which may be substituted by one or more groups selected from the group consisting of C _1-12 straight or branched alkyl, C _3-12 cycloalkyl, C _1-12 straight or branched alkenyl, C _1-12 straight or branched alkynyl, hydroxy, C _1-12 hydroxyalkyl, C _3-12 hydroxycycloalkyl, amino (-NH ₂ ), C _1-12 alkylamino, C _3-12 cycloalkylamino or C _1-12 dialkylamino, where the amino group may be acylated C _1-6 straight or a cyclic or aromatic carboxylic acid, or sulfonylated with a C _1-6 straight or cyclic or aromatic sulfonic acid; nitro (-NO ₂ ), cyano (nitrile), C _1-12 alkylcyano, C _3-12 cycloalkylcyano, C _1-12 saturated, unsaturated or or aromatic carboxylic acid, C _1-12 carboxylic acid amide formed with saturated, unsaturated or an aryl-amine, wherein the carboxylic acid amide is a group of the formula C(O)NH ₂ -, C(O)NHR ¹¹ - or C(O)NR ¹¹ R ¹² -, where R ¹¹ and R ¹² are each independently C _1-6 alkyl, C _3-12 cycloalkyl, C _1-6 alkenyl or C _6-12 aryl; a C _1-12 carboxylic acid ester formed with a saturated, unsaturated or aryl alcohol, C _1-12 alkoxy, C _1-12 alkenyloxy, C _1-12 alkynyloxy or C _1-12 alkoxyalkyl, where alkyl, cycloalkyl, alkenyl and alkynyl the groups may be substituted by one or more halogen atoms; halogen; C _1-12 alkylthio, C _3-12 cycloalkylthio, C _1-12 alkenylthio, C _1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more than one halogen; S(O) ₂ OH-, C _1-4 alkyl-S(O) ₂ OH- or C _3-6 cycloalkyl-S(O) ₂ OH-, S(O) ₂ OR ¹³ -, C _1-4 alkyl -S(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-S(O) ₂ OR ¹³ -, S(O)R ¹³ -, C _1-4 alkyl-S(O)R ¹³ - or C _{3- 6} cycloalkyl-S(O)R ¹³ -, S(O) ₂ R ¹³ , C _1-4 alkyl-S(O) ₂ R ¹³ - or C _3-6 cycloalkyl-S(O) ₂ R ¹³ -, P (O) ₂ OH-, C _1-4 alkyl-P(O) ₂ OH- or C _3-6 cycloalkyl-P(O) ₂ OH-P(O) ₂ OR ¹³ -, C _1-4 alkyl-P (O) ₂ OR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ OR ¹³ -, P(O) ₂ NH ₂ -, C _1-4 alkyl-P(O) ₂ NH ₂ - or C _{3- 6} cycloalkyl-P(O) ₂ NH ₂ -, P(O) ₂ NHR ¹³ -, C _1-4 alkyl-P(O) ₂ NHR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ NHR ¹³ - , P(O) ₂ NR ¹³ R ¹⁴ - or C _1-4 alkyl-P(O) ₂ NR ¹³ R ¹⁴ - or C _3-6 cycloalkyl-P(O) ₂ NR ¹³ R ^{14 -} group, where the groups R ¹³ and R ¹⁴ are selected from the group consisting of C _1-6 straight or branched alkyl, cycloalkyl or C _6-12 aryl; or R ⁷ , R ⁸ and R ⁹ can each independently be C _1-12 straight or branched alkyl, C _3-12 cycloalkyl, C _1-12 straight or branched alkenyl, C _1-12 straight or branched alkynyl, hydroxy, C _1-12 hydroxyalkyl, C _3-12 hydroxycycloalkyl, amino (NH ₂ ), C _1-12 alkylamino, C _3-12 cycloalkylamino or C _1-12 dialkylamino, where the amino group may be acylated with C _1-6 straight or cyclic, or an aromatic carboxylic acid, or sulfonylated with a C _1-6 straight or cyclic or aromatic sulfonic acid; nitro (-NO ₂ ), cyano (nitrile), C _1-12 alkyl cyano, C _1-12 saturated, unsaturated or or aromatic carboxylic acid, C _1-12 carboxylic acid amide formed with a saturated, unsaturated or aryl-amine, where a given carboxylic acid amide is a group according to any of the formulas C(O)NH ₂ -, C(O)NHR ¹¹ - or C(O)NR ¹¹ R ¹² -, where in these formulas R ¹¹ and R ¹² each independently represent C _1-6 alkyl; C _3-12 cycloalkyl, C _1-6 alkenyl or C _6-12 aryl; a C _1-12 carboxylic acid ester formed with a saturated, unsaturated or aryl alcohol, C _1-12 alkoxy, C _1-12 alkenyloxy, C _1-12 alkynyloxy or alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted one or more than one halogen atom; C _1-12 alkylthio, C _3-12 cycloalkylthio, C _1-12 alkenylthio, C _1-12 alkynylthio or alkylthioalkyl, wherein these alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more than one halogen; S(O) ₂ OH-, C _1-4 alkyl-S(O) ₂ OH- or C _3-6 cycloalkyl-S(O) ₂ OH-, S(O) ₂ OR ¹³ -, C _1-4 alkyl -S(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-S(O) ₂ OR ¹³ -, S(O)R ¹³ -, C _1-4 alkyl-S(O)R ¹³ - or C _{3- 6} cycloalkyl-S(O)R ¹³ -, S(O) ₂ R ¹³ , C _1-4 alkyl-S(O) ₂ R ¹³ - or C _3-6 cycloalkyl-S(O) ₂ R ¹³ -, P (O) ₂ OH-, C _1-4 alkyl-P(O) ₂ OH- or C _3-6 cycloalkyl-P(O) ₂ OH-P(O) ₂ OR ¹³ -, C _1-4 alkyl-P (O) ₂ OR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ OR ¹³ -, P(O) ₂ NH ₂ -, C _1-4 alkyl-P(O) ₂ NH ₂ - or C _{3- 6} cycloalkyl-P(O) ₂ NH ₂ -, P(O) ₂ NHR ¹³ -, C _1-4 alkyl-P(O) ₂ NHR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ NHR ¹³ - , P(O) ₂ NR ¹³ R ¹⁴ - or C _1-4 alkyl-P(O) ₂ NR ¹³ R ¹⁴ -, or C _3-6 cycloalkyl-P(O) ₂ NR ¹³ R ^{14 -} group, where R ¹³ and R ¹⁴ are selected from the group consisting of C _1-6 straight or branched alkyl, cycloalkyl or C _6-12 aryl; methanesulfonylaminomethyl, trifluoromethanesulfonylamino, N,N-dimethylaminocarbonylmethyl [CH ₂ -CO-N(CH ₃ ) ₂ ], acetyl, methanesulfonylamino, methoxymethyl;

or R ¹ is a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocycle, each independently containing one or more N, O, S atoms; which may be substituted by one or more groups selected from the group consisting of C _1-12 straight or branched alkyl, C _3-12 cycloalkyl, C _1-12 straight or branched alkenyl, C _1-12 straight or branched alkynyl, hydroxy, C _1-12 hydroxyalkyl, C _3-12 hydroxycycloalkyl, amino (-NH ₂ ), C _1-12 alkylamino, C _3-12 cycloalkylamino or C _1-12 dialkylamino, where the amino group may be acylated C _1-6 straight or a cyclic or aromatic carboxylic acid, or sulfonylated with a C _1-6 straight or cyclic or aromatic sulfonic acid; nitro (-NO ₂ ), cyano (nitrile), C _1-12 alkylcyano, C _3-12 cycloalkylcyano, C _1-12 saturated, unsaturated or aromatic carboxylic acid, C _1-12 carboxylic acid amide formed with saturated, unsaturated or aryl-amine, where the carboxylic acid amide is a group according to the formula C(O)NH ₂ -, C(O)NHR ¹¹ - or C(O)NR ¹¹ R ¹² -, where R ¹¹ and R ¹² are each independently C _1-6 alkyl, C _3-12 cycloalkyl, C _1-6 alkenyl or C _6-12 aryl; a C _1-12 carboxylic acid ester formed with a saturated, unsaturated or aryl alcohol, C _1-12 alkoxy, C _1-12 alkenyloxy, C _1-12 alkynyloxy or C _1-12 alkoxyalkyl, where alkyl, cycloalkyl, alkenyl and alkynyl the groups may be substituted by one or more halogen atoms; halogen, C _1-12 alkylthio, C _3-12 cycloalkylthio, C _1-12 alkenylthio, C _1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more than one halogen; S(O) ₂ OH-, C _1-4 alkyl-S(O) ₂ OH- or C _3-6 cycloalkyl-S(O) ₂ OH-, S(O) ₂ OR ¹³ -, C _1-4 alkyl -S(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-S(O) ₂ OR ¹³ -, S(O)R ¹³ -, C _1-4 alkyl-S(O)R ¹³ - or C _{3- 6} cycloalkyl-S(O)R ¹³ -, S(O) ₂ R ¹³ , C _1-4 alkyl-S(O) ₂ R ¹³ - or C _3-6 cycloalkyl-S(O) ₂ R ¹³ -, P (O) ₂ OH-, C _1-4 alkyl-P(O) ₂ OH- or C _3-6 cycloalkyl-P(O) ₂ OH-, P(O) ₂ OR ¹³ -, C _1-4 alkyl- P(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ OR ¹³ -, P(O) ₂ NH ₂ -, C _1-4 alkyl-P(O) ₂ NH ₂ - or C _{3 -6} cycloalkyl-P(O) ₂ NH ₂ -, P(O) ₂ NHR ¹³ -, C _1-4 alkyl-P(O) ₂ NHR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ NHR ¹³ -, P(O) ₂ NR ¹³ R ¹⁴ - or C _1-4 alkyl-P(O) ₂ NR ¹³ R ¹⁴ - or C _3-6 cycloalkyl-P(O) ₂ NR ¹³ R ¹⁴ , where the groups R ¹³ and R ¹⁴ is selected from the group consisting of C _1-6 straight or branched alkyl, cycloalkyl or C _6-12 aryl;

R ² , R ³ , R ⁴ and R ⁵ are selected from the group consisting of H, halogen, preferably F, or C _1-6 alkyl; And

each of one or more than one Q ¹ , Q ² , Q ³ and Q ⁴ is independently selected from the group consisting of an N atom and the remaining groups are CH;

where in formula (II)

R ¹ represents an H atom or a group according to the following formula

, Where

R ⁶ and R ¹⁰ represents an H atom; And

each of R ⁷ , R ⁸ and R ⁹ independently represents an H atom, a halogen, a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocycle, each independently containing one or more N, O atoms , S; which may be substituted by one or more groups selected from the group consisting of C _1-12 straight or branched alkyl, C _3-12 cycloalkyl, C _1-12 straight or branched alkenyl, C _1-12 straight or branched alkynyl, hydroxy, C _1-12 hydroxyalkyl, C _3-12 hydroxycycloalkyl, amino (-NH ₂ ), C _1-12 alkylamino, C _3-12 cycloalkylamino or C _1-12 dialkylamino, where the amino group may be acylated with a C _1-6 open or a cyclic or aromatic carboxylic acid, or sulfonylated with a C _1-6 open or cyclic or aromatic sulfonic acid; nitro (-NO ₂ ), cyano (nitrile), C _1-12 alkylcyano-, C _3-12 cycloalkylcyano, C _1-12 saturated, unsaturated or aromatic carboxylic acid, C _1-12 carboxylic acid amide formed with saturated, unsaturated or an aryl-amine, wherein the carboxylic acid amide is a group according to any of the following formulas C(O)NH ₂ -, C(O)NHR ¹¹ - or C(O)NR ¹¹ R ¹² -, where R ¹¹ and R ¹² are each independently represents C _1-6 alkyl; C _3-12 cycloalkyl, C _1-6 alkenyl or C _6-12 aryl; a C _1-12 carboxylic acid ester formed with a saturated, unsaturated or aryl alcohol, C _1-12 alkoxy, C _1-12 alkenyloxy, C _1-12 alkynyloxy or C _1-12 alkoxyalkyl, where alkyl, cycloalkyl, alkenyl and alkynyl the groups may be substituted by one or more halogen atoms; halogen, C _1-12 alkylthio, C _3-12 cycloalkylthio, C _1-12 alkenylthio, C _1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more than one halogen; S(O) ₂ OH-, C _1-4 alkyl-S(O) ₂ OH- or C _3-6 cycloalkyl-S(O) ₂ OH-, S(O) ₂ OR ¹³ -, C _1-4 alkyl -S(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-S(O) ₂ OR ¹³ -, S(O)R ¹³ -, C _1-4 alkyl-S(O)R ¹³ - or C _{3- 6} cycloalkyl-S(O)R ¹³ -, S(O) ₂ R ¹³ , C _1-4 alkyl-S(O) ₂ R ¹³ - or C _3-6 cycloalkyl-S(O) ₂ R ¹³ -, P (O) ₂ OH-, C _1-4 alkyl-P(O) ₂ OH- or C _3-6 cycloalkyl-P(O) ₂ OH-, P(O) ₂ OR ¹³ -, C _1-4 alkyl- P(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ OR ¹³ -, P(O) ₂ NH ₂ -, C _1-4 alkyl-P(O) ₂ NH ₂ - or C _{3 -6} cycloalkyl-P(O) ₂ NH ₂ -, P(O) ₂ NHR ¹³ -, C _1-4 alkyl-P(O) ₂ NHR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ NHR ¹³ -, P(O) ₂ NR ¹³ R ¹⁴ - or C _1-4 alkyl-P(O) ₂ NR ¹³ R ¹⁴ - or C _3-6 cycloalkyl-P(O) ₂ NR ¹³ R ¹⁴ , where the groups R ¹³ and R ¹⁴ is selected from the group consisting of C _1-6 straight or branched alkyl, cycloalkyl or C _6-12 aryl; or R ⁷ , R ⁸ and R ⁹ may each independently be C _1-12 straight or branched alkyl, C _3-12 cycloalkyl, C _1-12 straight or branched alkenyl, C _1-12 straight or branched alkynyl, hydroxy, C _1-12 hydroxyalkyl, C _3-12 hydroxycycloalkyl, amino (NH ₂ ), C _1-12 alkylamino, C _3-12 cycloalkylamino or C _1-12 dialkylamino, where the amino group may be C _1-6 open or cyclic acylated, or an aromatic carboxylic acid, or sulfonylated with a C _1-6 open or cyclic or aromatic sulfonic acid; nitro (-NO ₂ ), cyano (nitrile), C _1-12 alkyl cyano, C _1-12 saturated, unsaturated or aromatic carboxylic acid, C _1-12 carboxylic acid amide formed with a saturated, unsaturated or aryl amine, where given a carboxylic acid amide is a group according to any of the following formulas: C(O)NH ₂ -, C(O)NHR ¹¹ - or C(O)NR ¹¹ R ¹² - wherein R ¹¹ and R ¹² are each independently C _{1 -6} alkyl; C _3-12 cycloalkyl, C _1-6 alkenyl or C _6-12 aryl; a C _1-12 carboxylic acid ester formed with a saturated, unsaturated or aryl alcohol, C _1-12 alkoxy, C _1-12 alkenyloxy, C _1-12 alkynyloxy or alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted one or more than one halogen atom; C _1-12 alkylthio, C _3-12 cycloalkylthio, C _1-12 alkenylthio, C _1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more than one halogen; S(O) ₂ OH-, C _1-4 alkyl-S(O) ₂ OH- or C _3-6 cycloalkyl-S(O) ₂ OH-, S(O) ₂ OR ¹³ -, C _1-4 alkyl -S(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-S(O) ₂ OR ¹³ -, S(O)R ¹³ -, alkyl-S(O)R ¹³ - or C _3-6 cycloalkyl-S (O)R ¹³ -, S(O) ₂ R ¹³ , C _1-4 alkyl-S(O) ₂ R ¹³ - or C _3-6 cycloalkyl-S(O) ₂ R ¹³ -, P(O) ₂ OH-, C _1-4 alkyl-P(O) ₂ OH- or C _3-6 cycloalkyl-P(O) ₂ OH- P(O) ₂ OR ¹³ -, C _1-4 alkyl-P(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ OR ¹³ -, P(O) ₂ NH ₂ -, C _1-4 alkyl-P(O) ₂ NH ₂ - or C _3-6 cycloalkyl-P (O) ₂ NH ₂ -, P(O) ₂ NHR ¹³ -, C _1-4 alkyl-P(O) ₂ NHR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ NHR ¹³ -, P(O ) ₂ NR ¹³ R ¹⁴ - or C _1-4 alkyl-P(O) ₂ NR ¹³ R ¹⁴ - or C _3-6 cycloalkyl-P(O) ₂ NR ¹³ R ¹⁴ -group, where R ¹³ and R ¹⁴ are selected from the group consisting of C _1-6 straight or branched alkyl, cycloalkyl or C _6-12 aryl; methanesulfonylaminomethyl, trifluoromethanesulfonylamino, N,N-dimethylaminocarbonylmethyl [CH ₂ -CO-N(CH ₃ ) ₂ ], acetyl, methanesulfonylamino, methoxymethyl;

or R ¹ is a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocycle, each independently containing one or more N, O, S atoms; which may be substituted by one or more groups selected from the group consisting of C _1-12 straight or branched alkyl, C _3-12 cycloalkyl, C _1-12 straight or branched alkenyl, C _1-12 straight or branched alkynyl, hydroxy, C _1-12 hydroxyalkyl, C _3-12 hydroxycycloalkyl, amino (-NH ₂ ), C _1-12 alkylamino, C _3-12 cycloalkylamino or C _1-12 dialkylamino, where the amino group may be acylated with a C _1-6 open or a cyclic or aromatic carboxylic acid, or sulfonylated with a C _1-6 open or cyclic or aromatic sulfonic acid; nitro (-NO ₂ ), cyano (nitrile), C _1-12 alkylcyano, C _3-12 cycloalkylcyano, C _1-12 saturated, unsaturated or aromatic carboxylic acid, C _1-12 carboxylic acid amide formed with saturated, unsaturated or an aryl-amine, wherein the carboxylic acid amide is a group according to any of the following formulas: C(O)NH ₂ -, C(O)NHR ¹¹ - or C(O)NR ¹¹ R ¹² -, where R ¹¹ and R ¹² are each independently represents C _1-6 alkyl, C _3-12 cycloalkyl, C _1-6 alkenyl or C _6-12 aryl; a C _1-12 carboxylic acid ester formed with a saturated, unsaturated or aryl alcohol, C _1-12 alkoxy, C _1-12 alkenyloxy, C _1-12 alkynyloxy or C _1-12 alkoxyalkyl, where alkyl, cycloalkyl, alkenyl and alkynyl the groups may be substituted by one or more halogen atoms; halogen, C _1-12 alkylthio, C _3-12 cycloalkylthio, C _1-12 alkenylthio, C _1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more than one halogen; S(O) ₂ OH-, C _1-4 alkyl-S(O) ₂ OH- or C _3-6 cycloalkyl-S(O) ₂ OH-, S(O) ₂ OR ¹³ -, C _1-4 alkyl -S(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-S(O) ₂ OR ¹³ -, S(O)R ¹³ -, C _1-4 alkyl-S(O)R ¹³ - or C _{3- 6} cycloalkyl-S(O)R ¹³ -, S(O) ₂ R ¹³ , C _1-4 alkyl-S(O) ₂ R ¹³ - or C _3-6 cycloalkyl-S(O) ₂ R ¹³ -, P (O) ₂ OH-, C _1-4 alkyl-P(O) ₂ OH- or C _3-6 cycloalkyl-P(O) ₂ OH-, P(O) ₂ OR ¹³ -, C _1-4 alkyl- P(O) ₂ OR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ OR ¹³ -, P(O) ₂ NH ₂ -, C _1-4 alkyl-P(O) ₂ NH ₂ - or C _{3 -6} cycloalkyl-P(O) ₂ NH ₂ -, P(O) ₂ NHR ¹³ -, C _1-4 alkyl-P(O) ₂ NHR ¹³ - or C _3-6 cycloalkyl-P(O) ₂ NHR ¹³ -, P(O) ₂ NR ¹³ R ¹⁴ - or C _1-4 alkyl-P(O) ₂ NR ¹³ R ¹⁴ - or C _3-6 cycloalkyl-P(O) ₂ NR ¹³ R ¹⁴ , where the groups R ¹³ and R ¹⁴ is selected from the group consisting of C _1-6 straight or branched alkyl, cycloalkyl or C _6-12 aryl;

R ² , R ³ , R ⁴ and R ⁵ are selected from H, halogen, preferably F, or C _1-6 alkyl; And

each of Q ⁵ , Q ⁶ and Q ⁷ is independently selected from the group consisting of S, O, N, NH or CH, provided that the aromatic nature of the ring is maintained; where CH or NH may be substituted with C _1-6 alkyl or haloalkyl;

and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

2. Compounds of formula (I) or (II) according to claim 1;

where in formula (I)

R ¹ represents hydrogen or a group according to the following formula

, where in the above formula

R ⁷ , R ⁸ and R ⁹ are independently selected from the group consisting of H atom, morpholinyl, amino (-NH ₂ ), nitro (-NO ₂ ), cyano (nitrile), carboxylic acid amide (-CONH ₂ ), methoxy ( -OSH ₃ ), trifluoromethyl, fluoro-, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methanesulfonylaminomethyl, trifluoromethanesulfonylamino, N,N-dimethylaminocarbonylmethyl [CH ₂ -CO-N(CH ₃ ) ₂ -], acetyl, methanesulfonylamino, methoxymethyl, 1,4-oxazepan-4-yl, oxan-4-yl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4- yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or

R ¹ is selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And

one of the groups Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; And

where in formula (II)

R ¹ represents hydrogen or a group according to the following formula:

, where in the above formula

R ⁶ and R ¹⁰ represent an H atom, and

R ⁷ , R ⁸ and R ⁹ are independently selected from the group consisting of H atom, morpholinyl, amino (-NH ₂ ), nitro (-NO ₂ ), cyano (nitrile), carboxylic acid amide (-CONH ₂ ), methoxy ( -OSH ₃ ), trifluoromethyl, fluoro-, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methanesulfonylaminomethyl, trifluoromethanesulfonylamino, N,N-dimethylaminocarbonylmethyl [CH ₂ -CO-N(CH ₃ ) ₂ -], acetyl, methanesulfonylamino, methoxymethyl, 1,4-oxazepan-4-yl, oxan-4-yl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4- yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or

R ¹ is selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And

Q ⁵ , Q ⁶ and Q ⁷ are as follows: Q ⁵ represents an S atom, and Q ⁶ and Q ⁷ represent CH, or Q ⁷ represents an S atom, and Q ⁵ and Q ⁶ represent CH, or Q ⁵ represents is N-CH ₃ and Q ⁶ is N atom and Q ⁷ is CH, or Q ⁵ is S atom and Q ⁶ is C-CH ₃ and Q ⁷ is CH,

and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

3. Compounds of formulas (I) or (II) according to paragraph 1 or 2,

where in formula (I)

R ¹ represents hydrogen or a group according to the following formula

, where in the above formula

R ⁶ and R ¹⁰ represents an H atom, and

R ⁷ and R ⁹ are selected from the group consisting of an H atom, amino (-NH ₂ ), cyano or methoxy (-OCH ₃ ) and

R ⁸ is selected from the group consisting of H atom, morpholinyl, amino (-NH ₂ ), nitro (-NO ₂ ), cyano (nitrile), carboxylic acid amide (-CONH ₂ ), methoxy (-OCH ₃ ), trifluoromethyl, fluoro-, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methanesulfonylaminomethyl, trifluoromethanesulfonylamino, N,N-dimethylaminocarbonyl methyl [CH ₂ -CO-N(CH ₃ ) ₂ -], acetyl, methanesulfonylamino, methoxymethyl, 1,4-oxazepan- 4-yl, oxan-4-yl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4- yl, 1-methylpiperidin-4-yl; or

R ¹ is selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And

one of Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; And

where in formula (II)

R ¹ represents hydrogen or a group according to the following formula

where in the above formula

R ⁶ and R ¹⁰ represent an H atom and

R ⁷ and R ⁹ represent an H atom, amino (-NH ₂ ), cyano or methoxy (-OCH ₃ ) and

R ⁸ is selected from the group consisting of H atom, morpholinyl, amino (-NH ₂ ), nitro (-NO ₂ ), cyano (nitrile), carboxylic acid amide (-CONH ₂ ), methoxy (-OCH ₃ ), trifluoromethyl, fluoro-, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methanesulfonylaminomethyl, trifluoromethanesulfonylamino, N,N-dimethylaminocarbonyl methyl [CH ₂ -CO-N(CH ₃ ) ₂ -], acetyl, methanesulfonylamino, methoxymethyl, 1,4-oxazepan- 4-yl, oxan-4-yl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4- yl, 1-methylpiperidin-4-yl group; or

R ¹ is selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And

Q ⁵ , Q ⁶ and Q ⁷ are as follows: Q ⁵ represents an S atom, and Q ⁶ and Q ⁷ represent CH, or Q ⁷ represents an S atom, and Q ⁵ and Q ⁶ represent CH, or Q ⁵ represents is N-CH ₃ and Q ⁶ is N atom and Q ⁷ is CH, or Q ⁵ is S atom and Q ⁶ is C-CH ₃ and Q ⁷ is CH,

and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

4. Compounds of formula (I) or (II) according to paragraphs. 1-3,

in which in formula (I)

R ¹ represents hydrogen or a group according to the following formula

where in the above formula

R ⁶ , R ⁷ , R ⁹ and R ¹⁰ represent an H atom, and

R ⁸ represents an H atom or morpholinyl;

R ² , R ³ , R ⁴ and R ⁵ represent an H atom, and

one of Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; And

where in formula (II)

R ¹ represents hydrogen or a group according to the following formula

where in the above formula

R ⁶ , R ⁷ , R ⁹ and R ¹⁰ represent an H atom; And

R ⁸ represents an H atom or morpholinyl;

R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And

Q ⁵ , Q ⁶ and Q ⁷ are as follows: Q ⁵ represents an S atom, and Q ⁶ and Q ⁷ represent CH, or Q ⁷ represents an S atom, and Q ⁵ and Q ⁶ represent CH, or Q ⁵ represents is N-CH ₃ and Q ⁶ is a N atom and Q ⁷ is CH,

and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

5. The following compounds of formula (I) or (II) according to paragraphs. 1-4:

3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

9-hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

7-hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,11-trien-8-one,

9-hydroxy-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one,

8a-hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one,

9-hydroxy-5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

12-phenyl-9-hydroxy-6-methyl-4-thia-2,5,12-triazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

(9S)-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

(9S)-9-hydroxy-5-methyl-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5- trien-8-one,

(9S)-12-(4-aminophenyl)-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

(9S)-9-hydroxy-12-(4-methoxyphenyl)-4-thia-2,12-diazotricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

(9S)-9-hydroxy-12-[4-(trifluoromethoxy)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

(9S)-4-{9-hydroxy-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-12-yl}benzonitrile ,

(9S)-12-(4-acetylphenyl)-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

(9S)-2-(4-{9-hydroxy-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-12- yl}phenyl)acetonitrile,

(9S)-9-hydroxy-12-[4-(hydroxymethyl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

(9S)-9-hydroxy-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8- He,

(9S)-9-hydroxy-12-(6-methoxypyridin-3-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien- 8-he,

9-hydroxy-5-methyl-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5 -trien-8-one,

12-(4-aminophenyl)-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

9-hydroxy-12-(4-methoxyphenyl)-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

9-hydroxy-5-methyl-12-[4-(trifluoromethoxy)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

4-{9-hydroxy-5-methyl-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-12-yl}benzonitrile ,

12-(4-acetylphenyl)-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

2-(4-{9-hydroxy-5-methyl-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-12- yl}phenyl)acetonitrile,

9-hydroxy-12-[4-(hydroxymethyl)phenyl]-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

9-hydroxy-5-methyl-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8- He,

9-hydroxy-12-(6-methoxypyridin-3-yl)-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien- 8-he,

9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

(9S)-9-hydroxy-12-(4-methylphenyl)-4-thia-2,12-diazotricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one,

12-[4-(methyl)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

3a-hydroxy-1-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

1-(4-acetylphenyl)-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

1-[4-(methyl)phenyl]-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

3a-hydroxy-1-[4-(morpholin-4-yl)phenyl]-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

(9S)-12-[4-(dimethylamino)phenyl]-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

12-[4-(dimethylamino)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He,

1-[4-(dimethylamino)phenyl]-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one.

6. Connections according to any one of paragraphs. 1-5 for use in the treatment of conditions and diseases selected from the group consisting of platelet precursor formation, chemotherapy, cancer metastasis, leukemia cell migration, thrombosis, including arterial thrombosis, including ischemic stroke, nerve and muscle damage, including neuronal apoptosis and injury spinal cord, drug warning, including prevention of methamphetamine-associated relapse and drug-related diseases, peripheral neuropathy, hepatocarcinoma, lung carcinoma, benign prostate enlargement, sensorimotor neuropathy, fibrosis, including fibrosis of the lung, liver and joints, wound healing , hemostasis and thrombosis, including retention of blood clots, periodontitis, pathological apoptosis, immune diseases, including multiple sclerosis, viral diseases, including diseases caused by herpes, hypertension, pulmonary (arterial) hypertension, erectile dysfunction, thrombotic disorders, urinary system problems, including overactive bladder, bladder blockage, cardiomyopathies including hypertrophic cardiomyopathy and dilated cardiomyopathy, muscle spasms including non-specific low back pain, lumbar spasm or cramping, stress-induced occipital spasms, prolonged muscle spasms in the limbs in partial prolonged epilepsy, post-stroke spasticity, muscle spasms in cerebral palsy and multiple sclerosis, vaginismus, spasm of skeletal and smooth muscles during childbirth, drug-induced convulsions, myopathies in myocardial and skeletal muscles, including altered ability of myofilaments to apply force.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of formula (I) or (II), as described above in claim 1, where the identifiers in the formulas are as defined in claim 1, and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers , diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

The group of compounds of the present invention is a compound of formula (I) or (II) as described above, wherein the identifiers in the formulas are as defined in claim 2, and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof.

Another group of compounds of the present invention are compounds of formula (I) or (II), as described above in paragraph 3, where the identifiers in the formulas are as defined in paragraph 3, and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers , including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

Another group of compounds of the present invention are compounds of formula (I) or (II), as described above in paragraph 4, where the identifiers in the formulas are as defined in paragraph 4, and their pharmaceutically acceptable salts, solvates, tautomers, stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

Another group of compounds of the present invention is a compound of formula (I) or (II), as described above in paragraph 5, further identified by its chemical name, and its pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof.

As noted above, the compounds of the present invention may exist as racemic mixtures and as optical isomers, with a single enantiomer that is pure or predominant. It will be understood that both racemic mixtures and enantiomers, whether pure or predominant in a mixture over another enantiomer, are within the scope of the invention.

According to amine-imine tautomerism, 1,6-dihydro-7H-imidazo[4,5-b]pyridin-7-one is also known as 1,6-dihydro-7H-imidazo[4,5-b]pyridin-7-one , and these equilibrium forms differ from each other in the position of the proton and double bond. The same applies to certain compounds of the invention.

Some compounds of the present invention may contain one or more chiral centers and may therefore exist in enantiomeric or diastereomeric forms. It is intended that the subject matter of the present invention include all isomers as such, as well as a mixture of cis and trans isomers, a mixture of diastereomers and a mixture of enantiomers (optical isomers). In addition, well-known techniques can be used to separate the different forms, and the invention may include a purified or enriched form of a particular enantiomeric or diastereomeric compound.

The present invention further relates to pharmaceutically acceptable salts and solvates of the compounds of the invention.

Human myosin 2 isoforms play an important role in the development of medical indications related to neurology, skeletal, cardiac and smooth muscle, cell division and cell migration.

In neurological terms, their role is important in apoptotic and neuroregenerative processes during nerve damage, as well as in the development of specific memory associated with drug use. Based on these effects, the claimed myosin 2 inhibitors may be useful for improving the symptoms of neurodegenerative, neuropathic, psychiatric and neurological disorders and nerve injuries, such as schizophrenia, cerebral ischemia, stroke, neuropathic pain, spinal cord injury, Alzheimer's disease, Parkinson's, amyotrophic lateral sclerosis, Huntington's disease, addiction, brain tumors, brain asphyxia, post-traumatic stress syndrome and multiple sclerosis, but not limited to. Also, depression, obsessive-compulsive disorder, visual hallucinations, auditory hallucinations, eating disorders, bipolar disorder, cerebellar ataxia, cerebellar vascular injury, corticobasal ganglia degeneration, Creutzfeldt-Jakob syndrome, Dandy-Walker syndrome, dementia, encephalitis, encephalomyelitis, epilepsy , Hallervorden-Spatz syndrome, hydrocephalus, lacunar infarction, Landau-Kleffner syndrome, dementia with Lewy bodies, Machado-Joseph disease, Meige syndrome, Shy-Drager syndrome, neuroaxonal dystrophies, spinal ataxia, spinocerebellar degeneration, Tourette syndrome.

The active compounds of the present invention are suitable for alleviating symptoms of disorders associated with muscle spasms by relaxing skeletal muscles, said symptoms being such as non-specific pain in the lower abdomen, muscle spasms associated with lumbago or cartilaginous hernia, or partial prolonged epilepsy, prolonged muscle spasms in the limbs and, as additional symptoms, muscle spasms in multiple sclerosis, gynecological indications including vaginismus, spasms of skeletal and smooth muscles during childbirth, myopathies in the heart and skeletal muscles in case of obstruction (obstupatio), but are not limited to them.

Non-limiting additional indications for the claimed active ingredients include thrombotic diseases, hypertension, pulmonary (arterial) hypertension, hypertrophied or dilated myocardial distress, genitourinary problems such as overactive bladder, bladder blockage or erectile dysfunction.

Due to their role in cell migration, non-limiting indications for the claimed active ingredients include cancer metastasis, pulmonary, hepatic or articular fibrosis. In addition, non-limiting indications related to wound healing processes include idiopathic keloid and Dupuytren's contractures, desmoplastic (cancerous), autoimmune (sclerodermal), inflammatory (Crohn's disease) and infectious (cirrhosis) or traumatic (cicatricial ectopia) lesions.

The present invention also provides compounds of the invention for use in the treatment of conditions and diseases selected from the group consisting of platelet precursor formation, chemotherapy, cancer metastasis, leukemia cell migration, thrombosis, including arterial thrombosis, nerve injury, including neuronal apoptosis, and spinal injury. brain, drug use prevention, including prevention of methamphetamine-related relapse and drug addiction-related diseases, peripheral neuropathy, hepatocarcinoma, lung carcinoma, benign prostate enlargement, sensorimotor neuropathy, fibrosis, including fibrosis of the lung, liver and joints, wound healing, hemostasis and thrombosis, including retention of blood clots, periodontitis, pathological apoptosis, immune diseases, including multiple sclerosis, virus-induced diseases, including diseases caused by the herpes virus, hypertension, pulmonary (arterial) hypertension, erectile dysfunction, thrombotic disorders, urinary system problems, including overactive bladder, bladder blockage, cardiomyopathies including hypertrophic cardiomyopathy and dilated cardiomyopathy, muscle spasms including nonspecific low back pain, lumbago or spasms associated with herniated discs, stress-induced nuchal spasms, prolonged muscle spasms in the extremities during partial long-term epilepsy and, as additional symptoms, muscle spasms in multiple sclerosis, vaginismus, spasms of skeletal and smooth muscles during childbirth, drug-induced spasms, myopathies in cardiac and skeletal muscles, including altered ability of myofilaments to apply force.

Preparation of compounds according to the invention

The synthesis of compounds of the present invention having an aromatic heterocycle in ring A can be carried out through the following reaction scheme:

In Scheme 1, instead of the aromatic ring designated N, a 5-membered ring of formula (II) can also be used, in which the variables of the 5-membered ring are as defined in paragraph 1 above. In addition, the group R in Scheme 1 has the same meaning as R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ as defined in paragraph 1.

Examples of the compounds of the invention that can be prepared through the above Scheme 1 include, but are not limited to, the following compounds:

where Q represents C _1-6 alkyl or haloalkyl, and R is identical to the groups R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ as defined in the claims.

Examples of compounds of the invention that can be prepared based on Scheme 1 include, but are not limited to, compounds wherein ring A is a 5-membered aromatic ring containing the same or different heteroatoms selected from N, O or S.

The present invention will now be illustrated by way of typical embodiments, which, however, should not be construed as limiting the present invention.

EXAMPLES

Example 1: Preparation of 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1)

Step a) Preparation of ethyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-4-carboxylate (Compound 1a)

4.36 g (27.08 mmol, 1 eq.) of 1-phenylpyrrolidin-2-one was dissolved in dichloromethane (35 ml) under argon and 4.15 g (2.5 ml, 27.08 mmol, 1 eq.) was added .) POCl ₃ . After stirring for 3 hours at room temperature, a solution of 5.00 g (30.09 mmol, 1.1 eq.) ethyl 3-aminopyridine-4-carboxylate in dichloromethane (35 ml) was added over 5 minutes via a dropper top . This reaction mixture was refluxed for 16 hours. At the end of reflux, this reaction mixture was cooled to room temperature and stirred with saturated NaHCO ₃ solution to maintain an alkaline aqueous phase (pH 8). This solution is added carefully due to foaming. The organic phase is then dried over Na ₂ SO ₄ , filtered and concentrated. 5.80 g of crude ethyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-4-carboxylate (Compound 1a) was retained and used without further purification. M+H ⁺ equals 310.35.

Step b) Preparation of 1-phenyl-1H,2H,3H,4H,9H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1b)

5.80 g of the crude product (Compound 1a, 18.76 mmol) obtained in step a) was dissolved in dry tetrahydrofuran (140 ml). This was cooled with argon under a dry ice-acetone quench mixture, and 9.42 g of lithium hexamethyldisilazane (39.2 mL, 56.27 mmol, 3 eq.) in 20% tetrahydrofuran was added at a temperature below -60°C. The reaction mixture was then allowed to warm to room temperature after one hour. After 3 hours, the reaction mixture was treated with 2 M hydrochloric acid to dissolve the entire precipitate (approximately 100 ml). The organic layer was then separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The aqueous phase was concentrated on a vacuum evaporator until the remaining organic solvent was removed. This solution was then neutralized by adding NaHCO ₃ solution. The resulting precipitate was filtered off and dried under vacuum. This gives 3.61 g of crude product, which is recrystallized from 30 g of dimethylformamide. Yield: 1.74 g pale yellow crystals (6.61 mmol, 24% based on 1-phenylpyrrolidin-2-one)-1-phenyl-1H,2H,3H,4H,9H-pyrrolo[2,3-b ]1,7-naphthyridin-4-one (Compound 1b). M+H ⁺ equals 264.30.

¹ H NMR (nuclear magnetic resonance) (500 MHz, DMSO-d ₆ ): δ=3.22 (t, J=8.8 Hz, 2H), 4.13 (t, J=8.0 Hz, 2H ), 7.05 (t, J=7.3 Hz, 1H), 7.41 (dd, J=7.6, 8.1 Hz, 2H), 7.80 (d, J=5.3 Hz , 1 N), 8.06 (d, J=8.1 Hz, 2H), 8.28 (d, J=5.3 Hz, 1H), 8.89 (br, 1H), 10.94 ( br, 1H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=21.9, 48.2, 110.9, 114.3, 117.8, 121.6, 123.0, 128.6, 140.2, 141 ,6, 143.5, 149.2, 152.8, 160.9.

Step c) Preparation of 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1)

263 mg (1 mmol) 1-phenyl-1H,2H,3H,4H,9H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1b) was suspended in dry tetrahydrofuran (40 ml) under argon and cooled it with a mixture of dry ice and acetone. A solution of 334 mg (1.8 ml, 2 mmol, 2 eq.) of lithium hexamethyldisilazane in 20% by weight tetrahydrofuran was added at a temperature below -60°C. Then 2-(benzenesulfonyl)-3-phenyloxaziridine (522 mg, 2 mmol, 2 eq.) was added and dissolved in dry tetrahydrofuran (15 ml). After half an hour, the cooling was stopped and the mixture was allowed to warm to room temperature, stirring overnight. 1 M HCl (40 ml) was added to this reaction mixture and it was extracted with methyl tert-butyl ether (3 x 40 ml). The aqueous phase was concentrated under vacuum to approximately half its volume and then neutralized with NaHCO ₃ . The orange precipitate that formed was filtered through a P4 glass filter, washed with methyl tert-butyl ether and dried under vacuum. Yield: 131 mg (0.47 mmol, 47%), orange powder, 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridine-4 -on (Compound 1). M+H ⁺ equals 280.30.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=2.28 (dd, J=5.8, 13.3 Hz, 1H), 2.39 (ddd, J=9.2, 9.4 , 13.3 Hz, 1H), 4.00 (dd, J=9.2, 10.3 Hz, 1H), 4.13 (ddd, J=5.8, 9.4, 10.3 Hz, 1H), 7.04 (s, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.46 (t, J=7.9 Hz, 2H), 7.56 (d, J=4.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 2H), 8.32 (br, 1 N), 8.56 (br, 1 N).

DEPTq (500 MHz, DMSO-d ₆ ): δ=27.8, 47.8, 73.7, 118.2, 120.3, 124.2, 125.9, 128.7, 140.1, 143 ,8, 145.9, 148.1, 166.9, 193.9.

Preparation of 2-(benzenesulfonyl)-3-phenyloxaziridine: Org. Synth. 1988, 66, 203.

Example 2: Preparation of 9-hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one (Compound 2)

Step a) Preparation of methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-carboxylate (Compound 2a)

9.23 g (57.26 mmol, 1 eq.) of 1-phenylpyrrolidin-2-one was dissolved in 70 ml of dry dichloromethane, and 8.78 g of POCl ₃ (5.3 ml, 57.26 mmol, 1 eq.) was added. ) in an argon atmosphere. After stirring for three hours at room temperature, a suspension of methyl 2-aminothiophene-3-carboxylate (10 g, 63.61 mmol) in dichloromethane (150 ml) was added through a funnel. This reaction mixture was refluxed for 16 hours, cooled to room temperature and extracted with 1 M hydrochloric acid (5×100 ml). The combined aqueous phases were brought to pH 9-10 with a saturated Na ₂ CO ₃ solution. This mixture was extracted with dichloromethane (3×200 ml) and the combined organic layers were dried over Na ₂ SO ₄ . After filtering off the desiccant, 8.39 g of crude product remained after evaporation. It was purified on a silica gel column using hexane-ethyl acetate. Suitable fractions were combined, and the residue was recrystallized from a heptane:ethyl acetate 1:1 mixture. Yield: 5.27 g (17.53 mmol, 31%) methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-carboxylate (Compound 2a), pale yellow crystals.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=2.05 (m, 2H), 2.68 (t, J=7.8 Hz, 2H), 3.70 (s, 3H), 3 .92 (t, J=7.0 Hz, 2H), 6.91 (d, J=6.0 Hz, 1H), 7.12 (tt, J=1.1, 7.5 Hz, 1H) , 7.13 (d, J=6.0 Hz, 1 N), 7.37 (dd, J=7.5, 8.8 Hz, 2 H), 7.83 (d, J=8.8 Hz , 2H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=19.1, 29.3, 50.8, 50.9, 115.3, 115.7, 121.0, 123.7, 127.0, 128 ,3, 140.4, 162.3, 163.0, 163.5.

Step b) Preparation of 12-phenyl-4-thia-2,12-diazatricyclo-[7.3.0.0 ^3,7 ]dodeca-1(9),3(7),5-trien-8-one (Compound 2b)

Methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-caboxylate (Compound 2a) (3.38 g, 12.75 mmol) was dissolved in dry tetrahydrofuran (50 ml). To this was added a solution of 2.86 g of potassium tert-butoxide (14 ml, 25.51 mmol, 2 eq.) in tetrahydrofuran, and then the reaction mixture was refluxed under argon. After adding the base, this solution turns red and precipitates after a few minutes. This reaction was monitored by LC-MS (liquid chromatography mass spectrometry). After refluxing for three hours, the mixture was cooled to room temperature and 5 ml of acetic acid was added with stirring to dissolve the precipitate. This mixture was concentrated in vacuo to obtain a brown sticky substance, which was triturated with a mixture of 30 ml MeOH and 30 ml toluene 3 times to obtain a crystalline substance. It was mixed with water (30 ml), filtered and washed with water. This gives 3.25 g of crude product, which is crystallized from 14 g of acetonitrile and dried in vacuo at 40°C. Yield: 2.16 g (8.06 mmol, 63%) 12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),3(7),5- trien-8-one (Compound 2b), which is a light brown powder. M+H ⁺ =269.00

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=3.10 (t, J=8.4 Hz, 2H), 4.07 (t, J=8.4 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 7.22 (d, J=6.0 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 7.35 (t , J=7.5 Hz, 2H), 7.86 (d, J=8.2 Hz, 2H), 10.60 (br, 1H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=21.5, 48.8, 104.8, 116.8, 118.4, 118.6, 118.7, 120.5, 128.5, 142 ,1, 154.2, 159.6, 160.1.

Step c) 9-Hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one (Compound 2)

526 mg (1.96 mmol) 12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),3(7),5-trien-8-one (Compounds 2b) and 30 ml of dry tetrahydrofuran were weighed in a round-bottom flask sealed with a diaphragm, and an argon cylinder was placed on it. A thermometer and a stopper were placed in the other two necks of this flask. This vessel was cooled with dry ice-acetone, and a solution of 656 mg of lithium hexamethyldisilazane (3.6 mL, 3.92 mmol, 2 eq.) in tetrahydrofuran was added via syringe at a temperature below -60°C. A solution of 2-(benzenesulfonyl)-3-phenyloxaziridine (563 mg, 2.15 mmol, 1.1 eq) in dry tetrahydrofuran (5 ml) was then added at a temperature below -60°C. Then they allowed it to warm up for 1 hour. After a few hours, a yellow precipitate appears. This reaction mixture was stirred at room temperature overnight. The reaction was checked by thin layer chromatography. When the starting material was consumed, 40 ml of 2 M hydrochloric acid and 40 ml of methyl tert-butyl ether were added and shaken. The organic layer was extracted with 1 M hydrochloric acid (3 x 40 ml) and the combined aqueous phases were extracted with 30 ml of methyl t-butyl ether. The aqueous phase was extracted with dichloromethane (3×40 ml), the organic phases were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was crystallized from acetonitrile. Yield: 207 mg (0.73 mmol, 37%) 9-hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene -8-ona (Compound 2), orange crystals. M+H ⁺ =285.0.

^1H NMR (500 MHz, DMSO- _d6 ): δ=2.25 (m, 2H), 4.04 (m, 1H), 4.17 (m, 1H), 6.93 (s, 1H) , 6.96 (d, J=5.4 Hz, 1H), 7.10 (d, J=5.4 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7 .46 (t, J=7.5 Hz, 2H), 7.95 (d, J=8.0 Hz, 2H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=28.5, 49.0, 74.5, 117.2, 119.9, 120.4, 122.3, 124.7, 128.8, 139 ,6, 169.3, 170.6, 187.8.

Example 3: 7-Hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,11-trien-8-one (Compound 3)

Step a) Preparation of methyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-2-carboxylate (Compound 3a)

5.00 g (31.02 mmol, 1 eq.) of 1-phenylpyrrolidin-2-one was dissolved in 35 ml of dry dichloromethane, and 4.76 g (2.83 ml, 31.02 mmol, 1 eq.) POCl was added ₃ . After stirring for 3 hours under argon, a solution of 5.42 g (34.46 mmol, 1.1 eq.) of methyl 3-aminothiophene-2-carboxylate in 35 ml of dichloromethane was added. This reaction was then refluxed for 16 hours. A solution of 10% Na ₂ CO ₃ was added such that the pH of the aqueous phase was approximately 8-9 after 5 minutes of stirring. The aqueous phase was extracted with dichloromethane (3×50 ml) and the organic phases were combined and then evaporated. The crude product thus obtained was dissolved in 50 ml of isopropyl acetate and extracted with 5×40 ml of 1 M hydrochloric acid. The pH of the aqueous phases was adjusted to 8 using 10% Na ₂ CO ₃ and extracted with dichloromethane (3×50 ml). After drying over Na ₂ SO ₄ this solution was filtered and concentrated to about 2 ml. Then 20 ml of heptane was added, and evaporation was continued until colorless plate-like crystals appeared in the cloudy solution. They were filtered, washed with heptane and dried in vacuum. Yield: 2.78 g (9.24 mmol, 30%), methyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-2-carboxylate (Compound 3a). M+H ⁺ =301.10

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=1.99 (m, 2H), 2.50 (m, 2H), 3.71 (s, 3H), 3.86 (t, J= 6.8 Hz, 2H), 6.70 (d, J=5.2 Hz, 1H), 7.07 (tt, J=1.1, 7.5 Hz, 1H), 7.35 (dd, J=7.5, 8.5 Hz, 2H), 7.72 (d, J=5.2 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=19.1, 29.3, 50.2, 51.2, 111.9, 120.4, 122.9, 125.5, 128.2, 131 ,3, 141.0, 157.1, 160.4, 162.0.

Step b) 4-Phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),3(7),11-trien-8-one (Compound 3b)

To methyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-2-carboxylate (2.51 g, 8.35 mmol) was added 32 ml of dry tetrahydrofuran, followed by the addition of 1.87 g (10.3 ml, 16.69 mmol, 2 eq.) solution of potassium tert-butoxide in tetrahydrofuran. This reaction mixture was refluxed under argon for 3 hours (monitored using TLC). After cooling, 20 ml of 1 M hydrochloric acid was added and the tetrahydrofuran was evaporated in vacuo. A saturated solution of NaHCO ₃ was added to the aqueous residue until neural pH was reached and stirred for half an hour, then filtered, washed with water (2×10 ml) and dried in vacuum. Yield: 2.05 g (7.65 mmol, 92%) 4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),3(7),11- trien-8-one (Compound 3b).

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=3.15 (dd, J=7.9, 8.2 Hz, 2H), 4.07 (t, J=8.4 Hz, 2H) , 6.96 (t, J=7.3 Hz, 1H), 7.27 (d, J=5.4 Hz, 1H), 7.35 (dd, J=7.7, 8.5 Hz, 2H), 7.76 (d, J=5.4, 1H), 7.92 (d, J=8.5 Hz, 2H), 11.0 (w, 1H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=22.0, 48.9, 104.8, 115.9, 117.0, 120.5, 124.1, 128.0, 128.5, 142 ,3, 154.1, 160.2.

Step c) 7-Hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,11-trien-8-one (Compound 3)

537 mg (2 mmol, 1 eq.) 4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),3(7),11-trien-8-one (Compounds 3b) and 784 mg (3 mmol, 1.5 eq.) of 2-(benzenesulfonyl)-3-phenyloxaziridine and 20 ml of dry tetrahydrofuran were poured into a diaphragm sealed vessel. This vessel was sealed and a balloon filled with argon was placed in the diaphragm. The solution was cooled with ice water, and a solution of 669 mg (3.6 ml, 4 mmol, 2 eq.) of lithium hexamethyldisilazane in 20% tetrahydrofuran was added to this solution over 1 minute by syringe. This solution was allowed to warm to room temperature and stirred overnight. This solution had a light yellow precipitate after 1 hour. Then 40 ml of methyl tert-butyl ether and 40 ml of 2 M hydrochloric acid were added and shaken. The organic phase was extracted two more times with 20 ml of 2 M hydrochloric acid and the combined aqueous phases were adjusted to pH 8 with 40% NaOH. This mixture was extracted with 2-methyl-tetrahydrofuran (3×40 ml), and the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. The crude product crystallized from acetonitrile. Yield: 333 mg (1.17 mmol, 59% ⁾ -ona (Compound 3), light yellow crystals. M+H ⁺ =285.00

¹ H NMR (500 MHz, DMSO-d ₆ ): δ=2.23 (dd, J=5.8, 12.9 Hz, 1H), 2.29 (ddd, J=8.0, 9.8 , 12.9 Hz, 1H), 4.02 (dd, J=8.0, 9.5 Hz, 1H), 4.15 (ddd, J=5.8, 9.5, 9.8 Hz, 1H), 6.94 (s, 1H), 7.05 (d, J=5.1 Hz, 1H), 7.19 (tt, J=1.1, 7.4 Hz, 1H), 7, 44 (tdd, J=2.1, 7.4, 8.8 Hz, 2H), 8.01 (td, J=1.1, 8.8 Hz, 2H), 8.03 (d, J= 5.1 Hz, 1H).

DEPTq (500 MHz, DMSO-d ₆ ): δ=28.2, 48.7, 75.2, 117.2, 120.3, 124.3, 126.2, 128.7, 136.8, 140 ,0, 161.4, 170.7, 186.9.

Example 4A: Synthesis of pyrrolothienopyridine and pyrrolonaphthyridine derivatives

4A.1 Preparation of 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one

4-Chloro-N-[(4-methoxyphenyl)methyl]-butanamide:

To 768 g (554 mmol, 1 eq.) of 4-methoxybenzylamine in 370 ml of dry dichloromethane in an inert flask under argon were added 93 ml (67.34 g, 665 mmol, 1.2 eq.) of triethylamine and 39 g (28 mmol, 5 mol %) N,N-dimethylaminopyridine, and this reaction mixture was cooled to 5°C. A solution of 4-chlorobutyryl chloride (68.5 mL, 86.02 g, 610 mmol, 1.1 eq.) in 40 mL of dry dichloromethane was added dropwise to this reaction mixture at 5-15°C. The mixture was allowed to warm to room temperature, and then stirred at room temperature for 24 hours. This mixture was washed with water (400 ml), 5% citric acid solution (2×400 ml) and saturated NaHCO ₃ solution (100 ml) and separated. The organic layer was dried over Na ₂ SO ₄ . This solution was then filtered, evaporated and the precipitated crystals were stirred with 200 ml of heptane overnight. It was then filtered through a glass filter, washed with cold heptane and then dried at 40°C under vacuum. Yield: 107.27 g white solid (443 mmol, 80%). Rf is 0.66 dichloromethane:methanol 95:5.

^1H NMR ( _CDCl3 , 500 MHz): δ 2.12 (m, 2H), 2.37 (t, J=7.2 Hz, 2H), 3.60 (t, J=6.2 Hz, 2H), 4.36 (d , J=5.6 Hz, 2H), 5.87 (bs, 1H), 6.86 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H).

13C DEPTq NMR (CDCl ₃ , 500 MHz): δ 28.3, 33.4, 43.3, 44.7, 114.1, 114.3, 129.3, 130.4, 159.2, 171.5.

1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one:

In an inert flask under an argon atmosphere, 105.00 g (434 mmol, 1 eq.) of 4-chloro-N-[(4-methoxyphenyl)methyl]butanamide was dissolved in 330 ml of dry tetrahydrofuran, 321 ml of 20.1% weight of a solution of potassium tert-butoxide (58.49 g, 521 mmol, 1.2 eq.) in tetrahydrofuran, and rinsed the addition funnel with 40 ml of tetrahydrofuran into the flask. This reaction was exothermic and heated to boiling. The addition is controlled such that the reaction mixture remains at a gentle reflux. This mixture was then stirred at reflux temperature for 2 hours. The reaction was monitored by thin layer chromatography. 15 ml (15.74 g, 262 mmol, 0.6 eq) acetic acid was added to the cooled reaction mixture. An exothermic reaction then occurred. Water (60 ml) is then added and the solution is decanted from the solid residue. This solid was washed with 50 ml of methyl tert-butyl ether and the combined organic phases were evaporated. The residue was dissolved in 200 ml of methyl tert-butyl ether and then extracted with saturated NaHCO ₃ solution (100 ml). The pH of the aqueous phase was adjusted to 8. The organic phase was then separated. The aqueous phase was further extracted with 100 ml ethyl acetate and the combined organic layers were dried over 100 ml NaCl and then using Na ₂ SO ₄ . This solvent was then evaporated in vacuo. The product can be purified by vacuum distillation, melting point 151-158°C, 64 Pa. Yield: 77.03 g (375 mmol, 86%). Rf is 0.24-0.56 plot, dichloromethane: methanol 95:5. Identification: alkaline solution of KMnO ₄ . MS-ESI (electrospray ionization mass spectrometry) (M+H ⁺ ) is 206.

¹ H NMR (DMSO-d ₆ , 500 MHz): δ 1.97 (m, 2H), 2.42 (t, J=8.1 Hz, 2H), 3.24 (t, J=7.1 Hz, 2H), 3.79 (s, 3H), 4.38 (s, 2H), 6.85 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H).

¹³ C DEPTq NMR (DMSO-d ₆ , 500 MHz): δ 17.8, 31.2, 46.1, 46.6, 55.4, 114.2, 128.9, 129.6, 159.2, 174.9.

4A.2 Preparation of 1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-one

4-chloro-N-[4-(morpholin-4-yl)phenyl]butanamide

A three-neck, one-liter round-bottom flask was charged with 26.72 g (150 mmol, 1 eq.) of 4-(4-aminophenyl)-morpholine, 25 ml (18.20 g, 180 mmol, 1.2 eq.) of triethylamine and 260 ml of dry dichloromethane. This flask was equipped with a dropper, a CaCl ₂ tube and a thermometer, and then the flask was cooled to 5-10°C with ice water. 5-Chlorobutyric acid chloride (18.5 mL, 23.27 g, 165 mmol, 1.1 eq.) was then added at 5-10° C. for 1 hour 25 minutes. At the end of the addition, a precipitate forms. The reaction was monitored by thin layer chromatography. After consumption of the starting material (1 hour and 15 minutes after the end of addition), saturated NaHCO ₃ solution (170 ml) was slowly added (foaming!). After stirring for 10 minutes, the organic phase was separated with the precipitate and evaporated. The crude product was recrystallized from 300 ml ethanol by adding 5 spoons of carbon. Yield: 20.53 g (72.60 mmol, 48%). MS-ERI (M+H ⁺ ) is equal to 283. Rf is equal to 0.47 dichloromethane: methanol 10:2.

¹ H NMR (DMSO-d ₆ , 500 MHz): δ 2.01 (m, 2H), 2.43 (t, J=7.3 Hz, 2H), 3.02 (m, 4H), 3.69 (t, J=6, 6 Hz, 2H), 3.72 (m, 4H), 6.87 (d, J=9.1 Hz, 2H), 7.44 (d, J=9.1 Hz, 2H), 9.72 (s, 1H).

¹³ C DEPTq NMR (DMSO-d ₆ , 500 MHz): δ 28.0, 33.2, 45.0, 49.0, 66.1, 115.4, 120.2, 131.5, 147.0, 169.4.

1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-one

18.64 g (65.92 mmol, 1 eq.) 4-chloro-N-[4-(morpholin-4-yl)phenyl]butanamide was dissolved in 140 ml of dry tetrahydrofuran in a 250 ml three-neck round bottom flask. This flask was equipped with a thermometer, a dropper and a reflux condenser; the refrigerator was equipped with a diaphragm and a cylinder filled with argon. To this solution was slowly added potassium tert-butoxide (49 mL, 20.1%) (8.88 g KOtBu, 79.10 mmol, 1.2 eq.) in tetrahydrofuran. This solution was then boiled until the starting material was consumed. The reaction was monitored by thin layer chromatography. Water (50 ml) and saturated NaCl (50 ml) were then added and the mixture was shaken and separated. The aqueous phase was extracted with 2-methyl-tetrahydrofuran (3×50 ml). The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated. This substance, together with the crystals precipitated during extraction, was recrystallized from 80 g of ethanol. Yield: 12.76 g (51.82 mmol, 79%) white crystals. MS-ERI (M+H ⁺ ) is 247. Rf is 0.30 isopropyl acetate: methanol 10:1 plus 1% TEA.

^1H NMR (DMSO- _d6 , 500 MHz): δ 2.03 (m, 2H), 2.44 (t, J=8.0 Hz, 2H), 3.06 (m, 4H), 3.73 (m, 4H), 3.77 (t, J=7.0 Hz, 2H), 6.93 (d, J=9.1 Hz, 2H), 7.48 (d, J=9.1 Hz, 2H).

¹³ C DEPTq NMR (DMSO-d ₆ , 500 MHz): δ 17.4, 32.0, 48.2, 48.7, 66.0, 115.1, 120.6, 131.8, 147.6, 173.0.

4A.3 Preparation of 4-(4-iodophenyl)morpholine

25 g (140 mmol, 1 eq.) of 4-(4-aminophenyl)morpholine were dissolved in 300 ml of dry acetonitrile in a 500 ml three-neck round bottom flask. A thermometer, a dropper and a reflux condenser were placed on this flask, and a washing tower with silicone oil was placed on the refrigerator. Diiodomethane (34 mL, 112.7 g, 420 mmol, 3 eq.) was added to this solution. Argon was slowly passed through the unit and 28 ml (26.19 g, 210 mmol, 1.5 eq) 90% tert-butyl nitrite was added with stirring at room temperature. After stirring for 1 hour at room temperature, the mixture was stirred at 60°C for 2 hours and 40 minutes. At this point, thin layer chromatography no longer shows the presence of the starting material. The reflux condenser is then replaced by a 20 cm Vigreux column and a distillation column, and the volatiles are distilled off under vacuum. The residue was dissolved in 200 ml of dichloromethane and extracted with 20 ml of saturated NaHCO ₃ and 20 ml of 10% Na ₂ S ₂ O ₃ . The organic layer was separated, evaporated to 100 ml and filtered through silica gel with dichloromethane (150 g). Wash with dichloromethane until product is detected in the filtrate by TLC. After evaporation, 24.12 g of crude product are obtained, which is recrystallized from 280 g of acetone. Yield: 18.28 g (63 mmol, 45%) pale yellow crystals. Rf is 0.53 ethyl acetate: cyclohexane 2:1.

¹ H NMR (DMSO-d ₆ , 500 MHz): δ 3.08 (t, J=5.0 Hz, 4H), 3.71 (t, J=5.0 Hz, 4H), 6.77 (d, J=9, 0 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H).

¹³ C DEPTq NMR (DMSO-d ₆ , 500 MHz): δ 47.8, 65.9, 80.9, 117.4, 137.2, 150.6.

4A.4 Preparation of 9-hydroxy-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5 -triene-8-ona

Methyl 2-{[(2E)-1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-ylidene]amino}thiophene-3-carboxylate

In an inert three-neck flask under argon, 7.11 g (28.89 mmol, 1 eq.) of 1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-one were dissolved in 40 ml of dry dichloromethane. This flask was equipped with a dropper, a reflux condenser, and a tube with CaCl ₂ was placed on the top of the flask. A solution of 4.9 ml (8.15 g, 28.89 mmol, 1 eq.) trifluoromethanesulfonic acid anhydride in 5 ml dry dichloromethane was added dropwise at room temperature over 5 minutes. The temperature was raised to 35°C and the mixture was then allowed to cool to room temperature. The black gum was released in a few minutes, then a solution of 4.99 g (31.78 mmol, 1.1 eq) of 2-aminothiophene-3-carboxylic acid methyl ester in 40 ml of dry dichloromethane was added over 5 minutes. This reaction mixture was stirred under reflux for 24 hours. 60 ml of saturated Na ₂ CO ₃ solution was slowly added to the cooled reaction mixture and stirred for 10-15 minutes. After phase separation, the organic phase is concentrated. Dry over Na ₂ SO ₄ , filter and evaporate. The residue was used without further purification. Yield: 10.00 g dark brown oil, crude product. LC-MS (M+H ⁺ ) is 386.

12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.037]dodeca-1(9),3(7),5-trien-8-one

The crude methyl 2-{[(2E)-1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-ylidene]amino}thiophene-3-carboxylate obtained in the previous reaction was dissolved in 50 ml of dry tetrahydrofuran and poured into a three-neck round-bottomed flask. This flask was equipped with a dropper and a reflux condenser, the latter having a tube with CaCl ₂ . The unit was inertized using argon, and 32 mL of a 20.1 wt% potassium tert-butoxide solution (5.82 g, KOtBu, 51.88 mmol) was added dropwise from a dropper over 5 minutes. This solution was then boiled for six hours. It was then cooled, neutralized and evaporated. The residue was purified by column chromatography on 80% silica gel with ethyl acetate containing 1% pyridine-acetic acid-water 20:6:1. Yield 976 mg (2.76 mmol, 9.6%). MS-ERI (M+H ⁺ ) is equal to 354.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 3.04 (m, 4H), 3.07 (t, J=8.3 Hz, 2H), 3.74 (m, 4H), 4.01 (t, J =8.3 Hz, 2H), 6.96 (d, J=9.1 Hz, 2H), 7.17 (d, J=6 Hz, 1H), 7.32 (d, J=6.0 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 10.47 (s, 1H).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ ): 21.6, 49.1, 49.3, 66.1, 104.3, 115.7, 117.7, 117.9, 118.1, 118.7, 134.9, 145.5, 153.8, 159.9, 160.3.

9-hydroxy-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -on (188)

600 mg (1.69 mmol, 1 eq.) 12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9) ,3(7),5-trien-8-one and 665 mg (2.55 mmol, 1.5 eq.) of 2-(benzenesulfonyl)-3-phenyloxaziridine were weighed into a glass jar with a screw cap. Dry tetrahydrofuran (30 ml) was added, inertized using argon and sealed with a diaphragm cap. A balloon filled with argon was placed in the diaphragm. This vessel was then cooled with ice water. 3.1 g of a 20.7% solution of LiHMDS (568 mg LiHMDS, 3.39 mmol, 2 eq.) in tetrahydrofuran was added by syringe through the diaphragm. Stirred for 24 hours at room temperature. Then 40 ml of methyl tert-butyl ether and 40 ml of 2 M hydrochloric acid were added, shaken and separated. The organic layer was extracted twice with 20 ml of 2 M hydrochloric acid and the combined aqueous phases were extracted with 40 ml of methyl t-butyl ether. The aqueous phase was neutralized with 10% Na ₂ CO ₃ (foaming!). Meanwhile, an orange precipitate forms. It was filtered, washed with water and dried under vacuum at 40°C. Yield: 230 mg (0.62 mmol, 37%). A further 250 mg of product can be extracted from the aqueous phase using 3 x 40 ml of 2-methyltetrahydrofuran. The combined yield was 488 mg (1.32 mmol, 49%). MS-ERI (M+H ⁺ ) is equal to 370.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 2.22 (m, 2H), 3.12 (m, 4H), 3.75 (m, 4H), 3.99 (m, 1H), 4.13 (m, 1H ), 6.85 (s, 1 N), 6.88 (d, J=5.7 Hz, 1 N), 7.02 (d, J=9.1 Hz, 2H), 7.06 (d, J=5.7 Hz, 1 N), 7.77 (d, J=9.1 Hz, 2H).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ ): 28.7, 48.3, 49.3, 66.0, 74.6, 114.9, 116.4, 119.4, 121.7, 122.3, 131.4, 148.3, 168.7, 171.5, 187.7.

4A.5 Preparation of 9-hydroxy-5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one

Methyl 5-methyl-2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-carboxylate

In an inert three-neck flask under argon, 5.00 g (31.02 mmol, 1 eq.) of 1-phenylpyrrolidin-2-one was dissolved in 35 ml of dry dichloromethane. A dropper, a reflux condenser and a tube with CaCl ₂ were placed on this flask. A solution of trifluoromethanesulfonic acid anhydride (5.2 mL, 8.75 g, 31.02 mmol, 1 eq.) in 5 mL of dry dichloromethane was added dropwise at room temperature over 5 minutes. The temperature is increased to boiling, then cooled to room temperature and stirred for 15 minutes. A solution of 4.99 g (31.78 mmol, 1.1 eq) of 2-amino-5-methylthiophene-3-carboxylic acid methyl ester in 35 ml of dry dichloromethane was added dropwise over 5 minutes. This reaction mixture was stirred at reflux temperature for 24 hours. 100 ml of a saturated NaHCO ₃ solution was slowly added to the cooled reaction mixture and stirred for 10-15 minutes (foaming!). After phase separation, the aqueous phase was extracted with 30 ml of dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used without further purification. Yield: 4.59 g dark brown oil. MS-ERI (M+H ⁺ ) is 315. Rf is 0.52, cyclohexane: ethyl acetate 1:1.

5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,5,7-tetraen-8-ol

4.21 g (13.39 mmol, 1 eq.) methyl 5-methyl-2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-carboxylate was dissolved in 40 ml of dry tetrahydrofuran and poured into a three-neck round-bottomed flask. This flask was equipped with a dropper and a reflux condenser, the latter having a tube with CaCl ₂ . The apparatus was inertized using argon, and 15 mL of a 20.1 wt% potassium tert-butoxide solution (2.73 g KOtBu, 24.34 mmol, 1.8 eq.) was added dropwise over 5 minutes. To calculate the basis, the product of the previous stage is considered pure. After refluxing for 5 hours, the mixture was cooled to room temperature and 60 ml of saturated NH ₄ Cl solution was added. The organic phase was then extracted with saturated NaCl solution (2×30 ml), separated and dried over Na ₂ SO ₄ . After filtration and evaporation, 3.87 g of a brown solid remained which was used without further purification. MS-ERI (M+H ⁺ ) is 283. Rf is 0.40 cyclohexane: ethyl acetate 1:1.

9-Hydroxy-5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one (198)

1.00 g (3.55 mmol, 1 eq.) crude 5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3.7 ]dodeca-1(9),2.5 ,7-tetraen-8-ol and 1.39 g (5.32 mmol, 1.5 eq.) 2-(benzenesulfonyl)-3-phenyloxaziridine were weighed into a 100 ml round bottom flask. Dry tetrahydrofuran (30 ml) was added, inertized using argon and sealed using a diaphragm. A balloon filled with argon was placed in the diaphragm. This vessel was then cooled with ice water. 6.5 mL of a 20.7% solution of LiHMDS (1.19 g LiHMDS, 7.09 mmol, 2 eq.) in tetrahydrofuran was added via syringe. A yellow precipitate formed. This reaction mixture was stirred at room temperature for 24 hours. Then 40 ml of methyl tert-butyl ether and 40 ml of 2 M hydrochloric acid were added. The organic layer was extracted twice with 20 ml of 2 M hydrochloric acid and the combined aqueous phases were concentrated in vacuo to obtain organic solvents. The aqueous phase was neutralized with a saturated Na ₂ CO ₃ solution (foaming!) and then brought to 8 with a saturated NaHCO ₃ solution. Meanwhile, a yellow precipitate forms. It was filtered, washed with water and dried under vacuum at 40°C. Yield: 574 mg (1.92 mmol, 54%). MS-ERI (M+H ⁺ ) is 299. Rf is 0.54 cyclohexane: ethyl acetate 1:1.

^1H NMR (500 MHz, DMSO- _d6 ): δ=2.22 (m, 2H), 2.34 (s, 3H), 4.03 (m, 1H), 4.15 (m, 1H), 6.79 (d, J =1.0 Hz, 1H), 6.88 (s, 1H), 7.20 (t, J=7.4 Hz, 1H), 7.45 (dd, J-,=7.4, J ₂ =8.0 Hz, 2H), 7.93 (d, J=7.4 Hz, 2H).

¹³ C DEPTq (500 MHz, DMSO-d ₆ ): δ=15.1, 28.6, 48.9, 74.4, 119.6, 119.8, 120.3, 124.6, 128.8, 130.1, 139.6, 169.0, 169.2, 187.5.

4A.6 Preparation of 9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one

Methyl 2-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}-5-methiothiophene-3-carboxylate:

In an inert flask under an argon atmosphere, 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one (24.95 g, 121.54 mmol, 1 eq.) was dissolved in 100 ml of dry dichloromethane and cooled to 5-10°C . A solution of trifluoromethanesulfonic acid anhydride (20.45 mL, 34.29 g, 121.54 mmol, 1 eq.) in 20 mL of dry dichloromethane was added dropwise over approximately 20 minutes. Allow to warm to room temperature and stir for 1 hour. This reaction mixture was cooled to 5-15°C, and a solution of 22.89 g (133.7 mmol, 1.1 eq.) of 2-amino-5-methylthiophene-3 methyl ester was added dropwise to this mixture over 15 minutes -carboxylic acid in 160 ml of dry dichloromethane. This reaction mixture was stirred under reflux for 24 hours. This reaction mixture was monitored by thin layer chromatography (hexane:ethyl acetate 7:3). 140 ml of saturated Na ₂ CO ₃ solution was slowly added to the cooled reaction mixture and stirred for 10-15 minutes (foaming!). After phase separation, the organic layer was washed with water (2×100 ml) and evaporated. The residue was dissolved in 100 ml isopropyl acetate and extracted with 10% citric acid (10 x 60 ml). The combined aqueous extract was washed with 60 ml isopropyl acetate. The aqueous phase was basified to pH approximately 9 with saturated Na ₂ CO ₃ (100 ml) and 50% NaOH (50 ml) and extracted with isopropyl acetate (3×100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Yield: 20.1 g yellow oil (56.07 mmol, 46%). MS-ERI (M+H ⁺ ) is equal to 359.

¹ H-NMR (500 MHz DMSO-d ₆ T=300K): δ 1.90 (m, 2H), 2.27 (d, J=1.2 Hz, 3H), 2.49 (t, J=7.3 Hz, 2H ), 3.27 (t, J=7.3 Hz, 2H), 3.65 (s, 3H), 3.74 (s, 3H), 4.51 (s, 2H), 6.77 (q, J ₁ =1.2 Hz, 1H ), 6.91 (m, J ₁ =8.6 Hz, 2H), 7.30 (m, J ₁ =8.6 Hz, 2H).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ ): 15.0, 19.0, 27.9, 46.2, 48.1, 50.7, 55.0, 113.8, 114.7, 124.4, 126.8, 129.0, 129.2, 158.5, 3.0, 163.6

12-[(4-Methoxyphenyl)methyl]-5-methyl-4-thia-2,12-diazatricico[7.3.0.0 ^3,7 ]dodeca-1(9),2,5,7-tetraen-8-ol :

30.28 g (84.47 mmol, 1 eq.) methyl 2-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}-5-methylthiophene-3-carboxylate was dissolved in 750 ml of toluene, and 500 ml of toluene was distilled off using a water separator. The residual solvent was evaporated in vacuum. In an inert flask under argon, the residue after evaporation was dissolved in 340 ml of dry tetrahydrofuran, followed by the addition of 94.31 g (18.96 g KOtBu, 168.9 mmol, 2 eq.) 20.1% (wt/wt) solution of tert- potassium butoxide in tetrahydrofuran. This reaction mixture was stirred at reflux, and the reaction was monitored by thin layer chromatography (hexane:ethyl acetate 7:3). After consumption of the starting material, 38 ml (39.9 g 664.4 mmol, 7.8 eq.) acetic acid was added to the cooled reaction mixture, and the reaction mixture was concentrated in vacuo. The evaporation residue was suspended in 200 ml of toluene, the solvent was evaporated in vacuo and the residue was suspended in 300 ml of water. The pH of this mixture was then adjusted to approximately 8 using saturated NaHCO ₃ solution (600 ml) and stirred for at least 30 minutes. Filter on a glass filter, rinse with 3x150 ml of water, 3x150 ml of methyl tert-butyl ether. The filtered substance was dried in vacuum at room temperature. Yield: 18.83 g (57.69 mmol, 68.29%). MS-ERI (M+H ⁺ ) is equal to 327.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 2.42 (s, 3H), 2.87 (t, J=8.3 Hz, 2H), 3.32 (t, J=8.3 Hz, 2H ), 3.72 (s, 3H), 4.41 (s, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.94 (s, 1H), 7.20 (d, J=8.4 Hz, 2H) , 10.17(s, br, 1H).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ ): 15.8, 22.5, 48.2, 48.9, 54.9, 102.2, 113.7, 116.4, 117.4, 129.2, 129.4, 129.8, 153.3, 158.3, 159.9, 163.0.

5-Methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,5,7-tetraen-8-ol:

18.82 g (57.66 mmol, 1 eq.) 12-[(4-methoxyphenyl)methyl]-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]-dodeca-1 (9),2,5,7-tetraen-8-ol and 62 ml (61.69 g, 570.46 mmol, 9.89 eq) anisole were weighed into an inert flask under argon. Trifluoroacetic acid (35.5 mL, 52.56 g, 461.26 mmol, 8 eq.) was added dropwise at room temperature and the solution was stirred at 70°C for 19 hours. This reaction was monitored by thin layer chromatography (toluene: dioxane: acetic acid 10:3:1). After consumption of the starting material, this reaction mixture is cooled to 0-5°C. By adding 340 ml of concentrated hydrochloric acid, the hydrochloride salt of the product precipitates. This suspension was stirred for 10-15 minutes, then filtered through a glass filter (from this first filtrate 4.65 g of product can be obtained by alkalinization to a pH of about 9, filtering, washing with aqueous and cold acetonitrile), washed with 50 ml of cold acetonitrile and 50 ml of cold diethyl ether and dried under vacuum at 30°C. 7.76 g of the HCl salt thus obtained was suspended in 90 ml of saturated NaHCO ₃ solution and stirred for 30 minutes. It was filtered, washed on a glass filter with 2×40 ml of water and 20 ml of methyl tert-butyl ether and then dried under vacuum. Yield: 11.33 g of white solid (54.93 mmol, 95.29%).

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 2.38 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.2 Hz, 2H ), 6.0-3.5 (s, br, 1 N), 6.05 (s, br, 1 N), 6.93 (s, 1 N).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ ): 15.8, 24.5, 44.0 101.8, 116.8, 117.8, 128.6, 154.7, 159.9, 165.3.

9-Hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one (231):

3.0 g (14.55 mmol, 1 eq.) of 5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2, was dissolved in an inert flask under argon. 5,7-tetraen-8-ol and 5.70 g (21.81 mmol, 1.5 eq.) of 2-(benzenesulfonyl)-3-phenyloxaziridine in 30 ml dry tetrahydrofuran and cooled to 0-5°C with stirring. A solution of 26.5 mL (23.51 g, 4.87 g, 29.09 mmol, 2 eq.) LiHMDS in 20.7% (w/w) tetrahydrofuran was added dropwise to this reaction mixture and allowed to warm to room temperature. temperature. This reaction was monitored by thin layer chromatography (toluene:dioxane:acetic acid 10:3:1). After completion of this reaction, 50 ml of saturated ammonium chloride solution was added to the reaction mixture. Add 150 ml of 2-methyltetrahydrofuran and 50 ml of water to remove this emulsion. After phase separation, the aqueous layer was extracted with methyl tetrahydrofuran (4×50 ml). In the combined organic phase, the precipitated yellow powder was filtered through a glass filter and dried under vacuum (0.339 g). The organic filtrate was allowed to stand at room temperature overnight and separated from the aqueous phase. Dried over Na ₂ SO ₄ , filtered and evaporated under vacuum to approximately 100 ml. The precipitated product was filtered through a paper filter and washed with 2×0 ml of 2-methyltetrahydrofuran, dried at 30°C under vacuum (0.869 g). This filtrate was again concentrated to about 30 ml, and the precipitated product was again filtered through filter paper, dried under vacuum (1.265 g). Yield: 2.473 g (11.13 mmol, 76.56%). MS-ERI (M+H ⁺ ) is 223.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 2.02 (ddd, J ₁ =13.3 Hz, J ₂ =J ₃ =8.4 Hz, 1H,), 2.12 (dd, J ₁ =13.3 Hz, J ₂ =5.2 Hz, 1H), 2.27 (d, J = 0.9 Hz, 3H), 3.42 (dd, J ₁ =10.7 Hz, J ₂ =8.4 Hz , 1H), 3.57 (m, 1H), 6.57 (s, br, 1H), 6.64 (q, J=0.9 Hz, 1H), 8.96 (s, br, 1H).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ ): 15.0, 31.6, 42.3, 72.9, 118.4, 119.3, 127.2, 174.1, 187.5.

4A.7 Preparation of 9-hydroxy-5-methyl-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3( 7)5-trien-8-one (220):

400 mg (1.80 mmol, 1 eq.) 9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7)5-triene-8 -one, 412 mg (2.15 mmol, 1.2 eq.) copper(I) iodide, 304 mg (2.15 mmol, 1.2 eq.) N,N'-dimethylcyclohexanediamine, 676 mg (3. 60 mmol, 2 eq.) 4-(4-iodophenyl)morpholine, 1.76 g (5.40 mmol, 3 eq.) cesium carbonate, 20 ml of dry N,N-dimethylformamide and 8 g of dry molecular sieve were charged into 100 ml round bottom flask. The cesium carbonate was previously dried at 120°C using P ₂ O ₅ under vacuum for 2 hours. The flask was made inert using nitrogen and sealed with a diaphragm. A cylinder filled with nitrogen was placed in the diaphragm. This reaction mixture was stirred at 60°C until the starting material was consumed. The reaction was monitored by thin layer chromatography, eluting with ethyl acetate. After three days, this reaction no longer occurs, the mixture is then cooled, filtered through celite, washed with methanol until the filtrate turns yellow. The methanol was evaporated in vacuo and the residue was poured into saturated NaCl (100 ml). This was extracted with 2-methyl-tetrahydrofuran (3×100 ml). When an emulsion was formed, another 100 ml of NaCl solution and 100 ml of 2-methyltetrahydrofuran were added. The combined organic phases were extracted with 50 ml of saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and evaporated. 1.6 g of crude product was evaporated to 5 g of celite and purified by column chromatography (silica gel, ethyl acetate). Suitable fractions were evaporated, triturated with diethyl ether, and the orange precipitate was filtered off. Yield: 308 mg. It is then purified, if necessary, by preparative HPLC (high performance liquid chromatography). MS-ERI (M+H ⁺ ) is equal to 384.

^1H NMR (DMSO- _d6 , 500 MHz): δ 2.20 (m, 2H), 2.32 (s, 3H), 3.11 (m, 4H), 3.74 (m, 4H), 3.97 (m, 1H), 4.10 (m, 1H), 6.75 (s, 1H), 6.80 (s, 1H), 7.02 (d, J=9.0 Hz, 2H), 7.76 (d, J=9.0 Hz, 2H).

¹³ C DEPTq NMR (DMSO-d ₆ , 500 MHz): δ 15.1, 28.8, 48.3, 49.1, 74.4, 114.9, 119.3, 119.5, 121.6, 129.2, 131.4, 148.2, 168.5, , 187.3.

4A.8 Preparation of 9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one

Methyl 2-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}thiophene-3-carboxylate

A magnetic stirring bar was inserted into a dry 4-neck 500 ml round-bottom flask and equipped with a thermometer, a dropper, a reflux condenser and a gas inlet. A gas scrubber filled with silicone oil and a tube with CaCl ₂ were placed on top of the reflux condenser. 25.02 g (122 mmol, 1 eq.) of 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one are added to this flask and dissolved in 150 ml of dry dichloromethane. Argon gas is slowly introduced into this device. This solution was cooled to 5-10°C, and a solution of trifluoromethanesulfonic anhydride (20.5 ml, 34.39 g, 122 mmol, 1 eq.) in 20 ml of dry dichloromethane was added dropwise over 20 minutes. This reaction was exothermic and was maintained at a temperature of 5-15°C. This solution was then stirred at room temperature for two hours and then cooled again with ice water. A solution of methyl 2-aminothiophene-3-carboxylate (21.08 g, 134 mmol, 1.1 eq) in 100 ml of dry dichloromethane was added over a period of 15 minutes at 5-15°C. This reaction is exothermic and the mixture is refluxed for 24 hours after addition. In the meantime, the introduction of argon is no longer necessary.

Then 140 ml of saturated Na ₂ CO ₃ solution was slowly added to the cooled solution to room temperature, being careful due to foaming. The organic layer was separated, washed twice with water (100 ml) and concentrated in vacuo. The residue was dissolved in isopropyl acetate and extracted seven times with 70 ml of 10% citric acid solution. The organic phase was discarded for further processing. The combined aqueous phases were extracted with 60 ml isopropyl acetate and adjusted to pH 9 with saturated Na ₂ CO ₃ solution, observing foaming. This mixture was then extracted 3 times with 100 ml isopropyl acetate. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a dichloromethane/isopropyl acetate gradient. Yield: 10.70 g.

After extraction with citric acid, the separated organic phase was evaporated after drying and purified by the same chromatographic method. 6.84 g of pure product can be isolated and the combined yield is 17.54 g (51 mmol, 41.7%) of a yellow oil. Rf is 0.49 cyclohexane-ethyl acetate 1:1. MS-ERI (M+H ⁺ ) is 345.

¹ H-NMR (500 MHz DMSO-d ₆ T=300K): δ 1.90 (m, 2H), 2.48 (m, 2H), 3.29 (m, 2H), 3.67 (s, 3H), 3.74 (s, 3H ), 4.53 (s, 2H), 6.81 (d, J=5.9 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.09 (d, J=5.9 Hz, 1H ), 7.32 (d, J=8.6 Hz, 2H).

¹³ C DEPTq NMR (126 MHz DMSO-d ₆ ): δ 19.0, 27.9, 46.3, 48.1, 50.8, 55.0, 113.8, 114.5, 115.1, 127.1, 128.9, 129.2, 158.5, 163.2, 1 63.7, 165.4.

12-[(4-methoxyphenyl)methyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,5,7-tetraen-8-ol

Methyl 2-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}thiophene-3-carboxylate and 150 ml of toluene were added to a 250 ml round bottom flask. A water separator and a reflux condenser were placed on this flask and refluxing was carried out until the water was removed. After refluxing for 5 hours, measure the water content and, if it is less than 0.04%, cool and evaporate the toluene in vacuo. The residue is then dissolved in 75 ml of dry tetrahydrofuran and transferred to a 3-neck flask equipped with a reflux condenser, a dropper and a gas inlet. Potassium tert-butoxide (30 mL) in 20.1% tetrahydrofuran (5.35 g KOtBu, 47.7 mmol, 1.7 eq.) was then added slowly at room temperature. A yellow precipitate forms during addition. This solution was then refluxed under argon until the starting material was consumed, and the reaction was monitored by thin layer chromatography. After completion of the reaction, the contents of the flask were cooled to room temperature, and 10 ml of acetic acid was added dropwise. This reaction mixture was then poured into a one-neck round bottom flask and the solvent was evaporated in vacuo. The residue was suspended in 50 ml of toluene and the solvent was again evaporated in vacuo. The residue was suspended in 50 ml water and the pH was adjusted to 8 using 160 ml saturated NaHCO ₃ (foaming!). This suspension was stirred for 30 minutes and then filtered. The residue was washed three times with 100 ml of water and then with 50 ml of methyl tert-butyl ether and dried in vacuo. Yield: 7.19 g (23.0 mmol, 82%) light brown powder. Rf is 0.56 toluene: dioxane: acetic acid 10:3:1. MS-ERI (M+H ⁺ ) is equal to 313.

¹ H-NMR (500 MHz DMSO-d ₆ T=300K): δ 2.90 (t, J=8.4 Hz, 2H), 3.35 (t, J=8.4 Hz, 2H), 3.72 (s, 3H ), 4.45 (s,2H), 6.88 (d, J=8.6 Hz, 2H), 7.05 (d, J=5.9 Hz, 1H), 7.22 (d, J=8.6 Hz, 2H) , 7.26 (d, J=5.9 Hz, 1H), 10.36 (bs, 1H).

¹³ C DEPTq NMR (126 MHz DMSO-d ₆ ): δ 22.4, 48.0, 48.8, 55.0, 102.3, 113.8, 116.4, 117.3, 118.9, 129.2, 129.7, 153.9, 158.3, 163.7.

4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,5,7-tetraen-8-ol

4.95 g (15.9 mmol, 1 eq.) 12-[(4-methoxyphenyl)methyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2 ,5,7-tetraen-8-ol was weighed in a round bottom flask. This solid was suspended in 15.5 ml (15.43 g 143 mmol, 9 eq.) anisole. A dropper and a reflux condenser were placed on this flask. A tube containing CaCl ₂ was placed on top of the refrigerator. The vapor volume was purged with argon and 10 mL (14.90 g, 130 mmol, 8.2 eq) trifluoroacetic acid was added over 5 min. Meanwhile, the solids dissolve. This solution was stirred at 70°C for 72 hours, and the reaction was monitored by thin layer chromatography. The flask was cooled with ice water after consuming the starting material, and 10 ml of concentrated hydrochloric acid was added at 0-5°C. This mixture was stirred cold for 10 minutes to obtain the hydrochloride salt of the product. It was then filtered, washed with cold acetonitrile and diethyl ether. This hydrochloride salt was suspended in 20 ml of saturated NaHCO ₃ solution, stirred for 30 minutes, and then the precipitate was filtered off. It was washed with water (20 ml) and methyl tert-butyl ether (10 ml). Yield: 1.61 g (8.4 mmol, 53%) light brown powder. Rf is 0.19 toluene: dioxane: acetic acid 10:3:1. MS-ERI (M+H ⁺ ) is equal to 193.

¹ H-NMR (500 MHz DMSO-d ₆ T=300K): δ 2.94 (t, J=8.3 Hz, 2H), 3.49 (t, J=8.3 Hz, 2H), 6.32 (bs, 1H ), 7.00 (d, J=5.9 Hz, 1H), 7.23 (d, J=5.9 Hz, 1H), 10.21 (bs, 1H).

¹³ C DEPTq NMR (126 MHz DMSO-d ₆ ): δ 24.2, 43.9, 101.8, 116.1, 116.9, 118.8, 153.8, 160.6, 166.0.

9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one

A balloon filled with argon was placed in the diaphragm. The vessel was then cooled with ice water. Using a syringe, 2.6 mL of a 20.7% solution of LiHMDS (437 mg LiHMDS, 2.83 mmol, 2 eq.) in tetrahydrofuran was added through the diaphragm. This reaction mixture then turns brown and the solids dissolve. This reaction was monitored by thin layer chromatography and stirred at room temperature until the starting material was absorbed. Saturated NH ₄ Cl (15 ml) was then added and the mixture was extracted with 2-methyl-tetrahydrofuran (3×15 ml). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and evaporated. The crude product was purified by column chromatography. Yield: 74 mg (0.36 mmol, 25%) red solid. It was then purified by preparative HPLC. Rf is 0.32 toluene: dioxane: acetic acid 10:3:1. Rf is 0.38 ethyl acetate. MS-ERI (M+H ⁺ ) is equal to 209.

4A.9 Preparation of 8a-hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one

Methyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-2-carboxylate

In an inert three-neck flask under argon, 5.00 g (31.02 mmol, 1 eq.) of 1-phenylpyrrolidin-2-one was dissolved in 35 ml of dry dichloromethane. A dropper, a reflux condenser and a tube with CaCl ₂ were placed on this flask. A solution of trifluoromethanesulfonic anhydride (5.2 mL, 8.75 g, 31.02 mmol, 1 eq.) in 10 mL of dry dichloromethane was added dropwise over 2 min. The temperature increases until the solution slightly boils. Cooling to room temperature and stirring are provided for three hours. A suspension of 5.19 g (34.12 mmol, 1.1 eq) of 3-aminopyridine-2-carboxylic acid methyl ester in 35 ml of dry dichloromethane is then carefully added through a large funnel. This unit was re-inertized with argon and the reaction mixture was stirred at reflux for 24 hours. 60 ml of saturated Na ₂ CO ₃ solution was slowly added to the cooled reaction mixture with stirring. After phase separation, the aqueous phase was extracted with dichloromethane (2×40 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used without further purification. Yield: 10.12 g black oil, solidified on standing.

6-phenyl-6H,7H,8H-pyrrolo[2,3-b]1,5-naphthyridin-9-ol

The crude methyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-2-carboxylate obtained in the previous step was dissolved in 80 ml of dry tetrahydrofuran and poured into a three-neck round bottom flask. This flask was equipped with a dropper and a reflux condenser, the latter having a tube with CaCl ₂ . The setup was inertized with argon, and 42.5 mL of 20.1% (w/w) potassium tert-butoxide solution (7.68 g KOtBu, 68.53 mmol, 2 eq.) was added dropwise over 5 minutes. For calculating the basis, the previous stage is considered as 100%. This reaction mixture precipitated, and this precipitate dissolved during heating. After 24 hours at reflux, this mixture was cooled to room temperature and 5 ml of acetic acid was added. This reaction mixture was diluted with water (300 ml), and the precipitate was filtered off, washed with water and dried in vacuum at 50°C. The crude product was used without further purification. Yield: 4.11 g brown powder. MS-ERI (M+H ₊ ) is equal to 264.

8a-hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one (190):

1.06 g (4.00 mmol, 1 eq.) crude 6-phenyl-6H,7H,8H-pyrrolo[2,3-b]1,5-naphthyridin-9-ol and 1.57 g (6. 00 mmol, 1.5 eq.) 2-(benzenesulfonyl)-3-phenyloxaziridine is weighed into a 100 ml round bottom flask. Dry tetrahydrofuran (50 ml) was added, inert with argon and sealed with a diaphragm. A balloon filled with argon was placed in the diaphragm. This vessel was then cooled with ice water. 7.5 mL of a 20.7% solution of LiHMDS (1.34 g LiHMDS, 8.00 mmol, 2 eq.) in tetrahydrofuran was added via syringe. Stir for 5 days at room temperature. Then 40 ml of methyl tert-butyl ether and 40 ml of 2 M hydrochloric acid were added. A brown precipitate forms, which is removed by filtration. The filtrate is separated and the organic phase is extracted twice with 20 ml of 2 M hydrochloric acid and the combined aqueous phases are concentrated in vacuo to obtain organic solvents. The aqueous phase was neutralized with 10% Na ₂ CO ₃ (foaming!). Meanwhile, a dark orange precipitate forms. It was filtered, washed with water and dried under vacuum at 40°C. Yield: 185 mg of crude product, which was purified by preparative HPLC. MS-ERI (M+H ⁺ ) is equal to 280.

4A.10 Preparation of 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one

Methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-3-carboxylate

In an inert three-neck flask under argon, 5.00 g (31.02 mmol, 1 eq.) of 1-phenylpyrrolidin-2-one was dissolved in 35 ml of dry dichloromethane. A dropper, a reflux condenser and a tube with CaCl ₂ were placed on this flask. A solution of trifluoromethanesulfonic anhydride (5.2 mL, 8.75 g, 31.02 mmol, 1 eq.) in 10 mL of dry dichloromethane was added dropwise over 2 min. The temperature is increased until this solution begins to boil slightly. Then allow to cool to room temperature and stir for three hours. A solution of 2-aminopyridine-3-carboxylic acid methyl ester (5.19 g, 34.12 mmol, 1.1 eq) in dry dichloromethane (35 ml) was then added and the reaction mixture was stirred at reflux for 48 h. 60 ml of a saturated Na ₂ CO ₃ solution was slowly added to the cooled reaction mixture with stirring. After phase separation, the organic phase was extracted with 40 ml of dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was used without further purification. Yield: 3.31 g brown oil, partially solidifies on standing. MS-ERI (M+H ⁺ ) is 296.

1-phenyl-1H,2H,3H-pyrrolo[2,3-b]-1,8-naphthyridin-4-ol

The crude methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-3-carbxylate obtained in the previous step was dissolved in dry tetrahydrofuran (40 ml) and poured into a three-neck round bottom flask. This flask was equipped with a dropper and a reflux condenser, the latter having a tube with CaCl ₂ . This unit was inertized with argon, and 13.9 mL of 20.1% (w/w) potassium tert-butoxide solution (2.51 g KOtBu, 22.38 mmol, 2 eq.) was added dropwise over 5 min. ). To calculate the basis, the previous stage was considered as 100%. A brown precipitate appears. After refluxing for 3 hours, this mixture was cooled to room temperature and 5 ml of 2 M hydrochloric acid was added. The pH was then adjusted to 8 using saturated NaHCO ₃ . A yellow precipitate forms, which is filtered off, washed with water and then dried under vacuum. The crude product was used without further purification. Yield: 1.35 g yellow powder. MS-ERI (M+H ⁺ ) is equal to 264.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 3.25 (t, J=8.0 Hz, 2H), 4.27 (t, J=8.0 Hz, 2H), 7.21 (t, J =7.5 Hz, 1H), 7.45 (dd, J-,=7.5, J ₂ =8.5 Hz, 2H), 7.56 (dd, J ₁ =5.7 Hz, J ₂ =7.9 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 8.68 (dd, J ₁ =1.5 Hz, J ₂ =5.6 Hz, 1H), 8.81 (dd, J ₁ =1 .5 Hz, J ₂ =7.9 Hz, 1H), 10.91 (s, 1H).

¹³ C DEPTq NMR δ (126 MHz DMSO-d ₆ T=300K): 21.8, 50.0, 110.4, 117.0, 117.3, 120.1, 124.3, 128.8, 138.6, 139.7, 141.8, 153.6, 163.7.

3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one (189)

0.79 g (3.00 mmol, 1 eq.) crude 1-phenyl-1H,2H,3H-pyrrolo[2,3-b]1,8-naphthyridin-4-ol and 1.18 g (4. 50 mmol, 1.5 eq.) 2-(benzenesulfonyl)-3-phenyloxaziridine was weighed into a 50 ml round bottom flask. Dry tetrahydrofuran (30 ml) was added, inert with argon and sealed with a diaphragm. A balloon filled with argon was placed in the diaphragm. This vessel was then cooled with ice water. 5.5 mL of a 20.7% solution of LiHMDS (1.00 g LiHMDS, 6.00 mmol, 2 eq.) in tetrahydrofuran was added via syringe. Stir for 8 days at room temperature. Then 40 ml of methyl tert-butyl ether and 40 ml of 2 M hydrochloric acid were added. The filtrate was separated and the organic phase was extracted twice with 20 ml of 2 M hydrochloric acid. The combined aqueous phases were brought to pH 8 with a saturated NaHCO ₃ solution (foaming!). Meanwhile, a yellow precipitate forms. It was filtered, washed with water, and dried under vacuum at 40°C. Yield: 414 mg (1.48 mmol, 49%). MS-ERI (M+H ⁺ ) is equal to 280.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 2.27 (dd, J ₁ =5.7 Hz, J ₂ =13.2 Hz, 1H), 2.37 (ddd,, J ₁ =9, 0 Hz, J ₂ =9.3 Hz, J ₁ =13.2 Hz, 1H), 4.02 (dd,=9.1 Hz, J ₂ =9.3 Hz, 1H), 4.17 (ddd, J,= 6.0 Hz, J ₂ =9.0 Hz, J ₃ =9.4 Hz, 1H), 7.04 (s, 1H), 7.10 (dd, J ₁ =5.0 Hz, J ₂ =7.4 Hz , 1H), 7.22 (t, J=7.3 Hz, 1H), 7.46 (t, J=7.7 Hz, 2H), 8.06 (dd, J ₁ =1.6 Hz, J ₂ =7.1 Hz, 1H), 8.08 (d, J=8.4, 2H), 8.54 (dd, J,=1.6 Hz, J ₂ =5.0 Hz, 1H).

¹³ C-NMR DEPTq δ (126 MHz DMSO-d ₆ Т=300K): 27.9, 48.1, 73.1, 116.4, 118.5, 120.6, 124.5, 128.6, 135.0, 139.9, 154.7, 162.7, 168.0, 193.7.

4A.11 Preparation of 3α-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one

Ethyl 3-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}pyridine-4-carboxylate

A dry 4-neck 500 mL round bottom flask was equipped with a reflux condenser, thermometer, dropper and gas inlet. 28.53 g (139 mmol, 1.05 eq.) of 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one and 50 ml of dry chloroform were weighed into this flask. Argon was introduced slowly and phosphorus oxychloride (13 mL, 21.31 g, 139 mmol, 1.05 eq.) was added from the dropper over 5 min. This reaction is slightly exothermic. Then cool to room temperature and stir for three hours. A solution of ethyl 3-aminoisonicotinate (22.00 g, 132 mmol, 1 eq.) in 50 mL of dry chloroform was then added over 5 minutes. If this solution is boiling, slow down the addition to achieve a gentle boil. After addition, this reaction mixture is further refluxed for 48 hours under an argon atmosphere. This reaction was monitored by thin layer chromatography. After 48 hours, the reaction mixture was cooled to room temperature and 220 ml of saturated Na ₂ CO ₃ solution was slowly added (foaming!) with stirring. Then another 150 ml of water was added and the phases were separated. The aqueous phase was washed twice with 100 ml chloroform and the combined organic phases were extracted with water (100 ml) and dried over Na ₂ SO ₄ . After filtering, they were concentrated and dissolved in 50 ml of ethyl acetate. On a glass filter, 200 g of silica gel was moistened with ethyl acetate, and the product solution was filtered through this. Wash with ethyl acetate until product is detected in the filtrate by thin layer chromatography. The combined solutions were then concentrated and the residue was dissolved in isopropyl acetate and dried over Na ₂ SO ₄ . After filtering, it was concentrated in vacuo. Yield: 40.99 g (115 mmol, 88%). MS-ERI (M+H ⁺ ) is 354. Rf is 0.55 when run on the same plate three times in ethyl acetate.

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 1.20 (t, J=7.0 Hz, 3H), 1.87 (m, 2H), 2.30 (t, J=6.8 Hz, 2H ), 3.26 (t, J=6.8 Hz, 2H), 3.74(s, 3H), 4.21 (q, J=7.0 Hz, 2H), 4.50 (s, 2H), 6.90 (m, J, =8.5 Hz, 2H), 7.28 (m, J ₁ =8.5 Hz, 2H), 7.45 (d, J=5.0 Hz, 1H), 8.16 (s, br, 1H), 8.21 (d , J=5.0 Hz, 1H).

¹³ C-NMR δ (126 MHz DMSO-d ₆ T=300K): 13.9, 19.1, 27.7, 46.2, 48.0, 55.0, 60.8, 113.7, 122.0, 129.2, 129.3, 130.1, 145.9, 147.0, 157.5, 158.4 , 162.1, 166.1.

1-[(4-methoxyphenyl)methyl]-1H,2H,3H-pyrrolo[2,3-b]1,7-naphthyridin-4-ol

39.41 g (112 mmol, 1 eq.) ethyl 3-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}pyridine-4-carboxylate was added to 500 ml round bottom flask and dissolved in 300 ml of toluene. A water separator was placed on this flask, a reflux condenser was installed on the water separator, and boiling was carried out until water separation was observed. After two hours, the water content of this solution reaches 0.01% (w/w). This mixture was then cooled to room temperature and the toluene was evaporated in vacuo. The residue was dissolved in 300 ml of dry tetrahydrofuran and poured into a three-neck round-bottom flask. A reflux condenser, a drop collector and a thermometer were placed on the flask. Under argon, 105 mL of a 20.1% (w/w) solution of potassium tert-butoxide in tetrahydrofuran (18.76 g KOtBu, 167 mmol, 1.5 eq.) was added dropwise over 10 minutes with stirring. This solution was heated to 35°C during this time and a light brown precipitate formed. This reaction was monitored by thin layer chromatography and refluxing until the starting material was consumed (consumption of the starting material in the eluent was described in the previous intermediate). After cooling to room temperature, 20 ml of acetic acid was added. This reaction mixture was poured into a single neck round bottom flask and the solvents were evaporated in vacuo. The residue was suspended in 500 ml of water and adjusted to pH 9 with saturated Na ₂ CO ₃ solution (foaming!). The solid was filtered, washed with water (2×250 ml) and dried in vacuum. Yield: 33.01 g (107 mmol, 96%) light brown powder. MS-ERI (M+H ⁺ ) is equal to 308. Rf is equal to 0.78 dichloromethane: methanol 10:1, neutral E2 Al ₂ O ₃ .

¹ H-NMR δ (500 MHz DMSO-d ₆ T=300K): 3.01 (t, br, J=8.0 Hz, 2H), 3.45 (t, J=8.0 Hz, 2H), 3.72 (s , 3H), 4.59 (s, 2H), 6.88 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 7.70 (d, J=5.2 Hz, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.75 (s, 1H), 11.3-10.1 (br, 1H).

¹³ C-NMBC NMR δ (126 MHz DMSO-d ₆ T=300K): 22.7 47.1, 47.6, 55.0, 108.0, 113.9, 114.7, 123.7, 129.2, 139.3, 143.4, 147.0, 153.4, 158.4, 162.7.

1H,2H,3H-pyrrolo[2,3-b]1,7-naphthyridin-4-ol OH

26.00 g (85 mmol, 1 eq.) 1-[(4-methoxyphenyl)methyl]-1H,2H,3H-pyrrolo[2,3-b]1,7-naphthyridin-4-ol were weighed into 3- neck 250 ml round bottom flask. A dropper and a reflux condenser were installed on this flask, and a tube with CaCl ₂ was installed on it. The steam space was purged with argon. The starting material was suspended in anisole (83 mL, 82.33 g, 761 mmol, 9 eq.) and 52 mL (77.16 g, 677 mmol, 8 eq.) trifluoroacetic acid was added slowly with stirring. Meanwhile, the solids dissolve. This reaction mixture was stirred at 70°C until the starting material was consumed, followed by thin layer chromatography. The reaction takes about 10 days. The solution was cooled to room temperature, ethyl acetate (100 ml) and hexane (40 ml) were added and the mixture was extracted with 80 ml of 2 M hydrochloric acid. The resulting precipitate was filtered off, dissolved in water and added to the hydrochloric acid extract. The organic phase was extracted four more times with 40 ml of 2 M hydrochloric acid. The combined aqueous phases were extracted with 1:1 hexane-ethyl acetate (80 ml) and separated. The pH was adjusted to 8 using 10% NaOH, the precipitate was filtered off, washed with cold water (100 ml) and dried under vacuum. Yield: 13.97 g (75 mmol, 88%) yellow powder. Rf is 0.17 dichloromethane:methanol 10:1, neutral E-type Al ₂ O ₃ .

¹ H NMR δ (500 MHz DMSO-d ₆ T=300K): 2.96 (t, br J=8.4 Hz, 2H), 3.57 (t, J=8.4 Hz, 2H), 7.06 (s, br , 1H), 7.74 (d, J=4.9 Hz, 1H), 8.22 (d, J=4.9 Hz, 1H), 8.67 (s, br, 1H), 12.5-10.0 (br, 1H).

¹³ C (DEPTq, NMBC) NMR δ (126 MHz DMSO-d ₆ T=300K): 24.3, 43.6, 105.1, 115.9, 126.1, 139.1, 140.4, 143.8, 160.2, 161.4.

3α-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (255)

2.00 g (10.7 mmol, 1 eq.) 1H,2H,3H-pyrrolo[2,3-b]1,7-naphthyridin-4-ol and 5.18 g (19.8 mmol, 1, 9 equiv of 2-(benzenesulfonyl)-3-phenyloxaziridine was weighed in a three-necked 100 ml round bottom flask, and 20 ml of dry tetrahydrofuran was added. The flask was then inert with argon, and a balloon filled with argon, a thermometer and a stopper were placed on the flask. in ice water to 0-5°C and 19.3 ml of a 20.7% by weight solution of LiHMDS (4.87 g LiHMDS, 29.1 mmol, 2 eq.) in tetrahydrofuran was added by syringe. stirred at room temperature until no starting material was consumed. The reaction was monitored by thin layer chromatography (chloroform-methanol 10:1, run twice), water (2 ml) was added and the mixture was stirred for 10 min, then celite was added. (6 g) and the residue was purified by column chromatography (dichloromethane, 0-25% MeOH). The appropriate fractions were evaporated and the residue was taken up in 10 ml of methanol. The precipitate was filtered off (660 mg). The filtrate was evaporated, and this operation was repeated with a residue of 5 ml of methanol. The solids were combined. Yield: 807 mg (3.97 mmol, 37%). MS-ERI (M+H ⁺ ) is equal to 204.

^1H NMR (DMSO- _d6 , 500 MHz): δ 2.11 (dd, J=5.4, 13.5 Hz, 1H), 2.21 (m, 1H), 3.51 (m, 1H), 3.58 (m, 1H), 6.75 (s, 1H), 7.45 (d, J=4.7 Hz, 1H), 8.14 (d, J=4.7 Hz, 1H), 8.37 (s, 1H), 9.22 (bs, 1H ).

¹³ C DEPTq NMR (DMSO-d ₆ , 500 MHz): δ 30.8, 44.5, 118.5, 124.7, 141.4, 145.1, 194.0.

Example 4: Demonstration of the effectiveness of the compounds of the invention

The following methodology was used to demonstrate effectiveness:

steady-state measurement of actomyosin ATPase on the following myosin 2 isoforms:

a) recombinant human non-muscle myosin 2 on all three isoforms (NM2A, NM2B, NM2C),

b) isolated porcine cardiac ventricular myocardium (cardiac),

c) isolated rabbit skeletal muscle myosin (skeletal),

d) isolated chamois smooth muscle myosin

e) recombinant Dictyostelium myosin (Dictyostelium).

The present inventors determined (i) the maximum ATPase activity inhibition value for all myosin isoforms and for all compounds where the degree of inhibition was at least 20% at 50 micromolar concentration; (ii) the concentration required for half-maximal inhibition. The results are summarized in the tables below.

The following table lists the name, structure, and reference number of the compounds in the following examples by potency.

Example 6: Presentation of the Efficacy of the Compounds of the Invention Demonstration of efficacy was carried out according to the following methodology: steady state measurement of actomyosin ATPase on the myosin 2 isoforms of Example 4.

We have shown that for each myosin-2 isoform a narrow IC50 range can be defined within which the maximum inhibition values can be finely tuned, which can be very important for drug treatments. The results are summarized in the table below.

Example 7: Demonstration of the effectiveness of the compounds of the invention

Demonstration of effectiveness was carried out according to the following methodology: isometric measurement of quadriceps femoris muscle strength in live anesthetized rats using electrical stimulation.

The maximum isometric force induced by stimulation was determined after intraperitoneal injection of certain compounds of the invention. During the measurement, the following parameters of live anesthetized rats were continuously monitored:

a) heart rate

b) blood flow in the arteries of the neck

c) breathing rate

d) blood oxygen saturation ratio

Results from live anesthetized rats are summarized in the table below.

Example 8: Demonstration of the effectiveness of the compounds of the invention

To demonstrate efficacy, the following methodology was used: 6 mg of compound 188 was injected intraperitoneally into a live rat, and tissue concentrations were determined in the following tissues at specific time points:

a) blood

b) brain

c) lung

d) myocardium

e) liver

f) kidney

g) spleen

h) skeletal muscle

i) urine

The results for rat tissues are summarized in the following tables.

Example 9: Demonstration of Solubility of Compounds of the Invention

The solubility of the compounds in phosphate-buffered saline (Dulbecco's phosphate-buffered saline, w/v Mg, Ca (PBS)) was tested in the presence of 1% DMSO. Specific solubility values are given in the table below.

Example 10: Demonstration of mutagenicity of compounds of the invention

The mutagenicity of these compounds was determined in the Ames reverse mutagenicity assay (MPF Ames assay, Xenometrix Inc.), approved by the OECD (Organization for Economic Co-operation and Development), EMA (European Medicines Agency) and FDA (US Food and Drug Administration). ), on S. typhimurium strains TA98 and TA100, without or in the presence of rat liver fraction S9. Relative mutagenicity values were obtained using the table provided by the manufacturer. Relative mutagenicity values according to OECD, EMA and FDA standards cannot exceed 2 at any concentration, since in this case they are potentially mutagenic. The relative mutagenicity values are shown in the table and Fig. below.

Example 11: Examples of compounds of the invention include the following compounds, which should not be construed as limiting the present invention.

INDUSTRIAL APPLICABILITY

The compounds of the invention can be used as drugs for the indications described above.

Claims (164)

1. A compound of formula (I) or (II) or a pharmaceutically acceptable salt or enantiomer thereof: where in formula (I) R ¹ represents an H atom or a group of the following formula: wherein R ⁶ and R ¹⁰ represent an H atom; R ⁷ , R ⁸ and R ⁹ each independently represent: H atom; a saturated 6-membered heterocyclic group containing two heteroatoms selected from N and O; C _1-12 straight or branched alkyl; C _1-12 dialkylamino; C _1-12 alkoxy, which may be substituted by one to three halogen atoms; or acetyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And each of one or more than one Q ¹ , Q ² , Q ³ and Q ⁴ is independently selected from the group consisting of an N atom and the others are CH; And where in formula (II) R ¹ represents: H atom; a 5- or 6-membered aromatic heterocyclic group containing one heteroatom selected from N and S, which may be substituted with a C _1-12 alkoxy group; or group according to the following formula: Where R ⁶ and R ¹⁰ represent an H atom; And each of R ⁷ , R ⁸ and R ⁹ independently represents: H atom; a 6-membered saturated or partially saturated heterocyclic group containing two heteroatoms selected from N and O; _NH2 ; CN; C _1-12 straight or branched alkyl; C _1-12 alkoxy, which may be substituted by one to three halogen atoms; C _1-12 hydroxyalkyl; C _1-12 dialkylamino; C _1-12 alkylcyano; or acetyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And each of Q ⁵ , Q ⁶ and Q ⁷ is independently selected from the group consisting of S, N and CH, provided that the aromatic nature of the ring is maintained; where CH may be substituted with C _1-6 alkyl, and at least one of Q ⁵ , Q ⁶ and Q ⁷ is S or N. 2. A compound according to claim 1 or a pharmaceutically acceptable salt or enantiomer thereof, wherein in formula (I) R ¹ represents an H atom or a group according to the following formula: Where R ⁷ , R ⁸ and R ⁹ are independently selected from the group consisting of H atom, morpholinyl, -OCH ₃ , trifluoromethoxy, dimethylamino, acetyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And one of the groups Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; And where in formula (II) R ¹ represents an H atom, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl, or a group according to the following formula: Where R ⁷ , R ⁸ and R ⁹ are independently selected from the group consisting of H atom, morpholinyl, NH ₂ , CN, OCH ₃ , trifluoromethoxy, dimethylamino, cyanomethyl, acetyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And Q ⁵ , Q ⁶ and Q ⁷ are as follows: Q ⁵ is an S atom and Q ⁶ and Q ⁷ are CH, or Q ⁷ is an S atom and Q ⁵ and Q ⁶ are CH, or Q ⁵ is is an S atom, and Q ⁶ is C-CH ₃ , and Q ⁷ is CH. 3. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt or enantiomer thereof, where in formula (I) R ¹ represents an H atom or a group according to the following formula: Where R ⁷ and R ⁹ are selected from the group consisting of an H atom and OCH ₃ ; And R ⁸ is selected from the group consisting of H atom, morpholinyl, OCH ₃ , trifluoromethoxy, dimethylamino and acetyl; R ² , R ³ , R ⁴ and R ₅ represent an H atom; And one of Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; And where in formula (II) R ¹ represents an H atom, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl, or a group according to the following formula: Where R ⁷ and R ⁹ represent an H atom, NH ₂ , CN or OCH ₃ ; R ⁸ is selected from the group consisting of H atom, morpholinyl, NH ₂ , CN, OCH ₃ , trifluoromethoxy, dimethylamino and acetyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And Q ⁵ , Q ⁶ and Q ⁷ are as follows: Q ⁵ is an S atom and Q ⁶ and Q ⁷ are CH, or Q ⁷ is an S atom and Q ⁵ and Q ⁶ are CH, or Q ⁵ is is an S atom, and Q ⁶ is C-CH ₃ , and Q ⁷ is CH. 4. Connection according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt or enantiomer thereof, where in formula (I) R ¹ represents an H atom or a group according to the following formula: Where R ⁶ , R ⁷ , R ⁹ and R ¹⁰ represent an H atom; R ⁸ represents an H atom or morpholinyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And one of Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; And where in formula (II) R ¹ represents an H atom or a group according to the following formula: Where R ⁶ , R ⁷ , R ⁹ and R ¹⁰ represent an H atom; R ⁸ represents an H atom or morpholinyl; R ² , R ³ , R ⁴ and R ⁵ represent an H atom; And Q ⁵ , Q ⁶ and Q ⁷ are as follows: Q ⁵ represents an S atom, and Q ⁶ and Q ⁷ represent CH, or Q ⁷ represents an S atom, and Q5 and Q ⁶ represent CH. 5. A connection that is: 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one, 9-hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, 7-hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,11-trien-8-one, 9-hydroxy-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one, 8a-hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one, 9-hydroxy-5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, 12-phenyl-9-hydroxy-6-methyl-4-thia-2,5,12-triazatricyclo[7.3.0.03,7]dodeca-1,3(7),5-trien-8-one, (9S)-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, (9S)-9-hydroxy-5-methyl-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5- trien-8-one, (9S)-12-(4-aminophenyl)-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, (9S)-9-hydroxy-12-(4-methoxyphenyl)-4-thia-2,12-diazotricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, (9S)-9-hydroxy-12-[4-(trifluoromethoxy)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, (9S)-4-{9-hydroxy-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-12-yl}benzonitrile , (9S)-12-(4-acetylphenyl)-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, (9S)-2-(4-{9-hydroxy-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-12- yl}phenyl)acetonitrile, (9S)-9-hydroxy-12-[4-(hydroxymethyl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, (9S)-9-hydroxy-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8- He, (9S)-9-hydroxy-12-(6-methoxypyridin-3-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien- 8-he, 9-hydroxy-5-methyl-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5 -trien-8-one, 12-(4-aminophenyl)-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, 9-hydroxy-12-(4-methoxyphenyl)-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, 9-hydroxy-5-methyl-12-[4-(trifluoromethoxy)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, 4-{9-hydroxy-5-methyl-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-12-yl}benzonitrile , 12-(4-acetylphenyl)-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, 2-(4-{9-hydroxy-5-methyl-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-12- yl}phenyl)acetonitrile, 9-hydroxy-12-[4-(hydroxymethyl)phenyl]-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, 9-hydroxy-5-methyl-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8- He, 9-hydroxy-12-(6-methoxypyridin-3-yl)-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien- 8-he, 9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, (9S)-9-hydroxy-12-(4-methylphenyl)-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-trien-8-one, 12-[4-(methyl)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, 3a-hydroxy-1-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one, 1-(4-acetylphenyl)-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one, 1-[4-(methyl)phenyl]-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one, 3a-hydroxy-1-[4-(morpholin-4-yl)phenyl]-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one, (9S)-12-[4-(dimethylamino)phenyl]-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, 12-[4-(dimethylamino)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),5-triene-8 -He, 1-[4-(dimethylamino)phenyl]-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one, 3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one or a pharmaceutically acceptable salt or enantiomer thereof. 6. A compound according to claim 1 or a pharmaceutically acceptable salt or enantiomer thereof, wherein in formula (I) one of Q ¹ , Q ² , Q ³ and Q ⁴ represents an N atom, and the others represent CH; R ¹ represents Where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ represent an H atom; And R ⁸ represents a 6-membered saturated heterocyclic group containing two heteroatoms selected from N and O; where in formula (II) Q ⁵ represents an S atom, and Q ⁶ and Q ⁷ represent CH; or Q ⁵ represents an S atom, Q ⁶ represents C-CH ₃ , and Q ⁷ represents CH; R ¹ represents Where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ represent an H atom; And ^R8 is a 6-membered saturated heterocyclic group containing two heteroatoms selected from N and O. 7. A compound according to claim 6 or a pharmaceutically acceptable salt or enantiomer thereof, wherein R ⁸ is morpholinyl. 8. A compound according to claim 6 or a pharmaceutically acceptable salt or enantiomer thereof, wherein the compound is a compound of formula (I). 9. A compound according to claim 8 or a pharmaceutically acceptable salt or enantiomer thereof, wherein Q ² represents an N atom and Q ¹ , Q ³ and Q ⁴ represent CH. 10. The compound according to claim 9 or a pharmaceutically acceptable salt or enantiomer thereof, wherein R ⁸ represents morpholinyl. 11. A compound according to claim 6 or a pharmaceutically acceptable salt or enantiomer thereof, wherein the compound is a compound of formula (II). 12. The compound of claim 11, or a pharmaceutically acceptable salt or enantiomer thereof, wherein Q ⁵ represents an S atom, Q ⁶ represents C-CH ₃ , and Q ⁷ represents CH. 13. The compound according to claim 12 or a pharmaceutically acceptable salt or enantiomer thereof, wherein R ⁸ represents morpholinyl. 14. The connection according to claim 6, where the connection is or a pharmaceutically acceptable salt or enantiomer thereof. 15. The connection according to claim 6, where the connection is or a pharmaceutically acceptable salt or enantiomer thereof. 16. The connection according to claim 6, where the connection is or a pharmaceutically acceptable salt or enantiomer thereof. 17. Use of a compound according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of a condition or disease associated with inhibition of myosin 2 isoforms selected from the group consisting of nonspecific low back pain, lumbar spasm, cramping spasm, stress-induced nuchal spasms, prolonged muscle spasms , post-stroke spasticity, muscle spasms in cerebral palsy, muscle spasms in multiple sclerosis, vaginal spasms, musculoskeletal muscle spasms, smooth muscle spasms during childbirth, drug-induced convulsions, myocardial muscle myopathy and skeletal muscle myopathy, in a subject suffering from or having symptoms of a specified condition or disease. 18. Use of the compound according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of a condition or disease associated with inhibition of myosin 2 isoforms selected from nonspecific low back pain, muscle spasms, post-stroke spasticity, drug-induced convulsions, or skeletal muscle myopathy in a subject suffering from or having symptoms of a specified condition or disease. 19. Use of the compound according to any one of paragraphs. 1-13 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of muscle spasms in a subject suffering from or having symptoms of muscle spasms. 20. Use according to claim 19, wherein the muscle spasms are lumbar spasms, convulsive spasms, stress-induced occipital spasms, prolonged muscle spasms, muscle spasms in cerebral palsy, muscle spasms in multiple sclerosis, vaginal spasms, muscle spasms of the musculoskeletal system. 21. Use of a compound according to claim 14 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of a condition or disease associated with inhibition of myosin 2 isoforms selected from nonspecific low back pain, muscle spasms, post-stroke spasticity, drug-induced convulsions, or myopathies in skeletal muscle in a subject suffering from or having symptoms of the specified condition or disease. 22. Use of a compound according to claim 15 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of a condition or disease associated with inhibition of myosin 2 isoforms selected from nonspecific low back pain, muscle spasms, post-stroke spasticity, drug-induced convulsions, or myopathies in skeletal muscle in a subject suffering from or having symptoms of the specified condition or disease. 23. Use of a compound according to claim 16 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of a condition or disease associated with inhibition of myosin 2 isoforms selected from nonspecific low back pain, muscle spasms, post-stroke spasticity, drug-induced convulsions, or myopathies in skeletal muscle in a subject suffering from or having symptoms of the specified condition or disease. 24. Use of a compound according to claim 16 or a pharmaceutically acceptable salt or enantiomer thereof for the treatment of muscle spasms in a subject suffering from or having symptoms of muscle spasms. 25. Use according to claim 24, wherein the muscle spasms are lumbar spasms, convulsive spasms, stress-induced occipital spasms, prolonged muscle spasms, muscle spasms in cerebral palsy, muscle spasms in multiple sclerosis, vaginal spasms, muscle spasms of the musculoskeletal system.