Pharmaceutically effective compounds that selectively inhibit myosin 2 isoforms

Abstract

The present invention relates to: a compound of formula (I) or formula (II) #imgabs0# and its pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof; and the pharmaceutical uses of the compound.

Description

[0001] The present invention relates to a compound of formula (I) or formula (II)

[0002]

[0003] Its pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof; and pharmaceutical uses of the compounds.

[0004] Description of the Prior Art

[0005] Myosin 2 isoforms and their existence in human (animal) organisms

[0006] Myosin is a motor protein present in all eukaryotic cells that uses the free enthalpy from the hydrolysis of adenosine triphosphate (ATP) to move along the strands of the actin cytoskeleton. Myosin is composed of heavy chain subunits and light chain subunits. The heavy chain consists of: a motor domain responsible for ATP hydrolysis (ATPase) activity and power generation, which contains actin and ATP binding sites; a neck region that plays a role in power transmission and control and light chain connection; and a tail region that includes polymerization and effector functions. Based on phylogenetic analysis of heavy chain sequences, the superfamily of myosins has been divided into more than 30 categories [(Sellers, JR (1999)). Myosins. John Wiley & Sons Ltd; Coluccio, LM (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media].

[0007] Members of the myosin 2 class are present in all eukaryotic organisms except higher plants [Sellers, JR (1999). Myosins. John Wiley & Sons Ltd]. The heavy chains of these myosins form dimers that can settle into higher structures called fibers (filaments). The size and dynamics of the fibers in this category show great differences between the various isoforms (protein variants encoded by different genes). In transverse muscle (skeletal muscle, cardiac muscle), the sarcomeric myosin 2 isoforms constitute the so-called thick filaments. Non-sarcomeric myosin 2 isoforms include smooth muscle and non-muscle myosin (non-muscle myosin 2, NM2). Non-sarcomeric myosins are filaments that can be reversibly polymerized, and in the case of NM2, they are minifilaments.

[0008] The genome of mammals and humans contains 15 heavy chain isoforms of myosin (see Table 1). Various isoforms of the light chain of myosin 2 (the heavy chain combines the so-called essential light chain (ELC) and the so-called regulatory light chain (RLC)) are also known; however, the distribution and function of the light chain in the body are much less known than the distribution of the heavy chain. The active substances that are the subject of this application act via the heavy chain of myosin, so we limit our discussion to the heavy chain isoforms.

[0009] Among the sarcomomeric isoforms, MYH1, MYH2, and MYH4 are the major motor components of skeletal muscle [Coluccio, LM (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media]. MYH3 is expressed in fetal age, while MYH8 is expressed in the perinatal period. MYH7b also appears in the heart, adjacent to skeletal muscle. MYH13 is present in the oculomotor muscle, the function of MYH15 is less well known, and the MYH16 masticatory muscle myosin gene is inactivated in humans. Sarcoma isoforms also include two human cardiac myosins: MYH6 (α-cardiac myosin), which is the major protein component of the myocardium in the atria; and MYH7 (β-cardiac myosin), which is the major protein component of the myocardium in the ventricles. (In small mammals such as rodents, cardiac alpha-myosin is also the major isoform in the ventricular wall.

[0010] The only isoform of human smooth muscle myosin 2 (MYH11) or three NM2 (NM2A: MYH9, NM2B: MYH10, NM2C: MYH14) are phylogenetically close to each other; collectively, these are called non-sarcomeric myosin 2 isoforms [Coluccio, LM (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol. 7). Springer Science & Business Media]. Each of these myosins is regulated by phosphorylation of RLC or reversible filament polymerization linked to RLC. Smooth muscle myosin 2 is the major motor for smooth muscle of hollow organs (except the heart). Several splice forms of smooth muscle myosin 2 are known: In the loop-1 region of the ATP binding site of the motor domain, the SMA isoform contains a 7amino acid insert, while SMB does not contain this peptide segment.

[0011]

[0012]

[0013] Table 1: Human myosin 2 heavy chain gene and its encoded myosin heavy chain isoforms

[0014] NM2 isoforms are highly common in the human body, and they are even present in muscle cells. Several types of NM2 isoforms appear in most cell types. The NM2 isoforms of various organs and tissues also change during ontogeny. Platelets, many blood cell types, lymph nodes, spleen and thymocytes are rich in NM2A. NM2A and NM2C are expressed in the stomach and colon, while the 2A isoform is not present in cardiomyocytes. The brain and testes are also rich in NM2B [Coluccio, LM (Ed.). (2007). Myosins: a superfamily of molecular motors (Vol.7). Springer Science & Business Media].

[0015] Various splice forms are expressed by alternative splicing of the genes of NM2B and NM2C isoforms: B1 or C1 forms in the loop-1 region of the actin binding site, B2 and C2 forms in the loop-2 region contain insertions [Heissler, SM and Manstein, DJ (2013). Nonmuscle myosin-2: mix and match. Cellular and molecular life sciences, 70 (1), 1-21]. Any combination of the presence of these insertions occurs in vivo. B1, B2 and C2 forms are present in the brain and spinal cord, while the C1 form is present in all tissues containing NM2C except adult heart and skeletal muscle.

[0016] Each NM2B splice form is expressed in different regions of the adult mouse brain. The B2 isoform is present at low levels in the fetal and newborn mouse brain, but is present in higher amounts in the postpartum dendrites and synaptogenesis of cerebellar Purkinje cells. The C0 (no insert) and C1 forms are common, while the C2 form is present in neural tissue or the C1C2 form is present in neurites; the latter is the main form of NM2C during neuritogenesis.

[0017] In most tissues of adult mice, NM2C is present in minimal amounts of the three NM2 isoforms. However, immortalized cell lines (e.g., COS-7, HT29) contain large amounts of NM2C. In tumor cell lines, the C1 form was measured as increased compared to non-tumor cell lines from the same tissue.

[0018] Physiological roles of each isoform

[0019] Sarcomeric myosin 2 isoforms generate the driving force for skeletal muscle contraction, which is the basis for voluntary movement activities such as postural changes, walking, chewing, fine motor movements, and speaking. The physiological properties of each muscle fiber type (e.g., speed of muscle contraction and energy expenditure) are primarily determined by their myosin 2 heavy chain composition. The different mechanical properties of the atria and ventricles of the heart are also determined by the molecular functions of the faster mechanochemical cycling atrial (α) and slower acting ventricular (β) myocardial isoforms. Myosin mutations in the cardiac muscle cause a significant proportion of hereditary hypertrophic cardiomyopathies or, alternatively, dilatative cardiomyopathy.

[0020] Smooth muscle myosin 2 is responsible for the contraction or relaxation (toning) of the walls of most organs. The faster (having higher ATPase activity and potential for faster motility) SMB isoforms mainly drive the so-called phasic transient contractions (e.g., in the walls of the bladder or portal vein and in the longitudinal smooth muscle layers of the ileum), while the slower-acting SMA isoforms are mainly responsible for slow contractions and long-term force maintenance (e.g., in the walls of the aorta and trachea).

[0021] In most cell types, NM2 isoforms have essential or specialized functions for: cell motility, cell migration, cell adhesion, cytokinesis, morphogenetic movements (e.g., gastrulation), tissue formation, wound healing, angiogenesis, immune control functions, epithelial-renewal, growth and retraction of cell processes (e.g., neurites), membrane trafficking in cells, clathrin-mediated endocytosis, phagocytosis, exocytosis, plasma membrane fusion of secretory vesicles, and wound-induced exocytosis-dependent membrane repair [Newell-Litwa, KA, Horwitz, R. and Lamers, ML (2015). Non-muscle myosin II in disease: mechanisms and therapeutic opportunities. Disease models & mechanisms, 8 (12), 1495-1515]. NM2 isoforms perform these functions in interaction with several cellular actin structures, forming stress chains in the form of contractile rings during cytokinesis and peripheral rings during cell adhesion.

[0022] As with other myosins, the diversity of isoform molecular activities also serves as the basis for the physiological role of NM2 isoforms. Although all NM2 isoforms have much slower action speeds than muscle myosin, NM2A and NM2C isoforms are relatively faster and have lower duty ratios (steady-state actin binding rates), while NM2B is slower and its function is characterized by a significantly higher duty ratio. Among the splice variants, the B1 form exhibits increased ATPase activity and faster motility, while the B2 form has no detectable actin-activated ATPase activity and motility. Similar to the B1 form, the C1 insert also lends increased ATPase activity and provides myosin with the potential for faster motility, while the C1C2 variant has activity independent of RLC phosphorylation.

[0023] Among the above cellular processes, the role of NM2A in clathrin-mediated endocytosis and exocytosis has been demonstrated. In addition, NM2A isoforms play a role in platelet formation from megakaryocytes.

[0024] During cell adhesion, NM2 isoforms play a key role in the dynamic rearrangement of cell-cell contacts and the formation of apical junctional complexes between the apicolateral surfaces of epithelial cells [Vicente-Manzanares, M., Ma, X., Adelstein, RS and Horwitz, AR (2009). Non-muscle myosin II takes centre stage in cell adhesion and migration. Nature reviews Molecular cell biology, 10(11), 778-790].

[0025] During cell migration, NM2 isoforms play a role in the retraction of the cell rear and in the driving of retrograde actin flow in lamellae (lamellapodium). These myosins apply their power to the so-called local complexes (focalcomplexes) produced by stress cables (stress cable), play a core role in the mechanical stress of the extracellular matrix of the sensor, coordinate the elongation (protraction) and stable cell polarity of the cell. NM2B is an important component of the dynamic sensing structure present at the back of the cell, and NM2A isoforms are important factors in the dynamic actin network at the front of the cell. NM2A also plays an important role in the dynamic crosstalk (crosstalk) between actin fibers and microtubules.

[0026] NM2A and NM2B isoforms drive retrograde actin flow in axon ends [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] and cooperate in the growth and retraction of neurites. Reduced expression of the NM2C1C2 isoform leads to shortening of neurites.

[0027] During cell division, NM2 isoforms generate forces in the equatorial region of dividing cells and play a role in the generation of mitotic spindles [Wang, A., Ma, X., Conti, MA and Adelstein, RS (2011). Distinct and redundant roles of the non-muscle myosin II isoforms and functional domains]. The role of NM2C1 isoforms has also been confirmed in abnormal cell proliferation. Functional changes of NM2 in tumor metastasis can play a role in reducing cell adhesion, promoting tissue invasion and promoting tumor-induced angiogenesis.

[0028] Mutations in the NM2A gene cause May-Hegglin anomaly, which is characterized by a decrease in platelet count, bleeding problems, nephritis, deafness, or the development of cataracts [Ma, X. and Adelstein, RS (2014), The role of vertical nonmuscle Myosin II in development and human disease. Bioarchitecture, 4 (3), 88-102]. Deficiency of the NM2A protein in mice causes embryonic lethality through cell adhesion and gastrointestinal defects. Mutations in the NM2B gene in mice cause defects in the heart (cardiomyocyte polynuclease) and the brain. Ablation of the NM2B1 form induces hydrocephalus, while knockout of the NM2B2 form causes cerebellar disorders. In humans, deafness-activating point mutations of the NM2C isoform are known.

[0029] The role of myosin 2 in megakaryocytes (MK) in endomytosis was studied in WO2012113555A1 international patent publication, and it was found that adding blebbastatin to MK cell cultures resulted in a significant increase in MK polyploidy.

[0030] Myosin 2 inhibitor

[0031] The two most recent reviews of myosin inhibitors and their mechanisms of inhibition appeared in 2013 and 2016. The following table summarizes the structures and effects of myosin 2 inhibitors:

[0032]

[0033]

[0034] Table 2: Structure and effect of myosin 2 inhibitors

[0035] N-Benzyl-p-toluenesulfonamide (BTS)

[0036] Among myosin 2 isoforms, BTS inhibits fast skeletal muscle myosin-2 100-fold more potently than slow skeletal muscle myosin-2, cardiac myosin-2, or non-muscle myosin 2, and does not inhibit platelet myosin 2-t.

[0037] 2,3-Butanedione Monoxime(BDM)

[0038] BDM inhibits skeletal muscle myosin 2, but the binding is weak (IC50 ~ 5mM), the data on inhibition of other myosin isoforms are contradictory, and it has many other non-myosin targets.

[0039] Vanadate (Vi)

[0040] Vanadate is a phosphate analog that holds myosin in the ATP-bound state in the nucleotide-binding pocket complexed with ADP. Vanadate is a general ATP analog that broadly inhibits more than just the myosin 2 isoform.

[0041] Blebbistatin

[0042] The best known and most widely used myosin-specific inhibitor is Blebbistatin. Blebbistatin is a potent inhibitor of non-muscle myosin 2A and B, cardiac, skeletal and smooth muscle myosin forms, but Blebbistatin does not inhibit myosin 1, myosin 5 and myosin 10.

[0043] The Blebbistatin rings are referred to hereinafter as A, B, C and D, respectively.

[0044]

[0045] For example, International Patent Application Publication No. WO2009094718A1 discloses the use of certain inhibitors in the treatment of thromboembolic disorders. In particular, the referenced document also describes the study of the effect of myosin 2A isoform on the regulation of blood clot stability in vivo. In this case, Blebbistatin is used to inhibit myosin.

[0046] Non-muscle myosin 2 ATPase inhibitors are referred to as megakaryocyte modulator compounds in the international patent publication document WO2016180918A1. The cited document only relates to Blebbistatin and azidoblebbistatin as examples of the inhibitors.

[0047] US Patent Publication No. US2013071927A1 also discloses only two small molecule myosin 2 inhibitors: N-benzyl-p-toluenesulfonamide, and the best described and characterized myosin 2 inhibitor Blebbistatin.

[0048] European Patent Application Publication No. EP2777703A1 discloses non-muscle myosin 2 antagonists related to the treatment of certain diseases by stem cell therapy. As small molecule compounds among the myosin 2 antagonists, 2,3-butanedione-2-monoxime, Blebbistatin and its analogs, derivatives or variants, and pyrrolidone derivatives are mentioned, but the document does not provide information on the structures of the analogs, derivatives and variants.

[0049] International Patent Application Publication No. WO2016161192A1 discloses Blebbistatin and its analogs, such as p-nitro-Blebbistatin, (S)-nitro-Blebbistatin and S-(-)-7-desmethyl-8-nitro-Blebbistatin, and N-benzyl-p-methylsulfonamide and 2,3-butanedione monoxime in small molecule myosin 2 inhibitors. The inhibitors of the cited literature are structurally different from the small molecule inhibitors disclosed in the present invention.

[0050] International Patent Application Publication No. WO2017129782A1 discloses a Blebbistatin skeleton compound and its preparation, which is useful for inhibiting myosin 2 isoforms, particularly useful for in vivo inhibition of ATPase activity in neuronal non-muscle myosin 2 isoforms. The referenced document also discloses the use of the disclosed compound for treating or preventing myosin 2-mediated diseases (e.g., schizophrenia, Alzheimer's disease, Parkinson's disease, cerebral ischemia). The disclosed compound is characterized in that the A ring and the D ring of the Blebbistatin skeleton are replaced with various substituents, that is, the general formula of the disclosed compound does not contain an aromatic heterocycle at the position of the A ring.

[0051] US2017129886A1 US patent publication also discloses myosin 2 ATPase inhibitors. The document discloses that the disclosed compound is suitable for the treatment of overactive bladder. The compound disclosed therein is also a Blebbistatin skeleton compound, wherein the Blebbistatin skeleton A is at the nitrogen ring and position 2, and the C ring and / or the D ring are substituted by various substituents. The compound described therein does not contain an aromatic heterocycle at the A ring.

[0052] International patent application publication number WO2012158942A2 also relates to myosin 2 ATPase inhibitory compounds, processes for their preparation and their use in the treatment of overactive bladder. The disclosed compounds are blebbistatin derivatives substituted with different substituents at positions 6 and 7 on the blebbistatin skeleton, i.e., the A ring. The document also does not disclose compounds containing aromatic heterocycles at the A ring position of the blebbistatin skeleton.

[0053] International Patent Application Publication No. WO2010120785A2 mentions Blebbistatin and its various analogs as myosin 2 inhibitors. The analogs are compounds in which the A ring of the Blebbistatin skeleton is substituted by various substituents, that is, there is no heteroaromatic ring at the position of the A ring.

[0054] Problems to be solved by the present invention

[0055] There is a need for new compounds which, in addition to modular selective / specific inhibition of myosin 2 isoforms, have further advantageous properties, such as improved solubility and improved mutagenicity compared to the prior art, which properties make these compounds suitable for use in medicine.

[0056] According to the discovery of the present invention

[0057] We found

[0058] 1. The structures of the compounds of the present invention have improved solubility and better mutagenic properties compared to the Blebbistatin skeleton and, based on their ability to inhibit myosin 2, the compounds can be used for specific medical indications; and

[0059] 2. By modifying the D-loop, the variability and specificity of different myosin-2 isoforms (such as skeletal myosin-2, cardiac myosin-2, smooth myosin-2, non-muscle myosin-2 / NM2A, NM2B, NM2C) can be further modulated. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 : Measurement data for the mutagenicity test of S(-)-Blebbistatin (blue) and 188 (green) compounds on TA98 (light circles) and TA100 (dark circles) strains in the absence (open circles) or presence (full disease) of S9 liver fractions. Summary of the invention

[0061] 1. A compound of formula (I) or formula (II):

[0062]

[0063] Wherein, in formula (I),

[0064]

[0065] R 1 is hydrogen or a group of the formula,

[0066]

[0067] in

[0068] R 6 and R 10 It is an H-atom;

[0069] R 7 , R 8 and R 9R is independently an H-atom, a halogen, or a saturated, partially saturated, unsaturated or aromatic 5-, 6- or 7-membered heterocyclic group, each independently containing one or more N, O or S atoms; 7 , R 8 and R 9 The alkyl radicals may be substituted by one or more groups selected from the group consisting of: C1-12 straight or branched alkyl, C3-12 cycloalkyl, C1-12 straight or branched alkenyl, C1-12 straight or branched alkynyl, hydroxy, C1-12 hydroxyalkyl, C3-12 hydroxycycloalkyl, amino (-NH2), C1-12 alkylamino, C3-12 cycloalkylamino or C1-12 dialkylamino, wherein the amino group may be acylated by a C1-6 straight or cyclic or aromatic carboxylic acid, or sulfonylated by a C1-6 straight or cyclic or aromatic sulfonic acid; nitro (-NO2), cyano (nitrile), C1-12 alkylcyano, C3-12 cycloalkylcyano, C1-12 saturated, unsaturated or aromatic carboxylic acid, C1-12 carboxylic acid amide formed from a saturated, unsaturated or aromatic amine, wherein the carboxylic acid amide is of the formula C(O)NH2-, C(O)NHR-, or C(O)NH-. 11 - or C(O)NR 11 R 12 - a group, wherein R 11 and R 12 Each is independently C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkenyl or C6-12 aryl; C1-12 carboxylic acid ester formed from saturated, unsaturated or aromatic alcohol, C1-12 alkoxy, C1-12 alkenyloxy, C1-12 alkynyloxy or C1-12 alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; halogen, C1-12 alkylthio, C3-12 cycloalkylthio, C1-12 alkenylthio, C1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; S(O)2OH-, C1-4 alkyl-S(O)2OH- or C3-6 cycloalkyl-S(O)2OH-, S(O)2OR 13 -, C1-4 alkyl-S(O)2OR 13 - or C3-6 cycloalkyl-S(O)2OR 13 -,S(O)R 13 -, C1-4 alkyl-S(O)R 13 - or C3-6 cycloalkyl-S(O)R 13 -,S(O)2R 13 -, C1-4 alkyl-S(O)2R 13 - or C3-6 cycloalkyl-S(O)2R 13-, P(O)2OH-, C1-4 alkyl-P(O)2OH- or C3-6 cycloalkyl-P(O)2OH-, P(O)2OR 13 -, C1-4 alkyl-P(O)2OR 13 - or C3-6 cycloalkyl-P(O)2OR 13 -, P(O)2NH2-, C1-4 alkyl-P(O)2NH2- or C3-6 cycloalkyl-P(O)2NH2-, P(O)2NHR 13 -, C1-4 alkyl-P(O)2NHR 13 - or C3-6 cycloalkyl-P(O)2NHR 13 -, P(O)2NR 13 R 14 - or C1-4 alkyl-P(O)2NR 13 R 14 - or C3-6 cycloalkyl-P(O)2NR 13 R 14 - group, where R 13 and R 14 The group is selected from the group consisting of C1-6 straight or branched alkyl, cycloalkyl or C6-12 aryl; or R 7 , R 8 and R 9 Each of the amino groups may be independently a C1-12 straight chain or branched alkyl, a C3-12 cycloalkyl, a C1-12 straight chain or branched alkenyl, a C1-12 straight chain or branched alkynyl, a hydroxyl, a C1-12 hydroxy-alkyl, a C3-12 hydroxy-cycloalkyl, an amino (NH2), a C1-12 alkylamino, a C3-12 cycloalkylamino or a C1-12 dialkylamino, wherein the amino group may be acylated with a C1-6 straight chain or cyclic or aromatic carboxylic acid, or sulfonylated with a C1-6 straight chain or cyclic or aromatic sulfonic acid; a nitro-(-NO2), a cyano (nitrile), a C1-12 alkylcyano, a C1-12 saturated, unsaturated or aromatic carboxylic acid, a C1-12 carboxylic acid amide formed from a saturated, unsaturated or aromatic amine, wherein the carboxylic acid amide is according to the formula C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 - any one of the groups, wherein in the formula, R 11 and R 12Each is independently C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkenyl or C6-12 aryl; C1-12 carboxylic acid ester formed by saturated, unsaturated or aromatic alcohol, C1-12 alkoxy, C1-12 alkenyloxy, C1-12 alkynyloxy or alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; C1-12 alkylthio, C3-12 cycloalkylthio, C1-12 alkenylthio, C1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; S(O)2OH-, C1-4 alkyl-S(O)2OH- or C3-6 cycloalkyl-S(O)2OH-, S(O)2OR 13 -、C1-4 alkyl-S(O)2OR 13 - or C3-6 cycloalkyl-S(O)2OR 13 -、S(O)R 13 -、C1-4 alkyl-S(O)R 13 - or C3-6 cycloalkyl-S(O)R 13 -、S(O)2R 13 -、C1-4 alkyl-S(O)2R 13 - or C3-6 cycloalkyl-S(O)2R 13 -, P(O)2OH-, C1-4 alkyl-P(O)2OH- or C3-6 cycloalkyl-P(O)2OH-, P(O)2OR 13 -、C1-4 alkyl-P(O)2OR 13 - or C3-6 cycloalkyl-P(O)2OR 13 -, P(O)2NH2-, C1-4 alkyl-P(O)2NH2- or C3-6 cycloalkyl-P(O)2NH2-, P(O)2NHR 13 -、C1-4 alkyl-P(O)2NHR 13 - or C3-6 cycloalkyl-P(O)2NHR 13 -、P(O)2NR 13 R 14 - or C1-4 alkyl-P(O)2NR 13 R 14 - or C3-6 cycloalkyl-P(O)2NR 13 R 14 - group, where R 13 and R 14 Selected from the group consisting of C1-6 straight or branched alkyl, cycloalkyl or C6-12 aryl; methylsulfonylaminomethyl, trifluoromethylsulfonylamino, N,N-dimethylaminocarbonylmethyl [CH2-CO-N(CH3)2], acetyl, methylsulfonylamino, methoxymethyl;

[0070] or R 1 is a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic group, each of which independently contains one or more N, O or S atoms; R 1 The alkyl radicals may be substituted by one or more groups selected from the group consisting of: C1-12 straight or branched alkyl, C3-12 cycloalkyl, C1-12 straight or branched alkenyl, C1-12 straight or branched alkynyl, hydroxy, C1-12 hydroxyalkyl, C3-12 hydroxycycloalkyl, amino (-NH2), C1-12 alkylamino, C3-12 cycloalkylamino or C1-12 dialkylamino, wherein the amino group may be acylated with a C1-6 straight or cyclic or aromatic carboxylic acid, or sulfonylated with a C1-6 straight or cyclic or aromatic sulfonic acid; nitro (-NO2), cyano (nitrile), C1-12 alkylcyano, C3-12 cycloalkylcyano, C1-12 saturated, unsaturated or aromatic carboxylic acid, C1-12 carboxylic acid amide formed from a saturated, unsaturated or aromatic amine, wherein the carboxylic acid amide is according to the formula C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 - a group, wherein R 11 and R 12 each independently C1-6 alkyl-, C3-12 cycloalkyl-, C1-6 alkenyl- or C6-12 aryl; C1-12 carboxylic acid esters formed from saturated, unsaturated or aromatic alcohols, C1-12 alkoxy, C1-12 alkenyloxy, C1-12 alkynyloxy- or C1-12 alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; halogen;

[0071] R 2 , R 3 , R 4 and R 5 is selected from the group consisting of H-atoms, halogens, preferably F or C1-6 alkyl; and

[0072] Q 1 , Q 2 , Q 3 and Q 4 One or more of are each independently selected from the group consisting of N-atoms, and the remaining groups are CH;

[0073]

[0074] Wherein, in formula (II),

[0075] R 1 is an H-atom, or a group according to the formula

[0076] in

[0077] R 6 and R 10 is an H-atom; and

[0078] R 7 , R 8 and R 9 R is independently an H-atom, a halogen, a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic group, each independently containing one or more N, O or S atoms; 7 , R 8 and R 9 It may be substituted by one or more groups selected from the group consisting of: C1-12 straight or branched alkyl, C3-12 cycloalkyl-, C1-12 straight or branched alkenyl-, C1-12 straight or branched alkynyl-, hydroxyl, C1-12 hydroxyalkyl, C3-12 hydroxycycloalkyl-, amino (-NH2), C1-12 alkylamino, C3-12 cycloalkylamino or C1-12 dialkylamino, wherein the amino group may be substituted by ... alkenyl, C3-12 cycloalkyl-, C1-12 straight or branched alkenyl, C1-12 straight or branched alkynyl, acylated by a C1-6 open-chain, cyclic or aromatic carboxylic acid, or sulfonylated by a C1-6 open-chain, cyclic or aromatic sulfonic acid; nitro (-NO2), cyano-(nitrile), C1-12 alkylcyano-, C3-12 cycloalkylcyano, C1-12 saturated, unsaturated or aromatic carboxylic acid, C1-12 carboxylic acid amide formed from a saturated, unsaturated or aromatic amine, wherein the carboxylic acid amide is according to the following formula C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 - any one of the groups, wherein R 11 and R 12 Each is independently C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkenyl or C6-12 aryl; C1-12 carboxylic acid ester formed by saturated, unsaturated or aromatic alcohol, C1-12 alkoxy, C1-12 alkenyloxy, C1-12 alkynyloxy or C1-12 alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms, halogen, C1-12 alkylthio, C3-12 cycloalkylthio, C1-12 alkenylthio, C1-12 alkynylthio or alkylthioalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; S(O)2OH-, C1-4 alkyl-S(O)2OH- or C3-6 cycloalkyl-S(O)2OH-, S(O)2OR 13 -、C1-4 alkyl-S(O)2OR 13 - or C3-6 cycloalkyl-S(O)2OR 13-、S(O)R 13 -、C1-4 alkyl-S(O)R 13 - or C3-6 cycloalkyl-S(O)R 13 -、S(O)2R 13 -、C1-4 alkyl-S(O)2R 13 - or C3-6 cycloalkyl-S(O)2R 13 -, P(O)2OH-, C1-4 alkyl-P(O)2OH- or C3-6 cycloalkyl-P(O)2OH-, P(O)2OR 13 -、C1-4 alkyl-P(O)2OR 13 - or C3-6 cycloalkyl-P(O)2OR 13 -, P(O)2NH2-, C1-4 alkyl-P(O)2NH2- or C3-6 cycloalkyl-P(O)2NH2-, P(O)2NHR 13 -、C1-4 alkyl-P(O)2NHR 13 - or C3-6 cycloalkyl-P(O)2NHR 13 -、P(O)2NR 13 R 14 - or C1-4 alkyl-P(O)2NR 13 R 14 - or C3-6 cycloalkyl-P(O)2NR 13 R 14 , where R 13 and R 14 The group is selected from the group consisting of C1-6 straight or branched alkyl, cycloalkyl or C6-12 aryl; or R 7 , R 8 and R 9 Each of them can be independently a C1-12 straight chain or branched alkyl, a C3-12 cycloalkyl, a C1-12 straight chain or branched alkenyl, a C1-12 straight chain or branched alkynyl, a hydroxyl, a C1-12 hydroxyalkyl, a C3-12 hydroxycycloalkyl, an amino (NH2), a C1-12 alkylamino, a C3-12 cycloalkylamino or a C1-12 dialkylamino, wherein the amino group can be acylated with a C1-6 open chain or cyclic or aromatic carboxylic acid, or sulfonylated with a C1-6 open chain or cyclic or aromatic sulfonic acid; a nitro (-NO2), a cyano (nitrile), a C1-12 alkylcyano, a C1-12 saturated, unsaturated or aromatic carboxylic acid, a C1-12 carboxylic acid amide formed from a saturated, unsaturated or aromatic amine, wherein the carboxylic acid amide is a group according to any of the following formulae: C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 -, where R 11 and R 12Each is independently C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkenyl or C6-12 aryl; C1-12 carboxylic acid ester formed from saturated, unsaturated or aromatic alcohol, C1-12 alkoxy, C1-12 alkenyloxy, C1-12 alkynyloxy or alkoxyalkyl, wherein the alkyl, cycloalkyl, alkenyl and alkynyl groups may be substituted by one or more halogen atoms, C1-12 alkylthio, C3-12 cycloalkylthio, C1-12 alkenylthio, C1-12 alkynylthio or alkylthioalkyl, wherein the alkyl-, cycloalkyl-, alkenyl and alkynyl groups may be substituted by one or more halogen atoms; S(O)2OH-, C1-4 alkyl-S(O)2OH- or C3-6 cycloalkyl-S(O)2OH-, S(O)2OR 13 -、C1-4 alkyl-S(O)2OR 13 - or C3-6 cycloalkyl-S(O)2OR 13 -、S(O)R 13 -、C1-4 alkyl-S(O)R 13 - or C3-6 cycloalkyl-S(O)R 13 -、S(O)2R 13 -、C1-4 alkyl-S(O)2R 13 - or C3-6 cycloalkyl-S(O)2R 13 -, P(O)2OH-, C1-4 alkyl-P(O)2OH- or C3-6 cycloalkyl-P(O)2OH-, P(O)2OR 13 -、C1-4 alkyl-P(O)2OR 13 - or C3-6 cycloalkyl-P(O)2OR 13 -, P(O)2NH2-, C1-4 alkyl-P(O)2NH2- or C3-6 cycloalkyl-P(O)2NH2-, P(O)2NHR 13 -、C1-4 alkyl-P(O)2NHR 13 - or C3-6 cycloalkyl-P(O)2NHR 13 -、P(O)2NR 13 R 14 - or C1-4 alkyl-P(O)2NR 13 R 14 or C3-6 cycloalkyl-P(O)2NR 13 R 14 - group, where R 13 and R 14 Selected from the group consisting of C1-6 straight or branched alkyl, cycloalkyl or C6-12 aryl; methylsulfonylaminomethyl, trifluoromethylsulfonylamino, N,N-dimethylaminocarbonylmethyl [CH2-CO-N(CH3)2], acetyl, methylsulfonylamino, methoxymethyl;

[0079] or R 1 is a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic group, each of which independently contains one or more N, O or S atoms; R 1 The amino group may be substituted by one or more groups selected from the group consisting of: C1-12 straight chain or branched alkyl, C3-12 cycloalkyl, C1-12 straight chain or branched alkenyl, C1-straight chain or branched alkynyl, hydroxy, C1-12 hydroxyalkyl, C3-12 hydroxycycloalkyl, amino (-NH2), C1-12 alkylamino, C3-12 cycloalkylamino or C1-12 dialkylamino, wherein the amino group may be substituted by C1-6 open chain or cycloalkyl. acylated with a C1-6 open-chain or cyclic or aromatic carboxylic acid, or sulfonylated with a C1-6 open-chain or cyclic or aromatic sulfonic acid; nitro (-NO2), cyano (nitrile), C1-12 alkyl-cyano, C3-12 cycloalkyl-cyano, C1-12 saturated, unsaturated or aromatic carboxylic acid, C1-12 carboxylic acid amide formed from a saturated, unsaturated or aromatic amine, wherein the carboxylic acid amide is a radical according to any of the following formulae: C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 -, where R 11 and R 12 Each is independently C1-6 alkyl, C3-12 cycloalkyl, C1-6 alkenyl or C6-12 aryl; C1-12 carboxylic acid ester formed from saturated, unsaturated or aromatic alcohol, C1-12 alkoxy, C1-12 alkenyloxy-, C1-12 alkynyloxy or C1-12 alkoxyalkyl, wherein alkyl, cycloalkyl, alkenyl and alkynyl may be substituted by one or more halogen atoms; halogen;

[0080] R 2 , R 3 , R 4 and R 5 is selected from H-atom, halogen, preferably F or C1-6 alkyl; and

[0081] Q 5 , Q 6 and Q 7 Each is independently selected from the group consisting of S, O, N, NH or CH, provided that the aromatic nature of the ring is retained; wherein CH or NH may be substituted by C1-6 alkyl or haloalkyl;

[0082] And pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0083] 2. The compound of formula (I) or formula (II) according to item 1;

[0084] Wherein, in formula (I)

[0085]

[0086] R 1 is H or a group according to the formula

[0087] Among them, in the above formula

[0088] R 7 , R 8 and R 9 independently selected from the group consisting of: H-atom, morpholinyl, amino (-NH2), nitro (-NO2), cyano (nitrile), carboxamide (-CONH2), methoxy (-OCH3), trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, N,N-dimethylaminocarbonylmethyl [CH2-CO-N(CH3)2-], acetyl, methylsulfonylamino, methoxymethyl, 1,4-oxazepan-4-yl, oxa-4-yl, tetrahydro-thiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or

[0089] R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

[0090] R 2 , R 3 , R 4 and R 5 is an H-atom; and

[0091] Q 1 , Q 2 , Q 3 and Q 4 One of the groups is an N-atom and the other is CH; and

[0092] Wherein, in formula (II)

[0093]

[0094] R 1 is H or a group according to the formula

[0095] Among them, in the above formula

[0096] R 6 and R 10 is an H-atom; and

[0097] R 7 , R 8 and R 9 Independently selected from the group consisting of: H-atom, morpholinyl, amino (-NH2), nitro (-NO2), cyano (nitrile), carboxamide (-CONH2), methoxy (-OCH3), trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, N,N-dimethylaminocarbonylmethyl [CH2-CO-N(CH3)2-], acetyl, methylsulfonylamino, methoxymethyl, 1,4-oxazepine-4-yl, oxa-4-yl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or

[0098] R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

[0099] R 2 , R 3 , R 4 and R 5 is an H-atom; and

[0100] Q 5 , Q 6 and Q 7 As follows: Q 5 for S-atoms and Q 6 and Q 7 is CH, or Q 7 for S-atoms and Q 5 and Q 6 is CH, or Q 5 N-CH3 and Q 6 for N-atom and Q 7 is CH, or Q 5 for S-atoms and Q 6 C-CH3 and Q 7 For CH,

[0101] And pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0102] 3. The compound of formula (I) or formula (II) according to item 1 or 2,

[0103] Wherein, in formula (I)

[0104]

[0105] R 1 is H or a group according to the formula

[0106] Among them, in the above formula

[0107] R 6 and R 10 is an H-atom, and

[0108] R 7 and R 9 is selected from the group consisting of an H-atom, an amino group (-NH2), a cyano group or a methoxy group (-OCH3), and

[0109] R 8 Selected from the group consisting of: H-atom, morpholinyl, amino (-NH2), nitro (-NO2), cyano (nitrile), carboxamide (-CONH2), methoxy (-OCH3), trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, N,N-dimethylaminocarbonylmethyl [CH2-CO-N(CH3)2-], acetyl, methylsulfonylamino, methoxymethyl, 1,4-oxazepine-4-yl, oxa-4-yl, tetrahydro-thiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or

[0110] R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

[0111] R 2 , R 3 , R 4 and R 5 is an H-atom; and

[0112] Q 1 , Q 2 , Q 3 and Q 4 One of is an N-atom, and the other is CH; and

[0113] Wherein, in formula (II)

[0114]

[0115] R 1 is H or a group according to the formula

[0116] Among them, in the above formula

[0117] R 6 and R 10 is an H-atom, and

[0118] R 7 and R 9 is an H-atom, an amino group (-NH2), a cyano group or a methoxy group (-OCH3), and

[0119] R 8 Selected from the group consisting of: H-atom, morpholinyl, amino (-NH2), nitro (-NO2), cyano (nitrile), carboxamide (-CONH2), methoxy (-OCH3), trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, N,N-dimethylaminocarbonylmethyl [CH2-CO-N(CH3)2-], acetyl, methylsulfonylamino, methoxymethyl, 1,4-oxazepine-4-yl, oxa-4-yl, tetrahydro-thiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl group; or

[0120] R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl, 6-methoxy-3-pyridyl;

[0121] R 2 , R 3 , R 4 and R 5 is an H-atom; and

[0122] Q 5 , Q 6 and Q 7 As follows: Q 5 for S-atoms and Q 6 and Q 7 is CH, or Q 7 for S-atoms and Q 5 and Q 6 is CH, or Q 5 N-CH3 and Q 6for N-atom and Q 7 is CH, or Q 5 for S-atoms and Q 6 C-CH3 and Q 7 For CH,

[0123] And pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0124] 4. The compound of formula (I) or formula (II) according to items 1 to 3,

[0125] Wherein, in formula (I)

[0126]

[0127] R 1 is H or a group according to the formula

[0128] Among them, in the above formula

[0129] R 6 , R 7 , R 9 and R 10 for H-atoms, and

[0130] R 8 is an H-atom or a morpholinyl group;

[0131] R 2 , R 3 , R 4 and R 5 is an H-atom; and

[0132] Q 1 , Q 2 , Q 3 and Q 4 One of them is an N-atom and the other is CH; and

[0133] Wherein, in formula (II)

[0134]

[0135] R 1 is H or a group according to the formula

[0136] Among them, in the above formula

[0137] R 6 , R 7 , R 9 and R 10for H-atoms, and

[0138] R 8 is an H-atom or a morpholinyl group;

[0139] R 2 , R 3 , R 4 and R 5 is an H-atom; and

[0140] Q 5 , Q 6 and Q 7 As follows: Q 5 for S-atoms and Q 6 and Q 7 is CH, or Q 7 for S-atoms and Q 5 and Q 6 is CH, or Q 5 N-CH3 and Q 6 for N-atom and Q 7 For CH,

[0141] And pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0142] 5. The following compounds of formula (I) or formula (II) according to items 1 to 4:

[0143] 3a-Hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

[0144] 9-Hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0145] 7-Hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ]dodeca-1(9),2,11-trien-8-one,

[0146] 9-Hydroxy-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,

[0147] 3a-Hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one,

[0148] 8a-Hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one,

[0149] 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,

[0150] 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,

[0151] (9S)-9-Hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0152] (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,

[0153] (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,

[0154] (9S)-9-hydroxy-12-(4-methoxyphenyl)-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0155] (9S)-9-Hydroxy-12-[4-(trifluoromethoxy)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0156] (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,

[0157] (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,

[0158] (9S)-2-(4-{9-hydroxy-8-oxo-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] dodeca-1,3(7),5-trien-12-yl}phenyl)acetonitrile,

[0159] (9S)-9-hydroxy-12-[4-(hydroxymethyl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0160] (9S)-9-Hydroxy-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0161] (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-one,

[0162] 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,

[0163] 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,

[0164] 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,

[0165] 9-Hydroxy-5-methyl-12-[4-(trifluoromethoxy)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3 ,7 ]dodeca-1,3(7),5-trien-8-one,

[0166] 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,

[0167] 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,

[0168] 2-(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}phenyl)acetonitrile,

[0169] 9-Hydroxy-12-[4-(hydroxymethyl)phenyl]-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0170] 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,

[0171] 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-one,

[0172] 9-Hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0173] (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,

[0174] 12-[4-(Methyl)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0175] 3a-Hydroxy-1-[4-(trifluoromethoxy)phenyl]-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

[0176] 1-(4-acetylphenyl)-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

[0177] 1-[4-(Methyl)phenyl]-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

[0178] 3a-Hydroxy-1-[4-(morpholin-4-yl)phenyl]-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

[0179] (9S)-12-[4-(dimethylamino)phenyl]-9-hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one,

[0180] 12-[4-(Dimethylamino)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3 ,7 ]dodeca-1,3(7),5-trien-8-one,

[0181] 1-[4-(Dimethylamino)phenyl]-3a-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one,

[0182] 3a-Hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one.

[0183] 6. A compound according to any one of items 1 to 5 for use in the treatment of conditions and diseases selected from the group consisting of: proplatelet formation; chemotherapy; cancer metastasis; leukemia cell migration; thrombosis, including arterial thrombosis, including ischemic stroke; nerve and muscle damage, including neuronal apoptosis and spinal cord injury; drug prevention, including methamphetamine use-related relapse, and prevention of drug-related disorders; peripheral neuropathy; liver cancer; lung cancer; benign prostatic hyperplasia; length-dependent neuropathy; fibrosis, including pulmonary, liver and joint fibrosis; wound healing; hemostasis and thrombosis, including clot retention; periodontitis; pathological apoptosis; immune diseases, including multiple sclerosis; viral diseases, including those caused by herpes; hypertension; pulmonary (arterial) hypertension; erectile dysfunction; thrombotic disorders (thrombotic urinary problems, including overactive bladder and bladder obstruction; cardiomyopathies, including hypertrophic cardiomyopathy and dilated cardiomyopathy; muscle spasms, including nonspecific low back pain, lumbar spasms or spasmodic spasm, stress-induced occiput spasm, prolonged muscle spasms in limbs in epilepsia partialis continua, post-stroke spasticity, muscle spasms in cerebral palsy and multiple sclerosis, vaginismus, musculoskeletal muscle spasms during labor, and smooth muscle spasms; drug-induced seizures; and muscle disorders of cardiac and skeletal muscle, including altered ability of myofilaments to exert effort. DETAILED DESCRIPTION

[0184] The present invention relates to: a compound of formula (I) or formula (II) as described above in item 1, wherein the identifier in the formula is as defined in item 1; and pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0185] One group of compounds of the present invention is: compounds of formula (I) or formula (II) as described above, wherein the identifier in the formula is as defined in item 2; and pharmaceutically acceptable salts, solvates, tautomers; stereoisomers thereof, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0186] Another group of compounds of the present invention are: compounds of formula (I) or formula (II) as described above in item 3, wherein the identifier in the formula is as defined in item 3; and pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0187] Other groups of compounds of the present invention are: compounds of formula (I) or formula (II) as described above in item 4, wherein the identifier in the formula is as defined in item 4; and pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, wherein the stereoisomers include enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0188] Other groups of compounds of the present invention are compounds of formula (I) or formula (II), as described above in item 5, which are further identified by their chemical names; and pharmaceutically acceptable salts, solvates, tautomers, stereoisomers thereof, including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers, or combinations thereof.

[0189] As mentioned above, the compounds of the present invention may exist as racemic mixtures and as optical isomers, in the form of one enantiomer present in pure form or predominantly. It should be appreciated that racemic mixtures, as well as enantiomers present in pure form or predominantly in a mixture compared to the other enantiomer, are subject of the present invention.

[0190] According to imine-amine 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-on, whose equilibrium forms differ from each other in the positions of protons and double bonds. This applies to certain compounds of the present invention.

[0191] Some compounds of the present invention may contain one or more chiral centers, and therefore may exist in enantiomeric or diastereomeric forms. The subject matter of the present invention is intended to include all isomers of itself, and mixtures of cis and trans isomers, mixtures of diastereomers, and mixtures of enantiomers (optical isomers). In addition, well-known technology may be used to separate different forms, and the present invention may include purified or concentrated forms of specific enantiomers or diastereomeric species.

[0192] The present invention also relates to pharmaceutically acceptable salts and solvates of the compounds of the present invention.

[0193] Human myosin 2 isoforms play important roles in the development of medical indications related to neurological muscle, skeletal muscle, cardiac muscle and smooth muscle, as well as cell division and cell migration.

[0194] In the nervous system, the role of human myosin 2 isoforms in apoptosis and neural regeneration processes in neural injury is significant, as is the development of specific memories associated with drug use. Based on these effects, the claimed myosin 2 inhibitors can be used to improve the symptoms of neurodegenerative disorders, neurological disorders, psychiatric disorders and nervous system disorders and neuronal damage, such as but not limited to schizophrenia, cerebral ischemia, stroke, neuropathic pain, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotropic lateral sclerosis, Huntington's disease, addiction, brain tumors, brain asphyxia, post-traumatic stress syndrome and multiple sclerosis. In addition, depression, obsessive-compulsive disease, hallucinations, auditory hallucinations, eating disorders, bipolar disorder, cerebellar ataxia, cerebrovascular damage, corticobazal ganglion degeneration, Creutzfeldt-Jakob Syndrome, Dandy-Walker Syndrome, dementia, encephalitis, encephalomyelitis, epilepsy, Hallervorden-Spatz Syndrome, hydrocephalus, lacunar infarction, Landau-Kleffner Syndrome, Lewy-Body Disease, Machado-Joseph Disease, Meige Syndrome, Shy-Drager Syndrome, Syndrome), neuroaxoneal dystrophies, spinocerebellar ataxias, spinocerebellar degenerations, and Tourette syndrome.

[0195] The active compounds that are the subject of the present invention are suitable for relieving the symptoms of disorders associated with muscle spasms by relaxation of skeletal muscles, such as, but not limited to, nonspecific lower abdominal pain, muscle spasms associated with lumbago or cartilage hernia, or in epilepsy continua, prolonged muscle spasms of the limbs, and as an additional symptom, muscle spasms in multiple sclerosis, gynecological indications including vaginismus, skeletal and smooth muscle spasms during childbirth, muscle diseases of the heart and skeletal muscles in cases of constipation (obstipation).

[0196] Non-limiting further indications for the claimed active ingredient are thrombotic diseases, hypertension, pulmonary (arterial) hypertension, hypertrophic and dilated myocardial distress, urinary problems such as overactive bladder, bladder obstruction or erectile dysfunction.

[0197] Due to their role in cell migration, non-limiting indications for the claimed active ingredients are cancer metastasis, pulmonary fibrosis, liver fibrosis and arthrofibrosis. In addition, non-limiting indications related to wound healing processes are idiopathic keloid and Dupuytren contracture, desmoplastic (cancerous) lesions, autoimmune (sclerodermatous) lesions, inflammatory (Crohn's disease) lesions and infectious (cirrhosis) or traumatic (cicatricial ectropia) lesions.

[0198] The present invention also relates to compounds of the present invention for use in the treatment of conditions and diseases selected from the group consisting of: proplatelet formation; chemotherapy; cancer metastasis; leukemia cell migration; thrombosis, including arterial thrombosis; neural injury, including neuronal apoptosis and spinal cord injury; drug prevention, including prevention of methamphetamine-related relapse and drug abuse-related disorders; peripheral neuropathy; liver cancer; lung cancer; benign prostatic hyperplasia; length-dependent neuropathy; fibrosis, including pulmonary, hepatic and arthrofibrosis; wound healing; hemostasis and thrombosis, including clot retention; periodontitis; pathological apoptosis; immune diseases, including multiple sclerosis dyscrasias; viral diseases, including those caused by herpes viruses; hypertension; pulmonary (arterial) hypertension; erectile dysfunction; thrombotic disorders; urinary problems, including overactive bladder, bladder obstruction; cardiomyopathy, including hypertrophic cardiomyopathy and dilated cardiomyopathy; muscle spasms, including nonspecific low back pain, flank pain, or spasms associated with a herniated disk, stress-induced occipital spasms, prolonged limb muscle spasms in epilepsy continua partialis, and, as an additional symptom, muscle spasms in multiple sclerosis; vaginismus; skeletal and smooth muscle spasms during labor; and drug-induced spasms; muscle disorders of the myocardium and skeletal muscle, including alterations in the force-applying capacity of the myofilaments.

[0199] Preparation of the compounds of the present invention

[0200] The synthesis of the compounds of the present invention having an aromatic heterocycle in the A ring can be achieved by the following reaction scheme:

[0201]

[0202] In Scheme 1, instead of the aromatic ring designated as N, a five-membered ring of formula (II) may also be used, wherein the five-membered ring variables are as defined above in item 1. In addition, the radical R in Scheme 1 has the same radical as R as defined in item 1. 6 , R 7 , R 8 , R 9 , R 10 Same meaning.

[0203] Examples of compounds of the present invention that can be prepared by the above Scheme 1 include, but are not limited to, the following compounds:

[0204]

[0205]

[0206] wherein Q is a C1-6 alkyl group or a haloalkyl group, and R is the same as the R6, R7, R8, R9 and R10 groups as defined in the claims.

[0207] Examples of compounds of the present invention that can be prepared based on Scheme 1 include, but are not limited to, compounds wherein the A ring is a 5-membered aromatic ring containing the same or different heteroatoms selected from N, O or S.

[0208] Hereinafter, the present invention will be described by way of exemplary embodiments, however, these exemplary embodiments should not be construed as limiting the present invention.

[0209] Example

[0210] Example 1: Preparation of 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1)

[0211] Step a) Preparation of Ethyl-3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-4-carboxylate (Compound 1a)

[0212]

[0213] Under argon, 4.36g (27.08mmol, 1eq.) of 1-phenylpyrrolidine-2-one was dissolved in dichloromethane (35mL), and 4.15g POCl (2.5mL, 27.08mmol, 1eq.) was added. After stirring at room temperature for 3 hours, a solution of 5.00g (30.09mmol, 1.1eq.) of ethyl 3-aminopyridine-4-carboxylate in dichloromethane (35mL) was added by dripping top in 5 minutes. The reaction mixture was refluxed for 16 hours. At the end of reflux, the reaction mixture was cooled to room temperature and stirred with saturated NaHCO solution to keep aqueous phase alkaline (aqueous phase alkaline) (pH=8). Due to bubbling, the solution was slowly added. Subsequently, the organic phase was dried with NaSO, 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 + =310.35

[0214] Step b) 1-phenyl-1H,2H,3H,4H,9H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1b)

[0215]

[0216] 5.80 g of the crude product obtained in step a) (compound 1a, 18.76 mmol) was dissolved in dry tetrahydrofuran (140 mL). Under a dry ice-acetone cooling mixture, the crude product was cooled with argon and a solution of 9.42 g (39.2 mL, 56.27 mmol, 3 eq.) of lithium hexamethyldisilazane in 20% tetrahydrofuran was added below -60 ° C. After 1 hour, the reaction mixture was then warmed to room temperature. After 3 hours, the reaction mixture was treated with 2M hydrochloric acid to dissolve all precipitates (about 100 mL). Subsequently, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The aqueous phase was concentrated on a vacuum evaporator until the organic solvent residue was removed. Subsequently, the solution was neutralized by adding a NaHCO3 solution. The precipitate formed was filtered out and dried under vacuum. 3.61 g of crude product was obtained, which was recrystallized from 30 g of dimethylformamide. Yield: 1.74 g of 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). + =264.30

[0217] 1 H NMR (500MHz, DMSO-d6): δ=3.22 (t, J=8.8Hz, 2H), 4.13 (t, J=8.0Hz, 2H), 7.05 (t, J=7.3Hz, 1H), 7.41 (dd, J=7.6 , 8.1Hz, 2H), 7.80 (d, J=5.3Hz, 1H), 8.06 (d, J=8.1Hz, 2H), 8.28 (d, J=5.3Hz, 1H), 8.89 (br, 1H), 10.94 (br, 1H).

[0218] DEPTq (500MHz, DMSO-d6): 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.

[0219] Step c) Preparation of 3a-hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one (Compound 1)

[0220]

[0221] 263 mg (1 mmol) of 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) and cooled with a dry ice-acetone mixture under argon. Below -60 ° C, a solution of 334 mg (1.8 ml, 2 mmol, 2 eq.) of lithium hexamethyldisilazane in 20 wt % tetrahydrofuran was added. Subsequently, 2- (benzenesulfonyl) -3-phenyloxaziridine (522 mg, 2 mmol, 2 eq.) was added and dissolved in dry tetrahydrofuran (15 mL). After half an hour, cooling was stopped and the mixture was allowed to warm to room temperature and stirred overnight. 1M HCl (40 mL) was added to the reaction mixture and extracted with methyl-tert-butyl-ether (3×40 mL). The aqueous phase was concentrated under vacuum to about half its volume and then neutralized with NaHCO 3 . The precipitated orange precipitate was filtered through a glass filter P4, washed with methyl-tert-butyl-ether and dried in 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-naphthyridin-4-one (Compound 1). M+H + =280.30

[0222] 1 H NMR (500MHz, DMSO-d6): δ=2.28 (dd, J=5.8, 13.3Hz, 1H), 2.39 (ddd, J=9.2, 9.4, 13.3Hz, 1H), 4.00 (dd, J=9.2, 10.3Hz, 1H), 4.13 (ddd, J=5.8, 9.4, 10.3Hz, 1H), 7.04 (s, 1H), 7.20 (t, J=7.5Hz, 1H), 7.46 (t, J=7.9Hz, 2H), 7.56 (d, J=4.5Hz, 1H), 8.07 (d, J=8.0Hz, 2H), 8.32 (br, 1H), 8.56 (br, 1H).

[0223] DEPTq (500MHz, DMSO-d6): 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.

[0224] Preparation of 2-(phenylsulfonyl)-3-phenyloxazolidinone: Org. Synth. 1988, 66, 203.

[0225] Example 2: 9-Hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 Preparation of dodeca-1,3(7)-5-triene-8-one (Compound 2)

[0226] Step a) Methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-carboxylate (Compound 2a)

[0227]

[0228] 9.23 g (57.26 mmol, 1 eq.) of 1-phenylpyrrolidine-2-one was dissolved in 70 mL of dry dichloromethane, and 8.78 g (5.3 mL, 57.26 mmol, 1 eq.) of POCl was added under argon. After stirring at room temperature for 3 hours, a suspension of methyl-2-aminothiophene-3-carboxylate (10 g, 63.61 mmol) was added via a funnel in dichloromethane (150 mL). The reaction mixture was refluxed for 16 hours, cooled to room temperature, and extracted with 1 M hydrochloric acid (5×100 mL). The combined aqueous phase was adjusted to pH 9-10 with a saturated Na2CO3 solution. The mixture was extracted with dichloromethane (3×200 mL) and the combined organic layer was dried with Na2SO4. After filtering out the desiccant, 8.39 g of crude product remained after evaporation. The crude product was purified on a silica gel column with hexane-ethyl acetate. The appropriate fractions were combined and the residue was recrystallized from a 1:1 mixture of heptane:ethyl acetate. Yield: 5.27 g (17.53 mmol, 31%) of methyl 2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-3-carboxylate (Compound 2a), pale yellow crystals.

[0229] 1 H NMR (500MHz, DMSO-d6): δ=2.05 (m, 2H), 2.68t, J= (7.8Hz, 2H), 3.70 (s, 3H), 3.92 (t, J=7.0Hz, 2H), 6.91 (d, J=6. 0Hz, 1H), 7.12 (tt, J=1.1, 7.5Hz, 1H), 7.13 (d, J=6.0Hz, 1H), 7.37 (dd, J=7.5, 8.8Hz, 2H), 7.83 (d, J=8.8Hz, 2H).

[0230] DEPTq (500MHz, DMSO-d6): 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.

[0231] Step b) 12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 Preparation of 12-1(9),3(7),5-triene-8-one (Compound 2b)

[0232]

[0233] Methyl 2-{[(2E)-1-phenylpyrrolidine-2-ylidene]amino}thiophene-3-carboxylate (Compound 2a) (3.38 g, 12.75 mmol) was dissolved in dry tetrahydrofuran (50 mL). A tetrahydrofuran solution of 2.86 g potassium-tert-butylate (14 mL, 25.51 mmol, 2 eq.) was added thereto, and the reaction mixture was refluxed under argon. After adding alkali, the solution turned red and precipitated out after a few minutes. The reaction was tracked by LCMS. After reflux for 3 hours, the mixture was cooled to room temperature, and 5 ml of acetic acid was added under stirring to dissolve the precipitate. The mixture was concentrated in a vacuum to leave a brown viscous substance, which was ground 3 times with a mixture of 30 mL of MeOH and 30 mL of toluene to leave a crystalline substance. The crystalline substance was stirred with water (30 mL), filtered and washed with water. 3.25 g of crude product were obtained which were crystallized from 14 g of acetonitrile and dried in vacuo at 40° C. Yield: 2.16 g (8.06 mmol, 63%) of 12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1(9),3(7),5-triene-8-one (Compound 2b), which is a light brown powder. M+H + =269.00

[0234] 1 H NMR (500MHz, DMSO-d6): δ=3.10 (t, J=8.4Hz, 2H), 4.07 (t, J=8.4Hz, 2H), 6.96 (t, J=7.4Hz, 1H), 7.22 ( d, J=6.0Hz, 1H), 7.36 (d, J=6.0Hz, 1H), 7.35 (t, J=7.5Hz, 2H), 7.86 (d, J=8.2Hz, 2H), 10.60 (br, 1H).

[0235] DEPTq (500MHz, DMSO-d6): 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.

[0236] Step c) 9-hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Dodeca-1,3(7),5-triene-8-one (Compound 2)

[0237]

[0238] 526 mg (1.96 mmol) of 12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Twelve-1 (9), 3 (7), 5-triene-8-one (compound 2b) and 30 mL of dry tetrahydrofuran were weighed into a septum-filled round-bottom flask, and an argon balloon was placed on the round-bottom flask. A thermometer and a stopper were placed on the other two necks of the flask. The container was cooled with a dry ice-acetone mixture, and a solution of 656 mg (3.6 mL, 3.92 mmol, 2 eq.) of lithium hexamethyldisilazane in tetrahydrofuran was added via a syringe below -60 ° C. Subsequently, a solution of 2-(benzenesulfonyl)-3-phenyloxynitrocyclopropane (563 mg, 2.15 mmol, 1.1 eq.) in dry tetrahydrofuran (5 mL) was added below -60 ° C. It was then heated for 1 hour. After a few hours, a yellow precipitate appeared. The reaction mixture was stirred at room temperature overnight. The reaction was checked by thin layer chromatography. When the starting material is exhausted, add 40 mL of 2M hydrochloric acid and 40 mL of methyl-tert-butyl-ether and shake. The organic layer is extracted with 1M hydrochloric acid (3×40 mL), and the combined aqueous phase is extracted with 30 mL of methyl-tert-butyl-ether. The aqueous phase is extracted with dichloromethane (3×40 mL), the organic phases are combined, dried over Na2SO4, filtered and evaporated. The crude product is crystallized from acetonitrile. Yield: 207 mg (0.73 mmol, 37%) of 9-hydroxy-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Dodeca-1,3(7),5-triene-8-one (Compound 2), orange crystals. M+H + =285.00

[0239] 1H NMR (500MHz, DMSO-d6): δ = 2.25 (m, 2H), 4.04 (m, 1H), 4.17 (m, 1H), 6.93 (s, 1H), 6.96 (d, J = 5.4Hz , 1H), 7.10 (d, J=5.4Hz, 1H), 7.21 (t, J=7.5Hz, 1H), 7.46 (t, J=7.5Hz, 2H), 7.95 (d, J=8.0Hz, 2H).

[0240] DEPTq (500MHz, DMSO-d6): 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.

[0241] Example 3: 7-Hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ] Dodeca-1(9),2,11-triene-8-one (Compound 3)

[0242] Step a) Methyl 3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-2-carboxylate (Compound 3a)

[0243]

[0244] 5.00 g (31.02 mmol, 1 eq.) of 1-phenylpyrrolidone-2-one was dissolved in 35 mL of dry dichloromethane and 4.76 g (2.83 mL, 31.02 mmol, 1 eq.) of POCl was added. After stirring for 3 hours under argon, a solution of 5.42 g of methyl-3-aminothiophene-2-carboxylate (34.46 mmol, 1.1 eq.) in 35 mL of dichloromethane was added. Subsequently, the reaction mixture was refluxed for 16 hours. 10% NaCO solution was added so that the pH of the aqueous phase was about 8-9 after stirring for 5 minutes. The aqueous phase was extracted with dichloromethane (3×50 mL), and the organic phases were combined and subsequently evaporated. The crude product thus obtained was dissolved in 50 mL of isopropyl acetate and extracted with 5×40 mL of 1M hydrochloric acid. The pH of the aqueous phase was adjusted to 8 with 10% Na2CO3 and extracted with dichloromethane (3×50 mL). After drying with Na2SO4, the solution was filtered and concentrated to about 2 mL. Subsequently, 20 mL of heptane was added and evaporation was continued until colorless plate-like crystals appeared in the turbid solution. The crystals were filtered out, washed with heptane and dried in vacuo. Yield: 2.78 g (9.24 mmol, 30%), methyl 3-{[(2E)-1-phenylpyrrolidine-2-ylidene]amino}thiophene-2-carboxylate (Compound 3a). M+H+ =301.10

[0245] 1 H NMR (500MHz, DMSO-d6): δ=1.99 (m, 2H), 2.50 (m, 2H), 3.71 (s, 3H), 3.86 (t, J=6.8Hz, 2H), 6.70 (d, J=5.2Hz, 1H), 7.07 (tt, J=1.1, 7.5Hz, 1H), 7.35 (dd, J=7.5, 8.5Hz, 2H), 7.72 (d, J=5.2Hz, 1H), 7.86 (d, J=8.5Hz, 2H).

[0246] DEPTq (500MHz, DMSO-d6): 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.

[0247] Step b) 4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ]12-1(9),3(7),11-triene-8-one (Compound 3b)

[0248]

[0249] To methyl-3-{[(2E)-1-phenylpyrrolidine-2-ylidene]amino}thiophene-2-carboxylate (2.51 g, 8.35 mmol), 32 mL of dry tetrahydrofuran was added, followed by a solution of 1.87 g (10.3 mL, 16.69 mmol, 2 eq.) of potassium tert-butyrate in tetrahydrofuran. The reaction mixture was refluxed under argon for 3 hours (monitored by TLC). After cooling, 20 mL of 1 M hydrochloric acid was added and the tetrahydrofuran was evaporated in vacuo. Saturated NaHCO3 solution was added to the aqueous residue until neutral pH and stirred for half an hour, then filtered, washed with water (2×10 mL) and dried in vacuo. Yield: 2.05 g (7.65 mmol, 92%) 4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ]12-1(9),3(7),11-triene-8-one (Compound 3b)

[0250] 1H NMR (500MHz, DMSO-d6): δ=3.15 (dd, J=7.9, 8.2Hz, 2H), 4.07 (t, J=8.4Hz, 2H), 6.96 (t, J=7.3Hz, 1H), 7.2 7 (d, J=5.4Hz, 1H), 7.35 (dd, J=7.7, 8.5Hz, 2H), 7.76 (d, J=5.4, 1H), 7.92 (d, J=8.5Hz, 2H), 11.0 (w, 1H).

[0251] DEPTq (500MHz, DMSO-d6): 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.

[0252] Step c) 7-hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ]12-1(9),2,11-triene-8-one (Compound 3)

[0253]

[0254] 537 mg (2 mmol, 1 eq.) of 4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ] Twelve-1(9),3(7),11-triene-8-one (compound 3b) and 784mg (3mmol, 1.5eq.) of 2-(phenylsulfonyl)-3-phenyloxazine cyclopropane and 20mL of dry tetrahydrofuran were poured into a septum-sealed container. The container was sealed and a balloon filled with argon was placed in the septum. The solution was cooled with ice water and a solution of 669mg (3.6mL, 4mmol, 2eq.) of lithium hexamethyldisilazane in 20% tetrahydrofuran was added to the solution via a syringe within 1 minute. The solution was allowed to warm to room temperature and stirred overnight. After 1 hour, the solution had a bright yellow precipitate. Subsequently, 40mL of methyl-tert-butyl-ether and 40mL of 2M hydrochloric acid were added and shaken. The organic phase was extracted twice or more with 20mL of 2M hydrochloric acid, and the combined aqueous phase was adjusted to pH=8 with 40% NaOH. The 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 was crystallized from acetonitrile. Yield: 333 mg (1.17 mmol, 59%) of 7-hydroxy-4-phenyl-10-thia-2,4-diazatricyclo[7.3.0.0 3,7 ] Dodeca-1(9),2,11-triene-8-one (Compound 3), bright yellow crystals. M+H +=285.00

[0255] 1 H NMR (500MHz, DMSO-d6): δ=2.23 (dd, J=5.8, 12.9Hz, 1H), 2.29 (ddd, J=8.0, 9.8, 12.9Hz, 1H), 4.02 (dd, J=8.0, 9.5Hz, 1H), 4.15 (ddd, J=5.8, 9.5, 9.8Hz, 1H ), 6.94 (s, 1H), 7.05 (d, J = 5.1Hz, 1H), 7.19 (tt, J = 1.1, 7.4Hz, 1H), 7.44 (tdd , J=2.1, 7.4, 8.8Hz, 2H), 8.01 (td, J=1.1, 8.8Hz, 2H), 8.03 (d, J=5.1Hz, 1H).

[0256] DEPTq (500MHz, DMSO-d6): 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.

[0257] Example 4A: Synthesis of pyrrolothienopyridine and pyrrolonaphthyridine derivatives

[0258] 4A.1 Preparation of 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one

[0259] 4-Chloro-N-[(4-methoxyphenyl)methyl]-butyramide:

[0260]

[0261] To 768g (554mmol, 1eq.) 4-methoxybenzylamine in 370mL dry dichloromethane in an inert flask under argon, 93mL (67.34g, 665mmol, 1.2eq.) triethylamine and 39g (28mmol, 5mol%) N,N-dimethylaminopyridine were added, and the reaction mixture was cooled to 5°C. A solution of 4-chlorobutyryl-chloride (68.5mL, 86.02g, 610mmol, 1.1eq.) in 40mL dry dichloromethane was added dropwise to the reaction mixture at 5-15°C. The mixture was allowed to warm to room temperature and then stirred at room temperature for 24 hours. The mixture was washed with water (400mL), 5% citric acid solution (2×400mL) and a saturated solution of NaHCO3 (100mL) and separated. The organic layer was dried with Na2SO4. Subsequently, the solution was filtered, evaporated, and the precipitated crystals were stirred with 200 ml of heptane overnight. Subsequently, they were filtered through a glass filter, washed with cold heptane and then dried under vacuum at 40° C. Yield: 107.27 g of a white solid (443 mmol, 80%). Rf=0.66 Dichloromethane:methanol 95:5

[0262] 1 H NMR (CDCl3, 500MHz): δ2.12 (m, 2H), 2.37 (t, J=7.2Hz, 2H), 3.60 (t, J=6.2Hz, 2H), 4.36 (d, J=5.6Hz, 2H), 5.87 (bs, 1H), 6.86 (d, J=8.6Hz, 2H), 7.19 (d, J=8.6Hz, 2H).

[0263] 13C DEPTq NMR (CDCl3, 500MHz): δ28.3, 33.4, 43.3, 44.7, 114.1, 114.3, 129.3, 130.4, 159.2, 171.5.

[0264] 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one:

[0265]

[0266] In an inert flask under an argon atmosphere, 105.00g (434mmol, 1eq.) of 4-chloro-N-[(4-methoxyphenyl)methyl]butyramide was dissolved in 330mL of dry tetrahydrofuran, and 321mL (58.49g, 521mmol, 1.2eq.) of 20.1% by weight potassium tert-butyrate solution in tetrahydrofuran was added dropwise, and the dropping funnel was washed into the flask with 40mL of tetrahydrofuran. The reaction is exothermic and warms to boiling. The addition is controlled so that the reaction mixture maintains a gentle reflux. Subsequently, the mixture is stirred at reflux for 2 hours. The reaction is monitored by thin layer chromatography. 15mL (15.74g, 262mmol, 0.6eq.) of acetic acid is added to the cooled reaction mixture. Subsequently, an exothermic reaction occurs. Water (60mL) is subsequently added and the solution is poured out from the solid residue. The solid was washed with 50 mL of methyl tert-butyl ether and the combined organic phase was evaporated. The residue was dissolved in 200 mL of methyl tert-butyl ether and then extracted with saturated NaHCO3 (100 mL) solution. The pH of the aqueous phase was adjusted to 8. Subsequently, the organic phase was separated. The aqueous phase was further extracted with 100 mL of ethyl acetate and the combined organic phase layer was dried with 100 mL of NaCl and then dried with Na2SO4. Subsequently, the solvent was evaporated in vacuo. The product can be purified by vacuum distillation, mp 151-158°C, 0.64 mbar. Yield: 77.03 (375 mmol, 86%). Rf=0.24-0.56 patch, dichloromethane: methanol 95:5. Monitoring: alkaline KMnO4 solution. ESI-MS (M+H + )=206

[0267] 1 H NMR (DMSO-d6, 500MHz): δ1.97 (m, 2H), 2.42 (t, J=8.1Hz, 2H), 3.24 (t, J=7.1Hz , 2H), 3.79 (s, 3H), 4.38 (s, 2H), 6.85 (d, J=8.7Hz, 2H), 7.17 (d, J=8.7Hz, 2H).

[0268] 13 C DEPTq NMR (DMSO-d 6 , 500Mhz): δ17.8, 31.2, 46.1, 46.6, 55.4, 114.2, 128.9, 129.6, 159.2, 174.9.

[0269] 4A.2 Preparation of 1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-one

[0270] 4-Chloro-N-[4-(morpholin-4-yl)phenyl]butyramide

[0271]

[0272] In a one-liter three-necked round-bottom flask, 26.72g (150mmol, 1eq.) 4-(4-aminophenyl)-morpholine, 25mL (18.20g, 180mmol, 1.2eq.) triethylamine and 260mL dry dichloromethane were filled. The flask was equipped with a drip top, a CaCl2 tube and a thermometer, and then the flask was cooled to 5-10°C with ice water. Subsequently, 5-chloro-butyric acid chloride (18.5mL, 23.27g, 165mmol, 1.1eq.) was added at 5-10°C in 1 hour and 25 minutes. The precipitate was formed at the end of the addition. The reaction was monitored by thin layer chromatography. After the starting material was exhausted (1 hour and 15 minutes after the addition was completed), saturated NaHCO3 solution (170mL) was slowly added (bubbling!). After stirring for 10 minutes, the organic phase was separated from the precipitate and evaporated. The crude product was recrystallized from 300 mL of ethanol by adding 5 spoons of charcoal. Yield: 20.53 g (72.60 mmol, 48%). ESI-MS (M+H + )=283. Rf=0.47 Dichloromethane:methanol 10:2.

[0273] 1 H NMR (DMSO-d6, 500MHz): δ2.01 (m, 2H), 2.43 (t, J=7.3Hz, 2H), 3.02 (m, 4H), 3.69 (t, J =6.6Hz, 2H), 3.72 (m, 4H), 6.87 (d, J = 9.1Hz, 2H), 7.44 (d, J = 9.1Hz, 2H), 9.72 (s, 1H).

[0274] 13 C DEPTq NMR (DMSO-d 6 , 500Mhz): δ28.0, 33.2, 45.0, 49.0, 66.1, 115.4, 120.2, 131.5, 147.0, 169.4.

[0275] 1-[4-(Morpholin-4-yl)phenyl]pyrrolidin-2-one

[0276]

[0277] In a 250mL three-necked round-bottom flask, 18.64g (65.92mmol, 1eq.) of 4-chloro-N-[4-(morpholine)-4-yl)phenyl]butyramide was dissolved in 140mL of dry tetrahydrofuran. The flask was equipped with a thermometer, a drip top and a reflux condenser, and the cooler was equipped with a diaphragm and a balloon filled with argon. Potassium tert-butyrate (49ml, 20.1%) (8.88gKOtBu, 79.10mmol, 1.2eq.) in tetrahydrofuran was slowly added to the solution. Subsequently, the solution was boiled until the starting material was exhausted. The reaction was monitored by thin layer chromatography. Subsequently, water (50mL) and saturated NaCl (50mL) were added, and the mixture was shaken and separated. The aqueous phase was extracted with 2-methyl-tetrahydrofuran (3×50mL). The combined organic phase was dried, filtered and concentrated with Na2SO4. The material was recrystallized from 80 g of ethanol together with the crystals precipitated during the extraction. Yield: 12.76 g (51.82 mmol, 79%) of white crystals. ESI-MS (M+H + ) = 247. Rf = 0.30 Isopropyl acetate: methanol 10: 1 + 1% triethanolamine (TEA).

[0278] 1 H NMR (500MHz, DMSO-d6): δ2.03 (m, 2H), 2.44 (t, J=8.0Hz, 2H), 3.06 (m, 4H), 3.7 3 (m, 4H), 3.77 (t, J=7.0Hz, 2H), 6.93 (d, J=9.1Hz, 2H), 7.48 (d, J=9.1Hz, 2H).

[0279] 13 C DEPTq NMR (DMSO-d6, 500Mhz): δ17.4, 32.0, 48.2, 48.7, 66.0, 115.1, 120.6, 131.8, 147.6, 173.0.

[0280] 4A.3 Preparation of 4-(4-iodophenyl)morpholine

[0281]

[0282] In the three-necked round-bottomed flask of 500mL, 4-(4-aminophenyl) morpholine of 25g (140mmol, 1eq.) is dissolved in the dry acetonitrile of 300mL.On this flask, place thermometer, dripping liquid top and reflux condenser, and on condenser, place silicone oil scrubber.Methylene iodide (34mL, 112.7g, 420mmol, 3eq.) is added to solution.Argon gas lentamente passes through this equipment, and under stirring at room temperature, adds 90% tert-butyl nitrite of 28mL (26.19g, 210mmol, 1.5eq.).After stirring at room temperature for 1 hour, mixture was stirred at 60 ℃ for 2 hours and 40 minutes.At this moment, thin layer chromatography no longer shows starting material.Replace reflux condenser with 20cm Vigreux column and distillation column subsequently, and under vacuum, volatile matter is distilled out. The residue was dissolved in 200 mL of dichloromethane and extracted with 20 mL of saturated NaHCO and 20 mL of 10% Na2S2O3. The organic layer was separated, evaporated to 100 mL and filtered through silica gel with dichloromethane (150 g). Washed with dichloromethane until the product was detected in the filtrate by TLC. After evaporation, 24.12 g of crude product was obtained, which was recrystallized from 280 g of acetone. Yield: 18.28 g (63 mmol, 45%) of pale yellow crystals. Rf=0.53 ethyl acetate: cyclohexane 2:1.

[0283] 1 H NMR (DMSO-d6, 500MHz): δ3.08 (t, J=5.0Hz, 4H), 3.71 (t, J=5.0Hz, 4H), 6.77 (d, J=9.0Hz, 2H), 7.50 (d, J=9.0Hz, 2H).

[0284] 13 C DEPTq NMR (DMSO-d6, 500MHz): δ47.8, 65.9, 80.9, 117.4, 137.2, 150.6.

[0285] 4A.4 9-Hydroxy-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 Preparation of 1,3(7),5-triene-8-one

[0286] Methyl-2-{[(2E)-1-[4-(morpholin-4-yl)phenyl]pyrrolidin-2-ylidene]amino}thiophene-3-carboxylate

[0287]

[0288] In an inert three-necked flask under argon, 7.11g (28.89mmol, 1eq.) of 1-[4-(morpholine-4-yl)phenyl]pyrrolidin-2-one was dissolved in 40mL of dry dichloromethane. The flask was equipped with a drop top, a reflux condenser, and a CaCl2 tube was placed on the top of the flask. A solution of 4.9mL (8.15g, 28.89mmol, 1eq.) trifluoromethanesulfonic acid-anhydride was added dropwise in 5mL of dry dichloromethane at room temperature in 5 minutes. The temperature rose to 35°C and the mixture was allowed to cool to room temperature subsequently. In a few minutes, black tar was released, followed by a solution of 4.99g (31.78mmol, 1.1eq.) 2-aminothiophene-3-carboxylic acid-methyl ester added in 40ml of dry dichloromethane in 5 minutes. The reaction mixture was stirred at reflux for 24 hours. 60 mL of saturated Na2CO3 solution was slowly added to the cooled reaction mixture and stirred for 10-15 minutes. After phase separation, the organic phase was concentrated. It was dried over Na2SO4, filtered and evaporated. The residue was used without further purification. Yield: 10.00 g of dark brown oil, crude product. LCMS (M+H + )=386.

[0289] 12-[4-(Morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]12-1(9),3(7),5-trien-8-one

[0290]

[0291] 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-necked round-bottom flask. The flask was equipped with a drip top and a reflux condenser, the latter with a CaCl2 tube. The apparatus was made inert with argon and 32 mL of a 20.1 wt% solution of potassium tert-butyrate (5.82 g KOtBu, 51.88 mmol) was added dropwise from the drip top over 5 minutes. The solution was then boiled for 6 hours. The solution was then cooled, neutralized and evaporated. The residue was purified by column chromatography on 80x weight silica gel with ethyl acetate containing 1% pyridine-acetic acid-water 20:6:1 mixture. Yield 976 mg (2.76 mmol, 9.6%). ESI-MS (M+H + )=354.

[0292] 1H-NMRδ(500MHz DMSO-d6 T=300K): 3.04 (m, 4H), 3.07 (t, J=8.3Hz, 2H), 3.74 (m, 4H), 4.01 (t, J=8.3Hz, 2H), 6.96 (d, J= 9.1Hz, 2H), 7.17 (d, J=6Hz, 1H), 7.32 (d, J=6.0Hz, 1H), 7.70 (d, J=9.1Hz, 2H), 10.47 (s, 1H).

[0293] 13 C DEPTq NMRδ (126MHz DMSO-d6): 21.6, 49.1, 49.3, 66.1, 104.3, 115.7, 117.7, 117.9, 118.1, 118.7, 134.9, 145.5, 149.5, 153.8, 159.9, 160.3.

[0294] 9-Hydroxy-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]12-1,3(7),5-trien-8-one(188)

[0295]

[0296] 600 mg (1.69 mmol, 1 eq.) of 12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7] Twelve-1 (9), 3 (7), 5-triene-8-one and 665mg (2.55mmol, 1.5eq.) of 2- (benzenesulfonyl) -3- phenyloxy nitrogen cyclopropane were weighed into a spiral glass jar. Dry tetrahydrofuran (30mL) was added, and the spiral glass jar was made inert with argon and sealed with a septum cover. A balloon filled with argon was placed in the septum. The container was then cooled with ice water. 3.1g of 20.7% LiHMDS solution (568mgLiHMDS, 3.39mmol, 2eq.) in tetrahydrofuran was added through the septum via a syringe. Stir at room temperature for 24 hours. Subsequently, 40mL of methyl-tert-butyl-ether and 40mL of 2M hydrochloric acid were added, and shaken and separated. The organic layer was extracted twice with 20mL of 2M hydrochloric acid and the combined aqueous phase was extracted with 40ml of methyl tert-butyl ether. The aqueous phase was neutralized with 10% Na2CO3 (bubbling!). At the same time, an orange-red precipitate formed. The precipitate 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 could be extracted from the aqueous phase with 3×40 mL of 2-methyl-tetrahydrofuran. The combined yield was 488 mg (1.32 mmol, 49%). ESI-MS (M+H + )=370.

[0297] 1 H-NMRδ(500MHz DMSO-d6 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, 1H), 6 .88 (d, J=5.7Hz, 1H), 7.02 (d, J=9.1Hz, 2H), 7.06 (d, J=5.7Hz, 1H), 7.77 (d, J=9.1Hz, 2H).

[0298] 13 C DEPTq NMRδ (126MHz DMSO-d6): 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.

[0299] 4A.5 9-Hydroxy-5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 Preparation of 1,3(7),5-triene-8-one

[0300] Methyl 5-methyl-2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}thiophene-2-carboxylate

[0301]

[0302] In an inert three-necked flask under argon, 5.00g (31.02mmol, 1eq.) of 1-phenylpyrrolidine-2-one was dissolved in the dry dichloromethane of 35mL. Dropwise addition of a droplet top, reflux condenser and CaCl2 pipe was placed on the flask. The solution of trifluoromethanesulfonic anhydride (5.2mL, 8.75g, 31.02mmol, 1eq) in the dry dichloromethane of 5mL was dropwise added in 5 minutes at room temperature. The temperature rose to boiling, and then allowed to cool to room temperature and stirred for 15 minutes. The solution of 4.99g (31.78mmol, 1.1eq.) 2-amino-5-methylthiophene-3-carboxylic acid methyl ester was dropwise added in the dry dichloromethane of 35mL in 5 minutes. The reaction mixture was stirred for 24 hours under reflux. The saturated NaHCO3 solution of 100mL was added to the reaction mixture of cooling lentamente and stirred for 10-15 minutes (bubbling!). After phase separation, the aqueous phase was extracted with 30 mL of dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was used without further purification. Yield: 4.59 g of dark brown oil. ESI-MS (M+H + )=315. Rf=0.52, cyclohexane:ethyl acetate 1:1.

[0303] 5-Methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]12-1(9),2,5,7-tetraen-8-ol

[0304]

[0305] 4.21 g (13.39 mmol, 1 eq.) of methyl-5-methyl-2-{[(2E)-1-phenylpyrrolidine-2-ylidene]amino}thiophene-2-carboxylate was dissolved in 40 mL of dry tetrahydrofuran and poured into a three-necked round-bottom flask. The flask was equipped with a drop top and a reflux condenser, the latter equipped with a CaCl2 tube. The apparatus was made inert with argon and 15 mL of a 20.1 wt% potassium tert-butyrate solution (2.73 g KOtBu, 24.34 mmol, 1.8 eq.) was added dropwise over 5 minutes. For the calculation of the base, the product of the previous step was considered pure. After reflux for 5 hours, the mixture was cooled to room temperature and 60 mL of a saturated NH4Cl solution was added. Subsequently, the organic phase was extracted with a saturated solution of NaCl (2×30 mL), separated and dried over Na2SO4. After filtration and evaporation, 3.87 g of a brown solid remained which was used without further purification. ESI-MS (M+H+ )=283. Rf=0.40 Cyclohexane:ethyl acetate 1:1.

[0306] 9-Hydroxy-5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]12-1,3(7),5-trien-8-one

[0307] (198)

[0308] 1.00 g (3.55 mmol, 1 eq.) of crude 5-methyl-12-phenyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Twelve-1 (9), 2,5,7-tetraene-8-ol and 1.39g (5.32mmol, 1.5eq.) of 2- (phenylsulfonyl) -3- phenyloxy nitrogen cyclopropane were weighed into a 100mL round-bottom flask. Dry tetrahydrofuran (30mL) was added, and the round-bottom flask was made inert with argon and sealed with a septum. An argon-filled balloon was placed in the septum. The container was then cooled with ice water. 6.5mL of 20.7% LiHMDS solution (1.19g LiHMDS, 7.09mmol, 2eq.) in tetrahydrofuran was added via a syringe. A yellow precipitate was formed. The reaction mixture was stirred at room temperature for 24 hours. Subsequently, 40mL of methyl-tert-butyl-ether and 40mL of 2M hydrochloric acid were added. The organic layer was extracted twice with 20mL of 2M hydrochloric acid, and the combined aqueous phase was concentrated in vacuo to leave the organic solvent. The aqueous phase was neutralized with saturated Na2CO3 (bubbling!) and subsequently adjusted to 8 with saturated NaHCO3 solution. At the same time, a yellow precipitate formed. The precipitate was filtered, washed with water and dried under vacuum at 40°C. Yield: 574 mg (1.92 mmol, 54%). ESI-MS (M+H + )=299. Rf=0.54Cyclohexane:ethyl acetate 1:1.

[0309] 1 H NMR (500MHz, DMSO-d6): δ = 2.22 (m, 2H), 2.34 (s, 3H), 4.03 (m, 1H), 4.15 (m, 1H), 6.79 (d, J = 1.0Hz, 1H), 6.88 (s, 1H), 7.20 (t, J=7.4Hz, 1H), 7.45 (dd, J1=7.4, J2=8.0Hz, 2H), 7.93 (d, J=7.4Hz, 2H).

[0310] 13C DEPTq (500MHz, DMSO-d6): 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.

[0311] 4A.6 9-Hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 Preparation of 1,3(7),5-triene-8-one

[0312] Methyl 2-{[(2E)-1-(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}-5-methylthiophene-2-carboxylate:

[0313]

[0314] In an inert flask under an argon atmosphere, 1-[(4-methoxyphenyl)methyl]pyrrolidin-2-one (24.95g, 121.54mmol, 1eq.) was dissolved in 100mL of dry dichloromethane and cooled to 5-10°C. A solution of trifluoromethanesulfonic anhydride (20.45ml, 34.29g, 121.54mmol, 1eq) in 20mL of dry dichloromethane was added dropwise in about 20 minutes. Allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was cooled to 5-15°C, and a solution of 22.89g (133.7mmol, 1.1eq.) 2-amino-5-methylthiophene-3-carboxylic acid methyl ester in 160mL of dry dichloromethane was added dropwise to the mixture in 15 minutes. The reaction mixture was stirred at reflux for 24 hours. The reaction was monitored by thin layer chromatography (hexane: ethyl acetate 7:3). 140 ml of saturated Na2CO3 solution was slowly added to the cooled reaction mixture and stirred for 10-15 minutes (bubbling!). After phase separation, the organic layer was washed with water (2×100 mL) and evaporated. The residue was dissolved in 100 mL of isopropyl acetate and extracted with 10% citric acid (10×60 mL). The combined aqueous extracts were washed with 60 mL of isopropyl acetate. The aqueous phase was basified to pH~9 with saturated Na2CO3 (100 mL) and 50% NaOH (50 mL) and extracted with isopropyl acetate (3×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Yield: 20.1 g of yellow oil (56.07 mmol, 46%). ESI-MS (M+H + )=359.

[0315] 1H-NMR(500MHz DMSO-d6 T=300K): δ1.90 (m, 2H), 2.27 (d, J=1.2Hz, 3H), 2.49 (t, J=7.3Hz, 2H), 3.27 (t, J=7.3Hz, 2H), 3.65 (s, 3 H), 3.74 (s, 3H), 4.51 (s, 2H), 6.77 (q, J1=1.2Hz, 1H), 6.91 (m, J1=8.6Hz, 2H), 7.30 (m, J1=8.6Hz, 2H).

[0316] 13 C DEPTq NMRδ (126MHz DMSO-d6): 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, 163.0, 163.6

[0317] 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:

[0318]

[0319] 30.28g (84.47mmol, 1eq.) of methyl-2-{[(2E)-1-(4-methoxyphenyl)methyl]pyrrolidine-2-ylidene]amino}-5-methylthiophene-2-carboxylate was dissolved in 750mL toluene, and 500mL toluene was distilled out using a water separator. The residual solvent was evaporated in a vacuum. In an inert flask under argon, the evaporation residue was dissolved in 340mL of dry tetrahydrofuran, followed by addition of 94.31g (18.96g of KOtBu, 168.9mmol, 2eq.) of 20.1m / m% potassium tert-butyrate solution in tetrahydrofuran. The reaction mixture was stirred under reflux, and the reaction was monitored by thin layer chromatography (hexane: ethyl acetate 7:3). After the starting material was exhausted, 38mL (39.9g of 664.4mmol, 7.8eq.) of acetic acid was added to the cooled reaction mixture, and the reaction mixture was concentrated in a vacuum. 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. Subsequently, the pH of the mixture was adjusted to about 8 with saturated NaHCO3 solution (600 mL) and stirred for at least 30 minutes. The filtrate on the glass filter was washed with 3×150 mL of water, 3×150 mL of methyl-tert-butyl-ether. The filtered material was dried in vacuo at room temperature. Yield: 18.83 g (57.69 mmol, 68.29%). ESI-MS (M+H + )=327.

[0320] 1 H-NMRδ(500MHz DMSO-d6 T=300K): 2.42 (s, 3H), 2.87 (t, J=8.3Hz, 2H), 3.32 (t, J=8.3Hz, 2H), 3.72 (s, 3H), 4.4 1 (s, 2H), 6.88 (d, J=8.4Hz, 2H), 6.94 (s, 1H), 7.20 (d, J=8.4Hz, 2H), 10.17 (s, br, 1H).

[0321] 13 C DEPTq NMRδ (126MHz DMSO-d6): 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.

[0322] 5-Methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Dodeca-1(9),2,5,7-tetraen-8-ol:

[0323]

[0324] In an inert flask under argon, 18.82 g (57.66 mmol, 1 eq.) of 12-[(4-methoxyphenyl)methyl]-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Twelve-1 (9), 2,5,7-tetraene-8-ol and 62mL (61.69g, 570.46mmol, 9.89eq) of anisole. Trifluoroacetic acid (35.5mL, 52.56g, 461.26mmol, 8eq.) was added dropwise at room temperature, and the solution was stirred at 70°C for 19h. The reaction was monitored by thin layer chromatography (toluene: dioxane: acetic acid 10:3:1). After the starting material was exhausted, the reaction mixture was cooled to 0-5°C. The hydrochloride of the product was precipitated by adding 340mL of cc. hydrochloric acid. The suspension was stirred for 10-15 minutes and then filtered through a glass filter (by alkalizing to Filter, wash with aqueous and cold acetonitrile, 4.65 g of product can be obtained from the first filtrate), wash with 50 mL of cold acetonitrile and 50 mL of cold ether, and dry under vacuum at 30° C. The 7.76 g of HCl salt thus obtained are suspended in 90 mL of saturated NaHCO solution and stirred for 30 minutes. The HCl salt suspension is filtered on a glass filter with 2×40 mL of water and 20 mL of methyl-tert-butyl-ether, washed, and then dried under vacuum. Yield: 11.33 g of white solid (54.93 mmol, 95.29%).

[0325] 1 H-NMRδ (500MHz DMSO-d6 T=300K): 2.38 (s, 3H), 2.91 (t, J=6.2Hz, 2H), 3.44 (t, J=6.2Hz, 2H), 6.0-3.5 (s, br, 1H), 6.05 (s, br, 1H), 6.93 (s, 1H).

[0326] 13 C DEPTq NMRδ (126MHz DMSO-d6): 15.8, 24.5, 44.0, 101.8, 116.8, 117.8, 128.6, 154.7, 159.9, 165.3.

[0327] 9-Hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Dodeca-1,3(7),5-triene-8-one (231):

[0328]

[0329] In an inert flask under argon, 3.0 g (14.55 mmol, 1 eq.) of 5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Twelve-1 (9), 2,5,7-tetraene-8-ol and 5.70g (21.81mmol, 1.5eq.) 2- (phenylsulfonyl) -3-phenyl oxazolidinone were dissolved in 30mL of dry tetrahydrofuran and cooled to 0-5°C by stirring. A solution of 26.5mL (23.51g, 4.87g, 29.09mmol, 2eq.) LiHMDS in 20.7m / m% tetrahydrofuran was added dropwise to the reaction mixture and allowed to warm to room temperature. The reaction was monitored by thin layer chromatography (toluene: dioxane: acetic acid 10: 3: 1). After the reaction was completed, 50mL of saturated ammonium chloride solution was added to the reaction mixture. 150mL of 2-methyl-tetrahydrofuran and 50mL of water were added to remove the emulsion. After phase separation, the aqueous layer was extracted with methyl-tetrahydrofuran (4 × 50mL). 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 overnight at room temperature and separated from the aqueous phase. It was dried, filtered and evaporated to about 100 mL under vacuum with Na2SO4. The precipitated product was filtered through a paper filter and washed with 2×0 mL 2-methyl-tetrahydrofuran and dried under vacuum at 30°C (0.869 g). The filtrate was concentrated again to about 30 mL, and the precipitated product was filtered through a paper filter again and dried under vacuum (1.265 g). Yield: 2.473 g (11.13 mmol, 76.56%). ESI-MS (M+H + )=223.

[0330] 1 H-NMRδ(500MHz DMSO-d6 T=300K): 2.02 (ddd, J1=13.3Hz, J2=J3=8.4Hz, 1H), 2.12 (dd, J1=13.3Hz, J2=5.2Hz, 1H), 2.27 (d, J=0.9Hz, 3H ), 3.42 (dd, J1=10.7Hz, J2=8.4Hz, 1H), 3.57 (m, 1H), 6.57 (s, br, 1H), 6.64 (q, J=0.9Hz, 1H), 8.96 (s, br, 1H).

[0331] 13C DEPTq NMRδ (126MHz DMSO-d6): 15.0, 31.6, 42.3, 72.9, 118.4, 119.3, 127.2, 174.1, 187.5.

[0332] 4A.7 9-Hydroxy-5-methyl-12-[4-(morpholin-4-yl)phenyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Preparation of dodeca-1,3(7),5-triene-8-one (220):

[0333]

[0334] 400 mg (1.80 mmol, 1 eq.) of 9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Twelve-1,3(7),5-triene-8-one, 412mg (2.15mmol, 1.2eq) copper (I) iodide, 304mg (2.15mmol, 1.2eq.) N,N-dimethyl-cyclohexanediamine, 676mg (3.60mmol, 2eq.) 4-(4-iodophenyl)morpholine, 1.76g (5.40mmol, 3eq.) cesium carbonate, 20mL dry N,N-dimethyl-formamide and 8g dry molecular sieves were filled into a 100mL round-bottom flask. The cesium carbonate was previously dried with P2O5 under vacuum at 120°C for 2 hours. The flask was made inert with nitrogen and sealed with a diaphragm. A balloon filled with nitrogen was placed in the diaphragm. The reaction mixture was stirred at 60°C until the starting material was exhausted. The reaction was monitored by thin layer chromatography and eluted with ethyl acetate. After three days, the reaction no longer continued, and the mixture was subsequently cooled, filtered through Celite, and washed with methanol until the filtrate was yellow. The methanol was evaporated in vacuo, and the residue was poured into saturated NaCl (100 mL). It was extracted with 2-methyl-tetrahydrofuran (3×100 mL). When the emulsion formed, another 100 mL of NaCl solution and 100 mL of 2-methyl-tetrahydrofuran were added. The combined organic phase was extracted with 50 mL of saturated NaCl solution, dried, filtered and evaporated with Na2SO4. 1.6 g of the crude product was evaporated to 5 g of Celite and purified by column chromatography (silica gel, ethyl acetate). The appropriate fraction was evaporated, ground with ether, and the orange precipitate was filtered out. Yield: 308 mg. If necessary, the precipitate was then purified by preparative HPLC. ESI-MS (M+H + )=384.

[0335] 1H NMR (DMSO-d6, 500MHz): δ2.20 (m, 2H), 2.32 (s, 3H), 3.11 (m, 4H), 3.74 (m, 4H), 3.97 (m, 1 H), 4.10 (m, 1H), 6.75 (s, 1H), 6.80 (s, 1H), 7.02 (d, J=9.0Hz, 2H), 7.76 (d, J=9.0Hz, 2H).

[0336] 13 C DEPTq NMR (DMSO-d6, 500MHz): δ15.1, 28.8, 48.3, 49.1, 74.4, 114.9, 119.3, 119.5, 121.6, 129.2, 131.4, 148.2, 168.5, 170.2, 187.3.

[0337] 4A.8 9-Hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 Preparation of 1,3(7),5-triene-8-one

[0338] Methyl-2-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}thiophene-3-carboxylate

[0339]

[0340] Dry 4 neck 500mL round bottom flask is equipped with magnetic stirring bar, equipped with thermometer, drip top, reflux condenser and air inlet.On the top of reflux condenser, place gas scrubber and CaCl2 pipe that are filled with silicone oil.25.02g (122mmol, 1eq.) 1-[(4-methoxyphenyl) methyl] pyrrolidone is added to this flask and is dissolved in the dry dichloromethane of 150mL.Argon is slowly introduced into this device.Solution is cooled to 5-10 ℃, and in 20 minutes, dropwise add the solution of trifluoromethanesulfonic anhydride (20.5mL, 34.39g, 122mmol, 1eq) in 20mL dry dichloromethane.This reaction is exothermic, and maintains the temperature of 5-15 ℃.This solution is stirred at room temperature for 2 hours subsequently, and cools with ice water again subsequently. A solution of methyl-2-aminothiophene-3-carboxylate (21.08 g, 134 mmol, 1.1 eq.) in 100 mL of dry dichloromethane was added at 5-15° C. over a period of 15 minutes. The reaction was exothermic and the mixture was refluxed for 24 hours after the addition. At the same time, the introduction of argon was no longer necessary.

[0341] Subsequently, 140mL of saturated Na2CO3 solution was slowly added to the solution cooled to room temperature, noting foaming. The organic layer was separated, washed twice with water (100mL) and concentrated in vacuo. The residue was dissolved in isopropyl acetate and extracted 7 times with 70mL of 10% citric acid solution. The organic phase was discarded for further treatment. The combined aqueous phase was extracted with 60mL of isopropyl acetate and adjusted to pH 9 with saturated Na2CO3 solution, observing foaming. The mixture was then extracted 3 times with 100mL of isopropyl acetate. The combined organic phase was dried, filtered and concentrated in vacuo with Na2SO4. The residue was purified by column chromatography on silica gel with a gradient of dichloromethane / isopropyl acetate. Yield: 10.70g.

[0342] After extraction with citric acid, the separated organic phase was evaporated after drying and purified by the same chromatography. 6.84 g of pure product could be recovered and the combined yield was 17.54 g (51 mmol, 41.7%) of a yellow oil. Rf = 0.49 cyclohexane-ethyl acetate 1:1. ESI-MS (M+H + )=345.

[0343] 1 H-NMR(500MHz DMSO-d6 T=300K): δ1.90 (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=5.9Hz, 1H), 6.90 (d, J=8.6Hz, 2H), 7.09 (d, J=5.9Hz, 1H), 7.32 (d, J=8.6Hz, 2H).

[0344] 13 C DEPTq NMR (126MHz, DMSO-d6): δ19.0, 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, 163.7, 165.4.

[0345] 12-[(4-methoxyphenyl)methyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]12-1(9),2,5,7-tetraen-8-ol

[0346]

[0347] Methyl-2-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidine-2-ylidene]amino}thiophene-3-carboxylate and 150 mL of toluene are added to a 250 mL round bottom flask. A water separator and reflux condenser are placed on the flask, and reflux is performed until no water is removed. After reflux for 5 hours, the water content is measured and, if the water content is less than 0.04%, the toluene is evaporated in a vacuum. Subsequently, the residue is dissolved in 75 mL of dry tetrahydrofuran and transferred to a 3-necked flask equipped with a reflux condenser, a drip top and an air inlet. Subsequently, potassium tert-butyrate (30 mL) in 20.1% tetrahydrofuran (5.35 g KOtBu, 47.7 mmol, 1.7 eq.) is slowly added at room temperature. A yellow precipitate forms during the addition. The solution is then refluxed under argon until the starting material is exhausted, and the reaction is monitored by thin layer chromatography. After the reaction is completed, the contents of the flask are cooled to room temperature, and 10 mL of citric acid are added dropwise. Subsequently, the reaction mixture is poured into a single-necked round-bottom flask, and the solvent is evaporated in a vacuum. The residue is suspended in 50 mL of toluene, and the solvent is evaporated in a vacuum again. The residue is suspended in 50 mL of water, and the pH is adjusted to 8 (bubbling!) with 160 mL of saturated NaHCO3. The suspension is stirred for 30 minutes and then filtered. The precipitate is washed 3 times with 100 mL of water, followed by 50 mL of methyl-tert-butyl-ether, and dried in a vacuum. Yield: 7.19 g (23.0 mmol, 82%) of light brown powder. Rf = 0.56 Toluene: dioxane: ethyl acetate 10: 3: 1. ESI-MS (M+H + )=313.

[0348] 1 H-NMR(500MHz DMSO-d6 T=300K): δ2.90 (t, J=8.4Hz, 2H), 3.35 (t, J=8.4Hz, 2H), 3.72 (s, 3H), 4.45 (s, 2H), 6.88 (d, J=8 .6Hz, 2H), 7.05 (d, J=5.9Hz, 1H), 7.22 (d, J=8.6Hz, 2H), 7.26 (d, J=5.9Hz, 1H), 10.36 (bs, 1H).

[0349] 13 C DEPTq NMR (126MHz DMSO-d6): δ22.4, 48.0, 48.8, 55.0, 102.3, 113.8, 116.4, 117.3, 118.9, 129.2, 129.7, 153.9, 158.3, 160.9, 163.7.

[0350] 4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]12-1(9),2,5,7-tetraen-8-ol

[0351]

[0352] 4.95 g (15.9 mmol, 1 eq.) of 12-[(4-methoxyphenyl)methyl]-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ] Twelve-1 (9), 2,5,7-tetraene-8-ol was weighed into a round-bottom flask. The solid was suspended in 15.5 mL (143 mmol, 9 eq. of 15.43 g) of anisole. A drip top and reflux condenser were placed on the flask. A CaCl2 tube was placed on top of the cooler. The stream room was flushed with argon, and 10 mL (14.90 g, 130 mmol, 8.2 eq.) of trifluoroacetic acid was added within 5 minutes. At the same time, the solid dissolved. The solution was stirred at 70 ° C for 72 hours, and the reaction was monitored by thin layer chromatography. After the starting material was exhausted, the flask was cooled with ice water, and 10 mL of concentrated hydrochloric acid was added at 0-5 ° C. The mixture was stirred cold for 10 minutes to produce the hydrochloride of the product. Subsequently, the hydrochloride of the product was filtered and washed with cold acetonitrile and ether. The hydrochloride was suspended in 20 mL of saturated NaHCO3 solution, stirred for 30 minutes, and then filtered out the precipitate. The precipitate was washed with water (20 mL) and methyl-tert-butyl-ether (10 mL). Yield: 1.61 g (8.4 mmol, 53%) of light brown powder. Rf = 0.19 Toluene: dioxane: ethyl acetate 10:3:1. ESI-MS (M+H + )=193.

[0353] 1 H-NMR(500MHz DMSO-d6 T=300K): δ2.94 (t, J=8.3Hz, 2H), 3.49 (t, J=8.3Hz, 2H), 6.32 (bs, 1H), 7.00 (d, J=5.9Hz, 1H), 7.23 (d, J=5.9Hz, 1H), 10.21 (bs, 1H).

[0354] 13 C DEPTq NMR (126MHz DMSO-d6): δ24.2, 43.9, 101.8, 116.1, 116.9, 118.8, 153.8, 160.6, 166.0.

[0355] 9-Hydroxy-4-thia-2,12-diazatricyclo[7.3.0.0 3,7]12-1,3(7),5-trien-8-one

[0356]

[0357] An argon-filled balloon was placed in the diaphragm. The container was then cooled with ice water. With a syringe, 2.6 mL of 20.7% LiHMDS solution (437 mg LiHMDS, 2.83 mmol, 2 eq.) in tetrahydrofuran was added via the diaphragm. The reaction mixture then turned brown and the solid dissolved. The reaction was monitored by thin layer chromatography and stirred at room temperature until the starting material was exhausted. Subsequently, saturated NH4Cl (15 mL) was added, and the mixture was extracted with 2-methyl-tetrahydrofuran (3 × 15 mL). The organic phase was combined, dried with Na2SO4, filtered and evaporated. The crude product was purified by column chromatography. Yield: 74 mg (0.36 mmol, 25%) of red solid. The solid was then purified by preparative HPLC. Rf = 0.32 toluene: dioxane: ethyl acetate 10: 3: 1. Rf = 0.38 ethyl acetate. ESI-MS (M+H + )=209.

[0358] 4A.9 Preparation of 8a-hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one

[0359] Methyl-3-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-2-carboxylate

[0360]

[0361] In an inert three-necked flask under argon, 5.00g (31.02mmol, 1eq.) 1-phenylpyrrolidine-2-one is dissolved in the dry dichloromethane of 35mL. Dropwise addition of a droplet top, reflux condenser and CaCl2 pipe is placed on the flask. The solution of trifluoromethanesulfonic anhydride (5.2mL, 8.75g, 31.02mmol, 1eq) in 10mL dry dichloromethane is dropwise added in 2 minutes. Temperature rises until solution boils slightly. Allow to cool to room temperature and stir for 3 hours. Subsequently, the suspension of 5.19g (34.12mmol, 1.1eq.) 3-aminopyridine-2-carboxylic acid methyl ester is carefully added in 35mL dry dichloromethane by a large diameter funnel. The equipment is inerted again with argon, and the reaction mixture is stirred at reflux temperature for 24 hours. To the cooled reaction mixture was slowly added 60 mL of saturated Na2CO3 solution with stirring. After phase separation, the aqueous phase was extracted with dichloromethane (2×40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was used without further purification. Yield: 10.12 g of black oil, which solidified on standing.

[0362] 6-Phenyl-6H,7H,8H-pyrrolo[2,3-b]1,5-naphthyridin-9-ol

[0363]

[0364] The crude methyl 3-{[(2E)-1-phenylpyrrolidine-2-ylidene]amino}pyridine-2-carboxylate obtained in the previous step was dissolved in 80 mL of dry tetrahydrofuran and poured into a three-necked round-bottom flask. The flask was equipped with a drop top and a reflux condenser, the latter equipped with a CaCl2 tube. The apparatus was made inert with argon and 42.5 mL of a 20.1 m / m% potassium tert-butyrate solution (7.68 g KOtBu, 68.53 mmol, 2 eq.) was added dropwise over 5 minutes. For the calculation of the base number, the previous step was considered to be 100%. The reaction mixture precipitated and the precipitate dissolved during the heating. After 24 hours of reflux, the mixture was cooled to room temperature and 5 mL of acetic acid was added. The reaction mixture was diluted with water (300 mL), and the precipitate was filtered out, washed with water and dried in vacuo at 50°C. The crude product was used without further purification. Yield: 4.11 g brown powder. ESI-MS (M+H + )=264.

[0365] 8a-Hydroxy-6-phenyl-6H,7H,8H,8aH,9H-pyrrolo[2,3-b]1,5-naphthyridin-9-one (190):

[0366]

[0367] 1.06g (4.00mmol, 1eq.) of crude 6-phenyl-6H, 7H, 8H-pyrrolo [2,3-b] 1,5-naphthyridine-9-ol and 1.57g (6.00mmol, 1.5eq.) of 2- (phenylsulfonyl) -3-phenyl-oxaziridine cyclopropane were weighed into a 100mL round-bottomed flask. Dry tetrahydrofuran (50mL) was added, and the flask was made inert with argon and sealed with a septum. An argon-filled balloon was placed in the septum. The container was then cooled with ice water. 7.5mL of 20.7% LiHMDS solution (1.34g LiHMDS, 8.00mmol, 2eq.) in tetrahydrofuran was added via a syringe. Stir at room temperature for 5 days. Subsequently, 40mL of methyl-tert-butyl-ether and 40mL of 2M hydrochloric acid were added. A brown precipitate was formed, which was removed by filtration. The filtrate was separated and the organic phase was extracted twice with 20 mL of 2M hydrochloric acid and the combined aqueous phases were concentrated in vacuo to leave the organic solvent. The aqueous phase was neutralized with 10% Na2CO3 (bubbling!). At the same time, a dark orange precipitate formed. The precipitate was filtered, washed with water and dried under vacuum at 40°C. Yield: 185 mg of crude product, which was purified by preparative HPLC. ESI-MS (M+H + )=280.

[0368] 4A.10 3a-Hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one

[0369] Methyl-2-{[(2E)-1-phenylpyrrolidin-2-ylidene]amino}pyridine-3-carboxylate

[0370]

[0371] In an inert three-necked flask under argon, 5.00g (31.02mmol, 1eq.) of 1-phenylpyrrolidine-2-one was dissolved in 35mL of dry dichloromethane. Dropwise addition of a solution of trifluoromethanesulfonic anhydride (5.2mL, 8.75g, 31.02mmol, 1eq) in 10mL of dry dichloromethane was performed in 2 minutes. The temperature rose until the solution was slightly boiling. It was subsequently allowed to cool to room temperature and stirred for 3 hours. The solution of 2-aminopyridine-3-carboxylic acid-methyl-ester (5.19g, 34.12mmol, 1.1eq.) in dry dichloromethane (35mL) was subsequently added, and the reaction mixture was stirred for 48h under reflux. After phase separation, the organic phase was extracted with 40mL of dichloromethane. The combined organic layer was dried, filtered and concentrated with Na2SO4. The residue was used without further purification. Yield: 3.31 g brown oil, some of which solidified on standing. ESI-MS (M+H + )=296.

[0372] 1-phenyl-1H,2H,3H-pyrrolo[2,3-b]-1,8-naphthyridin-4-ol

[0373]

[0374] The crude methyl-2-{[(2E)-1-phenylpyrrolidine-2-ylidene]amino}pyridine-3-carboxylate obtained in the previous step was dissolved in dry tetrahydrofuran (40 mL) and poured into a three-necked round-bottom flask. The flask was equipped with a drop top and a reflux condenser, the latter of which was equipped with a CaCl2 tube. The equipment was made inert with argon and 13.9 mL of a 20.1 m / m% lithium tert-butoxide solution (2.51 g KOtBu, 22.38 mmol, 2 eq.) was added dropwise over 5 minutes. For the calculation of the base number, the previous step was considered to be 100%. A brown precipitate appeared. After reflux for 3 hours, the mixture was cooled to room temperature and 5 mL of 2M hydrochloric acid was added. Subsequently, the pH was adjusted to 8 with saturated NaHCO3. A yellow precipitate was formed, which was filtered out, washed with water and then dried under vacuum. The crude product did not require further purification and could be used. Yield: 1.35 g yellow powder. ESI-MS (M+H + )=264.

[0375] 1H-NMRδ(500MHz DMSO-d6 T=300K): 3.25 (t, J=8.0Hz, 2H), 4.27 (t, J=8.0Hz, 2H), 7.21 (t, J=7.5Hz, 1H), 7.45 (dd, J1=7.5, J2=8.5Hz, 2H), 7.56 (dd, J1=5.7 Hz, J2=7.9Hz, 1H), 7.95 (d, J=8.5Hz, 2H), 8.68 (dd, J1=1.5Hz, J2=5.6Hz, 1H), 8.81 (dd, J1=1.5Hz, J2=7.9Hz, 1H), 10.91 (s, 1H).

[0376] 13 C DEPTq NMRδ (126MHz DMSO-d6 T=300K): 21.8, 50.0, 110.4, 117.0, 117.3, 120.1, 124.3, 128.8, 138.6, 139.7, 141.8, 150.6, 153.6, 163.7.

[0377] 3a-Hydroxy-1-phenyl-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,8-naphthyridin-4-one(189)

[0378]

[0379] 0.79g (3.00mmol, 1eq.) of crude 1-phenyl-1H, 2H, 3H-pyrrolo [2,3-b] 1,8-naphthyridine-4-ol and 1.18g (4.50mmol, 1.5eq.) of 2- (phenylsulfonyl) -3- phenyloxy nitrogen cyclopropane were weighed into a 50mL round-bottomed flask. Dry tetrahydrofuran (30mL) was added, and the round-bottomed flask was made inert with argon and sealed with a septum. An argon-filled balloon was placed in the septum. The container was then cooled with ice water. 5.5mL of 20.7% LiHMDS solution (1.00g LiHMDS, 6.00mmol, 2eq.) in tetrahydrofuran was added by a syringe. Stir at room temperature for 8 days. Subsequently, 40mL of methyl-tert-butyl-ether and 40mL of 2M hydrochloric acid were added. The filtrate was separated, and the organic phase was extracted twice with 20mL of 2M hydrochloric acid. The combined aqueous phases were adjusted to pH = 8 with saturated NaHCO3 solution (bubbling!). At the same time, a yellow precipitate formed. The precipitate was filtered, washed with water and dried under vacuum at 40°C. Yield: 414 mg (1.48 mmol, 49%). ESI-MS (M+H + )=280.

[0380] 1H-NMRδ(500MHz DMSO-d6 T=300K): 2.27 (dd, J1=5.7Hz, J2=13.2Hz, 1H), 2.37 (ddd, J1=9.0Hz, J2=9.3Hz, J1=13.2Hz, 1H), 4.02 (dd, J1=9.1Hz, J2=9.3Hz, 1H), 4.17 (ddd, J1=6.0Hz, J2=9.0Hz, J3=9.4Hz, 1H), 7.0 4 (s, 1H), 7.10 (dd, J1=5.0Hz, J2=7.4Hz, 1H), 7.22 (t, J=7.3Hz, 1H), 7.46 (t, J=7.7Hz, 2H), 8.06 (dd, J1=1.6Hz, J2=7.1Hz, 1H), 8.08 (d, J=8.4, 2H), 8.54 (dd, J1=1.6Hz, J2=5.0Hz, 1H).

[0381] 13 C-NMR DEPTqδ (126MHz DMSO-d6 T=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.

[0382] 4A.11 Preparation of 3α-hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one

[0383] Ethyl-3-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}pyridine-4-carboxylate

[0384]

[0385] Dry 4 neck 500mL round bottom flask is equipped with reflux condenser, thermometer, drip top and air inlet.28.53g (139mmol, 1.05eq.) of 1-[(4-methoxyphenyl) methyl] pyrrolidin-2-one and 50mL of dry chloroform are weighed in flask.Argon is introduced slowly, and phosphorus oxychloride (phosphorusoxychloride) (13mL, 21.31g, 139mmol, 1.05eq.) is added from the drip top in 5 minutes.The reaction is slightly exothermic.It is subsequently allowed to cool to room temperature and stir for 3 hours.Subsequently, a solution of 3-amino-isonicotinate (ethyl 3-amino-isonicotinate) (22.00g, 132mmol, 1eq.) in 50mL dry chloroform is added in 5 minutes.If the solution boils, deceleration is added to reach slight boiling.After adding, the reaction mixture is further refluxed for 48 hours under argon atmosphere. The reaction was monitored by thin layer chromatography. After 48 hours, the reaction mixture was cooled to room temperature and 220 mL of saturated Na2CO3 solution (bubbling!) was slowly added under stirring. Subsequently, another 150 ml of water was added and the phases were separated. The aqueous phase was washed twice with 100 mL of chloroform, and the combined organic phase was extracted with water (100 mL) and dried with Na2SO4. After filtration, it was 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 solution of the product was filtered through the silica gel. It was washed with ethyl acetate until the product was detected in the filtrate by thin layer chromatography. Subsequently, the combined solution was concentrated, and the residue was dissolved in isopropyl acetate and dried with Na2SO4. After filtration, it was concentrated in a vacuum. Yield: 40.99 g (115 mmol, 88%). ESI-MS (M+H + ) = 354. Rf = 0.55 The same plate was run three times in ethyl acetate.

[0386] 1 H-NMRδ(500MHz DMSO-d6 T=300K): 1.20 (t, J=7.0Hz, 3H), 1.87 (m, 2H), 2.30 (t, J=6.8Hz, 2H), 3.26 (t, J=6.8Hz, 2H), 3.74 (s, 3H), 4.21 (q, J=7.0Hz, 2H ), 4.50 (s, 2H), 6.90 (m, J1=8.5Hz, 2H), 7.28 (m, J1=8.5Hz, 2H), 7.45 (d, J=5.0Hz, 1H), 8.16 (s, br, 1H), 8.21 (d, J=5.0Hz, 1H).

[0387] 13CNMRδ(126MHz DMSO-d6 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, 141.9, 145.9, 147.0, 157.5, 158.4, 162.1, 166.1.

[0388] 1-[(4-methoxyphenyl)methyl]-1H,2H,3H-pyrrolo[2,3-b]1,7-naphthyridin-4-ol

[0389]

[0390] 39.41g (112mmol, 1eq.) of ethyl-3-{[(2E)-1-[(4-methoxyphenyl)methyl]pyrrolidin-2-ylidene]amino}pyridine-4-carboxylate is added to a 500mL round-bottomed flask and dissolved in 300mL of toluene. A water separator is placed on the flask, and a reflux condenser is installed on the water separator, and it is boiled until water separation is observed. After 2 hours, the water content of the solution reaches 0.01m / m%. Subsequently, the mixture is cooled to room temperature, and toluene is evaporated in a vacuum. The residue is dissolved in 300mL of dry tetrahydrofuran, and poured into a three-necked round-bottomed flask. A reflux condenser, a drip tray and a thermometer are placed on the flask. In an argon atmosphere, 105 mL of a 20.1 m / m% solution of potassium tert-butyrate in tetrahydrofuran (18.76 g KOtBu, 167 mmol, 1.5 eq.) was added dropwise over 10 minutes with stirring. During this period, the solution was warmed to 35 ° C and a light brown precipitate formed. The reaction was monitored by thin layer chromatography and refluxed until the starting material was exhausted (the exhaustion of the starting material was described in the previous intermediate in the eluent). After cooling to room temperature, 20 mL of acetic acid was added. The reaction mixture was poured into a single-necked round-bottom flask and the solvent was evaporated in vacuo. The residue was suspended in 500 mL of water and adjusted to pH=9 with a saturated Na2CO3 solution (bubbling!). The solid was filtered out, washed with water (2×250 mL) and dried in vacuo. Yield: 33.01 g (107 mmol, 96%) of light brown powder. ESI-MS (M+H + )=308. Rf=0.78 Dichloromethane:methanol 10:1, neutral E2 Al2O3.

[0391] 1H-NMRδ(500MHz DMSO-d6 T=300K): 3.01 (t, br, J=8.0Hz, 2H), 3.45 (t, J=8.0Hz, 2H), 3.72 (s, 3H), 4.59 (s, 2H), 6.88 (d, J=8.6Hz, 2 H), 7.24 (d, J=8.6Hz, 2H), 7.70 (d, J=5.2Hz, 1H), 8.18 (d, J=5.2Hz, 1H), 8.75 (s, 1H), 11.3-10.1 (br, 1H).

[0392] 13 C-HMBC NMRδ (126MHz DMSO-d6 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.

[0393] 1H,2H,3H-Pyrrolo[2,3-b]1,7-naphthyridin-4-ol

[0394]

[0395] 26.00g (85mmol, 1eq.) of 1-[(4-methoxyphenyl)methyl]-1H, ​​2H, 3H-pyrrolo[2,3-b]1,7-naphthyridine-4-ol was weighed in a 3-neck 250mL round-bottom flask. The drip top and reflux condenser were loaded to the flask, and a CaCl2 tube was fitted thereon. The steam chamber was flushed with argon. The starting material was suspended in anisole (83mL, 82.33g, 761mmol, 9eq.), and 52mL (77.16g, 677mmol, 8eq.) of trifluoroacetic acid was slowly added under stirring. Meanwhile, the solid dissolved. The reaction mixture was stirred at 70°C until the starting material was exhausted, followed by thin layer chromatography. The reaction occurred in about 10 days. The solution was cooled to room temperature, and ethyl acetate (100mL) and hexane (40mL) were added, and the mixture was extracted with 80mL of 2M hydrochloric acid. The formed precipitate was filtered off, dissolved in water, and added to the hydrochloric acid extract. The organic phase was extracted 4 more times with 40 mL of 2M hydrochloric acid. The combined aqueous phase was extracted with 1:1 hexane-ethyl acetate (80 mL) and separated. The pH was adjusted to 8 with 10% NaOH, the precipitate was filtered off, washed with cold water (100 mL) and dried under vacuum. Yield: 13.97 g (75 mmol, 88%) of yellow powder. Rf = 0.17 Dichloromethane: methanol 10: 1, neutral E-type Al2O3.

[0396] 1 H NMRδ (500MHz DMSO-d6 T=300K): 2.96 (t, br J=8.4Hz, 2H), 3.57 (t, J=8.4Hz, 2H), 7.06 (s, br, 1H), 7.74 (d, J=4.9Hz, 1H), 8.22 (d, J=4.9Hz, 1H), 8.67 (s, br, 1H), 12.5-10.0 (br, 1H).

[0397] 13 C(DEPTq, HMBC) NMRδ (126MHz DMSO-d6 T=300K): 24.3, 43.6, 105.1, 115.9, 126.1, 139.1, 140.4, 143.8, 160.2, 161.4.

[0398] 3α-Hydroxy-1H,2H,3H,3aH,4H-pyrrolo[2,3-b]1,7-naphthyridin-4-one(255)

[0399]

[0400] 2.00g (10.7mmol, 1eq.) of 1H, 2H, 3H-pyrrolo [2,3-b] 1,7-naphthyridine-4-ol and 5.18g (19.8mmol, 1,9eq.) of 2- (phenylsulfonyl) -3- phenyloxy nitrogen cyclopropane were weighed into 3 neck 100mL round bottom flasks, and 20mL of dry tetrahydrofuran was added. Subsequently, the flask was made inert with argon, and a balloon, thermometer and stopper filled with argon were placed on the flask. The mixture was cooled to 0-5 ° C in cold water, and 19.3mL of 20.7m% LiHMDS solution (4.87g LiHMDS, 29.1mmol, 2eq.) in tetrahydrofuran was added by a syringe. Subsequently, the reaction mixture was stirred at room temperature until the starting material was exhausted. The reaction was monitored by thin layer chromatography (with 10: 1 chloroform-methanol, run twice). After 41 h water (2 mL) was added and the mixture was stirred for 10 min, then Celite (6 g) was added 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 methanol. The precipitate was filtered off (660 mg). The filtrate was evaporated and the operation was repeated with the residue in 5 ml methanol. The solids were combined. Yield: 807 mg (3.97 mmol, 37%). ESI-MS (M+H + )=204.

[0401] 1H NMR (DMSO-d6, 500MHz): δ2.11 (dd, J=5.4, 13.5Hz, 1H), 2.21 (m, 1H), 3.51 (m, 1H), 3.58 (m, 1H), 6.75 (s, 1H), 7.45 (d, J=4.7Hz, 1H), 8.14 (d, J=4.7Hz, 1H), 8.37 (s, 1H), 9.22 (bs, 1H).

[0402] 13 C DEPTq NMR (DMSO-d6, 500MHz): δ30.8, 44.5, 118.5, 124.7, 141.4, 145.1, 194.0.

[0403] Example 4: Demonstration of the effectiveness of the compounds of the present invention

[0404] To demonstrate validity, the following method was used: Actomyosin steady-state ATPase measurements for the following myosin 2 isoforms:

[0405] a) Recombinant human non-muscle myosin 2 for all three isoforms (NM2A, NM2B, NM2C)

[0406] b) isolated porcine heart ventricular myosin (cardiac),

[0407] c) isolated rabbit skeletal muscle myosin (skeletal),

[0408] d) Isolated chamois smooth muscle myosin

[0409] e) Recombinant Dictyostelium miozin (Dictyostelium).

[0410] We determined: (i) the maximum inhibition of ATPase activity for all myosin isoforms and for all compounds where, at a concentration of 50 micromolar, the degree of inhibition was at least 20%; and (ii) the concentration required for semi-maximal inhibition. The results are summarized in the table below.

[0411] The following table gives the names, structures and reference numbers of the compounds in the following efficacy examples.

[0412] Table 3A

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420] Table 3: Data on % inhibition of certain compounds of the present invention

[0421]

[0422]

[0423]

[0424] Table 4: Further data on % inhibition for certain compounds of the invention

[0425]

[0426]

[0427]

[0428]

[0429] Table 5: Further data on % inhibition for certain compounds of the invention

[0430]

[0431]

[0432]

[0433] Table 6: Further data on % inhibition for certain compounds of the invention

[0434]

[0435]

[0436]

[0437] Example 6: Demonstration of the effectiveness of the compounds of the present invention

[0438] The validation was performed according to the following method: Myosin steady-state ATPase measurement of myosin 2 isoforms of Example 4

[0439] We have demonstrated that for each myosin-2 isoform, a narrow IC50 range can be determined within which the maximal inhibition value can be fine-tuned, which may be important for drug treatment. The results are summarized in the table below.

[0440] Table 7: Data used to refine the maximum inhibition values ​​induced by certain compounds of the invention within a narrow IC50 range

[0441]

[0442]

[0443]

[0444] Example 7: Demonstration of the effectiveness of the compounds of the present invention

[0445] The demonstration of validity was carried out according to the following method: Isometric force measurements of the quadriceps femoris of living, anesthetized rats were performed due to electrical stimulation of the muscle.

[0446] After intraperitoneal injection of certain compounds of the invention, the maximum isometric force induced by the stimulus was determined. During the measurement, the following parameters of living, anesthetized rats were continuously monitored:

[0447] a) Heartbeat

[0448] b) Blood flow in the carotid artery

[0449] c) Respiratory rate

[0450] d) Blood oxygen saturation

[0451] Results from live, anesthetized rats are summarized in the table below.

[0452] Table 8: Data on the effectiveness of certain compounds of the invention in an in vivo measurement system

[0453]

[0454]

[0455] Example 8: Demonstration of the effectiveness of the compounds of the present invention

[0456] To demonstrate efficacy, the following method was used: 6 mg of 188 compound was injected intraperitoneally into living rats, and tissue concentrations were determined at specific times in the following tissues:

[0457] a) Blood

[0458] b) Brain

[0459] c) Lungs

[0460] d) Myocardium

[0461] e) Liver

[0462] f) Kidneys

[0463] g) Spleen

[0464] h) Skeletal muscle

[0465] i) Urine

[0466] The results for rat tissues are summarized in the following table.

[0467] Table 9: Tissue distribution data of certain compounds of the present invention in an in vivo measurement system

[0468]

[0469]

[0470] Example 9: Demonstration of the solubility of the compounds of the present invention

[0471] The compounds were tested for solubility in phosphate buffered saline (Dulbecco's Phosphate Buffered Saline, w / o Mg, Ca (PBS)) in the presence of 1% DMSO. Specific solubility values ​​are given in the table below.

[0472] Table 10: Maximum solubility data in PBS-1% DMSO solution

[0473] Compound No. Maximum solubility in PBS-1% DMSO solution 174 ≥1000μM 180 2400μM 188 1450μM 210 1360μM 211 510μM 213 410μM 214 820μM 220 710μM

[0474] Example 10: Demonstration of the mutagenicity of the compounds of the present invention

[0475] The mutagenicity of the compounds was determined in the Ames Reverse Mutagenicity Assay (Ames MPF Test, Xenometrix) approved by the Organization for Economic Co-operation and Development (OECD), the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) against S. ryphimurium TA98 and TA100 strains in the absence or presence of S9 rat liver fractions. Relative mutagenicity values ​​were prepared using the tables provided by the manufacturer. According to the standards of the OECD, EMA and FDA, the relative mutagenicity values ​​at any concentration may not exceed 2, because in this case, they are potentially mutagenic. The relative mutagenicity values ​​are shown in the tables and figures below.

[0476] Table 11: Data of mutagenicity testing of S(-)-Blebbistatin and Compound 188

[0477]

[0478] Example 11: Examples of compounds of the present invention include the following compounds, which should not be construed as limiting the present invention.

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505] Industrial Applicability

[0506] The compounds of the present invention can be used as medicaments for the above-mentioned indications.

Claims

1. A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof: in, In formula (I) or formula (II): Q 1 , Q 2 , Q 3 and Q 4 One or more of them are independently N, and the rest are CH; Q 5 , Q 6 and Q 7 Each independently selected from the group consisting of S, O, N, NR' or CR', wherein R' is H, C1-6 alkyl or C1-6 haloalkyl, provided that the aromatic nature of the ring is retained; R 2 , R 3 , R 4 and R 5 Each is H, halogen or C1-6 alkyl; R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl and 6-methoxy-3-pyridyl; Or, R 1 is a group of the formula, in: R 6 and R 10 is H; R 7 , R 8 and R 9 Each independently is: H； halogen; C1-12 straight chain alkyl; C3-12 branched alkyl; C3-12 cycloalkyl; C2-12 straight chain alkenyl; C3-12 branched alkenyl; C2-12 straight chain alkynyl; C3-12 branched alkynyl; OH; C1-12 hydroxyalkyl; C3-12 hydroxycycloalkyl; NH2; C1-12 alkylamino, C3-12 cycloalkylamino or C1-12 dialkylamino, wherein The amino group can be acylated by a C1-6 straight chain or branched chain or cyclic or aromatic carboxylic acid, or sulfonylated by a C1-6 straight chain or branched chain or cyclic or aromatic sulfonic acid; NO2; CN; C1-12 alkyl cyano; C1-12 carboxylic acid amide, the C1-12 carboxylic acid amide is formed by a saturated amine, an unsaturated amine or an aromatic amine, wherein the carboxylic acid amide is according to the formula C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 -A group of any one of; C1-12 alkoxy, C2-12 alkenyloxy, C2-12 alkynyloxy or C1-12 alkoxyalkyl, wherein the alkyl, alkenyl and alkynyl groups can be substituted with one or more halogen atoms; Methylsulfonylaminomethyl; trifluoromethylsulfonylamino; CH2-CO-N(CH3)2; Acetyl; Methylsulfonylamino; Methoxymethyl; Among them, R 11 and R 12 Each is independently a C1-6 alkyl, a C3-12 cycloalkyl, a C2-6 alkenyl or a C6-12 aryl; Or, R 7 , R 8 and R 9 One of them can be a 5-, 6- or 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic group, each of which independently contains one or more N, O, S atoms; R 7 , R 8 and R 9 The other two of R can be independently H atoms or halogens; 7 , R 8 and R 9 can be substituted by one or more groups selected from the group consisting of: C1-12 straight chain alkyl; C3-12 branched alkyl; C2-12 straight chain alkenyl; C3-12 branched alkenyl; C2-12 straight chain alkynyl; C3-12 branched alkynyl; OH; C1-12 hydroxyalkyl; Amino, C1-12 alkylamino or C1-12 dialkylamino, wherein the amino group can be acylated with a C1-6 straight or branched chain carboxylic acid, or sulfonylated with a C1-6 straight or branched chain sulfonic acid; NO2; CN; C1-12 alkyl cyano; C1-12 carboxylic acid amide, the C1-12 carboxylic acid amide is formed by a saturated amine or an unsaturated amine, wherein the carboxylic acid amide is of the formula C(O)NH2-, C(O)NHR 11 - or C(O)NR 11 R 12 -group; C1-12 alkoxy, C2-12 alkenyloxy, C2-12 alkynyloxy or C1-12 alkoxyalkyl, wherein the alkyl, alkenyl and alkynyl groups can be substituted by one or more halogen atoms; halogen; C1-12 alkylthio, C2-12 alkenylthio, C2-12 alkynylthio or C1-12 alkylthioalkyl, wherein the alkyl, alkenyl and alkynyl groups can be substituted by one or more halogen atoms; S(O)2OH or C1-4 alkyl-S(O)2OH; S(O)2OR 13 or C1-4 alkyl-S(O)2OR 13 ; S(O)R 13 or C1-4 alkyl-S(O)R 13 ; S(O)2R 13 or C1-4 alkyl-S(O)2R 13 ; Among them, R 11 and R 12 Each is independently a C1-6 alkyl or a C2-6 alkenyl; Among them, R 13 and R 14 The group is selected from the group consisting of C1-6 straight or branched chain alkyl groups.

2. A compound of formula (I) or formula (II) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: In formula (I) R 1 is H, or a group according to the formula: Among them, in the above formula: R 6 and R 10 is H; and R 7 , R 8 and R 9 are independently selected from the group consisting of: H, amino, nitro, cyano, CONH2, OCH3, trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, CH2-CO-N(CH3)2, acetyl, methylsulfonylamino and methoxymethyl; among which, R 7 , R 8 and R 9 One of them can be morpholinyl, 1,4-oxazepin-4-yl, oxa-4-yl, tetrahydro-thiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl and 1-methylpiperidin-4-yl; or R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl and 6-methoxy-3-pyridyl; R 2 , R 3 , R 4 and R 5 is H; and Q 1 , Q 2 , Q 3 and Q 4 One of the groups is N and the other is CH; and In formula (II), R 1 is H, or a group according to the formula Among them, in the above formula: R 6 and R 10 is H; and R 7 , R 8 and R 9 are independently selected from the group consisting of: H, amino, nitro, cyano, CONH2, OCH3, trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, CH2-CO-N(CH3)2, acetyl, methylsulfonylamino, methoxymethyl; wherein R 7 , R 8 and R 9 One of them can be morpholinyl, 1,4-oxazepin-4-yl, oxa-4-yl, tetrahydrothiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl and 6-methoxy-3-pyridyl; R 2 , R 3 , R 4 and R 5 is H; and Q 5 , Q 6 and Q 7 As follows: Q 5 S and Q 6 and Q 7 is CH, or Q 7 S and Q 5 and Q 6 is CH, or Q 5 is N-CH3 and Q 6 For N and Q 7 is CH, or Q 5 S and Q 6 C-CH3 and Q 7 For CH.

3. A compound of formula (I) or formula (II) according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: In formula (I): R 1 is H or a group according to the formula: Among them, in the above formula: R 6 and R 10 is H; and R 7 and R 9 is selected from the group consisting of H, amino, cyano or -OCH3, and R 8 Selected from the group consisting of: H, morpholinyl, amino, nitro, cyano, CONH2, OCH3, trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, CH2-CO-N(CH3)2, acetyl, methylsulfonylamino, methoxymethyl, 1,4-oxazepin-4-yl, oxa-4-yl, tetrahydro-thiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl; or R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl and 6-methoxy-3-pyridyl; R 2 , R 3 , R 4 and R 5 is H; and Q 1 , Q 2 , Q 3 and Q 4 One of is N and the other is CH; and Wherein, in formula (II): R 1 is H or a group according to the formula Among them, in the above formula R 6 and R 10 is H, and R 7 and R 9 is H, amino, cyano or OCH3, and R 8 is selected from the group consisting of: H, morpholinyl, amino, nitro, cyano, CONH2, OCH3, trifluoromethyl, fluoro, trifluoromethoxy, dimethylamino, hydroxymethyl, cyanomethyl, aminomethyl, methylsulfonylaminomethyl, trifluoromethylsulfonylamino, CH2-CO-N(CH3)2, acetyl, methylsulfonylamino, methoxymethyl, 1,4-oxazepin-4-yl, oxa-4-yl, tetrahydro-thiopyran-4-yl, 1,1-dioxo-tetrahydropyran-4-yl, thiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, tetrahydropyran-4-yl, 1-methylpiperidin-4-yl group; or R 1 Selected from the group consisting of 3-pyridyl or 4-pyridyl, 2-thienyl, 3-thienyl, 2-methoxy-4-pyridyl and 6-methoxy-3-pyridyl; R 2 , R 3 , R 4 and R 5 is H; and Q 5 , Q 6 and Q 7 As follows: Q 5 S and Q 6 and Q 7 is CH, or Q 7 S and Q 5 and Q 6 is CH, or Q 5 is N-CH3 and Q 6 For N and Q 7 is CH, or Q 5 S and Q 6 C-CH3 and Q 7 For CH.

4. A compound of formula (I) or formula (II) according to claim 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: In formula (I): R 1 is H or a group according to the formula Among them, in the above formula R 6 , R 7 , R 9 and R 10 is H, and R 8 is H or morpholinyl; R 2 , R 3 , R 4 and R 5 is H; and Q 1 , Q 2 , Q 3 and Q 4 One of is N and the other is CH; and Wherein, in formula (II) R 1 is H or a group according to the formula Among them, in the above formula R 6 , R 7 , R 9 and R 10 is H, and R 8 is H or morpholinyl; R 2 , R 3 , R 4 and R 5 is H; and Q 5 , Q 6 and Q 7 As follows: Q 5 S and Q 6 and Q 7 is CH, or Q 7 S and Q 5 and Q 6 is CH, or Q 5 is N-CH3 and Q 6 For N and Q 7 For CH.

5. A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: The compound 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-trien-8-one, 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-diazatricyclo[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-trien-8-one, (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-trien-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-trien-8-one, (9S)-9-Hydroxy-12-(thiophen-2-yl)-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one, (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-one, 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-trien-8-one, 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-trien-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-trien-8-one, 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, 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-one, 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-trien-8-one, 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-trien-8-one, 12-[4-(Dimethylamino)phenyl]-9-hydroxy-5-methyl-4-thia-2,12-diazatricyclo[7.3.0.0 3,7 ]dodeca-1,3(7),5-trien-8-one, 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. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating thrombotic disorders.

7. The use according to claim 6, wherein The thrombotic disorder includes thrombosis.

8. The use according to claim 7, wherein The thrombosis is arterial thrombosis or ischemic stroke.

9. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating overactive bladder.

10. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating cardiomyopathy.

11. The use according to claim 10, wherein The cardiomyopathy is hypertrophic cardiomyopathy or dilated cardiomyopathy.

12. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating myocardial muscle diseases.

13. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating skeletal muscle diseases.

14. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating muscle spasm.

15. The use according to claim 14, wherein The muscle spasms are non-specific lower back pain, lumbar spasms, intermittent spasms, stress-induced occipital spasms, prolonged limb muscle spasms in epilepsy continua partialis, muscle spasms in cerebral palsy, muscle spasms in multiple sclerosis, vaginismus, or musculoskeletal muscle spasms or smooth muscle spasms during labor.

16. Use of a compound according to any one of claims 1 to 5 in the preparation of a medicament for treating drug-induced convulsions.

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