Novel tricyclic derivative and pharmaceutically acceptable salts thereof, method for production thereof and pharmaceutical composition containing said derivative

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

 

The technical field to which the present invention

The present invention relates to new tricyclic derivative, which has an excellent inhibitory activity of poly(ADP-ribose)polymerase, or its pharmaceutically acceptable salts, method of production thereof and containing pharmaceutical compositions.

The level of technology

Poly(ADP-ribose)polymerase (PARP), which is an enzyme in the nuclei of cells, found in most eukaryotic cells, and it catalyzes the transfer of ADP-ribosome fragment to the protein of the nuclear receptor, using nicotinamide adenine dinucleotide (NAD+as the substrate, and causes the formation of Homo-ADP-ribosome polymer originating from protein-coupled lines. PARP consists of 7 isozyme, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), tankyrase, such as PARP-5 (TANK-1, TANK-2 TANK-3), PARP-7 and PARP-10 [de la Lastra CA., et al., Curr Pharm Des., 13(9), 933-962, 2007]. Among the above, the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1) is the main enzyme and is 97% poly(ADP-ribose)polymerase synthesized in the brain [Strosznajder R.P., et al. Mol Neurobiol., 31, (1-3), 149-167, 2005]. Among the many functions of PARP, especially PARP-1, the main function is to promote DNA repair by ADP-ribosylate and regulation of a number of proteins in DNA repair. PARP activation in cells enormous very near to the DNA damage results in a significant decrease in concentration and the severe lack of NDA +. PARP-1 is a 116 kDa of nucleoprotein, which contains three domains, which include the N-terminal DNA-binding domain containing two zinc finger domain of spontaneous modification and C-terminal catalytic domain. Poly(ADP-ribose)polymerase enzyme synthesizes poly(ADP-ribose), which is a polymer with a branched structure, which may consist of 200 or more fragments of ADP-ribose. Poly(ADP-ribose)protein receptor may participate directly or indirectly to the maintenance of DNA integrity. This includes the histone, topoisomerase, DNA and RNA polymerase, DNA ligase, and Ca2+and Mg2+-dependent endonuclease. PARP proteins are expressed in many tissues, especially with a large concentration in the immune system, heart, brain and cell lines of microorganisms. Although PARP proteins still have minimum PARP activity in normal biological conditions, PARP activity increased up to 500 times when DNA damage.

PARP activation and the formation of poly(ADP-Robotnik) reaction products caused by destruction of DNA after chemotherapy, ionizing radiation, oxygen free radicals or nitric monoxide (NO). When DNA damage caused by radiotherapy or chemotherapy, the process of transfer of ADP-ribose cells can contribute mouth is echeveste, which may occur in different types during cancer treatment, as it relates to the repair of damaged DNA. Therefore, PARP inhibition can inhibit the repair of DNA damage in cells and may enhance the anticancer effect of cancer therapy. Moreover, it was recently reported that tankyrase, which is associated with the telomeric protein, TRF-1, factor negative control telomere length has a catalytic domain with substantial homogeneity with PARP and hasin vitroPARP activity. In addition, it is assumed that the function of telomeres in human cells is regulated by poly(ADP-ribosyl)funding. PARP inhibitor is suitable as a tool for studying the regulation of telomere length regulation of telomeric activity by tankyrase [BA., et al., Int J Biochem Cell Biol., 37, 1043-1053, 2005]. For example, PARP inhibitor can be used to treat cancer by reducing the life cycle of immortalized cancer cells or to apply as a regulator of the life cycle of cells or drugs against aging due to the relationship between telomere length and aging cells.

It was also reported that PARP inhibition may increase the resistance to damage of the brain. Ischemic brain damage caused by depletion of NAD+mediated poly(ADP-ribose)polymerase activity, etc which leads to lack of energy [Endres M., et al., J Cereb Blood Flow Metab., 17(11), 1143-1151, 1997]. Treating cerebral ischemia, activation of PARP depending on the DNA damaging effect on apoptosis induced seizures, brain damage and neurodegenerative diseases. It is believed that apoptosis occurs as a result of lower energy, corresponding NAD+consumption in the PARP reaction, catalyzed by enzymes, and DNA damage occurs as a result of excessive amounts of nitrogen monoxide generated as activation synthetase monoxide nitrogen products resulting from the release of glutamic acid from depolarized nerve endings. The lack of oxygen in neurons causes a stroke or ischemic brain damage, and then the neuron releases a large amount of glutamate. Excess glutamate causes hyperstimulation (excitotoxicity) N-methyl-D-aspartate (MMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolidinone acid (AMPA), kainite and metabotropic glutamate receptor (MGR), which opens the ion channel and thus provides unregulated flow of ions (for example, allowing Ca2+and Na+in cells, causing K+the release of cells), causing hyperstimulation of neurons. Hyperstimulatory neurons cause greater release of glutamate, generating a cycle about the military connection or Domino effect and ultimately causing damage or cell death through the generation protease, lipase and free radicals. Excessive activation of glutamate receptors is associated with a number of neuropathic diseases, including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, neuronal damage after hypoxia, external damage and neuronal povidoneiodine damage.

PARP inhibitor can be used to treat not only diseases of the Central nervous system, but also diseases of the peripheral nervous system, such as neuropathic pain caused by chronic compression (CCI) normal sciatic nerve [Di Cesare Mannelli L., et al., Eur J Neurosci., 26(4), 820-827, 2007]. The exact mechanism of the effectiveness of PARP inhibitors in the treatment of neuropathic pain is not yet fully explained, but is considered positive.

PARP inhibitor also affects the treatment of inflammatory symptoms, such as arthritis [SzabC., et al., Proc. Natl. Acid. Sci. USA 95(7), 3867-3872, 1998]. Poly(ADP-ribose) synthesis is involved in induced expression of many genes that are essential for inflammatory reactions. PARP inhibitor inhibits the formation of macroporosity induced synthase nitric oxide (iNOS) of the P-type selectin and intercellular adhesion molecules (1cAM-1) on endothelial cells. The above activity are the two which is the basis for a strong anti-inflammatory effect of PARP inhibitor. Moreover, PARP inhibition may reduce necrosis, preventing translocation and infiltration of neutrophils into the injured tissue. Accordingly, the PARP inhibitor is suitable for the treatment of inflammatory symptoms.

PARP inhibition is suitable for protection against myocardial ischemia [SzabC., Curr Vase Pharmacol., 3(3), 301-303, 2005] and reperfusion damage [Zingarelli B., Cardiovascular Research, 36, 205-215, 1997]. It is believed that the main cause of tissue damage is accompanying the formation of free radicals during reperfusion. During ischemia and reperfusion some typical ATP reduction in many organisms may be associated with NAD+the disadvantage of that is the result of the conversion of poly(ADP-ribose). Accordingly, it is expected that PARP inhibition is to maintain cellular energy and subsequently to increase the survival of ischemic tissue after damage. Accordingly, the PARP inhibitor is suitable for the treatment of cardiovascular diseases.

Recently, the assumption has been made about the effectiveness of PARP inhibitor for the treatment of diabetic neuropathy [Obrosova IG., Diabetes. 54(12), 3435-3441, 2005].

To date on the development of poly(ADP-ribose)polymerase (PARP) was reported in the following documents: INO-1001 (Inotek Pharmaceuticals) is being developed for the treatment of cardiovascular diseases and locates the public melanoma. AG014699 (Pfizer) is being developed for the treatment of malignant melanoma. BS-201 and Bs-401 (Bipar Sciences) are being developed for the treatment of cancer and pancreatic cancer, respectively. In addition, AstraZeneca develops AZD2281 treatment for breast cancer, and MGI Pharma conducts research sensitizing agent for radiotherapy and chemotherapy [News, Nature biotechnology, 24(10), 1179-1180, 2006].

However, the development of inhibitors of poly(ADP-ribose)polymerase (PARP) in connection with neurodegenerative diseases, which are not conducted studies to date, very necessary, given the increasing population of the elderly population and to improve the quality of life.

Accordingly, a primary requirement is the development of an inhibitor of poly(ADP-ribose)polymerase (PARP), which will be able to minimize side effects, particularly at the moment when not developed noteworthy methods of treatment of the aforementioned diseases.

The authors of the present invention investigated the molecular PARP inhibitor, which can be used for treatment of various diseases resulting from excessive activation of poly(ADP-ribose)polymerase (PARP), has received new tricyclic derivatives, confirmed excellent PARP inhibitory activity of these compositions and thus completed the present izaberete is used.

The technical problem

The present invention is to provide a new tricyclic derivatives with excellent inhibitory activity of poly(ADP-ribose)polymerase, or their pharmaceutically acceptable salts, a method of receiving and containing the pharmaceutical composition.

Technical solution

In order to achieve the above objectives, the present invention provides a new tricyclic derivatives or their pharmaceutically acceptable salts.

In addition, the present invention provides a method of obtaining a new tricyclic derivatives.

In addition, the present invention provides a pharmaceutical composition comprising new tricyclic derivatives or their pharmaceutically acceptable salts as an active ingredient for preventing or treating diseases resulting from excessive activation of poly(ADP-ribose)polymerase.

Beneficial effects

Tricyclic derivatives according to the present invention inhibit the activity of poly(ADP-ribose)polymerase (PARP), whereby they may be suitable for the prevention or treatment of diseases resulting from excessive activation of PARP, and in particular, neuropathic pain, neurodegenerative diseases, cardiovascular diseases any, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

Brief description of drawings

FIGURE 1 is a graphical representation of the amount of NAD(P)H, depending on the concentration of the compound variant implementation of the present invention.

FIGURE 2 is a graphical representation of the volume of infarction, depending on the dose connection variant implementation of the present invention.

The best option exercise

Below the present invention will be explained in more detail.

The present invention relates to new tricyclic derivatives or their pharmaceutically acceptable salts represented by chemical formula 1.

Chemical formula 1

where each Y1, Y2and Y3independently represents H, C1-C10alkyl linear or branched chain, hydroxy, C1-C10alkoxy, -COOR1, -NR2R3or-A-B;

A represents-O-, -CH2-, -CH(CH3)-, -CH=N -, or-CONH-;

B represents -(CH2n1-Z, -(CH2n2-NR2R3or -(CH2n3-OR1;

Z represents a C5-C20aryl, unsubstituted or substituted R5and selectively R6C3-C10cycloalkyl, unsubstituted or substituted R5and selectively 6C1-C20heterocyclic compound, unsubstituted or substituted R5and selectively R6;

R1represents H or C1-C10alkyl linear or branched chain;

each R2and R3independently represents H, C1-C10alkyl linear or branched chain, or -(CH2n4R7;

R5represents H, C1-C10alkyl linear or branched chain, C5-C20aryl or C1-C20heterocyclic compound;

R6represents H or C1-C10alkyl linear or branched chain;

R7represents-NR8R9, -COOR1,-OR1, -CF3, -CN, halogen, or Z;

R8and R9independently represent H or C1-C10alkyl linear or branched chain;

n1-n4represent an integer from 0 to 15, respectively;

Y4represents H or C1-C10alkyl linear or branched chain.

Preferably, Y1and Y2independently represent H, C1-C5alkyl linear or branched chain, hydroxy, C1-C5alkoxy, -COOR1, -NR2R3or-A-B,

where A represents-O-, -CH2-, -CH(CH3)-, -CH=N -, or-CONH-;/p>

B represents -(CH2n1-Z, -(CH2n2-NR2R3or -(CH2n3-OR1;

Z represents a group selected from the group consisting of structural formulas below:

where R1represents H or C1-C5alkyl linear or branched chain;

R2and R3independently represent H, C1-C5alkyl linear or branched chain, or -(CH2n4R7;

R5represents H, C1-C5alkyl linear or branched chain, phenyl or morpholino;

R6represents H or C1-C5alkyl linear or branched chain;

R7represents-NR8R9, -COOR1, -OR1, -CF3, -CN, F, Cl, or Z;

R8and R9independently represent H or C1-C5alkyl linear or branched chain;

n1-n4represent an integer from 0 to 10, respectively;

Y3represents H, hydroxy, C1-C5alkoxy or-O(CH2n3-OR1;

Y4represents H or C1-C5alkyl linear or branched chain.

More preferably, Y1and Y2independently represent H, methyl, ethyl, hydroxy, methoxy,ethoxy, -COOR1, -NR2R3or-A-B,

where A represents-O-, -CH2-, -CH(CH3)-, -CH=N -, or-CONH-;

B represents -(CH2n1-Z, -(CH2n2-NR2R3or - (CH2n3-OR1;

Z represents a group selected from the group consisting of structural formulas below:

R1represents H, methyl, ethyl or isopropyl;

R2and R3independently represent H, methyl, ethyl, propyl, isopropyl,tert-butyl or -(CH2n4R7;

R5represents H, methyl, ethyl, propyl, phenyl or morpholino;

R6represents H, methyl or ethyl;

R7represents-NR8R9,-COOR1, -OR1, -CF3, -CN, F, Cl, or Z;

R8and R9independently represent H or methyl;

n1-n4represent respectively an integer from 0 to 5;

Y3represents H, hydroxy, methoxy, ethoxy, propoxy or methoxyethoxy; and

Y4represents H, methyl, ethyl or propyl.

Preferably, the connection tricyclic derivatives represented by chemical formula 1 of the present invention, includes:

1) 8-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

2) 10-Methoxy-1,2,3,-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

3) 9-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

4) 9-Methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

5) Ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate;

6) 9-Methoxy-1-propyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

7) 1-Methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

8) 9-Methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

9) 1-Ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

10) 1-Methyl-9-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

11) 9-(1-Propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

12) 9-(1-Methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

13) 1-Methyl-9-(piperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

14) 1-Methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

15) 5-Oxo-N-[2-(piperidine-1-yl)ethyl]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide;

16) 9-[2-(Dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

17) 9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

18) 9-(2-Methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

19) 9-[2-(Piperazine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

20) 9 Ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

21) 9-[3-(piperidine-1-yl)propoxy]-1,2,3,4-tetrahydro is the site, located between[h][1,6]naphthiridine-5(6H)-he;

22) 9-(2-Aminoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

23) 9-[2-(4-Phenylpiperazin-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

24) 9-(2-Hydroxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

25) 9 Intoxi-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

26) 9-[2-(Diethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

27) 9-(2-Morpholinoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

28) 1,1-Diethyl-4-[2-(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9 yloxy]ethyl)piperazine-1-s;

29) 9-[4-(piperidine-1-yl)butoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

30) 1-Methyl-9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

31) 9-[2-(Dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

32) 8-[2-(Dimethylamino)ethoxy]-1,2,3,4,-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

33) 9-[3-(Dimethylamino)propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

34) 8-[2-(Dimethylamino)ethoxy]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide;

35) 8-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

36) 8-[3-(Dimethylamino)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

37) 8-(Dimethylamino)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

38) 8-[1-(Dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

39) 8-[1-(Methylamino)ethyl]-1,2,3,4-h][1,6]naphthiridine-5(6H)-he;

40) 8-Ethyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

41) 8-[(Dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

42) 8-[(Diethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

43) 8-[(Ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

44) 8-(Pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

45) 8-[(Isopropylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

46) 8-[(Propylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

47) 8-{[Ethyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

48) 8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

49) 8-(Morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

50) 9-[(Dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

51) 8-{[Benzyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

52) 8-[(Methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

53) 8-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

54) 8-{[(2-(Dimethylaminoethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

55) 8-[(4-Methylpiperazin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

56) 8-[(Methyl(propyl)amino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

57) Ethyl-3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]NAF is iridin-8-yl)methyl]amino}propionate;

58) 3-{Methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl) methyl]amino}propanoic acid;

59) 8-{[Isopropyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

60) 8-{[(2-Methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

61) Ethyl-3-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]propionate;

62) 8-[(2,2,2-Triptoreline)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

63) 2-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]acetonitrile;

64) 8-[(1H-Imidazol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

65) 8-[(1H-Pyrrol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

66) 8-[(Dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

67) 1-Methyl-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

68) 8-[(Diethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

69) 1-Methyl-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

70) 1-Methyl-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

71) 8-{[Ethyl(methyl)amino]methyl}-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

72) 8-[(Dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

73) 10-Methoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

74) 10-Methoxy-8-(morph is linoleyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

75) 8-[(Ethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

76) 8-{[Ethyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

77) 10-Methoxy-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

78) 10-Methoxy-8-[(4-oxopiperidin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

79) 8-{[4-(Hydroxyimino)piperidine-1-yl]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

80) 10-Methoxy-8-[(4-(methoxyimino)piperidine-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

81) 10-Methoxy-8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

82) 8-[(2,5-Dihydro-1H-pyrrol-1-yl)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

83) 8-{[(2-Isopropoxyphenyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

84) 10-Methoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

85) 8-{[(2-Chloroethyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

86) 8-[(Diethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

87) 8-[(tert-Butylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

88) 8-[(Isopropylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

89) 8-[(Cyclopentylamine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][,6]naphthiridine-5(6H)-he;

90) 8-[(2,6-dimethylmorpholine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

91) Chloride N-[(10-methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]-N,N-dimethylcyclopentane;

92) 8-{[Cyclopentyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

93) 8-{[Isopropyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

94) 8-{[(2-Foradil)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

95) 8-[(1H-Tetrazol-5-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

96) 10-Methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

97) 10-Methoxy-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

98) (E)-10-Methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

99) 8-[(Dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-he;

100) 8-[(Dimethylamino)methyl]-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

101) 10-Ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

102) 10-Ethoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

103) 10-Ethoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he,

104) 10-Ethoxy-8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

105) 8-(Hydroxymet is)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

106) 10-Methoxy-8-(thiomorpholine)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

107) 10-Methoxy-8-[(2-morpholinoethyl)methyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

108) 10-Methoxy-8-[(4-morpholinopropan-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

109) 8-(Aminomethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

110) 8-[(Dimethylamino)methyl)]-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

111) 8-(Morpholinomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

112) 8-(Aminomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

113) 8-(Aminomethyl)-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

114) 8-(Aminomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

115) 10-Methoxy-8-{[methyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

116) 8-[(Dimethylamino)methyl]-10-(2-methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

117) 10-(2-Methoxyethoxy)-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he; and

118) 1-[(10-Methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]-1H-pyrrole-2,5-dione.

The present invention provides a method of obtaining a compound represented by chemical formula 1.

The present invention provides a method for receiving tricyclic derivatives presented him the standard formula 1. Preferably, the compound of chemical formula 1 can be obtained by following the reaction schemes described below, but not limited to. Accordingly, specialists in the art it is clear that the compound of chemical formula 1 of the present invention can be produced by various methods known technologies.

The following reaction formulas apply to successive stages of the method of obtaining the compounds of the present invention, and various compounds of the present invention can be obtained by replacing or modifying reagent, solvent, or the sequence of reactions used in the production process. Some of the compounds of the present invention was obtained by methods that are not included in the scope of formulas of the reactions described below, and specific ways to obtain these compounds are described, respectively, in each of the examples below.

The method of obtaining 1

In one embodiment, the tricyclic derivatives or their pharmaceutically acceptable salts according to the present invention can be obtained by the method represented by reaction formula 1 below, the method involves the following stages:

1) the conversion of carboxylic acid, 2-chloronicotinic acid represented by chemical formula 2, the acid chloride of the carboxylic acid represented by chemical formula 3 (with the adiya 1);

2) obtain the compounds of chemical formula 5 by the amidation reaction of acid chloride of the carboxylic acid chemical formula 3 obtained in stage 1, aniline chemical formula 4, substituted in the meta and/or para-position (stage 2);

3) introduction of a protective group in the compound of chemical formula 5 obtained in stage 2, in order to obtain the N-protected compound of chemical formula 6 (stage 3);

4) obtain the compounds of chemical formula 7 by cyclization of compounds of chemical formula 6 obtained in stage 3, in terms of metal catalyst (T4);

5) obtain the compounds of chemical formula 8 by restoring the aromatic rings of the compounds of chemical formula 7 obtained in stage 4, the gaseous hydrogen in the presence of palladium (Pd) catalyst, or by restoring the aromatic rings of the compounds of chemical formula 7 obtained in stage 4, the gaseous hydrogen in the presence of palladium (Pd) catalyst, and then by reacting alkylhalogenide connection or arylhalides connections and grounds (stage 5); and

6) remove the protection compounds of chemical formula 8, obtained in stage 5, in order to obtain the tricyclic compound of chemical formula 1 (stage 6).

Reaction formula 1

where Y1/sup> -Y4such as defined in formula 1, and 'pro' is a protective group such as aryl group, benzyl group, benzoyloxymethyl group,pair-methoxybenzyl group or methoxymethyl group, preferably a pair of methoxyaniline group or methoxymethyl group.

Each stage will be explained in more detail below.

In stage 1, the acid chloride of acid (3) is obtained by transformation of commercially available 2-chloronicotinic acid (2) acid chloride acid using a reagent such as thionyl chloride or oxalicacid. For the reaction of stage 1 solvent is not used, or used solvent, such as dichloromethane, chloroform or toluene, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but in General the reaction is carried out at from room temperature to elevated temperature and preferably at elevated temperature.

In stage 2, the compound of chemical formula 5 is obtained by amidation reaction of a carboxylic acid chemical formula 3 and aniline chemical formula 4, substituted in the meta and/or para-position. At this stage the reaction is carried out without or in the presence of an organic amine, such as pyridine, triethylamine, diethylethanolamine, which is usually used for the amidation reaction using dichlo is methane, chloroform, tetrahydrofuran, diethyl ether, toluene or N,N-dimethylformamide, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but usually the reaction is carried out at from low temperature to room temperature.

At stage 3 the protective group is introduced into the compound of chemical formula 5 obtained in stage 2, for synthesizing N-protected amide intermediate of chemical formula 6. Introduced protective group may include alkoxymethyl, including methoxymethyl (MOM), benzoyloxymethyl (BOM) or benzyl (Bn) orp-methoxybenzyl (PMB). The base used in the reaction may be represented as sodium hydride,tert-piperonyl potassium, potassium carbonate, and the solvent may be tetrahydrofuran, N,N-dimethylformamide, acetonitrile or toluene, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but usually the reaction is preferably carried out at from low temperature to high temperature, and more preferably at low temperature.

In stage 4 of the lactam chemical formula 7 is obtained by conducting ciclisti N-protected amide intermediate product obtained in stage 3, in the presence of a metal catalyst. At this stage of the palladium (0) usually use is as a metal catalyst, and you can use tetranitroaniline palladium(0) ((PPh3)4Pd), palladium (II) acetate (Pd(OAc)2), Tris(dibenzylideneacetone) diplegia(0) (Pd2dba3) dichloride and bis(triphenylphosphine)palladium (II) (PdCl2(PPh3)2separately or in combination with tributylphosphine (Bu3P). The reaction can be carried out without ligand or ligand, usually used for cyclization in terms of a metal catalyst, including, for example, triphenylphosphine ((PPh3)4), 1,2-bis(diphenylphosphino)propane (DPPP), (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((R)-BiNAP). You can apply the Foundation, including potassium carbonate, sodium carbonate, silver carbonate, or diethylethanolamine for the reaction, and the reaction is carried out using a solvent including N,N-dimethylformamide, benzene, xylene or acetonitrile, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but the reaction is usually carried out at from room temperature to elevated temperature, and preferably at elevated temperature.

On stage 5, piperidine-lactam (8) is obtained by recovery of the aromatic ring pyridine-lactam (7), obtained in stage 4, the gaseous hydrogen in the presence of palladium (Pd) catalyst. At this stage you can apply organic solvents, including alcohol, chloroform, dichloro the'étang or ethyl acetate, which has no adverse effect on the reaction, or a mixture. The reaction temperature is not specifically limited, but the reaction is usually carried out at room temperature.

Further, in addition, the resulting piperidine-lactam (8) and alkylhalogenide connection or arylhalides connection can interact in the presence of a base such as potassium carbonate, to obtain the N-substituted piperidine-lactam (Y4=alkyl or aryl). The reaction is carried out in the presence of a base, which is used under standard alkylation or allilirovanii amine compounds, and alkylhalogenide or helgaleena. The base can be one of a sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium alkoxide or potassium. Further, the reaction is preferably carried out in the presence of a solvent which has no adverse effect on the reaction, and the solvent may include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide or acetonitrile. The reaction temperature is not specifically limited, but the reaction is usually carried out at from low temperature to high temperature, and preferably at room temperature.

On stage 6 tricyclic compound of chemical formula 1 is obtained by removing protection piperidine-lactam (8)obtained in stage 5, by the way, the usual well-known in the field of organic chemistry.

The method of obtaining 2

In one embodiment, the tricyclic derivatives or their pharmaceutically acceptable salts can be obtained by the method represented by reaction formula 2 below, and the method comprises the stages:

1) demethylation of compound (7a)obtained in stage 4, the reaction formula 1 tribromide boron to obtain hydroxyl compounds (7a-1) (stage 1);

2) interaction of hydroxyl compounds (7a-1)obtained in stage 1, with alkylhalogenide connection, including 4-bromopyridin, or 2-chlorocyphidae in the presence of bases including potassium carbonate and a catalytic amount of sodium iodide, to obtain alkoxysilane (7a-2) (stage 2);

3) get piperidine-lactam (8a) recovering aromatic ring pyridine-lactam compounds (7a-2)obtained in stage 2, the gaseous hydrogen in the presence of palladium (Pd) catalyst (stage 3); and

4) remove the protection compounds (8a), obtained in stage 3, in acidic conditions, such as chloromethane acid, to obtain the compounds of chemical formulas (1a) (stage 4).

The reaction formula 2

where 'pro' is methoxymethyl (MOM) group, benzyl group,pair-methoxybenzyl (PMB) group, R1represents the same as defined in chem the political formula 1, X denotes a leaving group including halogen, methanesulfonyl group,p-toluensulfonyl group or trifloromethyl group, and preferably, halogen (chlorine, bromine, iodine) or methanesulfonyl group, and formula 1a include in chemical formula 1 according to the present invention.

According to reaction formula 2 of the present invention to obtain the compounds of chemical formula (1a), first, in stage 1, demetilirovanie hydroxyl compound (7a-1) are obtained using the compound (7a)obtained in stage 4 of the reaction formula 1, using tribromide boron. You can apply organic solvent, such as dichloromethane or chloroform, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but the reaction is usually carried out at from low temperature to high temperature, and preferably at room temperature.

In stage 2 alkoxysilane (7a-2) is produced by adding catalytic amounts of sodium iodide to hydroxycoumarin (7a-1)obtained in stage 1, and alkylhalogenide compounds, such as 4-bromopyridin or 2-chlorethylene, in the presence of a base such as potassium carbonate. The above reaction is normally of the esterification between alcohol compound and alkylhalogenide and its conduct in p is outstay Foundation, which can be used for esterification. The base used in the above reaction, may include sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate or sodium alkoxide or potassium. Can be used in the reaction solvent, do not have a negative effect on the reaction, such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide or acetonitrile. The reaction temperature is not specifically limited, but the reaction is usually carried out at from low temperature to high temperature, preferably at from room temperature to elevated temperature.

At stage 3 piperidine-lactam (8a) is obtained by recovery of the aromatic ring pyridine-lactam (7a-2)obtained in stage 2, the gaseous hydrogen in the presence of palladium (Pd) catalyst. The above reaction is carried out under the same conditions as the conditions for the recovery of aromatic rings for the conversion of compounds of chemical formula 7 in the compound of chemical formula 8 in the reaction formula 1.

In stage 4, the compound of chemical formula (1a) is obtained by conducting the reaction unprotect compounds (8a), obtained in stage 3, in acidic conditions, such as chloromethane acid.

The method of obtaining 3

In one embodiment, the tricyclic derivatives or their formats whitesky acceptable salts can be obtained by way represented by the reaction formula 3 below, and the method comprises the stages:

1) hydrolysis of the compound (7b)obtained in stage 4 of the reaction formula 1, slowly adding dropwise an aqueous solution of potassium hydroxide or sodium hydroxide to the compound (7b) to obtain a carboxylic acid (7b-1) (stage 1);

2) amidation of carboxylic acid (7b-1)obtained in stage 1, amines, using a condensing reagent to obtain the compound of chemical formula (7b-2) (stage 2);

3) get piperidine-lactam (8b) recovering aromatic ring pyridine-lactam (7b-2)obtained in stage 2, the gaseous hydrogen in the presence of palladium (Pd) catalyst (stage 3); and

4) remove the protection compounds (8b), obtained in stage 3, in acidic conditions, such as chloromethane acid, to obtain compounds of chemical formula (1b) (stage 4).

The reaction formula 3

where 'Alk' represents a C1-C10alkyl linear or branched chain, 'pro' is methoxymethyl (MOM) group, benzyl group or pair-methoxybenzyl (PMB) group, R2and R3such as defined in chemical formula 1 and chemical formula 1b included in the chemical formula 1 of the present invention.

According to the reaction formula 3 to obtain soedineniyami formula (1b) according to the present invention, in stage 1 receive carboxylic acid (7b-1), which slow hydrolyzing by adding dropwise an aqueous solution of potassium hydroxide or sodium hydroxide to the compound (7b)obtained in stage 4 of the reaction formula 1. The reaction is carried out in the presence of an alcoholic solvent such as methanol or ethanol, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but the reaction is usually carried out at from low temperature to high temperature, preferably at from room temperature to elevated temperature. The reaction can be carried out in standard conditions of hydrolysis of the ether.

In stage 2, the compound of chemical formula (7b-2) receive standard amidation reaction in which the carboxylic acid (7b-1)obtained in stage 1, and aminosidine interact with each other in the presence of a condensing agent. Usually the condensing agent may be a commercially available (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1,3-dicyclohexylcarbodiimide (DCC), 1,1-carbonyldiimidazole. The reaction of stage 2 can be performed without the use of reason, or in the presence of a base, which is usually used in the amidation reaction, such as 4-dimethylaminopyridine, pyridine, triethylamine, diethylethanolamine, N-methylmorpholine or dimethylphenylamine, p is imanae solvent, not having a negative effect on the reaction, such as acetonitrile, dimethylformamide or dichloromethane. The reaction temperature is not specifically limited, but the reaction is carried out at from low temperature to high temperature, and, preferably, from low temperature to room temperature.

At stage 3 piperidine-lactam (8b) is obtained by recovery of the aromatic ring pyridine-lactam (7b-2)obtained in stage 2, the gaseous hydrogen in the presence of palladium (Pd) catalyst.

The reaction is usually carried out in the same conditions as the reaction of the recovery of the aromatic ring, which makes the compound of chemical formula 7 of the reaction formula 1, the compound of chemical formula 8.

In stage 4, the compound (8b), obtained in stage 3, is converted into a compound of chemical formula (1b) the reaction of removing the protection in acidic conditions, including chloroethanol acid.

The method of obtaining 4

In one embodiment, the tricyclic derivatives or their pharmaceutically acceptable salts according to the present invention can be obtained by the method represented by reaction formula 4 below, and the method comprises the stages:

1) recovery of the lactam compound (8c)obtained in stage 6 of the reaction formula 1, to the corresponding alcohol (8c-1), using vosstanavlivayuschie, including socialogical (LAH) (stage 1);

2) get diaminooctane connection (8c-2) halogenoalkanes and aminating the alcohol compound (8c-1)obtained in stage 1 (stage 2); and

3) remove the protection of the compound (8c-2)obtained in stage 2, in acidic conditions, such as chloromethane acid, to obtain the tricyclic compounds of chemical formula (1c) (stage 3).

The reaction formula 4

where 'Alk' represents a C1-C10alkyl linear or branched chain, 'pro' is methoxymethyl (MOM) group, benzyl group, orpair-methoxybenzyl (PMB) group, R1-R3such as defined in chemical formula 1 and chemical formula 1c is included in the chemical formula 1 of the present invention.

According to the reaction formula 4 to obtain the compound of chemical formula (1c) of the present invention, in stage 1 lactam compound (8c)obtained in stage 6 of the reaction formula 1, reduced to the corresponding alcohol (8c-1), using a reducing agent such as socialogical (LAH). Usually you can use commercially available reducing agent, including, for example, socialogical (LAH), detribalized (NaBH4or diisobutylaluminum (DIBAL-H). The reaction can be carried out in the presence of dissolve is I, which has no adverse effect on the reaction, such as tetrahydrofuran, diethyl ether or alcohol. The reaction temperature is not specifically limited, but the reaction is carried out usually at from low temperature to high temperature and preferably at a lower temperature.

In stage 2 diaminooctane connection (8c-2) is produced by halogenoalkanes and aminating the alcohol compound (8c-1)obtained in stage 1. The transformation in the halogen compound is conducted by applying tribromide phosphorus, tetrabromomethane or thionyl chloride, which usually turns hydroxyl group into a halogen, in the presence of a solvent, such as chloroform, acetonitrile or dichloromethane, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but the reaction is usually carried out at from low temperature to room temperature. Further, the conversion of halogen compounds in diaminooctane connection (8c-2) can be a standard reaction amination. The reaction is usually carried out in the presence of an organic amine, such as pyridine, triethylamine or diethylethanolamine or potassium carbonate, which is a base, generally used in the amination reaction using an alcohol, such as methanol or ethanol, dichloromethane, chloroform, tetrahydrofuran, di is tilby ether, toluene or N,N-dimethylformamide, which has no adverse effect on the reaction. The reaction temperature is not specifically limited, but the reaction is usually carried out at from low temperature to high temperature and preferably at from room temperature to elevated temperature.

At stage 3 tricyclic compound of chemical formula (1c) is obtained by reaction of removing the protection connection (8c-2)obtained in stage 2, in acidic conditions, such as chloromethane acid.

The method of obtaining 5

In one embodiment, the tricyclic derivative or its pharmaceutically acceptable salt can be obtained by the method represented by reaction formula 5 below, and the method comprises the stages:

1) obtaining amino-lactam compounds of chemical formula (8d-1) standard amination reaction lactam compound (8d) of the reaction formula 1 obtained in stage 5, and substituted-amine; and

2) receiving tricyclic compounds of chemical formula (1d) reaction unprotect connection (8d-1)obtained in stage 1, in acidic conditions, such as chloromethane acid.

The reaction formula 5

where R1represents H or -(CH2)n-X, 'pro' is methoxymethyl (MOM) group, benzyl group,pair-methoxybenzyl the ing (PMB) group, R2, R3and n are defined in chemical formula 1 and chemical formula 1d is included in the chemical formula 1 of the present invention.

According to the reaction formula 5 to obtain the compounds of chemical formula (1d) of the present invention, in stage 1 amino-lactam compound of the chemical formula (8d-1) receive the standard amination reaction lactam compound (8d)obtained in stage 5 of the reaction formula 1, with substituted amine. The reaction of stage 1 is carried out in the same reaction conditions amination, as conditions stage 2 reaction formula 4 stage 2, which turns the halogen compound of chemical formula (8c-1) in the compound of chemical formula (8c-2).

In stage 2 of the tricyclic compound of chemical formula (1d) is produced by reaction of removing the protection connection (8d-1)obtained in stage 1, in acidic conditions, such as chloromethane acid.

The target compounds obtained in the reaction formulas, can be cleaned by using common methods such as, for example, column chromatography or recrystallization.

The compound of chemical formula 1 of the present invention can be obtained in the form of a pharmaceutically acceptable salt and solvate conventional ways, as is known in the art.

Can be effectively used salt accession acid, which is formed from the pharmacy is automatic acceptable free acid. Salt accession acid you can get a conventional manner, for example by dissolving the compound in an excessive amount of acidic aqueous solution, and the precipitation of the compounds with water-soluble organic solvent including methanol, ethanol, acetone or acetonitrile. The same number of connections and acid in water or alcohol (e.g., glycolmonomethyl air) is heated, and the mixture is evaporated to dryness, or salt, extracted from the mixture, it is possible to suck and filter.

The free acid can be an organic acid and inorganic acid. The inorganic acid may be chloroethanol acid, phosphoric acid, sulfuric acid or nitric acid, and organic acid may be methanesulfonate, p-toluensulfonate, acetic acid, triperoxonane acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, almond acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid or iodomethane acid, but not limited to.

D is more, pharmaceutically acceptable salt of the metal can be obtained by applying the Foundation. Salts of alkaline and alkaline-earth metal can be obtained by dissolving the compound in an excessive amount of an aqueous solution of hydroxide of alkali metal or alkali earth metal hydroxide, filtering the insoluble salts of the compounds and process of evaporation and drying of the remaining solvent.

Salt of the metal may preferably be a salt of sodium, potassium or calcium, which is suitable for a pharmaceutical product, but not limited to. Further, it is possible to obtain the corresponding salt of silver by reacting salts of the alkali or alkaline earth metal with a suitable silver salt (e.g. silver nitrate).

Pharmaceutically acceptable salt of the compound of chemical formula 1 includes, unless otherwise specified, salt acidic or basic groups that may be contained in the compound of chemical formula 1. For example, pharmaceutically acceptable salt may include sodium, calcium and potassium hydroxyl group, and other pharmaceutically acceptable salt of the amino group may include the hydrobromide, sulfate, hydrosulfate, phosphate, hydrogen phosphate, dihydrophosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesilate) orp-toluensulfonate (toilet), and you can get them pic is the means of obtaining salts, known in this technical field.

In one embodiment, the pharmaceutically acceptable salt of the tricyclic derivative of the formula 1 includes:

1) 8-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

2) 10-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

3) 9-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

4) 9-Methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

5) Ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate hydrochloride;

6) 9-Methoxy-1-propyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

7) 1-Methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

8) 9-Methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

9) 1-Ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

10) 1-Methyl-9-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

11) 9-(1-Propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

12) 9-(1-Methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

13) 1-Methyl-9-(piperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

14) 1-Methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

15) 5-Oxo-N-[2-(piperidine-1-yl)what Teal]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide the dihydrochloride;

16) 9-[2-(Dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

17) 9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

18) 9-(2-Methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

19) 9-[2-(Piperazine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

20) 9 Ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

21) 9-[3-(piperidine-1-yl)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

22) 9-(2-Aminoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

23) 9-[2-(4-Phenylpiperazin-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

24) 9-(2-Hydroxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

25) 9 intoxi-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

26) 9-[2-(Diethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

27) 9-(2-Morpholinoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

28) 1,1-Diethyl-4-[2-(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9 yloxy]ethyl)piperazine-1-rd dihydrochloride;

29) 9-[4-(piperidine-1-yl)butoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

30) 1-Methyl-9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

31) 9-[2-(Dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

32) 8-[2-(Dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

33) 9-[3-(Dimethylamino)propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

34) 8-[2-(Dimethylamino)ethoxy]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide the dihydrochloride;

35) 8-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

36) 8-[3-(Dimethylamino)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

37) 8-(Dimethylamino)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

38) 8-[1-(Dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

39) 8-[1-(Methylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

40) 8-Ethyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

41) 8-[(Dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

42) 8-[(Diethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

43) 8-[(Ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

44) 8-(Pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

45) 8-[(Isopropylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

46) 8-[(Propylamine is)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

47) 8-{[Ethyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

48) 8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

49) 8-(Morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

50) 9-[(Dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

51) 8-{[Benzyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

52) 8-[(Methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

53) 8-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

54) 8-{[(2-(Dimethylaminoethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

55) 8-[(4-Methylpiperazin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

56) 8-[(Methyl(propyl)amino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

57) Ethyl-3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propionate the dihydrochloride;

58) 3-{Methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}popinova acid dihydrochloride;

59) 8-{[Isopropyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

60) 8-{[(2-Methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6)-he dihydrochloride;

61) Ethyl-3-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]the propionate dihydrochloride;

62) 8-[(2,2,2-Triptoreline)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

63) 2-[(5-Oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]the acetonitrile dihydrochloride;

64) 8-[(1H-Imidazol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

65) 8-[(1H-Pyrrol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

66) 8-[(Dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

67) 1-Methyl-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

68) 8-[(Diethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

69) 1-Methyl-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

70) 1-Methyl-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

71) 8-{[Ethyl(methyl)amino]methyl}-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

72) 8-[(Dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

73) 10-Methoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

74) 10-Methoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

75 8-[(Ethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

76) 8-{[Ethyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;

77) 10-Methoxy-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

78) 10-Methoxy-8-[(4-oxopiperidin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

79) 8-{[4-(Hydroxyimino)piperidine-1-yl]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

80) 10-Methoxy-8-[(4-(methoxyimino)piperidine-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

81) 10-Methoxy-8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

82) 8-[(2,5-Degidro-1H-pyrrol-1-yl)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

83) 8-{[2-Isopropoxyphenyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

84) 10-Methoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

85) 8-{[(2-Chloroethyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

86) 8-[(Diethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

87) 8-[(tert-Butylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

88) 8-[(Isopropylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,]naphthiridine-5(6H)-he dihydrochloride;

89) 8-[(Cyclopentylamine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

90) 8-[(2,6-dimethylmorpholine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

91) N-[(10-Methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]-N,N-dimethylcyclopentane hydrochloride;

92) 8-{[Cyclopentyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

93) 8-{[Isopropyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

94) 8-{[(2-Foradil)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

95) 8-[(1H-Tetrazol-5-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

96) 10-Methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

97) 10-Methoxy-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

98) (E)-10-Methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

99) 8-[(Dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-he dihydrochloride;

100) 8-[(Dimethylamino)methyl]-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

101) 10-Ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-on the dihydrochloride;

102) 10-Ethoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

103) 10-Ethoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

104) 10-Ethoxy-8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

105) 8-(Hydroxymethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride;

106) 10-Methoxy-8-(thiomorpholine)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

107) 10-Methoxy-8-[(2-morpholinoethyl)methyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

108) 10-Methoxy-8-[(4-morpholinopropan-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride;

109) 8-(Aminomethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

110) 8-[(Dimethylamino)methyl)]-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

111) 8-(Morpholinomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

112) 8-(Aminomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

113) 8-(Aminomethyl)-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

114) 8-(Aminomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

115) 10-Methoxy-8-{[methyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]NAF is iridin-5(6H)-he dihydrochloride;

116) 8-[(Dimethylamino)methyl]-10-(2-methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride;

117) 10-(2-Methoxyethoxy)-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride; and

118) 1-[(10-Methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]-1H-pyrrol-2,5-Dion dihydrochloride.

Further, since the compound of chemical formula 1 has an asymmetric center, the connection may be in the form of various mirror isomeric forms, and all optical isomers of compounds of chemical formulas 1 and stereometry R or S type and their mixtures are also included in the scope of the present invention. The present invention includes all racemic form, one or more mirrored isomeric forms, one or more diastereomeric forms, or mixtures thereof, and it also includes known methods of separation or the method of obtaining isomers.

Moreover, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases resulting from excessive activation of PARP, which contains a tricyclic derivative of chemical formula 1 or its pharmaceutically acceptable salt.

Diseases resulting from excessive activation of PARP may include neuropathic pain; neurodegenerative diseases, including epilepsy, stroke, disease al the gamer, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic and acute pain, ischemia, neuronal damage after hypoxia, external damage and neuronal damage; cardiovascular diseases, including atherosclerosis, hyperlipidemia, damage to the heart tissue, coronary artery disease, myocardial infarction, angina, cardiogenic shock; diabetic neuropathy; inflammatory disease, such as osteoarthritis, osteoporosis, or cancer.

Tricyclic derivative of the present invention inhibits the activity of poly(ADP-ribose)polymerase and can be used to prevent or treat diseases caused by excessive activation of PARP, and especially neuropathic pain, neurodegenerative diseases, cardiovascular disease, diabetic neuropathy, inflammatory diseases, osteoporosis or cancer.

In addition, the pharmaceutical composition comprising the compound according to option implementation may further comprise a suitable carrier, excipient or diluents suitable for use in the methods known in the art. Media, excipients and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, aritra, ▫ maltitol, starch, latex, acacia, alginate, Gelati is, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

A composition comprising a compound according to option exercise, can be obtained in a unit dosage form, including, for example, oral medication, including powder, granules, tablet, capsule, suspension, emulsion, syrup or aerosol preparations for external application, suppository or sterile solution for injection.

Specifically, the composition according to option implementation can be obtained in a unit dosage form using diluents or excipients such as a filler, dry filler, a binder, a wetting agent, a leavening agent or surfactant. Solid dosage form can be obtained by mixing the compounds with at least one or more excipients, such as, for example, starch, calcium carbonate, sucrose, lactose or gelatin. Next, you can apply a lubricating substance, such as magnesium stearate or talc, in addition to simple excipient. Liquid dosage forms for oral administration may include suspension, liquid for internal use, the emulsion or syrup, and it may contain various excipients other than the simple diluents, such as water or paraffin oil, such as, for example, a wetting agent, a sweetener, flavoring agent or preservative. Liquid dosage form for refererlog introduction may include sterile aqueous solution, nonaqueous solvent, suspension, emulsion, freeze-dried composition and suppository. Non-aqueous solvent and the suspension can include vegetable oil, such as propylene glycol, polyethylene glycol or olive oil, or ether for use by injection, such as etiloleat. Witepsol, macrogol, tween, cocoa butter, butter, maple or glycerin-gelatin can be used as a base for suppositories.

Although the dosage of the compounds of the present invention can vary depending on the status or weight of the patient, severity of disease, dosage form, route or duration of administration, the dose can be appropriately selected by a person skilled in the art. However, for the desired effect, the compound of the chemical formula of the present invention can be introduced in a dose of 0.0001-1000 mg/kg, or preferably 0.01 to 500 mg/kg from one to several times a day. In one embodiment, the compound of chemical formula 1 can be mixed to 0.0001 to 50% by weight relative to the total amount of the composition.

Further, the pharmaceutical form for entering connection in the present invention may contain pharmaceutically acceptable salt of the compound, and application of the compounds alone or in combination with other pharmaceutically active compounds.

The pharmaceutical composition of the present invention can be introduced mammal, including a mouse, pet, or person, in different ways. All routes of administration, which may include oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine, epidural or intracerebral injection, are predictable.

A variant of the present invention

The present inventive technical concept will be explained more fully below on the basis of examples and experimental data, which should not be construed as limiting the present inventive concept.

<Example 1> Obtain hydrochloride of 8-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 2-Chloro-N-(3-methoxyphenyl)nicotinamide

To a stirred solution of 2-chloronicotinic acid (500 mg, 3,17 mmol) in anhydrous dichloromethane (10 ml) was added dropwise oxalicacid (0,407 ml, 4.76 mmol) at room temperature. Was added a drop of anhydrous N,N-dimethylformamide, and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction intermediate product, i.e. the 2-chlor cotiniere, acquired by concentration in vacuo. Added anhydrous dichloromethane (10 ml) and then the solution of the above mixture was added dropwise at 0°C 3-anisidine (0,390 ml, 3,49 mmol) in anhydrous dichloromethane (5 ml). Was added triethylamine (0,885 ml, 6,347 mmol) and the mixture was stirred for one hour at 0°C. After completion of the reaction was added water and the resulting mixture was extracted with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure to obtain specified in the title compound (970 mg, cream the butter).

1H NMR (400 MHz, CDCl3); δ 8,49 (DD, J=2.0 Hz, 4.8 Hz, 1H), compared to 8.26 (s, 1H), 8,14 (DD, J=1.6 Hz, 7.2 Hz, 1H), 7,40 (s, 1H), 7,41-7,37 (m, 1H), 7,28 (t, J=8.0 Hz, 1H), 7,13-7,10 (m, 1H), 6.75 in (DD, J=2,4 Hz and 8.4 Hz, 1H), 3,84 (s, 3H).

Stage 2: Obtain 2-Chloro-N-(4-methoxybenzyl)-N-(3-methoxyphenyl)nicotinamide

N,N-Dimethylformamide was added to the compound (972,4 mg, 3,1736 mmol)obtained in stage 1, and the mixture was cooled to 0°C. was Slowly added sodium hydride (380 mg, 9,52 mmol) and the resulting mixture was stirred at 0°C for 20 minutes. Was added at 0°Cp-methoxybenzylamine (0,646 ml, 4.76 mmol) and the mixture was stirred for 3 hours at room temperature. After completion of the reaction was added dichloromethane and water, the organic layer dried the over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate=2,5:l) to obtain the specified title compound (1.01 g, yield: 84%, cream the butter).

1H NMR (400 MHz, CDCl3); δ to 8.20 (DD, J=1.6 Hz, 4.4 Hz, 1H), 7,44 (DD, J=1.6 Hz and 7.6 Hz, 1H), 7,25 (d, J=8,8 Hz, 2H), 7,05 (DD, J=4,8 Hz, 7.2 Hz, 1H), 7,01 (t, J=7,6 Hz, 1H), at 6.84 (d, J=8,8 Hz, 2H), only 6.64 (DD, J=2,8 Hz and 8.4 Hz, 1H), 6,55-6,53 (m, 1H), 6,50 (s, 1H), to 5.03 (s, 2H), 3,80 (s, 3H), 3,61 (s, 3H).

Stage 3: Getting 8-Methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthiridine-5(6H)-it

To a stirred solution of compound (873 mg, 2.28 mmol), obtained in stage 2, N,N-dimethylformamide (6.0 ml) was added sequentially a palladium (II) acetate (153,6 mg, 0,684 mmol), 1,3-bis(diphenylphosphino)propane (282 mg, 0,684 mmol), tributylphosphine (0,563 ml, 2.28 mmol) and potassium carbonate (630 mg, 4,56 mmol)and the mixture is boiled under reflux for four hours at 120°C. After completion of the reaction, the reaction mixture was cooled to room temperature and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate:dichloromethane=1:1:1) to obtain specified in the connection header (192,4 mg, yield: 24%, white solid).

1H NMR (400 MHz, CDCl ); δ 8,96 (DD, J=1.6 Hz, 4.4 Hz, 1H), 8,771 (d, J=8,8 Hz, 1H), 8,767 (d, J=8.0 Hz, 1H), 7,46 (DD, J=4.4 Hz, and 8.4 Hz, 1H), 7,24 (d, J=8,8 Hz, 2H), 6,91 (DD, J=2.0 Hz, 8,8 Hz, 1H), 6,85 (s, 1H), at 6.84 (d, J=8,8 Hz, 2H), of 5.55 (s, 2H), 3,81 (s, 3H), 3,76 (s, 3H).

In this reaction 10-methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthiridine-5(6H)-he (243,8 mg, yield: 31%, white solid) was obtained as a side product.

1H NMR (400 MHz, CDCl3); δ to 9.15 (m, 1H), 8,88 (m, 1H), 7,53 (m, 1H), 7,43 (t, J=8,4 Hz, 1H), 7,20 (d, J=8,4 Hz, 2H), 7,05 (d, J=8,4 Hz, 1H), 6,92 (d, J=8,4 Hz, 1H), at 6.84 (d, J=8,4 Hz, 2H), of 5.55 (s, 2H), 4,10 (s, 3H), 3,76 (s, 3H).

Stage 4: Getting 8-Methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

To a stirred solution of compound 8-methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthiridine-5(6H)-she (192,4 mg, 0,555 mmol), obtained in stage 3, in a mixture of ethyl acetate/dichloromethane/methanol, was added 10%-palladium (Pd) (20 mg)and the mixture was stirred for 18 hours in hydrogen gas. After completion of the reaction, 10%-palladium (Pd) was filtered and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (192,7 mg, yield: 99%, solid cream color).

1H NMR (400 MHz, CDCl3); δ 7,40 (d, J=8,4 Hz, 1H), to 7.09 (d, J=8,8 Hz, 2H), 6,72 (d, J=8,8 Hz, 2H), 6,63 (s, 1H), 6,62 (d, J=8,4 Hz, 1H), lower than the 5.37 (s, 2H), 3,66 (s, 3H), of 3.65 (s, 3H), 3,39-to 3.34 (m, 2H), 2,68-to 2.65 (m, 2H), 1,90-1,87 (m, 2H).

Stage 5: Getting 8-Methoxy-1,2,3,4-tetrahydrobenzo[h[1,6]naphthiridine-5(6H)-it

Triperoxonane acid (2 ml) was added to the compound (102,9 mg, 0,294 mmol)obtained in stage 4, and the mixture was stirred in a sealed tube for 20 hours at 100°C. After completion of the reaction, the reaction mixture was cooled to room temperature and was extracted with dichloromethane. The organic layer was washed with an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was stirred in a mixture of ethyl acetate/hexane/diethyl ether and the resulting solid was filtered. The filtered solid is washed with diethyl ether and dried in vacuum to obtain specified in the connection header (57,8 mg, yield: 85,5%, solid cream color).

1H NMR (400 MHz, DMSO-d6); δ 10,65 (s, 1H), 7,69 (d, J=9.6 Hz, 1H), 6,85 (s, 1H), 6,70 (s, 1H), 6,70 of 6.68 (m, 1H), 3,76 (s, 3H), of 3.27 (m, 2H), 2.40 a-a 2.36 (m, 2H), 1,78 is 1.75 (m, 2H).

Step 6: obtain the hydrochloride of 8-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Connection of 57.8 mg, 0,251 mmol)obtained in stage 5, was dissolved in 1,4-dioxane (1 ml), was added 3,6 called 1,4-dioxane solution chloroethanol acid (1 ml) and then was stirred for 24 hours. After completion of the reaction the solvent was removed under reduced pressure and the meet is but the resulting residue was stirred for 30 minutes in a mixture of ethyl acetate/diethyl ether. The resulting solid was filtered and washed with diethyl ether to obtain specified in the connection header (38,1 mg, yield: 56.9%of green solid).

1H NMR (400 MHz, DMSO-d6); δ 11,78 (s, 1H), 7,95 (d, J=8,8 Hz, 1H), 6,93 (s, 1H), 6,94-of 6.90 (m, 1H), 3,82 (s, 3H), 3,37-to 3.35 (m, 2H), 2,55-2,52 (m, 2H), 1,83 and 1.80 (m, 2H).

<Example 2> Obtaining hydrochloride 10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

10-Methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthiridine-5(6H)-he (244 mg, 0.70 mmol), obtained in stage 3 of example 1, interacted in the same way as for stages 4-6 of example 1, to obtain the specified title compound (115 mg, yield: 61%, white solid).

1H NMR (400 MHz, DMSO-d6); δ 12,02 (s, 1H), 8,46 (user., 1H), of 7.48 (t, J=8.0 Hz, 1H), 7,05 (DD, J=0.8 Hz, and 8.4 Hz, 1H), at 6.84 (DD, J=0.8 Hz, and 8.4 Hz, 1H), 3,94 (s, 3H), 3,42 is 3.40 (m, 2H), 2.57 m-of 2.54 (m, 2H), 1,80-to 1.77 (m, 2H).

<Example 3> Obtain hydrochloride of 9-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Except that 4-anisidin used instead of 3-anisidine in stage 1, was applied the same way as in example 1, obtaining specified in the connection header.

1H NMR (400 MHz, DMSO-d6); δ 11,76 (s, 1H), 7,83 (user., 2H), 7,50 (d, J=2.0 Hz, 1H), was 7.36 (d, J=8,8 Hz, 1H), 7,20 (DD, J=9,2 Hz, 2.4 Hz, 1H), 3,81 (s, 3H), 3,90 (t, J=5,2 Hz, 2H), by 2.55 (t, J=5.6 Hz, 2H), 1,84-of 1.81 (m,2H).

<4> Obtain hydrochloride of 9-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Except that methoxymethane (MOM-Cl) was used instead ofp-methoxybenzylamine in stage 2, was applied the same way as in example 1, obtaining specified in the connection header.

1H NMR (400 MHz, DMSO-d6); δ 11,72 (s, 1H), 7,79 (s, 1H), was 7.36 (d, J=8,4 Hz, 1H), 7,30 (d, J=8,4 Hz, 1H), 3,34 (t, J=5.6 Hz, 2H), 2,52 (t, J=6.0 Hz, 2H), 2,53 (s, 3H), of 1.80 (t, J=5,2 Hz, 2H).

<Example 5> Obtain hydrochloride of ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate

Stage 1: Obtain ethyl 4-(2-chloronicotinamide)benzoate

2-Chloronicotinic acid (500 mg, 3,17 mmol) was dissolved in dichloromethane (10 ml), was added oxalicacid (0,41 ml, 4.76 mmol) and N,N-dimethylformamide (cat. 1 drop) properly and then was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (5 ml). Was added at room temperature ethyl 4-aminobenzoate (576 mg, of 3.48 mmol) and triethylamine (0.88 to ml, 6,34 mmol) and then the mixture was stirred for one hour. The mixture was poured into ice water, extracted with dichloromethane and then washed with brine. The organic layer was dried over anhydrous su is hatom sodium, was filtered and concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate=1:1) to obtain the specified title compound (1.04 g, yield: quantitative yield, white solid).

1H NMR (400 MHz, CDCl3); δ 8,54 are 8.53 (m, 1H), 8,40 (users, 1H), 8,23 (m, 1H), of 8.09 (d, J=8,8 Hz, 2H), of 7.75 (d, J=8,4 Hz, 2H), 7,44-7,41 (m, 1H), 4,40-of 4.35 (m, 2H), 1,40 (t, J=7,1 Hz, 3H).

Stage 2: Obtain ethyl 4-[2-chloro-N-(4-methoxybenzyl)aminonicotinamide]benzoate

To a stirred solution of the compound (800 mg, 2,62 mmol)obtained in stage 1, N,N-dimethylformamide (10 ml), was added potassium carbonate (1,09 g, 7.87 mmol) and 4-methoxybenzylamine (0,43 ml of 3.15 mmol) at room temperature. The mixture was heated at 90°C during the night. The mixture was poured into ice water and was extracted with CHLOROFORMATES. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate=1:1) to obtain the specified title compound (990 mg, yield: 89%, white solid).

1H NMR (400 MHz, CDCl3); δ 8,21 (m, 1H), 7,81 (d, J=8,4 Hz, 2H), 7,47-the 7.43 (m, 1H), 7,27-7,19 (m, 2H), 7.03 is-7,00 (m, 3H), 6,83 (d, J=8,4 Hz, 2H), 5,07 (users, 2H), 4,30-4,24 (m, 2H), 3,79 (s, 3H), of 1.33 (t, J=7,1 Hz, 3H).

Stage 3: Obtain ethyl 6-(4-methoxybenzyl)-5-oxo-5,6-d is hydrobenzo[h][1,6]naphthiridine-9-carboxylate

Compound (45 mg, 0.10 mmol)obtained in stage 2, was dissolved in N,N-dimethylformamide (10 ml) was added 1,3-bis(diphenylphosphino)propane (13 mg, 0,031 mmol), palladium (II) acetate (7 mg, 0,031 mmol), tributylphosphine (26 μl, 0.10 mmol) and potassium carbonate (29 mg, 0.21 mmol). The mixture was stirred for one hour at 140°C. the Mixture was poured into ice water and was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate=2:l) to obtain specified in the connection header (34.7 mg, yield: 89%, white solid).

1H NMR (400 MHz, CDCl3); δ of 9.56 (s, 1H), which is 9.09-remaining 9.08 (m, 1H), 8,84-8,81 (m, 1H), 8,18-8,16 (m, 1H), to 7.61-7,58 (m, 1H), 7,44 (d, J=8,8 Hz, 1H), 7,22 (d, J=8,4 Hz, 2H), 6,85 (d, J=8.0 Hz, 2H), 5,62 (users, 2H), of 4.44 (q, J=7,3, 6,9 Hz, 2H), 3,76 (s, 3H), USD 1.43 (t, J=7,1 Hz, 3H).

Stage 4: Obtain ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate

The compound (27 mg, 0,069 mmol), obtained in stage 3, was dissolved in methanol (5 ml) and dichloromethane (5 ml) was added 10%-palladium. The mixture was stirred for 18 hours at room temperature in hydrogen gas. After completion of the reaction, 10%-palladium (Pd) was removed by filtration through celite and the filtrate was concentrated the ri reduced pressure. The residue was dissolved in triperoxonane acid (TFA, 2 ml) and the resulting mixture was added anisole (0,64 ml of 0.58 mmol) and 12 N. aqueous solution of sulfuric acid (0,097 ml of 1.17 mmol). The reaction mixture was stirred for 18 hours at 100°C. the Mixture was stirred for one hour at 140°C. the Mixture was poured into cold aqueous sodium bicarbonate solution and was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified flash column-chromatography (dichloromethane:methanol=7:1) to obtain the specified title compound (7.5 mg, yield: 47%, yellow solid).

1H NMR (400 MHz, CDCl3); δ of 8.25 (s, 1H), 8,08 (d, J=8,4 Hz, 1H), 7.23 percent (d, J=8,8 Hz, 1H), to 4.41 (q, J=7,3 Hz, 2H), 3,48 (t, 5.5 Hz, 2H), to 2.67 (t, J=6.2 Hz, 2H), 2.00 in was 1.94 (m, 2H), 1,42 (t, J=7,1 Hz, 3H).

Stage 5: obtain the hydrochloride of ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate

Compound (7.5 mg, or 0.027 mmol), obtained in stage 4, was dissolved in 1,4-dioxane (1 ml), was added to 3.7 called 1,4-dioxane solution chloroethanol acid (1 ml) and then stirred for 18 hours at room temperature. After completion of the reaction, the formed solid was filtered, washed with ethyl acetate and dried in vacuum to obtain specified in the title compound (4.5 mg, o is d: 25%, white solid).

1H NMR (400 MHz, DMSO-d6); δ 11,17 (s, 1H), 8,48 (s, 1H), 7,95 (d, J=8,8 Hz, 1H), 7,26 (d, J=8,8 Hz, 1H), 4,35-the 4.29 (m, 2H), 3,31 of 3.28 (m, 2H), 2,46 is 2.44 (m, 2H), 1,81-of 1.74 (m, 2H), 1,35-of 1.32 (m, 3H).

<Example 6> Obtain hydrochloride of 9-methoxy-1-propyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: get a 9-methoxy-6-(4-methoxybenzyl)-1-propyl-1,2,3,4-tetrahydrobenzo[h][ 1,6]naphthiridine-5(6H)-it

Connection 9-methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he (100 mg, 0,285 mmol)obtained in stage 4 of example 3, was dissolved in N,N-dimethylformamide (5 ml), was added sodium hydride (17 mg, 0,428 mmol) at 0°C. the Reaction mixture was stirred for 1 hour at room temperature. Then was added 1-bromopropane (0,039 ml, 0,428 mmol) and the mixture was stirred for one hour at room temperature. The mixture was poured into ice water, extracted with chloroform. The organic layer was washed saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate=1:1) to obtain the specified title compound (56 mg, yield: 50%, yellow solid).

1H NMR (400 MHz, CDCl3); δ 7,26-7,14 (m, 4H), 6,98-to 6.95 (m, 1H), 6,82-for 6.81 (m, 2H), 5,45 (user., 2H), 3,83 (s, 3H), of 3.75 (s, 3H), 3,17-3,15 (m,2H), 3,01-of 2.97 (m, 2H), 2,71 (t, J=6,8 Hz, 2H), 1,94-of 1.85 (m, 4H), 0,981 (t, J=6.8 Hz, 3H).

Stage 2: Getting 9-methoxy-1-propyl-1,2,3,4-tetrahydro[h][1,6]naphthiridine-5(6H)-it

Compound (56 mg, 0,142 mmol)obtained in stage 1, was dissolved in triperoxonane acid (3 ml) and the resulting mixture was stirred at 100°C for one day. After completion of the reaction the mixture was concentrated under reduced pressure and the residue was purified flash column-chromatography (chloroform:methanol=15:l) to obtain the specified title compound (31 mg, yield: 82%, yellow solid).

1H NMR (400 MHz, DMSO-d6); δ are 11.62 (s, 1H), 7,30 (d, J=4.4 Hz, 1H), 7,13 (s, 1H), 7,07? 7.04 baby mortality (m, 1H), 3,85 (s, 3H), 3,17-3,14 (m, 2H), 3.04 from-3,00 (m, 2H), 2,70 (t, J=6,8 Hz, 2H), 1,92 of-1.83 (m, 5H), 0,99 (t, J=7.2 Hz, 3H).

Stage 3: obtain the hydrochloride of 9-methoxy-1-propyl-1,2,3 tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (31 mg, 0,114 mmol), obtained in stage 2, was dissolved in 1,4-dioxane (1 ml), was added to 3.7 called 1,4-dioxane solution chloroethanol acid (1 ml) and then was stirred for one day at room temperature. After completion of the reaction the mixture was concentrated under reduced pressure and washed with ethyl acetate to obtain specified in the title compound (24 mg, yield: 70%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 1139 (s, 1H), 9,25-8,66 (user., 1H), 7,25 (d, J=8,8 Hz, 1H), of 3.78 (s, 3H), is 3.08 (m, 2H), 2.95 points (t, J=7,6 Hz, 2H), 2,43 (t, J=6,8 Hz, 2H), 1,88 of-1.83 (m, 2H), 1,73 (m, 2H), of 0.93 (t, J=7,6 Hz, 3H).

Following the reaction of example 6, were obtained the following compounds.

<Example 7> hydrochloride of 1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 8> hydrochloride of 9-methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 9> hydrochloride of 1-Ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 10> hydrochloride of 1-methyl-9-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound obtained in example 9, was dissolved in dichloromethane (2 ml) and 1M dichloromethane solution tribromide boron (4,2 ml). The mixture was stirred over night at room temperature. The reaction mixture was poured into ice water and the precipitate was filtered to obtain specified in the connection header.

ExampleChemical structureThese NMR spectrum
71H NMR (400 MHz, DMSO-d6) δ for 11.55 (s, 1H), 10,11 (user., 1H), 7,76 (d, J=8.0 Hz, 1H), 7,41 (m, 1H), 7,29 (d, J=8,4 Hz, 1H), 7,15 (m, 1H), 3,11 (m, 2H), 2,96 (s, 3H), 2,43 (t, J=6.0 Hz, 2H), 1,76 (m, 2H)
8 1H NMR (400 MHz, DMSO-d6) δ 11,51 (s, 1H), 7,26 (d, J=8,8 Hz, 1H), 7,19 (s, 1H), 7,11 (d, J=8,8 Hz, 1H), 3,80 (s, 3H), of 3.12 (m, 2H), 2,96 (s, 3H), of 2.45 (t, J=6.0 Hz, 2H), 1,76 (m, 2H)
91H NMR (400 MHz, DMSO-d6)δ 11,38 (s, 1H), 7,24 (d, J=8,8 Hz, 1H), to 7.09 (d, J=8,8 Hz, 1H), 7,02 (s, 1H), 3,79 (s, 3H), 3,06 (m, 4H), 2,42 (t, J=6.0 Hz, 2H), 1,72 (m, 2H), of 1.34 (t, J=6.4 Hz, 3H)
101H NMR (400 MHz, DMSO-d6) δ 11,12 (s, 1H), 9,29 (s, 1H), to 7.09 (d, J=8,8 Hz, 1H), 7,07 (d, J=2.4 Hz, 1H), to 6.88 (DD, J=8,8 Hz, 2.4 Hz, 1H), 3,05-to 3.02 (m, 2H), 2,85 (s, 3H), 2,39 (t, J=6.4 Hz, 2H), 1,75-1,72 (m, 2H)

<Example 11> Getting dihydrochloride 9-(1-propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Getting 9 methoxybenzo[h][1,6]naphthiridine-5(6H)-it

9-Methoxy-6-(4-methoxybenzyl)benzo[h][1,6]naphthiridine-5(6H)-he (50 mg, 0.14 mmol), obtained in stage 3 of example 3, was dissolved in triperoxonane acid (5 ml)was sequentially added anisole (157 μl, 1.44 mmol) and 12 N. sulfuric acid (240 μl, 2.89 mmol). The mixture was stirred for one day at 90°C. the Reaction mixture was cooled to room temperature and poured into cold saturated aqueous rest the R sodium bicarbonate. After extraction with chloroform, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent the residue was washed with ethyl acetate, filtered and dried in vacuum to obtain specified in the title compound (25 mg, yield: 77%, white solid).

1H NMR (400 MHz, DMSO-d6); δ 11,83 (s, 1H), 9,06 (d, J=6.0 Hz, 1H), 8,61 (DD, J=8.0 Hz, 2.8 Hz, 1H), of 8.09 (d, J=2.4 Hz, 1H), 7,71-to 7.67 (m, 7,34 (d, J=8,8 Hz, 1H), 7.23 percent (DD, J=8,8 Hz, 2.4 Hz, 1H), 3,86 (s, 3H).

Stage 2: Getting 9 hydroxybenzo[h][1,6]naphthiridine-5(6H)-it

The compound (190 mg, 0.84 mmol)obtained in stage 1, was dissolved in dichloromethane (2 ml)was added 1 M dichloromethane solution trichromate boron (4,2 ml). The mixture was stirred over night at room temperature. The reaction mixture was poured into ice water and the precipitate was collected by filtration to obtain specified in the title compound (125 mg, yield: 70%, yellow solid).

1H NMR (400 MHz, DMSO-d6); δ 11,70 (s, 1H), of 9.56 (s, 1H), 9,03 (m, 1H), 8,58 (d, J=7,6 Hz, 1H), to 7.99 (s, 1H), 7,65 (DD, J=7,6 Hz, 1.2 Hz, from 7.24 (d, J=8,8 Hz, 1H), 7,05 (DD, J=8,8 Hz, 1.6 Hz, 1H).

Stage 3: Gettingtert-butyl 4-(5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9 yloxy)piperidine-1-carboxylate

The compound (60 mg, 0.28 mmol)obtained in stage 2, and potassium carbonate (120 mg, 0.85 mmol) Rast is orally in a mixture of acetonitrile (6 ml)/N,N-dimethylformamide (3 ml), addedtert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (240 mg, 0.85 mmol). The resulting mixture was stirred for 3 days at 100-110°C and cooled to room temperature. After extraction with chloroform, the reaction mixture was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified flash column-chromatography (chloroform:methanol=10:l) to obtain the specified title compound (65 mg, yield: 58%, white solid).

1H NMR (400 MHz, CDCl3); δ 11,06 (s, 1H), 9,03 (m, 1H), 8,80 (d, J=7,6 Hz, 1H), 8,27 (d, J=2.4 Hz, 1H), 7,56 (m, 1H), 7,34 (d, J=8,8 Hz, 1H), 7,20 (DD, J=8,8 Hz, 2.4 Hz, 1H), 4,67 (m, 1H), 3.75 to 3,70 (m, 2H), 3,42-to 3.36 (m, 2H), 1,98-of 1.97 (m, 2H), 1,83-of 1.81 (m, 2H), 1,47 (s, 9H).

Stage 4: 9-(piperidine-4-yloxy)benzo[h][1,6]naphthiridine-5(6H)-it

Compound (110 mg, 0.28 mmol), obtained in stage 3, was dissolved in 1,4-dioxane, was added to 3.7 called 1,4-dioxane solution chloroethanol acid. The resulting mixture was stirred over night at room temperature and the precipitate was collected by filtration to obtain specified in the title compound (90 mg, yield: 98%, yellow solid).

1H NMR (400 MHz, DMSO-d6); δ 11,89 (s, 1H), 9,10 (user., 2H), 9,06 (m, 1H), 8,64 (DD, J=8.0 Hz, 1.6 Hz, 1H), to 8.20 (s, 1H), 7,71 (DD, J=7,6 Hz, 4.0 Hz, 1H), 7,37 (d, J=8,8 Hz, 1H), 7,31 (DD, J=8,8 is C, the 3.2 Hz, 1H), 4,78 was 4.76 (m, 1H), 3,24 is 3.23 (m, 2H), 3,12-3,10 (m, 2H), 2,16-2,12 (m, 2H), 1.93 and-a 1.88 (m, 2H).

Stage 5: 9-(1-propylpiperidine-4-yloxy)benzo[h][1,6]naphthiridine-5(6H)-it

Compound (55 mg, 0,17 mmol)obtained in stage 4, and potassium carbonate (70 mg, 0.50 mmol) was dissolved in acetonitrile (10 ml), was added 1-bromopropane (53 ál,0,058 mol) at room temperature. The resulting mixture was stirred over night at 60°C and was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then the residue was purified flash column-chromatography (chloroform:methanol=5:1) to obtain the specified title compound (34 mg, yield: 61%, white solid).

1H NMR (400 MHz, CDCl3); δ 10,59 (s, 1H), 9,04 (m, 1H), 8,80 (DD, J=8.0 Hz, 2.0 Hz, 1H), 8,27 (d, J=2.4 Hz, 1H), 7,56 (DD, J=8.0 Hz, 4.8 Hz, 1H), 7,29 (d, J=8,8 Hz, 1H), 7,21 (DD, J=8,8 Hz, 2.4 Hz, 1H), 4,56 (m, 1H), 2,82 (m, 2H), to 2.41 (m, 4H), and 2.14 (m, 2H), 1,95 (m, 2H), 1,58 (m, 2H), of 0.93 (t, J=7.2 Hz, 3H).

Stage 6: 9-(1-propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (30 mg, 0.09 mmol)obtained in stage 5, was dissolved in a mixture of ethanol (4 ml)/dichloromethane (2 ml), was added 10%-palladium (Pd) (6 mg) at room temperature. The resulting mixture paramashiva and in one day in gaseous hydrogen. Using celite, removed the 10%-palladium (Pd), and the filtrate was concentrated under reduced pressure. Added ethyl acetate and the precipitate was collected by filtration to obtain specified in the title compound (28 mg, yield: 92%, white solid).

1H NMR (400 MHz, CDCl3+ CD3OD); δ 7,18-7,14 (m, 2H), 7,05 (d, J=8,8 Hz, 1H), with 4.64 (m, 1H), 3,44 (m, 2H), 2,66 (m, 2H), 2,35 (m, 2H), 2,12-of 2.09 (m, 2H), 1,98-of 1.92 (m, 2H), 1,80 (m, 2H), and 1.00 (t, J=7.2 Hz, 3H).

Step 7: obtain the dihydrochloride 9-(1-propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (28 mg, 0.08 mmol), obtained in stage 6, was dissolved in a mixture of ethanol/1,4-dioxane was added to 3.7 called 1,4-dioxane solution chloroethanol acid. The resulting mixture was stirred over night at room temperature. After completion of the reaction the mixture was concentrated under reduced pressure and washed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain specified in the title compound (27 mg, yield: 79%, yellow solid).

1H NMR (400 MHz, DMSO-d6); δ 11,77 (m, 1H), of 10.73 (user., 2H), to 7.75 (m, 1H), 7,39 was 7.36 (m, 1H), 7,27-of 7.23 (m, 1H), 4,81-4,69 (m, 1H), 3,53 (m, 2H), 3,38 (m, 2H), 3.15 and was 3.05 (m, 4H), of 2.54 (m, 2H), 2.23 to-2,19 (m, 2H), 2,08 is 2.00 (m, 2H), equal to 1.82 (m, 2H), 1,73 (m, 2H), 0,91 (t, J=7.2 Hz, 3H).

<Example 12> Getting dihydrochloride 9-(1-metile ridin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Except that 1-bromatan used instead of bromopropane on stage 5 of example 11 was carried out by the same method as in example 11, to obtain specified in the connection header.

1H NMR (400 MHz, DMSO-d6); δ to 11.52 (d, J=12.0 Hz, 1H), or 10.60 (s, 1H), 7,65 (s, 1H), 7,34-7,31 (m, 1H), 7,25-7,20 (m, 1H), 4,76-4,59 (m, 1H), 3,50 be 3.29 (m, 4H), 3,15-of 3.06 (m, 2H), to 2.67 (m, 4H), 2.23 to-2,04 (m, 3H), of 1.88 and 1.80 (m, 4H).

<Example 13> Getting dihydrochloride of 1-methyl-9-(piperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain tert-butyl 4-(1-methyl-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9 yloxy)piperidine-1-carboxylate

9-Hydroxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-one (60 mg, 0.26 mmol)obtained in example 10, was dissolved in a mixture of acetonitrile (8 ml)/N,N-dimethylformamide (4 ml), was addedtert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (220 mg, 0.78 mmol) at room temperature. The resulting mixture was stirred for four days at 90-100°C and was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure. Then the residue was purified flash column-chromatography (chloroform:methanol=20:1) to obtain the specified title compound (70 mg, yield: 5%, brown butter).

1H NMR (400 MHz, CDCl3); δ 11,35 (s, 1H), 7,27 (m, 2H), 7,06 (DD, J=8,8 Hz, 3.2 Hz, 1H), 4,49-of 4.44 (m, 1H), 3.75 to 3,68 (m, 2H), 3,38-of 3.31 (m, 2H), 3,17-3,15 (m, 2H), 2,98 (s, 3H), 2,69 (t, J=6.4 Hz, 2H), 1,95 is 1.75 (m,6H), of 1.47 (s, 9H).

Stage 2: Obtain 1-methyl-9-(piperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (70 mg, 0,17 mmol)obtained in stage 1, was dissolved in 1,4-dioxane (3 ml), was added to 3.7 called 1,4-dioxane solution chloroethanol acid. The resulting mixture was stirred over night at room temperature and the precipitate was collected by filtration to obtain specified in the title compound (56 mg, yield: 86%, brown solid).

1H NMR (400 MHz, DMSO-d6); δ 11,35 (s, 1H), 8,97-8,83 (m, 2H), 7.24 to 7,22 (m, 2H), 7,15 (d, J=8,8 Hz, 1H), with 4.64 (m, 1H), 3,20 (m, 2H), of 3.07 (m, 4H), 2,90 (s, 3H), 2,42 (t, J=6.4 Hz, 2H), 2,08 (m, 2H), 1,86-to 1.77 (m, 4H).

<14> Getting dihydrochloride of 1-methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 1-methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (45 mg, 0.13 mmol)obtained in stage 2 of example 13, was dissolved in methanol (3 ml)/dichloromethane (3 ml)was sequentially added formaldehyde (29 ál,0.38 mmol), acetic acid (12 μl,0.22 mmol) and Tria is maximalized sodium (108 mg, 0.51 mmol) at room temperature. The resulting mixture was stirred over night at room temperature and poured into a chilled 2 N. aqueous sodium hydroxide solution. The mixture was extracted with chloroform and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then the residue was purified flash column-chromatography (chloroform:methanol=5:1) to obtain the specified title compound (28 mg, yield: 66%, yellow oil).

1H NMR (400 MHz, CDCl3); δ 10,99 (3, 1H), 7,26-7,22 (m, 2H), 7,06 (DD, J=8,8 Hz, 2.0 Hz, 1H), 4,36 (m, 1H), 3,17-3,15 (m, 2H), 2,98 (s, 3H), was 2.76 (m, 2H), 2,68 (t, J=6.4 Hz, 2H), 2,43 of-2.32 (m, 5H), 2,07 (m, 2H), 1.91 a-to 1.87 (m, 4H).

Stage 2: obtain the dihydrochloride of 1-methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (25 mg, 0.08 mmol), obtained in stage 1, was dissolved in 1,4-dioxane (3 ml), was added to 3.7 called 1,4-dioxane solution chloroethanol acid. The resulting mixture was stirred for 3 days at room temperature and the precipitate was collected by filtration to obtain specified in the title compound (524 mg, yield: 79%, yellow solid).

1H NMR (400 MHz, DMSO-d6); δ of $ 11.48 (s, 1H), 10,90 (m, 1H), 7,32-7,14 (m, 3H), 4.75 V-of 4.54 (m, 1H), 3.45 points-of 3.42 (m, 1H), 3,24-3,11 (m, 5H), of 2.93 (s, 3H), was 2.76-2.71 to (m, 3H), 2,44 (m, 2H), 2,22-1,90 (m, 4H),to 1.79 (m, 2H).

<Example 15> Getting dihydrochloride 5-oxo-N-[2-(piperidine-1-yl)ethyl]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide

Stage 1: Obtain 6-(4-methoxybenzyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9-carboxylic acid

The compound (200 mg, 0.51 mmol), obtained in stage 3 of example 5, was dissolved in methanol, was added 1 n sodium hydroxide (5 ml). The resulting mixture was boiled under reflux for 18 hours, cooled to room temperature. The mixture was concentrated under reduced pressure and added water. The aqueous layer was acidified using 1 N. chloroethanol acid and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Got mentioned in the title compound (140 mg, yield: 76%, white solid) without purification stages.

1H NMR (400 MHz, CDCl3): δ 9,37 (s, 1H), 9,14-9,13 (m, 1H), 8,73 (d, J=8.0 Hz, 1H), of 8.09 (d, J=8.0 Hz, 1H), 7,78 to 7.75 (m, 1H), 7,60 (d, J=8,4 Hz, 1H), 7,24 (d, J=7.7 Hz, 2H), 6.87 in (d, J=7,3 Hz, 2H), 5,58 (users, 2H), 3,69 (s, 3H).

Stage 2: Obtain 6-(4-methoxybenzyl)-5-oxo-N-[2-piperidine-1-yl)ethyl]-5,6-dihydrobenzo[h][1,6]naphthiridine-9-carboxamide

The compound (30 mg, 0.09 mmol)obtained in stage 1, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 48 mg, 0.25 mmol) and hydrate 1-hydrox is benzotriazole (HOBt, 34 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (5 ml) was added 1-(2-amino-ethyl)piperidine (0,033 ml, 0.23 mmol) at room temperature. The resulting mixture was stirred for 18 hours and poured into ice-cold water. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Then the residue was purified flash column-chromatography (chloroform:methanol =7:1) to obtain the specified title compound (82 mg, yield: 92%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,26 (s, 1H), 9,02-9,00 (m, 1H), 8,80-8,78 (m, 1H), 8,05-8,02 (m, 1H), EUR 7.57-rate of 7.54 (m, 1H), 7,42 (d, J=8,8 Hz, 1H), 7,32 (users, 1H), 7,21 (d, J=8,4 Hz, 2H), at 6.84 (d, J=8,8 Hz, 2H), 5,58 (users, 2H, in), 3.75 (s, 3H), 3,62 is 3.57 (m, 2H), 2,64 (t, J=6.2 Hz, 2H), of 2.51 (users, 4H), 1,68-of 1.62 (m, 4H), 1,49 is 1.48 (m, 2H).

Stage 3: obtain the hydrochloride of 5-oxo-N-(2-(piperidine-1-yl)ethyl)-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide

Compound (82 mg, 0,17 mmol), obtained in stage 2, worked in the same way as in stage 4 and 5 of example 1, to obtain specified in the title compound (9.1 mg, yield: 15%, yellow solid).

1H NMR (400 MHz, DMSO-d6); δ to 11.28 (s, 1H), 9,99 (users, salt), 8,94-of 8.92 (m, 1H), 8,83 (s, 1H), of 7.97 (d, J=8,4 Hz, 1H), 7,28 (d, J=8,8 Hz, 1H), 3,70-3,68 (m, 2H), 3,56-of 3.53 (m, 2H), 3.33 and is 3.25 (m, 4H), 2,92-2,87 (m, 2H), 2,47 at 2.45 (m, 2H,), 1,82-of 1.78 (m, 6H), 1,71 by 1.68 (m, 1H), 1,39-of 1.36 (m, 1H).

<Example 16> Getting dihydrochloride 9-[2-(dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 4-AMINOPHENYLtert-BUTYLCARBAMATE

4-NITROPHENOL (2 g, 14,37 mmol) was dissolved in dichloromethane (25 ml), was added di-tert-BUTYLCARBAMATE (3,76 g, 17,25 mmol) and 4-dimethylaminopyridine (2.28 g, 18,68 mmol). The resulting mixture was stirred for 10 hours at room temperature and poured into water. After extraction with chloroform, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) was added 10%-palladium (Pd) (300 mg). Then the mixture was stirred in atmosphere gaseous hydrogen for one day at room temperature. After completion of the reaction, 10%-palladium (Pd) was removed by filtration through celite and the filtrate was concentrated to dryness. The residue was purified column flash chromatography (hexane:ethyl acetate=3:1) to obtain the specified title compound (2.7 g, yield: 90%, white solid).

1H NMR (400 MHz, CDCl3): δ 6,94 (d, J=4.4 Hz, 2H), only 6.64 (d, J=4.4 Hz, 2H), 3,62 (user., 2H), and 1.54 (s, 9H).

Stage 2: Obtain tert-butyl 4-(chloronicotinamide)phenylcarbamate

To a stirred solution of the 2-chloronicotinic acid (1 g, 6,35 mmol) in dichloromethane was added dropwise oxalicacid and a catalytic amount of N,N-dimethylformamide at 0°C. the resulting mixture was boiled under reflux for 3 hours and concentrated in vacuum. Thenthe residue was dissolved in dichloromethane, was added compound 4-AMINOPHENYLtert-BUTYLCARBAMATE (1,46 g, 7 mmol), obtained in stage 1, and triethylamine at 0°C. the Mixture was stirred for 12 hours at room temperature and was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=10:1) to obtain specified in the connection header (2,05 g, yield: 93%, white solid).

1H NMR (400 MHz, CDCl3): δ 8,54-charged 8.52 (m, 1H), 8,21-8,19 (m, 1H) 8.17 and (OSiR., 1H), EUR 7.57 (d, J=4,2 Hz, 2H), 7,42-7,39 (m, 1H), 7,24 (d, J=4,2 Hz, 2H), and 1.54 (s, 9H).

Stage 3: Obtain tert-butyl 4-[2-chloro-N-(methoxymethyl)nicotinamide]phenylcarbamate

Compound (2 g, 5,09 mmol), obtained in stage 2, was dissolved in N,N-dimethylformamide was slowly added at 0°C, sodium hydride (407 mg, 10,02 mmol). After stirring for 30 minutes chloromethylation ether was added dropwise and stirring was continued for 1 hour at room temperature. After completion of the reaction was added to hloroform and water and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=2:1) to obtain specified in the connection header (1,16 g, yield: 52%, yellow solid).

1H NMR (400 MHz, CDCl3): δ 8,24 is 8.22 (m, 1H), 7,47 was 7.45 (m, 7,12? 7.04 baby mortality (m, 5H), 5,26 (s, 3H)and 3.59 (s, 3H), and 1.54 (s, 9H).

Stage 4: Obtain tert-butyl 6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9-ylcarbamate

Connection (1,16 g of 3.23 mmol), obtained in stage 3, was dissolved in N,N-dimethylformamide, was sequentially added palladium(II) acetate (218 mg, 0.97 mmol), 1,3-bis(diphenylphosphino)propane (400 mg, 0.97 mmol), tributylphosphine (0,80 ml of 3.23 mmol) and potassium carbonate (894 mg,6,47 mmol). The resulting mixture was boiled under reflux for 5 hours and cooled to room temperature. Added water and dichloromethane and the mixture was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=3:1) to obtain the specified title compound (580 mg, yield: 55%, yellow solid).

1H NMR (400 MHz, CDCl3): δ 9,01-9,00 (m, 1H), 8,78 is 8.75 (m, 1H), at 8.36 (d, J=1.4 Hz, 1H), 7,58-7,52 (m, 2H), 7,29-7,26 (m, 2H), of 5.82 (s, 2H), 3,47 (s, 3H), and 1.54 (s, 3H).

Stage 5: 9-hydroxy-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

The compound (580 mg, 1,627 mmol)obtained in stage 4, was dissolved in 1,4-dioxane (10 ml), was added to 3.7 called 1,4-dioxane solution chloroethanol acid (6 ml). The resulting mixture was stirred for one day at room temperature and the precipitate was collected by filtration to obtain specified in the title compound (410 mg, yield: 98%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 9,60-9 ,15 (user., 1H), 9,07-9,05 (s, 1H), 8,66-8,64 (m, 1H), 8,14 (s, 1H), 7,70-to 7.67 (m, 1H), 7,47 (d, J=4,6 Hz, 1H), 7,15 for 7.12 (m, 1H), 5,71 (s, 2H), 3,32 (s, 3H).

Stage 6: 9-[2-(dimethylamino)ethoxy]-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

The compound (60 mg, 0,234 mmol)obtained in stage 5, was dissolved in N,N-dimethylformamide (5 ml), was added potassium carbonate (161 mg, 1,17 mmol) and potassium iodide (8 mg, 0,047 mmol). After stirring for 30 minutes was added at room temperature, the hydrochloride of N,N-dimethylaminoethoxide and the resulting mixture was stirred for one day at 70°C. the Mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=10:1) to obtain specified in the header is VCE compound (40 mg, yield: 53%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,01-9,00 (m, 1H), 8,78 is 8.75 (m, 1H), at 8.36 (d, J=1.4 Hz, 1H), EUR 7.57-7,52 (m, 2H), 7,29-7,26 (m, 2H), of 5.82 (s, 2H), 4.26 deaths (t, J=5.6 Hz, 2H), 3,47 (s, 3H), of 2.81 (t, J=5,2 Hz, 2H), of 2.38 (s, 6H).

Stage 7: 9-[2-(dimethylamino)ethoxy]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (40 mg, 0,122 mmol)obtained in stage 6, was dissolved in a mixture of dichloromethane/methanol (5 ml), was added 10%-palladium (Pd) (4 mg). The resulting mixture was stirred in hydrogen gas for one day at room temperature. After completion of the reaction the solution was filtered through celite and the filtrate was concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=10:1) to obtain the specified title compound (40 mg, yield: 99%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,47-7,44 (m, 2H), 7,08-7,06 (m, 1H), 5,75 (user., 1H), 5,71 (s, 2H), 4,53 (t, J=5.6 Hz, 2H), 3,48 (m, 2H), 3,40 (s, 3H), up 3.22 (t, J=5.6 Hz, 2H), 2,78 (s, 6H), 2,69 (t, J=6.4 Hz, 2H), 1,95 (m, 2H).

Step 8: obtain the hydrochloride of 9-[2-(dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (40 mg, 0,120 mmol)obtained in stage 7, was dissolved in ethanol (3 ml), was added 12 N. chloroethanol acid (2 ml). The resulting mixture was heated with reverse x is Hladilnika for 12 hours at 90°C. After completion of the reaction the mixture was concentrated under reduced pressure and the residue was washed with ethyl acetate to obtain specified in the title compound (36 mg, yield: 84%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,70 (s, 1H), 10,61 (user., 1H), 7,99-7,80 (user., 1H), 7,69 (8, 1H), 7,38 (d, J=4.4 Hz, 1H), 7,24 (d, J=4,8 Hz, 1H), 4,43 (t, J=4.4 Hz, 2H), 3,54-of 3.53 (m, 2H), 3,38 (m, 1H), 2,86 (s, 3H), 2,85 (s, 3H), 2,56 is 2.51 (m, 2H), equal to 1.82 (m, 2H).

The reaction of example 16 was obtained the following compounds.

<Example 17> 9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

<Example 18> 9-(2-Methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride

<Example 19> 9-[2-(Piperazine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he trihydrochloride

<Example 20> 9 Ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride

<Example 21> 9-[3-(piperidine-1-yl)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

<Example 22> 9-(2-Aminoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

<Example 23> 9-[2-(4-Phenylpiperazin-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

<Example 24> 9-(2-Hydroxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he hydrochloride

<Example 25> 9 Intoxi-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he is hydrochlorid

<Example 26> 9-[2-(Diethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

<Example 27> 9-(2-Morpholinoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

<Example 28> Chloride 1,1-diethyl-4-[2-(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9 yloxy]ethyl)piperazine-1-FL

<Example 29> 9-[4-(piperidine-1-yl)butoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he dihydrochloride

ExampleChemical structureThese NMR spectrum
171H NMR (400 MHz, DMSO-d6): δ a 12.03 (c, 1H), 10,87 (user., 1H), 7,78 (c, 1H), 7,45 (m, 1H), 7,28 (m, 1H), 4.53-in (m, 2H), 3,56-3,39 (m, 6H), 3,01 (m, 2H), 2.57 m) {m, 2H), 1,80-1,71 (m, 7H), to 1.38 (m, 1H)
181H NMR (400 MHz, DMSO-d6): δ 11,73 (m, 1H), 7,75 (user., 1H), 7,51 (c, 1H), 7,35 (d, J=4,8 Hz, 1H), 7,21 (d, J=6.0 Hz, 1H), 4,14 (t, J=3,6 Hz, 2H), 3,69 (t, J=5,2 Hz, 2H), 3,38-3,37 (m, 2H), 3,32 (c, 3H), 2,55 of $ 2.53 (m, 2H), 1,84-of 1.81 (m, 2H)
191H NMR (400 MHz, CD3OD): δ 7,70 (c, 1H), 7,53 (m, 2H), 4,58 (c, 2H), 3,79-of 3.48 (m, 6H, a 2.71 (m, 2H), 2,01 (t, J=7,6 Hz, 2H)
201H NMR (400 MHz, DMSO-d6): δ 11,93 (c, 1H), 7,97 (user., 2H), 7,52 (c, 1H), 7,38 (d, J=8,8 Hz, 1H), 7,20 (d, J=8,4 Hz, 1H), 4,06 (cut, J=6,4 Hz, 2H), 3,37 (m, 2H), 2,54 (m, 2H), is 1.81 (m, 2H), 1,33 (t, J=6.4 Hz, 3H)
211H NMR (400 MHz, DMSO-d6): δ 10.30 a.m. (users, 1H), 7.23 percent-7,20 (m, 2H), 6.87 in-6,94 (m, 1H), 5,06 (users, 2H), Android 4.04 (t, J=6,7 Hz, 2H), 3,47-of 3.43 (m, 2H), was 2.76-of 2.72 (m, 2H), 2,64-of 2.56 (m, 6H), 2,07-2,02 (m, 4H), 1,69-to 1.63 (m, 4H), 1,47-of 1.42 (m, 2H)
221H NMR (400 MHz, DMSO-d6): δ 12,02 (c, 1H), 8,13 (user., 3H), 7,79 (c, 1H), 7,47 (d, J=8,8gts, 1H), 7,25 (m, 1H), 4,47 (m, 2H), 3,50 (m, 2H), 3,41 (m, 2H), 2,52 (m, 2H), of 1.85 (m, 2H)
231H NMR (400 MHz, DMSO-d6): δ 11,10 (c, 1H), 10,34 (user., 1H), 7,51 (c, 1H), 7,35-7,31 (m, 3H), 7,24-7,22 (m, 3H), 7.18 in-7,16 (m, 1H), 4,43 (c, 2H), 3,67-to 3.64 (m, 4H), 3,36-to 3.33 (m, 2H), 3,19-3,14 (m, 4H), 2,86-2,78 (m, 2H), 2.06 to 2,00 (m, 4H), 1,79-of 1.78 (m, 2H)
241H NMR (400 MHz, DMSO-d6); δ 11,54 (c, 1H), 7,72-7,46 (user., 1H), 7,46 {s, 1H), 7,31 (d, J=4.0 Hz, 1H), 7,17 (d, J=4,8 Hz, 1H),was 4.02-4,01 (m, 2H), 3,74-to 3.73 (m, 2H), 3,36 (m, 2H), 2,54 (10, 2H), equal to 1.82 (m, 2H)
251H NMR (400 MHz, DMSO-d6): δ 12,08 (c, 1H), 8,07 (user., 2H), EUR 7.57 (d, J=2.4 Hz, 1H), 7,43 (d, J=9,2 Hz, 1H), was 7.36-7,29 (m, 4H), 7,25-7,16 (m, 2H), 4,22 (t, J=6,8 Hz, 2H), 3,38-to 3.36 (m, 2H), of 3.07 (t, J=6,8 Hz, 2H), 2.57 m (t, J=6.0 Hz, 2H), 1,83 and 1.80 (m, 2H)
261H NMR (400 MHz, DMSO-d6): δ 12,00 (c, 1H), 10,76 (c, 1H), 8,28 (user., 2H), 7,78 (d, J=2.0 Hz, 1H), 7,45 (d, 7=8,8 Hz, 1H), 7,27 (DD, J=8,8 Hz, 1.6 Hz, 1H), 4,48 (t, J=4,8 Hz, 2H), 3,52 (m, 2H), 3,40 (m, 2H), 3,23-3,20 (m, 4H), to 2.57 (t, J=5.8 Hz, 2H)and 1.83 (m, 2H), 1.26 in (t, J=7.2 Hz, 6H)
271H NMR (400 MHz, DMSO-d6): δ 11,78 (c, 1H), 11,40 (c, 1H), 7,69 (d, J=2.4 Hz, 1H), 7,49 (d, J=8,8 Hz, 1H), 7,25 (DD, J=2,4 Hz and 8.8 Hz, 1H), 4,51 (t, J=4,8 Hz, 2H), 3,97 (d, J=12 Hz, 2H), 3,84 (t, J=12 Hz, 2H), only 3.57 (m, 2H), 3,51 (d, J=12 Hz, 2H), 3,40-3,37 (m, 2H), 3,23-3,20 (m, 2H), 2,56 of $ 2.53 (m, 2H), 1,84-of 1.81 (m, 2H)
281H NMR (400 MHz, DMSO-d6): δ up 11,86 (c, 1H), 7,75 (c, 1H), 7,40 (d, J=8,8 Hz, 1H), 7,26 (d, J=7,6 Hz, 1H), 4,51 (c, 2H), 3,79 (c, 8H), 3,71 (c, 2H), 3,54 (users, 4H), 3,39 (t, J=7.2 Hz, 2H), 2,54 (c, 2H), 1,81 (s, 2H), 1,21 (t, J=6,4 Hz, 6H)
29 1H NMR (400 MHz, DMSO-d6): δ to 11.56 (m, 1H), there is a 10.03 (d, J=17.6 Hz, 1H), 8,57 (user., 1H), 7,75 (user., 1H), 7,53 (d, J=7,4 Hz, 1H), 7,32 (d, J=4,8 Hz, 1H), 7,17 (d, J=4.4 Hz, 1H), 4,06-Android 4.04 (m, 2H), 3,43-3,37 (m, 6H), 3,11 totaling 3.04 (m, 1H), 3,01-to 2.94 (m, 1H), 2,88 is 2.75 (m, 2H), 1,81 is 1.70 (m, 10H), 1,5 (m, 2H)

<30> Getting dihydrochloride of 1-methyl-9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: get a 9-methoxy-6-(4-methoxybenzyl)-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

9-Methoxy-6-(4-methoxybenzyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he (500 mg, of 1.36 mmol) was dissolved in N,N-dimethylformamide (10 ml), was added sodium hydride (140 mg, 2.04 mmol) at 0°C. After stirring for 30 minutes was added logmean (0,13 ml, 2.04 mmol) and the resulting mixture was stirred for 3 hours at 0°C. After the mixture was poured into ice water and was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=1:1) to obtain the specified title compound (445 mg, yield: 90%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,32-7,31 (m, 1H), 7,22-7,20 (m, 1H), 7,17 (d, J=8,8 Hz, 2H), 6,98-to 6.95 (m, 1H), 6,83 (d, J=8,8 Hz, 1H), 3,84 (s, 3H), of 3.75 (s, 3H), 318-3,15 (m, 2H), 2,97 (s, 3H), 2,71 (t, J=6.6 Hz, 2H), 1.93 and (m, 2H).

Stage 2: Getting 9-Methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (440 mg, 1.20 mmol)obtained in stage 1, was dissolved in excess triperoxonane acid (3 ml) and the resulting mixture was heated at 100°C for 18 hours in a sealed tube. The mixture was poured into ice water and was podslushivaet 2 N. aqueous sodium hydroxide solution. After neutralization with 2 N. aqueous solution chloroethanol acid raw solution was extracted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:methanol=10:1) to obtain the specified title compound (260 mg, yield: 88%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,89 (users, 1H), 7.24 to 7,21 (m, 1H), 7,15 (d, J=8,8 Hz, 1H), 7,06-7,03 (m, 1H), a 3.87 (s, 3H), 3,18 is 3.15 (m, 2H), 3.00 and (s, 3H), to 2.67 (t, J=6.4 Hz, 2H), 1,91-of 1.85 (m, 2H).

Stage 3: obtain the dihydrochloride of 1-methyl-9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (50 mg, 0.20 mmol)obtained in stage 2, was dissolved in dichloromethane (3 ml)was added 1 M dichloromethane solution trichromate boron (and 0.61 ml, 0.61 mmol) at 0°C. According to the scientists the resulting mixture was stirred for 18 hours at room temperature and was poured into a cooled aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to dryness. And then the residue was dissolved in N,N-dimethylformamide (10 ml), was added potassium carbonate (72 mg, 10 0.52 mmol) and 1-(2-chloroethyl)piperidine (48 mg, 0.26 mmol). The resulting mixture was stirred for 18 hours at 90°C and cooled to room temperature. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified flash column-chromatography (chloroform:methanol=7:1) to obtain specified in the connection header (to 24.7 mg, yield: 34%, white solid). The obtained compound (23 mg, 0,067 mmol) interacted in the same way as in stage 5 of example 5, to obtain the specified title compound (21 mg, yield: 73%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,41 (users, 1H), 10,42 (users, salt), 7,27-7,22 (m, 2H), 7,16-7,14 (m, 1H), 4,45-4,43 (m, 2H), 3,56-of 3.46 (m, 4H), 3,09-to 3.02 (m, 2H), 2,99 vs. 2.94 (m, 2H), 2,92 (s, 3H), 2,45-to 2.41 (m, 2H), 1,79-to 1.67 (m, 4H), 1,39-1,35 (m, 2H).

<Example 31> Getting dihydrochloride 9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: gettert-buildkey (4 nitrophenoxy)silane

4-Nitrophenetole alcohol (1.0 g, 5,98 mmol) was dissolved in tetrahydrofuran (20 ml)was sequentially addedtert-b is sildenafilcitrate (990 mg, to 6.58 mmol) and imidazole (450 mg, to 6.58 mmol). The resulting mixture was stirred for one day and were extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (ethyl acetate:hexane=1:8) to obtain the specified title compound (1.65 g, yield: 98%, yellow oil).

1H NMR (400 MHz, CDCl3): δ 8,19 (d, J=8,8 Hz, 2H), 7,43 (d, J=8,8 Hz, 2H), 3,90 (t, J=6.4 Hz, 2H), 2,96 (t, J=6.4 Hz, 2H), 0,89 (s, 9H), 0.00 to (s, 6H).

Stage 2: Obtain 4-[2-(tert-Butyldimethylsilyloxy)ethyl]aniline

The compound (1.65 g, 5,86 mmol)obtained in stage 1, was dissolved in ethyl acetate (20 ml), was added 10%-palladium (Pd) (165 mg) at room temperature. The reaction mixture was stirred for 3 days in gaseous hydrogen. Removed 10%-palladium (Pd), using a filter with telicom, and the filtrate was concentrated under reduced pressure. Then the residue was purified flash column-chromatography (ethyl acetate:hexane=1:4) to obtain the specified title compound (1.4 g, yield: 95%, colorless oil).

1H NMR (400 MHz, CDCl3): δ 7,00 (d, J=8.0 Hz, 2H), 6,63 (d, J=8.0 Hz, 2H), 3,74 (t, J=7.4 Hz, 2H), only 3.57 (s, 2H), 2,72 (t, J=7.4 Hz, 2H), 0,89 (s, 9H), 0.00 to (s, 6H).

Stage 3: Obtain 9-[2-(tert-butylmethacrylate)ethyl]-6-(methoxymethyl)benzo[h][1,6]is aftereden-5(6H)-it

Was carried out by the same method as in stages 2-4 of example 16 using 2-chloronicotinic acid (800 mg, 5.08 mmol), to obtain the specified title compound (950 mg, yield (4 steps): 47%, yellow oil).

1H NMR (400 MHz, CDCl3): δ 9,01 (DD, J=4.4 Hz, 2.0 Hz, 1H), up 8.75 (DD, J=8.0 Hz, 2.0 Hz, 1H), to 8.70 (d, J=2.0 Hz, 1H), 7,56-of 7.48 (m, 3H), of 5.83 (s, 2H), 3,88 (t, J=6,8 Hz, 2H), 3.46 in (s, 3H), 2,98 (t, J=6,8 Hz, 2H), 0,87 (s, 9H), 0.00 to (s, 6H).

Stage 4: 9-(2-hydroxyethyl)-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

The compound (850 mg, 2,13 mmol), obtained in stage 3, was dissolved in a solution of 3.7 N. chloromethane acid/1,4-dioxane, and the solution was stirred over night at room temperature. After completion of the reaction the precipitate was collected by filtration to obtain specified in the title compound (540 mg, yield: 89%, yellow solid).

1H NMR (400 MHz, DMSO-d6+ CDCl3): δ 9,06-9,04 (m, 1H), 8,83-8,79 (m, 2H), 7,66 (DD, J=8.0 Hz, 4.8 Hz, 1H), to 7.59-rate of 7.54 (m, 2H), of 5.81 (s, 2H), 3,85 (t, J=6,8 Hz, 2H), 3,44 (s, 3H), 2,99 (t, J=6,8 Hz, 2H).

Stage 5: Obtain 2-[6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9-yl]acetaldehyde

The compound (50 mg, 0.18 mmol)obtained in stage 4, was dissolved in dichloromethane (10 ml), was added periodinane dess-Martin (112 mg, 0.26 mmol) at 0°C. the resulting mixture is eremetical for 90 minutes at room temperature and poured into saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (ethyl acetate:hexane=1:1) to obtain the specified title compound (25 mg, yield: 50%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,85 (s, 1H), 9,01 (DD, J=4.4 Hz, 1.6 Hz, 1H), 8,78-a total of 8.74 (m, 2H), to 7.64 (d, J=8,8 Hz, 1H), 7,55 (DD, J=8.0 Hz, 4.4 Hz, 1H), 7,46 (DD, J=8,8 Hz, 2.0 Hz, 1H), of 5.84 (s, 2H), 3,88 (s, 2H), 3,47 (s, 3H).

Stage 6: 9-([2-(dimethylamino)ethyl]-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

Compound (35 mg, 0.12 mmol)obtained in stage 5, was dissolved in methanol (5 ml)was sequentially added dimethylamine (0,52 ml, 1.04 mmol), cyanoborohydride sodium (8 mg, 0.13 mmol), zinc chloride (II) (8 mg, 0.06 mmol) and 1.25 N. methanol solution chloroethanol acid (0,58 ml, to 0.72 mmol) at 0°C. the resulting mixture was stirred for one hour at 0°C and was poured into aqueous sodium bicarbonate solution. The mixture was extracted with chloroform and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=5:1) to obtain the specified title compound (22 mg, yield: 59%, white solid prophetic the CTV).

1H NMR (400 MHz, CDCl3): δ 9,02 (DD, J=4.4 Hz, 1.6 Hz, 1H), 8,76 (DD, J=8.0 Hz, 1.6 Hz, 1H), 8,69 (d, J=2.4 Hz, 1H), 7,58-7,47 (m, 3H), of 5.83 (s, 2H), 3,47 (s, 3H), of 2.97 (t, J=8.0 Hz, 2H), to 2.67 (t, J=8.0 Hz, 2H), a 2.36 (s, 6H).

Stage 7: 9-[2-(dimethylamino)ethyl]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (22 mg, 0.07 mmol), obtained in stage 6, was dissolved in a mixture of ethanol (4 ml)/dichloromethane (2 ml), was added 10%-palladium (Pd) (5 mg) at room temperature. The resulting mixture was stirred for one day in a gaseous hydrogen and filtered using celite to remove 10%-palladium (Pd). Then the filtrate was concentrated under reduced pressure to obtain specified in the title compound (20 mg, yield: 90%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,58 (s, 1H), 7,46 (d, J=8,8 Hz, 1H), 7,29 (DD, J=8,8 Hz, 1.6 Hz, 1H), 5,71 (s, 2H), are 5.36 (s, 1H), 3.46 in (m, 2H), 3,40 (s, 3H), of 3.07 (m, 2H), 2,97 (m, 2H), 2,68 (t, J=6.4 Hz, 2H), 2,59 (s, 6H), 1,99-of 1.93 (m, 2H).

Step 8: obtain the hydrochloride of 9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (20 mg, 0.06 mmol)obtained in stage 7, was dissolved in ethanol (4 ml) was added conc. chloroethanol acid (0.5 ml). The resulting mixture was stirred for 8 hours at 80°C and cooled to room temperature. Then the MCA is ü concentrated under reduced pressure to obtain specified in the title compound (18 mg, yield: 82%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,91 (s, 1H), 10,97 (s, 1H), 8,12 (s, 1H), 7,46-the 7.43 (m, 2H), 3,37 (m, 4H), to 3.09 (m, 2H), and 2.79 (s,6H), to 2.55 (m, 2H), is 1.81 (m, 2H).

<Example 32> Getting dihydrochloride 8-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Used the same method as the method of example 31, with the receipt specified in the connection header.

1H NMR (400 MHz, DMSO-d6): δ 10,99 (s, 1H), 10,76 (user., 1H), 8,79 (user., 1H), 7,83-7,81 (m, 1H), 7,22-7,19 (m, 1H), 6,92-to 6.80 (m, 1H), 4,37 is 4.35 (m, 2H), 3,37-to 3.34 (m, 2H), 3,06-to 3.02 (m, 2H), 2,82 (s, 6H), 2,46 is 2.43 (m, 2H), 1,79-of 1.78 (m, 2H).

<Example 33> Getting dihydrochloride 9-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain ethyl 3-(4-AMINOPHENYL)propionate

Ethyl 3-(4-nitrophenyl)acrylate (3 g, 13.56 mmol) was dissolved in methanol/tetrahydrofuran (20 ml), was added 10%-palladium (Pd) (300 mg). The resulting mixture was stirred for one day in gaseous hydrogen at room temperature and was filtered using celite to remove 10%-palladium (Pd). Then the filtrate was concentrated under reduced pressure. Then the residue was purified column flash chromatography (hexane:ethyl acetate=3:1) to obtain the specified title compound (2.14 g, yield: 82%, colorless liquid).

1H the Mr (400 MHz, DMSO-d6): δ of 6.99 (d, J=4.0 Hz, 2H), 6,62 (d, J=4,2 Hz, 2H), 4,12 (kV, J=3,6 Hz, 2H), to 3.58 (user., 2H), 2,84 (t, J=8,0, 2H), has 2.56 (t, J=7,6 Hz, 2H), 1,24 (t, J=6.4 Hz, 3H).

Stage 2: Obtain ethyl 3-[4-(2-chloronicotinamide)phenyl]propionate

2-Chloronicotinic acid (1 g, 6,35 mmol) was dissolved in dichloromethane and added oxalicacid and a catalytic amount of N,N-dimethylformamide at 0°C. the resulting mixture was boiled under reflux for 3 hours and concentrated under reduced pressure and then the resulting acid chloride acid was dissolved in dichloromethane and cooled to 0°C. was Added ethyl 3-(4-nitrophenyl)acrylate (1.35 g, 7 mmol), obtained in stage 1, and triethylamine, and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=10:1) to obtain the specified title compound (2.1 g, yield: 92%, colorless liquid).

1H NMR (400 MHz, CDCl3): δ 8,53-8,51 (m, 1H), 8,21-8,19 (m, 3H) 8,15 (user., 1H), EUR 7.57 (d, J=3,4 Hz, 2H), 7,43-7,39 (m, 1H), 7,30-7,22 (m, 2H), 4,15-4.09 to (m, 2H), 2,96 (t, J=8.0 Hz, 2H), 2,62 (t, J=8.0 Hz, 2H), 1,25 (m, 3H).

Stage 3: Obtain ethyl 3-{4-[2-chloro-N-(methoxymethyl)nicotinamide]phenyl}propionate

The compound (100 is g, 0.31 mmol)obtained in stage 2, was dissolved in N,N-dimethylformamide (3 ml), was added sodium hydride (407 mg, 10,02 mmol) at 0°C. After stirring for 30 minutes was added dropwise chloromethylation ether and the resulting mixture was stirred for 8 hours. The mixture was poured into ice water and was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=2:1) to obtain the specified title compound (57 mg, yield: 50%, yellow liquid).

1H NMR (400 MHz, CDCl3): δ 8,24 (m, 1H), 7,47 was 7.45 (m, 1H), 7,12? 7.04 baby mortality (m, 5H), of 5.26 (s, 2H), 4.09 to (kV, J=3,6 Hz, 2H)and 3.59 (s, 3H), and 2.83 (t, J=8,4 Hz, 2H), of 2.51 (t, J=7,6 Hz, 2H), 1,21 (t, J=7.2 Hz, 3H).

Stage 4: Obtain ethyl 3-[6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9-yl]propionate

Compound (55 mg, 0,146 mmol), obtained in stage 3, was dissolved in N,N-dimethylformamide (3 ml)was sequentially added palladium (II) acetate (9,83 mg, 0,0438 mmol), 1,3-bis(diphenylphosphino)propane (18 mg, 0,0438 mmol), tributylphosphine (0.036 ml, 0,146 mmol) and potassium carbonate (40 mg, 0,292 mmol). The resulting mixture was boiled under reflux for 5 hours. Added to the above solution of water and the mixture was extracted with chloroform. The organization is practical layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=3:1) to obtain the specified title compound (31 mg, yield: 64%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,02-9,00 (m, 1H), 8,77-8,71 (m, 2H), EUR 7.57-of 7.48 (m, 3H), of 5.83 (s, 2H), 4,15 (kV, J=3,6 Hz, 2H), 3,47 (s, 3H), 3,11 (t, J=8.0 Hz, 2H), by 2.73 (t, J=7,6 Hz, 2H), 1.26 in (t, J=6.8 Hz, 3H).

Stage 5: Obtain 3-[6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9-yl]propranolol acid

Connection (1,15 g, to 3.38 mmol)obtained in stage 4, was dissolved in a mixture of dichloromethane/methanol (20 ml), was added 4 N. aqueous sodium hydroxide solution at room temperature. The resulting mixture was stirred for 12 hours and acidified 4 N. chloroethanol acid. Then the precipitate was collected by filtration to obtain specified in the title compound (780 mg, yield: 74%, white solid).

1H NMR (400 MHz, DMSO-d6): δ 12,17 (s, 1H), 9,06-9,05 (m, 1H), 8,64-8,58 (m, 2H), 7,69-to 7.67 (m, 1H), 7,53 (m, 2H) 5,73 (s, 2H), and 3.31 (s, 3H),2.95 points (t, J=7,6 Hz, 2H), 2,61 (t, J=7,6 Hz, 2H).

Stage 6: 9-(3-hydroxypropyl)-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

The compound (780 mg, of 2.50 mmol)obtained in stage 5, was dissolved in tetrahydrofuran, was added dropwise 2 M tertrahydrofuran ring solution of dimethyl sulfide complex and borane (6,24 ml, 12,49 mmol). Received the th resulting mixture was stirred for 3 hours at room temperature and was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=15:1) to obtain the specified title compound (45 mg, yield: 75%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,02-9,00 (m, 1H), 8,78-to 8.70 (m, 2H), 7,58-7,47 (m, 3H), of 5.84 (s, 2H), of 3.73 (t, J=6.4 Hz, 2H), 3,48 (s, 3H), 2,88 (t, J=7,6 Hz, 2H), 2,02-to 1.98 (m, 2H).

Step 7: Obtain 3-[6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-9-yl]propanal

The compound (200 mg, 0.67 mmol)obtained in stage 6, was dissolved in dichloromethane, was added chlorproma pyridinium (289 mg, of 1.34 mmol) and silica gel (289 mg) at room temperature. The resulting mixture was stirred for 2 hours at room temperature and was filtered to remove the silica gel. The filtrate was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=15:1) to obtain the specified title compound (151 mg, yield: 76%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,87 (s, 1H), 9,02-9,00 (m, 1H), 8,77-to 8.70 (m, 2H), 7,58-7,46 (m, 3H), of 5.83 (s, 2H), 3,47 (s, 3H), 3,14-3,10 (m, 2H), 2,93-2,89 (m, 2H).

Step 8: Obtain 9-[3-(dimethylamino)propyl]-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

The compound (151 mg, 0.51 mmol)obtained in stage 7, was dissolved in methanol, was sequentially added 2 M dimethylamine (2,18 ml of 4.38 mmol), cyanoborohydride sodium (35 mg, 0,56 mmol), zinc chloride (II) (35 mg, 0,255 mmol) and 1.25 M chloroethanol acid (2,44 ml of 3.06 mmol) at 0°C. the resulting mixture was stirred for one hour at room temperature. The mixture was poured into ice water and was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=15:1) to obtain the specified title compound (152 mg, yield: 92%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,03-9,01 (m, 1H), 8,76 is 8.75 (m, 1H), 8,69 (m, 1H), EUR 7.57-of 7.48 (m, 3H), of 5.83 (s, 2H), 3,48 (s, 3H), 2,80 (t, J=7,6 Hz, 2H), 2,58 (s,6H), a 2.36 (t, J=7,6 Hz, 2H), 1,92-to 1.87 (m, 2H).

Step 9: Obtain 9-[3-(dimethylamylamine)propyl]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (110 mg, 0.67 mmol)obtained in stage 8, was dissolved in a mixture of dichloromethane/methanol (10 ml), was added 10%-palladium (11 mg). The resulting mixture was stirred for one day at room temperature in hydrogen gas. After completion of the reaction the solution was filtered through celite and the filtrate was concentrated to dryness. Then the remainder of the PTS is looking in column flash chromatography (chloroform:methanol=10:1) to obtain the specified title compound (112 mg, yield: 99%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,87 (s, 1H), 7,44 (d, J=4.4 Hz, 1H), 7.23 percent (d, J=4,2 Hz, 2H), 6.42 per (s, 1H), 5,72 (s, 2H), 3,49 (m, 2H), 3,41 (s, 3H), 2,93-2,89 (m, 4H), 2,77 (s, 6H), 2,68 (t, J=6.0 Hz, 2H), 2,39-of 2.36 (m, 2H), 1,95-of 1.93 (m, 2H).

Step 10: obtain the dihydrochloride 9-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (112 mg, 0.34 mmol)obtained in stage 9, was dissolved in ethanol (3 ml) and added 12 N. chloroethanol acid (2 ml). The resulting mixture was boiled under reflux for 12 hours. After completion of the reaction the mixture was concentrated and recrystallized from methanol/ethyl acetate to obtain specified in the title compound (110 mg, yield: 90%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ to 11.79 (s, 1H), to 10.62 (s, 1H), of 7.97 (s, 1H), 7,44 (d, J=4,2 Hz, 1H), 7,37 (d, J=4,2 Hz, 1H), 3,37 (m, 2H), 3,01 (m, 2H), by 2.73 (s, 3H), of 2.72 (s, 3H), 2,70 of 2.68 (m, 2H), 2,56 of $ 2.53 (m, 2H), 2,07-2,04 (m, 1H), 1,83 and 1.80 (m, 2H).

<Example 34> Getting dihydrochloride 8-[2-(dimethylamino)ethoxy]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide

Stage 1: Getting 8-[2-(dimethylamino)ethoxy]-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

8-Hydroxy-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-he (58 mg, 0.22 mmol) and potassium carbonate (94 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (5ml) was added 2-(dimethylamino)ethylchloride (39 mg, 0.27 mmol). The resulting mixture was stirred for 2 hours at 90°C and poured into ice-cold water. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (chloroform:methanol=6:1) to obtain the specified title compound (53 mg, yield: 73%, white solid).

1H NMR (400 MHz, CDCl3): δ 8,97-8,82 (m, 1H), 8,77-8,72 (m, 1H), 8,70-8,67 (m, 1H), 7,46-7,42 (m, 1H), 7,18 (s, 1H), 7,02-6,98 (m, 1H), 5,79 (user., 2H), 4,22-4,17 (m, 2H), 3.43 points (s, 3H), 2,83-2,78 (m, 2H), of 2.38 (s, 6H).

Stage 2: Getting dihydrochloride 8-[2-(dimethylamino)ethoxy]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide

To obtain an intermediate product used in the same way as in stage 4 of example 6, using the compound (50 mg, 0.15 mmol)obtained in stage 1. The intermediate product was dissolved in ethanol (5 ml) was added conc. chloroethanol acid (1 ml). The resulting mixture was boiled under reflux for 18 hours and cooled to room temperature. The mixture was concentrated under reduced pressure and recrystallized from methanol/ethyl acetate to obtain specified in the title compound (51 mg, yield: 94%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,09 (s, 1H), of 10.21 (users, salt), 7,83 (d, J=9.1, or the C, 1H), 6,85 (d, J=8,8 Hz, 1H), 6,80 (s, 1H), 4,37 is 4.35 (m, 2H), 3,59-3,44 (m, 2H), 3,32 be 3.29 (m, 2H), 2,85 (s, 3H), 2,84 (s, 3H), 2,46 is 2.43 (m, 2H), 1,79-of 1.78 (m, 2H).

The reaction of example 34 was obtained the following compounds.

<Example 35> Dihydrochloride 8-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 36> Dihydrochloride 8-[3-(dimethylamino)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

ExampleChemical structureThese NMR spectrum
3351H NMR (400 MHz, DMSO-d6); δ 11,29 (c, 1H), 10,41 (c, 1H), 7,87 (d, J=8,8 Hz, 1H), 6,86-6,84 (m, 2H), 4,43 (t,J=4,6 Hz, 2H), 3,50-to 3.49 (m, 4H), of 3.32 (m, 2H), 3.04 from-2,95 (m, 2H), 2,47 (m, 2H), 1,79 (m, 6H), 1,71-to 1.67 (m, 1H), 1,38 (m, 1H)
3361H NMR (400 MHz, DMSO-d6); δ 11,65 (c, 1H), 10,59 (c, 1H), 7,94 (d, J=4.4 Hz, 1H), of 7.90-to 7.61 (user., 1H), 6.90 to-to 6.88 (m, 2H), 4,11 (t, J=6.0 Hz, 2H), 3,34 (m, 2H), 3.25 to 3,18 (m, 2H), 2,78 (c, 3H), 2,77 (c, 3H), 2,53 is 2.51 (m, 2H), 2,20-of 2.16 (m, 2H), 1,82-to 1.79 (m, 2H)

<Example 37> Obtaining hydrochloride 8-(dimethylamino)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtaining N,N-dimethyl-3-nitroaniline

3-Nitroaniline (1.0 g, of 7.25 mmol) was dissolved in N,N-dimethylformamide (50 ml), was added sodium hydride (1.7 g, and 21.7 mmol) and jodean (2.7 ml, and 21.7 mmol) at 0°C. the resulting mixture was stirred for 4 hours at room temperature and poured into ice-cold water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=1:1) to obtain the specified title compound (2.0 g, yield: 86%, yellow solid).

1H NMR (400 MHz, CDCl3): δ 7,53-of 7.48 (m, 1H), 7,33 (t, J=8.0 Hz, 1H), of 6.96 (d, J=8.0 Hz, 1H), 3.04 from (s, 6H).

Stage 2: Obtaining N',N'-xylene-1,3-diamine

The compound (1.0 g, between 6.08 mmol), obtained in stage 1, was dissolved in methanol (25 ml) was added 10%-palladium (Pd) (100 mg). The mixture was first made for 15 hours at room temperature in hydrogen gas. After completion of the reaction, 10%-palladium (Pd) was removed using a filter with telicom, and the filtrate was concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=1:1) to obtain the specified title compound (700 mg, yield: 90%, colorless liquid).

1H NMR (400 MHz, CDCl3): δ? 7.04 baby mortality (t, J=7,6 Hz, 1H), 6,2 (d, J=8.0 Hz, 1H), 6,11-between 6.08 (m, 1H), 3,60 (users, 2H), 2,92 (s, 6H).

Stage 3: Obtain 8-(dimethylamine is)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Using 2-chloronicotinic acid (700 mg, 8.9 mmol), was carried out by the same method as in stages 2-4 of example 16, to obtain the specified title compound (1.08 g, yield (stage 4): 43%, yellow solid).

1H NMR (400 MHz, CDCl3): δ of 7.64 (d, J=9,2 Hz, 1H), 6.90 to (s, 1H), 6,63 (d, J=8,8 Hz, 1H), 6,50 (s, 1H), 5,54 (s, 2H), 3,25 (s, 2H), 3,21 (s, 3H), 2,96 (s, 6H), 2,42 (t, J=6.0 Hz, 2H), 1,76 (t, J=5,2 Hz, 2H).

Stage 4: Getting hydrochloride 8-(dimethylamino)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (100 mg, 0.34 mmol), obtained in stage 3, was dissolved in ethanol (5 ml) was added conc. chloroethanol acid (1.0 ml). The mixture was stirred over night at 80°C, cooled to room temperature and concentrated under reduced pressure to obtain specified in the connection header (89,6 mg, yield: 92%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 12,22 (s, 1H), to 7.99 (d, J=9.6 Hz, 1H), 6,95 (d, J=9.6 Hz, 1H), 6,65 (s, 1H), 3,38 (t, J=5,2 Hz, 2H), 3,01 (s, 6H), 2,58 (t, J=6.4 Hz, 2H), 1,81 (t, J=5,2 Hz, 2H).

<Example 38> Getting dihydrochloride 8-[1-(dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 1-(3-AMINOPHENYL)ethanol

3-Aminoacetophenone (2.0 g, 14,80 mmol) was dissolved in ethanol (25 ml) was added sodium borohydride (1.4 g, 36,99 mmol) n and 0°C. The resulting mixture was stirred for 3 hours and poured into ice-cold water. The mixture was neutralized 2 N. aqueous solution chloroethanol acid and was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain specified in the title compound (1.7 g, yield: 84%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,13 (t, J=8.0 Hz, 1H), 6,76-6,72 (m, 2H), 6,60 (DD, J=8.0 Hz, 2.4 Hz, 1H), to 4.81 (m, 1H), 1,46 (d, J=6.8 Hz, 3H).

Stage 2: Obtain 3-[1-(tert-butyldimethylsilyloxy)ethyl]aniline

Compound (1.7 g, KZT 12.39 mmol), obtained in stage 1, was dissolved in tetrahydrofuran (30 ml)was sequentially addedtert-butyldimethylsilyloxy (2.8 g, 18,59 mmol) and imidazole (1.26 g, 18,59 mmol). The resulting mixture was stirred overnight and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated to dryness. Then the residue was purified column flash chromatography (hexane:ethyl acetate=4:1) to obtain the specified title compound (2.2 g, yield: 72%, yellow oil).

1H NMR (400 MHz, CDCl3): δ was 7.08 (t, J=7.8 Hz, 1H), of 6.71-6,69 (m, 2H), 6,55 (DD, J=7,8 Hz, 2.4 Hz, 1H), 4,77 (cut, J=6,4 Hz, 1H), 3,63 (user., 2H), 1,37 (d, J=6.0 Hz, 3H), of 0.90 (s, 9H), of 0.04 (s,3H), of 0.01 (s, 3H).

Stage 3: Getting 8-[1-(tert-butyldimethylsilyloxy)ethyl]-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

Using 2-chloronicotinic acid (1.0 g, 6,35 mmol), was carried out by the same method as in stages 2-4 of example 16, to obtain the specified title compound (1.06 g, yield (4 steps): 42%, yellow oil).

1H NMR (400 MHz, CDCl3): δ 8,99 (DD, J=4.4 Hz, 2.0 Hz, 1H), 8,79 (d, J=8,4 Hz, 1H), total of 8.74 (DD, J=8.0 Hz, 2.0 Hz, 1H), to 7.67 (s, 1H), 7,49 (DD, J=8.0 Hz, 4.4 Hz, 1H), 7,34 (d, J=8,4 Hz, 1H) of 5.89-5,79 (m, 2H), 5,02 (cut, J=6,4 Hz, 1H), 3,47 (s, 3H), 1,49 (d, J=7,0 Hz, 3H), of 0.93 (s, 9H), and 0.09 (s, 3H), of 0.02 (s, 3H).

Stage 4: Getting 8-(1-hydroxyethyl)-6-(methoxymethyl)benzo[h][1,6]naphthiridine-5(6H)-it

The compound (1.04 g, 2,61 mmol), obtained in stage 3, was dissolved in 3.7 called 1,4-dioxane solution chloroethanol acid and was stirred over night at room temperature. After completion of the reaction the precipitate was collected by filtration and dried in vacuum to obtain specified in the title compound (760 mg, yield: 100%, yellow solid).

1H NMR (400 MHz, CDCl3): δ was 9.33 (DD, J=8.0 Hz, 1.6 Hz, 1H), 9,26-which 9.22 (m, 2H), 8,02 (DD, J=8.0 Hz, 5.6 Hz, 1H), 7,76 (s, 1H), 7,56 (d, J=8,8 Hz, 1H) of 5.85 (s, 2H), 5,04 (m, 1H), 3,50 (s, 3H), and 1.54 (d, J=6.8 Hz, 3H).

Stage 5: Obtain 8-(1-hydroxyethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (650 mg, to 2.29 mmol)obtained in stage 4, was dissolved in a mixture of ethanol (10 ml)/dichloromethane (10 ml) was added 10%-palladium (Pd) (200 mg) at room temperature. The resulting mixture was stirred for one day in a gaseous hydrogen and 10%palladium was removed by applying a filter with telicom. The filtrate was concentrated under reduced pressure and the residue was purified flash column-chromatography (chloroform:methanol=30:1) to obtain the specified title compound (320 mg, yield: 49%, white solid).

1H NMR (400 MHz, CDCl3): δ of 7.48 (s, 1H), 7,41 (d, J=8,4 Hz, 1H), 7,26-of 7.23 (m, 1H), 5,69 (s, 2H), 4,99 (m, 1H), a 4.86 (s, 1H), of 3.45 (m, 2H), 3,40 (s, 3H), 2,68 (t, J=6.4 Hz, 2H), of 1.97 (m, 2H), 1,53 (d, J=6.4 Hz, 3H).

Further, in this reaction was obtained 8-ethyl-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he (140 mg, yield: 22%, white solid).

1H NMR (400 MHz, CDCl3): δ was 7.36-7,33 (m, 2H), 7,06 (d, J=8,4 Hz, 1H), 5,73 (s, 2H), around 4.85 (s, 1H), 3,44 (m, 2H), 3,42 (s, 3H), 2,75 (cut, J=7,6 Hz, 2H), 2,69 (d, J=6,4 Hz, 2H), of 1.97 (m, 2H), 1,28 (t, J=7,6 Hz, 3H).

Step 6: Obtain 8-[1-(dimethylamino)ethyl]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (50 mg, 0,17 mmol)obtained in stage 5, was dissolved in tetrahydrofuran (5 ml)was sequentially added pyridine (56 μl, 0.69 mmol) and tribromide phosphorus (33 ál,0.35 mmol) at room temperature. According to the scientists the resulting mixture was stirred for 3 hours and poured into a cooled saturated aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was dissolved in tetrahydrofuran (4 ml) was added dropwise 2.0 M tertrahydrofuran ring solution of dimethylamine (1.7 ml, 3,47 mmol). The resulting mixture was stirred over night at room temperature and concentrated to dryness. The residue was purified flash column-chromatography (chloroform:methanol=10:1) to obtain stated in the title compound (15 mg, output (stage 2): 27%, colorless oil).

1H NMR (400 MHz, CDCl3): δ 7,44 (s, 1H), 7,41 (d, J=8,4 Hz, 1H), 7,24 (d, J=8,4 Hz, 1H), 5,74 (s, 2H), 4,88 (s, 1H), of 3.45 (m, 2H), 3,42 (s, 3H), 2,69 (t, J=6.4 Hz, 2H), 2,24 (s, 6H), of 1.97 (m, 2H), 1,42 (d, J=6.0 Hz, 3H).

Step 7: obtain the dihydrochloride 8-[1-(dimethylamino)ethyl])-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (15 mg, 0.05 mmol), obtained in stage 6, was dissolved in ethanol (4 ml) was added conc. chloroethanol acid (0.5 ml). The mixture was stirred over night at 80°C and the precipitate was collected by filtration to obtain specified in the title compound (14 mg, yield: 86%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ to 11.28 (s, 1H), 10,85 (s, 1H), 7,95 (d, J=8,8 Hz, 1H), 7,45 (d, J=8,8 Hz, 1H), 7,30 (s, 1H), 4,48 (m, 1H), 3,32 (m, 2H), 2,74 (s, 3H), 2,50 (m, 5H), to 1.79 (m, 2H), and 1.63 (d, J=6.8 Hz, 3H).

<Example 39> Getting on the hydrochloride of 8-[1-(methylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stated in the title compound was obtained using the same method as in example 38.

1H NMR (400 MHz, DMSO-d6): δ 11,10 (s, 1H), 9,41 (s, 1H), 9,05 (s, 1H), 7,88 (d, J=8.0 Hz, 1H), 7,29 (d, J=8.0 Hz, 1H), 7,21 (s, 1H), 4,29 (m, 1H), 3,29 (m, 2H), 2,43-of 2.38 (m, 5H), 1,76-of 1.73 (m, 2H), 1,53 (d, J=6.4 Hz, 3H).

<Example 40> Obtain hydrochloride of 8-ethyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

8-Ethyl-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he (130 mg, 0.48 mmol)obtained in stage 5 of example 38 was dissolved in ethanol (8 ml) was added conc. the solution chloroethanol acid (2.5 ml). The mixture was stirred over night at 80°C and the precipitate was collected by filtration to obtain specified in the title compound (120 mg, yield: 95%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,88 (s, 1H), 8,18 (user., 2H), 7,95 (d, J=8,4 Hz, 1H), 7,26 (s, 1H), 7,17 (d, J=8,4 Hz, 1H), 3,37 (t, J=5.6 Hz, 2H), 2,68 (cut, J=7.8 Hz, 2H), by 2.55 (t, J=6.0 Hz, 2H), equal to 1.82 (m, 2H), 1,20 (t, J=7.8 Hz, 3H).

<Example 41> Getting dihydrochloride 8-[(dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain ethyl 3-(2-chloronicotinamide)benzoate

To a stirred solution of 2-chloronicotinic acid (500 mg, 3,17 mmol) in anhydrous dichloromethane (10 ml) was added oxalicacid (0,407 ml, 4.76 mmol) and a drop of betwedn the th of N,N-dimethylformamide at room temperature. The resulting mixture was stirred at room temperature for 2.5 hours and concentrated in vacuum. Thenthe residue was dissolved in anhydrous dichloromethane (10 ml) and added dropwise at 0°C ethyl 3-aminobenzoate (0,521 ml, 3,49 mmol) in anhydrous dichloromethane (5 ml) and triethylamine (0,885 ml, 6,337 mmol). The mixture was stirred for 1 hour at room temperature and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the connection header (1,16 g, yield: quantitative, beige oil).

1H NMR (400 MHz, CDCl3): δ 8,53 (DD, J=1.6 Hz, 4.4 Hz, 1H), to 8.41 (s, 1H), 8,21 (DD, J=2.0 Hz, 8.0 Hz, 1H), 8,14 (s, 1H), 8,08-with 8.05 (m, 1H), 7,89-7,87 (m, 1H), 7,49 (t, J=8.0 Hz, 1H), 7,42 (DD, J=4,8 Hz, 7.2 Hz, 1H), 4,37 (kV, J=6,8 Hz, 2H), 1,38 (t, J=6.8 Hz, 3H)

Stage 2: Obtain ethyl 3-[2-chloro-N-(methoxymethyl)nicotinamide]benzoate

Connection (1,017 g 3,337 mmol)obtained in stage 1, was dissolved in anhydrous tetrahydrofuran (10 ml)was slowly added at 0°Ctert-piperonyl potassium (749 mg, 6,674 mmol). After stirring for 30 minutes was added chloromethylation ether (0,379 ml 4,995 mmol), and stirring was continued for 1 hour at room temperature. After completion of the reaction was added ethyl acetate and water and the mixture was extracted. Organizes the second layer was dried over anhydrous magnesium sulfate and was kontsetrirovannoe dry. Then the residue was purified flash column-chromatography (dichloromethane:ethyl acetate=9:1) to obtain specified in the connection header (981 mg, yield: 84%, colorless oil).

1H NMR (400 MHz, CDCl3): δ 8,24 (d, J=4,8 Hz, 1H), 7,87-a 7.85 (m, 2H), 7,53-7,41 (m, 2H), 7,31 (t, J=8.0 Hz, 1H), 7,12-to 7.09 (m, 1H), and 5.30 (s, 2H), 4,34 (kV, J=6,8 Hz, 2H), 3,55 (s, 3H), of 1.38 (t, J=6.8 Hz, 3H).

Stage 3: Obtain ethyl 6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-8-carboxylate

Connection (981 mg, of 2.81 mmol), obtained in stage 2, was dissolved in N,N-dimethylformamide (10.0 ml), was added palladium (II) acetate (206 mg, services, 0.844 mmol), 1,3-bis(diphenylphosphino)propane (348 mg, services, 0.844 mmol), tributylphosphine (0,693 ml of 2.81 mmol) and potassium carbonate (777 mg, 5,62 mmol). The resulting mixture was boiled under reflux for 5 hours at 120°C and cooled to room temperature. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:ethyl acetate=5:1) to obtain specified in the connection header (657,3 mg, yield: 75%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,05 (DD, J=2.0 Hz, 4.4 Hz, 1H), 8,93-8,91 (m, 1H), 8,78-a total of 8.74 (m, 1H), 8.30 to (s, 1H), 8,05-8,03 (m, 1H), to 7.59 (DD, J=4.4 Hz, 8.0 Hz, 1H), 5,88 (s, 2H), 4,46 (kV, J=6,8 Hz, 2H), 3,50 (s, 3H), of 1.46 (t, J=6,8 Hz, 1H)

Next, ethyl 6-(methoxymethyl)-5-oxo-5,6-dihydr the benzo[h][1,6]naphthiridine-10-carboxylate was obtained in the above reaction.

1H NMR (400 MHz, CDCl3): δ 8,93-8,91 (m, 1H), 8,78-a total of 8.74 (m, 1H), 7,72 (d, J=8,8 Hz, 1H), to 7.64 (t, J=7,6 Hz, 1H), 7,53 (DD, J=4,8 Hz, 8.0 Hz, 1H), 7,34 (d, J=7,6 Hz, 1H), to 5.85 (s, 2H), to 4.52 (q, J=6,8 Hz, 2H), 3.46 in (s, 3H), 1,40 (t, J=6.8 Hz, 3H).

Stage 4: Obtain ethyl 6-(methoxymethyl)-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-carboxylate

Connection (639 mg, 2,047 mmol), obtained in stage 3, was dissolved in dichloromethane and methanol, was added 10%-palladium (Pd) (70.0 mg). The resulting mixture was stirred at room temperature for 20 hours in hydrogen gas. After completion of 10%-palladium (Pd) was removed by filtration through celite and the solvent was concentrated under reduced pressure. Then the residue was purified flash column-chromatography (dichloromethane:ethyl acetate=3:1) to obtain the specified title compound (423 mg, yield: 65,3%, white solid).

1H NMR (400 MHz, CDCl3): δ by 8.22 (d, J=1.2 Hz, 1H), 7,86 (DD, J=1.2 Hz, and 8.4 Hz, 1H), 7,49 (d, J=8,4 Hz, 1H), 5,78 (s, 2H), 4,42 (kV, J=7.2 Hz, 2H), 3,49-of 3.46 (m, 1H), 3.43 points (s, 3H), of 2.72 (t, J=6,4 Hz, 1H), 2.00 in to 1.98 (m, 1H), 1,43 (t, J=7.2 Hz, 3H).

Stage 5: Obtain 8-(hydroxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

To mix the solution lydialydia with 72.9 mg, 1.92 mmol) in anhydrous tetrahydrofuran (5 ml) was added at 0°C compound (405 mg, 1.28 mmol)obtained h is stage 4. The resulting mixture was stirred at 0°C for 1 hour and extinguished aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:methanol=7:1) to obtain the specified title compound (339 mg, yield: 94%, solid cream color).

1H NMR (400 MHz, CDCl3+ CD3OD): δ 7,73 (d, J=8.0 Hz, 1H), 7,55 (d, J=1.6 Hz, 1H), 7,26 (DD, J=1.6 Hz, 8.0 Hz, 1H), 5,74 (s, 2H), and 4.75 (s, 2H), 3.46 in-to 3.41 (m, 1H), 3,40 (s, 3H), 2,65 (t, J=6,4 Hz, 1H), 1,98-of 1.95 (m, 1H).

Step 6: Obtain 8-(chloromethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

Anhydrous dichloromethane (10 ml) was added to the compound (50.0 mg, of 0.182 mmol), obtained in stage 5, and added dropwise at room temperature thionyl chloride (0,016 ml, 0,219 mmol). The resulting mixture was stirred at room temperature for 2 hours and was poured into aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the connection header (51,4 mg, yield: 96%, white solid). The compound was used in next reaction without further purification.

1H NMR (400 MHz, CDCl3): δ 7,4 (s, 1H), the 7.43 (d, J=8,4 Hz, 1H), 7,25 (d, J=8,4 Hz, 1H), 5,74 (s, 2H), and 4.68 (s, 2H), 3,47 is-3.45 (m, 2H), 3.43 points (s, 3H), 2,70 (t, J=6.4 Hz, 2H), 1,99-of 1.95 (m, 2H).

Step 7: Getting 8-[(dimethylamino)methyl]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

Connection (to 25.3 mg, 0,0864 mmol)obtained in stage 6, was dissolved in methanol (3.0 ml)was added a 2.0 M dimethylamine (0,864 ml methanol solution). The resulting mixture was stirred at room temperature for 19 hours and then concentrated under reduced pressure. Was added to the concentrated residue aqueous solution of sodium bicarbonate and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:methanol=7:1) to obtain specified in the connection header (17,8 mg, yield: 68%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,46 (s, 1H), 7,39 (d, J=8.0 Hz, 1H), 7,22 (d, J=8.0 Hz, 1H), of 5.75 (s, 2H), 4,96 (s, 1H), 3,54 (s, 2H), 3,47-3,44 (m, 2H), 3,42 (s, 3H), 2,70 (t, J=6,8 Hz, 2H), 2,28 (s, 6H), 1,99 is 1.96 (m, 2H).

Step 8: obtain the dihydrochloride 8-[(dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

Connection of 57.8 mg, 0,192 mmol)obtained in stage 7, was dissolved in ethanol (3 ml), was added 12 N. aqueous solution chloroethanol acid (3.0 m is). The resulting mixture was heated to 90°C and was stirred for 3 hours. The mixture was concentrated to dryness and dissolved in ethyl acetate. After stirring for 30 minutes the precipitate was filtered and washed with diethyl ether to obtain specified in the connection header (of 53.5 mg, yield: 84,5%, solid cream color).

1H NMR (400 MHz, DMSO): δ 11,50 (s, 1H), 10,80 (s, 1H), 7,98 (d, J=8,4 Hz, 1H), 7,43 (d, J=8,4 Hz, 1H), was 7.36 (s, 1H), or 4.31 (d, J=5,2 Hz, 1H), 3,35-to 3.33 (m, 1H), 2,69 (8, 3H), 2,68 (s, 3H), 1,82-to 1.79 (m, 1H).

The following compounds were obtained, using the reaction of example 41.

<Example 42> dihydrochloride 8-[(diethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 43> dihydrochloride 8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 44> dihydrochloride 8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 45> dihydrochloride 8-[(isopropylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 46> dihydrochloride 8-[(propylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 47> dihydrochloride 8-{[ethyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 48> dihydrochloride 8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 49> dihydrochloride 8-(morpholinomethyl)-1,2,3,4-those whom rogerebert[h][1,6]naphthiridine-5(6H)-it

<Example 50> dihydrochloride 9-[(dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 51> dihydrochloride 8-{[benzyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][ 1,6]naphthiridine-5(6H)-it

<Example 52> dihydrochloride 8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 53> dihydrochloride 8-{[(2-hydroxyethyl)(methyl)amino]methyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 54> trihydrochloride 8-{[(2-(dimethylaminoethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 55> trihydrochloride 8-[(4-methylpiperazin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 56> dihydrochloride 8-[(methyl(propyl)amino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 57> dihydrochloride ethyl-3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propionate

<Example 58> the dihydrochloride of 3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propionic acid

<Example 59> dihydrochloride 8-{[isopropyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 60> dihydrochloride 8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4 - tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 61> dihydrochloride ethyl-3-[(5-oxo-1,2,3,4,5,6-Huck is hydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]propionate

<Example 62> dihydrochloride 8-[(2,2,2-triptoreline)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 63> the dihydrochloride of 2-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]acetonitrile

<Example 64> hydrochloride of 8-[(1H-imidazol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 65> hydrochloride of 8-[(1H-pyrrol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

ExampleChemical structureThese NMR spectrum
421H NMR (400 MHz, DMSO-d6): δ 11,49 (s, 1H), being 9.61 (users, 1H), 7,88 (d, J=8,4 Hz, 1H), 7,27 (s, 1H), 7,14 (users, 1H), 4,32-4,30 (m, 2H), 3,34-of 3.31 (m, 2H), 3,07-3,03 (m, 4H), 1,90-to 1.79 (m, 2H), 1,22 (t, J=6.9 Hz, 6H)
431H NMR (400 MHz, DMSO-d6): δ 11,20 (s, 1H), 9,12 (users, 1H), 7,88 (d, J=8.0 Hz, 1H), 7,32 (d, J=8,4 Hz, 1H), 7,27 (s, 1H), 4,13 (t, J=6.0 Hz, 2H), 3,32 (users, 2H), 2,98-to 2.94 (m, 2H), 2,46 is 2.44 (m, 2H), 1,79-users, 2H), 1,22 (t, J=7,1 Hz, 3H)
441H NMR (400 MHz, DMSO-d6): δ 1133 (C, 1H), was 10.82 (s, 1H), to 7.93 (d, J=4,2 Hz, 1H), 7,43 (d, J=3.6 Hz, 1H), 7,33 (s, 1H), 6,20-5,80 (users, 1H), 4,37 (d, J=3.0 Hz, 2H), 3,34-of 3.32 (m, 4H), 3,06-to 3.02 (m, 2H), of 2.51-2,47 (m, 2H), 2,03 is 2.01 (m, 2H), 1,88 (m, 4H)
451H NMR (400 MHz, DMSO-d6): δ 11,17 (s, 1H), of 9.02 (s, 1H), 8,54 (user., 1H), 7,89 (d, J=4,2 Hz, 1H), 7,32 (d, J=4.0 Hz, 1H), 7,28 (s, 1H), 7,22-7,03 (user., 1H), 4,15 (m, 2H), 3,32 (m, 2H), 2,53 2,52 (m, 2H), 2,46 at 2.45 (m, 1H), 1,80 (m, 2H), 1,3 (s, 3H), of 1.29 (s, 3H)
461H NMR (400 MHz, DMSO-d6): δ 11,41 (s, 1H), 9.28 are (s, 2H), 7,94 (d, J=8,4 Hz, 1H), 7,38 (d, J=8,4 Hz, 1H), 7,33 (s, 1H), 4,14 (t, J=5.4 Hz, 2H), 3.33 and (t, J=5.0 Hz, 2H), 2,84 (m, 2H), 2,48 (m, 2H), 1,80 (t, J=5.4 Hz, 2H), 1,69-to 1.63 (m, 2H), 0,89 (t, J=7.4 Hz, 3H)
471H NMR (400 MHz, DMSO-d6): δ of $ 11.48 (s, 1H), a 10.74 (s, 1H), 7,98 (d, J=8.0 Hz, 1H), 7,47 (d, J=8.0 Hz, 1H), 7,38 (s, 1H), 4,39 (m, 1H), 4,23 (m, 1H), 3,16-3,10 (m, 1H), 3,34 (t, J=5,2 Hz, 2H), 3.04 from are 2.98 (m, 1H), 2,60 (d, J=4,8 Hz, 3H), 2,50-2,49 (m, 2H), 1,80 (t, J=5,2 Hz, 2H), 1.27mm (t, J=7.0 Hz, 3H)
481H NMR (400 MHz, DMSO-d6): δ 7,47 (s, 1H), 7,38 (d, J=8,4 Hz, 1H), 7,32 (d, J=8,4 Hz, 1H), 5,74 (s, 2H), 4,87 (s, 1H), to 3.58 (s, 2H), 3.46 in-of 3.43 (m, 2H), 3,42 (s, 3H), 2,69 (t, J=6.4 Hz, 2H), 2,41 (user., 4H), 1,98-of 1.95 (m, 2H), 1.60-to of 1.56(m, 4H), 1,42-of 1.44 (m, 2H)
491H NMR (400 MHz, DMSO-d6): δ 7,49 (s, 1H), 7,40 (d, J=8.0 Hz, 1H), 7,27-7,21 (m, 1H), 5,74 (s, 2H), 4,94 (s, 1H), and 3.72 (t, J=4.4 Hz, 4H), of 3.60 (s, 2H), 3,48-3,44 (m, 2H), 3,42 (s, 3H), 2,69 (t, J=4.6 Hz, 2H), 2,47 (user., 4H), 2.00 in was 1.94 (m, 2H)

501H NMR (400 MHz, DMSO-d6): δ 11,09 (s, 1H), 10,98 (users, salt), of 8.00 (s, 1H), 7,58 (d, J=8,4 Hz, 1H), 7,27 (d, J=8,4 Hz, 1H), 4,22-4,20 (m, 2H), 3.33 and-3,30 (m, 2H), 2,70, 3H), 2,69 (s, 3H), 2,46 is 2.44 (m, 2H), 1,98-to 1.79 (m, 2H)
511H NMR (400 MHz, DMSO-d6): δ 11,22 (s, 1H), 10,70 (user., 1H), 7,92 (d, J=8,4 Hz, 1H), to 7.61-7,58 (m, 2H), of 7.48-7,46 (m, 3H), 7,39 (d, J=8,4 Hz, 1H), 7,32 (s, 1H), 4,42-4,39 (m, 2H), 4.26 deaths-is 4.21 (m, 2H), 3,32 (user., 2H), 2,47 at 2.45 (m, 2H), 1,79 (user., 2H)
521H NMR (400 MHz, DMSO-d6): δ of 11.45 (s, 1H), of 9.30 (s, 1H), 7,95 (d, J=3,4 Hz, 1H), 7,35 (d, J=8,4 Hz, 1H), 7,33 (s, 1H), 4,14 (t, J=5.6 Hz, 2H), 3,35-of 3.32 (m, 2H), 2,55-2,47 (m, 5H), 1,81-to 1.79 (m, 2H)
531H NMR (400 MHz, DMSO-d6 ): δ for 11.55 (s, 1H), 10,45 (s, 1H), 8,01 (d, J=8,4 Hz, 1H), 7,45 (d, J=8,4 Hz, 1H), 7,41 (s, 1H), 4,46-to 4.41 (m, 1H), 4,36-or 4.31 (m, 1H), of 3.77 (m, 2H), 3,34 (t, J=5,2 Hz, 2H), 3,10 (m, 2H), 2,71 (d, J=4,8 Hz, 3H), 2,52 (m, 2H), 1,80 (m, 2H)
541H NMR (400 MHz, DMSO-d6): δ 11,37 (s, 1H), 11,29 (user., 1H), 11,02 (user., 1H), of 7.97 (d, J=4,2 Hz, 1H), 7,51 (d, J=4.4 Hz, 1H), 7,38 (s, 1H), br4.61-4,58 (m, 1H), 4,34-or 4.31 (m, 1H), 3,64-to 3.52 (m, 4H), to 3.34 (s, 2H), and 2.83 (s, 6H), 2,68 (s, 3H), 2,48 (s, 2H), 1,80 (s, 2H)
551H NMR (400 MHz, DMSO-d6): δ 11,70 (user., 1H), 11,31 (s, 1H), to 7.93 (d, J=8,4 Hz, 1H), 7,44 (d, J=8,4 Hz, 1H), 7,34 (s, 1H), 4,39 (user., 2H), 3,63-to 3.33 (m, 10H), 2,79 (user., 3H), 2,48 is 2.46 (m, 2H), 1,82-to 1.79 (m, 2H)
561H NMR (400 MHz, DMSO-d6): δ 11,20 (s, 1H), 10,36 (s, 1H), 7,89 (d, J=8.0 Hz, 1H), 7,35 (d, J=8.0 Hz, 1H), 7,28 (s, 1H), 4,39-4,34 (m, 1H), 4,24-4,19 (m, 1H), 3,30 (m, 2H), 2,97 is 2.80 (m, 2H), 2,61 (d, J=4,8 Hz, 3H), of 2.45 (m, 2H)that is 1.77 (m, 2H), 1.70 to (m, 2H), of 0.85 (t, J=7,6 Hz, 3H)
571H NMR (400 MHz, DMSO-d6): δ made 11.32 (s, 1H), 10,70 (user., 1H), to 7.93 (d, J=4.0 Hz, 1H), 7,41 (d, J=4.0 Hz, 1H), 7,33 (s, 1H), 4,46-to 4.28 (m, 2H), 4,11-4,06 (m, 2H), 3,37-up 3.22 (m, 4H), to 2.94 (t, J=7.2 Hz, 2H), 2,65 (d, J=2.2 Hz, 3H), 2,48 (m, 2H), 1,80 (m, 2H), 1,22-to 1.15 (m, 3H)
581H NMR (400 MHz, DMSO-d6): δ 11,37 (s, 1H), of 10.58 (user., 1H), 7,95 (d, J=4,2 Hz, 1H), 7,41 (d, J=4,2 Hz, 1H), 7,34 (s, 1H), 4,45-to 4.28 (m, 2H), 3.33 and (OSiR., 3H), 3,23-3,20 (m, 1H), 2,85 (t, J=7,6 Hz, 2H), 2,65 (d ,J=2.0 Hz, 3H), of 2.53 (m, 2H), 1,82 (user., 2H)
591H NMR (400 MHz, DMSO-d6): δ 11,47 (s, 1H), 10,44 (user., 1H), to 7.99 (d, J=4,2 Hz, 1H), 7,52 (d, J=3.8 Hz, 1H), 7,41 (s, 1H), 4,42-4,17 (m, 2H), 3,47-of 3.42 (m, 1H), 3,35-to 3.33 (m, 2H), 2,54 (d, J=2,6 Hz, 3H), of 1.80 (t, J=4,8 Hz, 2H), 1,32 of 1.28 (m, 6H)
601H NMR (400 MHz, DMSO-d6): δ 11,57 (s, 1H), 10,69 (s, 1H), 8,01 (d, J=7,6 Hz, 1H), 7,46 (d, J=7,6 Hz, 1H), 7,41 (s, 1H), of 4.44-and 4.40 (m, 1H), 4,33-to 4.28 (m, 1H), and 3.72 (m, 2H), 3,34 (m, 2H), 3.27 to (s, 3H), up 3.22 (m, 2H), 2,68 (s, 3H), of 2.51 (m, 3H), of 1.80 (m, 2H)
611H NMR (400 MHz, DMSO-d6): δ 11,57 (s, 1H), 9,56 (s, 2H), of 7.96 (s, 1H), 7,39 (s, 1H), 7,35 (s, 1H), 4.16 the (s, 2H), of 4.05 (s, 2H), and 3.31 (s, 2H), 3,11 (s, 2H), 2,80 (s, 2H), 1.77 in (s, 2H)and 1.15 (s, 3H)
621H NMR (400 MHz, DMSO-d6): δ 11,35 (s, 1H), to 10.09 (user., 1H), to 7.93 (d, J=4.0 Hz, 1H), 7,38-7,35 (m, 2H, of 4.25 (s, 2H), 4,01 (d, J=4,6 Hz, 2H), 3.33 and (m, 2H), 1,80 (m, 2H)
631H NMR (400 MHz, DMSO-d6): δ 11,43 (s, 1H), 7,83 (d, J=4.0 Hz, 1H), 7,30 (s, 1H), to 7.09 (d, J=4.0 Hz, 1H), of 4.54 (s, 2H), 3,36 (s, 2H), 3,32 (m, 2H), 2,53 (m, 2H), 1,79 (m, 2H)

641H NMR (400 MHz, DMSO-d6): δ 11,58 (s, 1H), 9,36 (s, 1H), 8,02 (d, J=8,4 Hz, 1H), 7,80 (s, 1H), 7,74 (s, 1H), 7,22 (s, 1H), 7,16 (d, J=1.6 Hz, 1H), of 5.53 (s, 2H), 3,32 (s, 2H), 2.49 USD (s, 2H), 1,78 (s, 2H)
651H NMR (400 MHz, DMSO-d6): δ 11,49 (s, 1H), 7,86 (d, J=7,6 Hz, 1H), to 7.09 (s, 1H), 6,94 (d, J=8,4 Hz, 1H), 6,78 (m, 2H), 6,01 (m, 2H), further 5.15 (s, 2H), 3,30 (m, 2H), 2,47 (m, 2H), 1.77 in (m, 2H)

<Example 66> Getting dihydrochloride 8-[(dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Getting 8-[(dimethylamino)methyl]-6-(methoxymethyl)-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Specified in the title compound (16 mg, yield: 56%, yellow solid) was obtained by carrying out the reaction of 8-[(dimethylamino)methyl]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it (30 mg,0.09 mmol) in the same way, as in stage 1 of example 30.

1H NMR (400 MHz, CDCl3): δ 7,80 (d, J=8,4 Hz, 1H), 7,47 (s, 1H), 7.24 to 7,22 (m, 1H), 5,75 (users, 2H), only 3.57 (s, 2H), 3.43 points (s, 3H), 3,17-3,14 (m, 2H), 2,99 (s, 3H), 2.63 in (t, J=6.6 Hz, 2H), 2,31 (s,6H), 1,89 is 1.86 (m, 2H).

Stage 2: obtain the hydrochloride of 8-[(dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The reaction of the compound (16 mg, 0.05 mmol), obtained in stage 1, was carried out in the same way as in stage 2 of example 34, with the receipt specified in the title compound (18 mg, yield: 99%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,71 (s, 1H), 10,70 (users, 1H), to 10.62 (s, 1H), 8,01 (d, J=8.0 Hz, 1H), 7,41 (d, J=8.0 Hz, 1H), 7,34 (s, 1H), 4,33-4,32 (m, 2H), 2,69 (s, 9H), 1,78-1,71 (m, 2H).

The following compounds were obtained, using the reaction of example 66.

<Example 67> dihydrochloride 8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 68> dihydrochloride 8-[(diethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 69> the dihydrochloride of 1-methyl-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 70> the dihydrochloride of 1-methyl-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 71> dihydrochloride 8-{[ethyl(methyl)amino]methyl}-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

ExampleChemical structureThese NMR spectrum
671H NMR (400 MHz, DMSO-d6): δ of 11.69 (s, 1H), 11,09 (user., 1H), or 10.60 (user., 1H), to 7.99 (d, J=4.0 Hz, 1H), 7,47 (d, J=4,2 Hz, 1H), was 7.36-7,34 (m, 1H), 3.33 and (OSiR., 2H), and 3.16 (user., 2H), 2,85 (user., 2H), 2,66-of 2.64 (m, 2H), 2,44 is 2.43 (m, 2H), 2.00 (evens of user., 2H), 1,87-to 1.77 (m, 4H)
681H NMR (400 MHz, DMSO-d6): δ 11,67 (s, 1H), to 10.62 (users, 1H), 8,78 (users, 1H), to 7.99 (d, J=8,4 Hz, 1H), 7,49 (d, J=8,3 Hz, 1H), 7,39 (s, 1H), USD 5.76 (s, 1H), 4,35-to 4.33 (m, 2H), 3,03-only 2.91 (m, 4H), 2,85 (users, 2H), 2,67-of 2.64 (m, 2H), 1,79-1,77 (m, 2H), 1,26 is 1.23 (m, 6H)
691H NMR (400 MHz, DMSO-d6): δ of 11.69 (s, 1H), 10,61 (m, 2H), to 7.99 (d, J=8,4 Hz, 1H), 7,47 (d ,7=8,4 Hz, 1H), 7,35 (s, 1H), 4,29 (m, 2H), 3,24 (m, 2H), 2.91 in-2,84 (m, 4H), 2,66 (t, 7=6.8 Hz, 2H), 2,50 (m, 3H), of 1.76 (m, 6H), 1,69-of 1.65 (m, 1H), 1,33 (m, 1H)
701H NMR (400 MHz, DMSO-d6): δ 11,60 (s, 1H), 11,14 (s, 1H), 7,78 (d, J=8,4 Hz, 1H), 7,44 (d, J=8,4 Hz, Hi), was 7.36 (s, HI)4,37 (d, J=4,8 Hz, 2H), 3,94-of 3.77 (m, 4H), 3,24-to 3.09 (m, 6H), of 2.92 (s, 3H), 2,43 (t, J=6.4 Hz, 2H), 1.77 in (m, 2H)
711H NMR (400 MHz, DMSO-d6): δ of 11.69 (s, 1H), is 10.68 (s, 1H), to 10.62 (s, 1H), 8,00 (d, J=8,4 Hz, 1H), 7,45 (d, J=8,4 Hz, 1H), was 7.36 (s, 1H), 4,43-to 4.38 (m, 1H), 4,27-4,22 (m, 1H), 3,13-3,00 (m, 2H), 2,84 (m, 2H), 2,66 (t, J=6,8 Hz, 2H), 2,60 (s, 3H), 2,52 (m, 3H), 1,80-to 1.77 (m, 2H)

<Example 72> Getting dihydrochloride 8-[(dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 3-methoxy-5-nitrobenzoic acid

To a stirred solution of 3,5-dinitrobenzoic acid (2.0 g, 9,42 mmol) in 2,6-dimethylcyclohexanone (20,0 ml) was added lithium methoxide (1,43 g, 37.8 mol). The resulting mixture was stirred at room temperature for 20 hours and poured into a chilled dilute aqueous solution of sulfuric acid. The mixture was extracted with diethyl ether, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (1.31 g, yield: 70,25%, reddish-brown solid).

1H NMR (400 MHz, CDCl3): δ at 8.36 (s, 1H), of 7.97 (s, 1H), of 7.90 (s, 1H), a 4.03 (s, 3H).

Stage 2: Obtain ethyl 3-methoxy-5-nitrobenzoate

Connection (5,33 g of 27.0 mmol), obtained in stage 1, was dissolved in absolute ethanol (55,0 ml), was added dropwise tio is illore (2,96 ml, 40,55 mmol) at 0°C. the resulting mixture was boiled under reflux for 6 hours. After completion the reaction mixture was concentrated under reduced pressure and mixed with an aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:hexane=4:1) to obtain the specified title compound (5.1 g, yield: 85,6%, solid cream color).

1H NMR (400 MHz, CDCl3): δ to 8.45 (s, 1H), to $ 7.91 (s, 1H), 7,88 (s, 1H), 4,43 (t, J=7.2 Hz, 2H), 3,95 (s, 3H), of 1.44 (t, J=7.2 Hz, 3H).

Stage 3: Obtain ethyl 3-amino-5-methoxybenzoate

Connection (5,1 g of 23.1 mmol), obtained in stage 2, was dissolved in ethyl acetate (50,0 ml), was added 10%-palladium (Pd) (100 mg). Then the resulting mixture was stirred at room temperature for 24 hours in the presence of gaseous hydrogen. After completion of 10%-palladium (Pd) was removed by filtration through celite and the filtrate was concentrated to dryness. The residue was purified column flash chromatography 15 (hexane:ethyl acetate=2:1) to obtain specified in the connection header (4,36 g, output: 96,8%, white solid).

1H NMR (400 MHz, CDCl3): δ of 6.99 (m, 2H), 6,41 (s, 1H), 4,34 (kV, J=7.2 Hz, 2H), 3,79 (s, 3H), of 1.37 (t, J=7.2 Hz, 3H).

One hundred of the Oia 4: Obtain ethyl 3-(2-chloronicotinamide)-5-methoxybenzoate

To a stirred solution of 2-chloronicotinic acid (410 mg, 2,60 mmol) in anhydrous dichloromethane (10 ml) was added oxalicacid (0,667 ml, 7,80 mmol) and a drop of anhydrous N,N-dimethylformamide at room temperature. The resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure and dried in vacuum.Anhydrous dichloromethane solution (5 ml) of the compound (760 mg, 3.90 mmol), obtained in stage 3, was added dropwise at 0°C and then added triethylamine (1,36 ml of 9.75 mmol). Stirring was continued for 1 hour at 0°C and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (1.24 g, yield: 95.3 per cent, solid cream color).

1H NMR (400 MHz, CDCl3): δ 8,53 (s, 1H), 8,49 (d, J=4,8 Hz, 1H), 8,14 (d, J=7,6 Hz, 1H), 7,78 (s, 1H), 7,66 (s, 1H), 7,40-7,37 (m, 2H), 4,33 (cut, J=7,6 Hz, 2H), 3,88 (s, 3H), of 1.38 (t, J=7,6 Hz, 3H).

Stage 5: Obtain ethyl 3-[2-chloro-N-(methoxymethyl)nicotinamide]-5-methoxybenzoate

The compound (1.24 g, 3.72 mmol), obtained in stage 4, was dissolved in anhydrous tetrahydrofuran (20 ml)was slowly added at 0°Ctert-piperonyl potassium (83 mg, the 7.43 mmol). After stirring for 30 minutes was added bromatology ether (0,455 ml, to 5.57 mmol) and the stirring was continued for 1 hour at room temperature. After completion of the reaction was added dichloromethane and water and the mixture was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:ethyl acetate=10:1) to obtain specified in the connection header (1,11 g, output: 79,0%, brown oil).

1H NMR (400 MHz, CDCl3): δ of 8.25 (d, J=4.0 Hz, 1H), 8,14 (d, J=7,6 Hz, 1H), 7,42 (s, 1H), was 7.36 (8, 1H), 7,10 (DD, J=4.0 Hz and 7.6 Hz, 1H), 6,98 (s, 1H), from 5.29 (s, 2H), 4,30 (cut, J=7.2 Hz, 2H, in), 3.75 (s, 3H), of 3.56 (s, 3H), of 1.36 (t, J=7,6 Hz, 3H).

Step 6: Obtain ethyl 10-methoxy-6-(methoxymethyl)-5-oxo-5,6-dihydrobenzo[h][1,6]naphthiridine-8-carboxylate

Connection (1,11 g, to 2.94 mmol)obtained in stage 5, was dissolved in N,N-dimethylformamide (10.0 ml), was added palladium (II) acetate (215 mg, 0,881 mmol), 1,3-bis(diphenylphosphino)propane (363 mg, 0,881 mmol), tributylphosphine (0,724 ml, to 2.94 mmol) and potassium carbonate (812 mg, by 5.87 mmol). The resulting mixture was boiled under reflux for 3 hours and cooled to room temperature. Added water and dichloromethane and the mixture was extracted. The organic layer was dried over anhydrous magnesium sulfate and concentrated to the ear. Then the residue was purified flash column-chromatography (dichloromethane:ethyl acetate=4:l) to obtain specified in the connection header (776,5 mg, yield: 77,3%, white solid).

1H NMR (400 MHz, CDCl3): δ 9,17 is 9.15 (m, 1H), 8,83 (TD, J=2.0 Hz, 8.0 Hz, 1H), 8,00 (s, 1H), 7,63 (s, 1H), EUR 7.57-rate of 7.54 (m, 1H), by 5.87 (s, 2H), 4,46 (cut, J=6,8 Hz, 2H), 4,17 (s, 3H), 3,51 (s, 3H), of 1.46 (t, J=6.8 Hz, 3H).

Step 7: Obtain ethyl 10-methoxy-6-(methoxymethyl)-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-carboxylate

Connection (776,5 mg of 2.27 mmol)obtained in stage 6, was dissolved in dichloromethane and methanol, was added 10%-palladium (Pd) (80.0 mg). The resulting mixture was stirred at room temperature for 20 hours in hydrogen gas. After completion of 10%-palladium (Pd) was removed by filtration through celite and the solvent was concentrated under reduced pressure. Then the residue was purified flash column-chromatography (dichloromethane:ethyl acetate=3:1) to obtain the specified title compound (458 mg, yield: 58,2%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,89 (s, 1H), 7,34 (s, 1H), USD 5.76 (s, 2H), 4,42 (kV, J=7.2 Hz, 2H), Android 4.04 (s, 3H), 3,44 (s, 3H), 3,44-to 3.41 (m, 2H), 2,75 (t, J=6.0 Hz, 2H), 1,94 is 1.91 (m, 2H), USD 1.43 (t, J=7.2 Hz, 3H).

Step 8: Obtain 8-(hydroxymethyl)-10-methoxy-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

Tetr hydrofuran (10.0 ml) was added to socialogical (125 mg, 3,30 mmol) and cooled to 0°C. Compound (457 mg, of 1.32 mmol)obtained in stage 7, was dissolved in tetrahydrofuran (10.0 ml) and slowly added dropwise at 0°C and the resulting mixture was stirred at the same temperature for 1 hour. After completion, was added an aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:methanol=10:l) to obtain the specified title compound (399 mg, 15 output: 99.2%, and the solid cream color).

1H NMR (400 MHz, CDCl3): δ 7,47 (s, 1H), 6,97 (s, 1H), 6,77 (s, 1H), 5,70 (s, 2H), 4,70 (s, 2H), of 3.97 (s, 3H), 3,40-to 3.36 (m, 2H), 3,35 (s, 3H), of 2.66 (t, J=6.0 Hz, 2H), 1.93 and-of 1.87 (m, 2H).

Step 9: obtain the dihydrochloride 8-[(dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

The compound obtained in stage 8, worked in the same way as in the stages 6-8 of example 41, obtaining specified in the connection header (30,5 mg, yield: 96.1 per cent, solid cream color).

1H NMR (400 MHz, DMSO-d6): δ 11,37 (s, 1H), 10,75 (s, 1H), 7,14 (s, 1H), 6.90 to (s, 1H), 4.26 deaths (d, J=4,8 Hz, 2H), 3,95 (s, 3H), 3,34 (m, 2H), 2,70 (s, 3H), 2,69 (s, 3H), 2,50 is 2.46 (m, 2H), 1.77 in is 1.75 (m, 2H).

The following compounds were obtained, using the eakly example 72.

<Example 73> dihydrochloride 10-methoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 74> dihydrochloride 10-methoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 75> dihydrochloride 8-[(ethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 76> 8-{[ethyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he

<Example 77> dihydrochloride 10-methoxy-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 78> dihydrochloride 10-methoxy-8-[(4-oxopiperidin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 79> trihydrochloride 8-{[4-(hydroxyimino)piperidine-1-yl]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 80> trihydrochloride 10-methoxy-8-[(4-(methoxyimino)piperidine-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 81> dihydrochloride 10-methoxy-8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 82> dihydrochloride 8-[(2,5-dihydro-1H-pyrrol-1-yl)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 83> dihydrochloride 8-{[(2-isopropoxyphenyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<P the emer 84> the dihydrochloride 10-methoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 85> dihydrochloride 8-{[(2-chloroethyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 86> dihydrochloride 8-[(diethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 87> dihydrochloride 8-[(tert-butylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 88> dihydrochloride 8-[(isopropylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 89> dihydrochloride 8-[(cyclopentylamine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 90> dihydrochloride 8-[(2,6-dimethylmorpholine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 91> hydrochloride chloride N-[(10-methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]-N,N-dimethylcyclopentane

<Example 92> dihydrochloride 8-{[cyclopentyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 93> dihydrochloride 8-{[isopropyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 94> dihydrochloride 8-{[(2-foradil)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

ExampleChemical structureThese NMR spectrum
731H NMR (400 MHz, DMSO-d6): δ 11,35 (s, 1H), 8,42 (s, 2H), of 6.96 (s, 1H), 6,86 (s, 1H), 3,97 (m, 2H), 3,91 (s, 3H), of 3.32 (m, 2H), 2,53 is 2.43 (m, 5H), at 1.73 (m, 2H)
741H NMR (400 MHz, DMSO-d6): δ 11,40 (s, 1H), 11,38 (user., 1H), 7,81 (user., 1H), 7,24 (s, 1H), 6,92 (s, 1H), or 4.31 (m, 2H), 3.96 points (s, 3H), 3,93-3,81 (m, 4H), to 3.34 (m, 2H), 3,22-to 3.09 (m, 4H), 2,47 (m, 2H), of 1.75 (m, 2H)
751H NMR (400 MHz, DMSO-d6): δ 11,33 (s, 1H), 9,206 (s, 1H), 7,07 (s, 1H), 6.90 to (s, 1H), 4,10-4,07 (m, 2H), 3,95 (s, 3H), 3,34 (m, 2H), 2,99-2,95 (m, 2H), 2.49 USD at 2.45 (m, 2H), of 1.75 (m, 2H), 1,23 (t, J=7,6 Hz, 3H)

1H NMR (400 MHz, DMSO-d6): δ 11,59 (user., 1H) , 11,30 (s, 1H), 7,78 (user., 1H), 7,19 (s, 1H), 6,93 (s, 1H), of 5.92 (s, 2H), 4,46 (d, J=2,8 Hz, 2H), 4,11-of 4.05 (m, 2H), 3.96 points (s, 3H), 3,91-3,90 (m, 2H), 1.77 in-1,74 (m, 2H)
761H NMR (400 MHz, CDCl3): δ 10,82 (user., 1H), 7,34 (s, 1H), 6,85 (s, 1H), 6,79 (user., 1H), of 3.97 (s, 3H)and 3.59 (s, 2H), 3,40 (s, 2H), 2,72 (m, 2H), 2.57 m (m, 2H), to 2.29 (s, 3H), 1,94-1,90 (m, 1H), 1.18 to to 1.15 (m, 3H)
77 1H NMR (400 MHz, DMSO-d6): δ 11,82 (s, 1H), 11,47 (s, 1H), 7,35 (s, 1H), 7,01 (s, 1H), of 3.97 (s, 3H), 3,37-of 3.32 (m, 4H), of 3.00 (t, J=8,4 Hz, 2H), 2,52 (s, 2H), 1,99-of 1.74 (m, 6H)
781H NMR (400 MHz, DMSO-d6): δ 11,88 & 11,17 (s, 1H), 11,50 (d, J=13,2 Hz, 1H), 7,34 (s, 1H), of 6.96 (s, 1H), to 4.41 & 4,32 (s, 2H), 3,98 (d, J=7,6 Hz, 3H), 3,53-3,11 (m, 4H), 3,41-to 3.36 (m, 2H), 2,96-to 2.94 (m, 2H), 1,76 (m, 2H), 1,17-1,01 (m, 4H)
791H NMR (400 MHz, DMSO-d6): δ 11,38 (user., salt), to 7.77 (users, 1H), 7.23 percent (users, 1H), 6,86 (user., 1H), to 4.38 (user., 2H), 3.33 and-up 3.22 (m, 4H), 3,18-of 2.93 (m, 4H), 1,76-of 1.74 (m, 2H)
801H NMR (400 MHz, DMSO-d6): δ 11,38 (user., salt), 7,79 (user., 1H), 7,26 (user., 1H), 6,97 (user., 1H), or 4.31-to 4.28 (m, 2H), of 3.97 (s, 3H), 3,76 (s, 3H), 3,40-to 3.34 (m, 4H), 3,15-of 2.93 (m, 4H), 1,76-of 1.74 (m, 2H)
811H NMR (400 MHz, DMSO-d6): δ 11,67 (s, 1H), 11,00 (s, 1H), 7,28 (s, 1H), 6,99 (s, 1H), to 4.41 is 4.36 (m, 1H), 4,28-of 4.25 (m, 1H), 3.96 points (s, 3H), of 3.75 (m, 2H), 3,36 (m, 2H), 3,28 (s, 311), 3,23 (m, 2H), 2,69 (s, 3H), 2.49 USD (m, 2H), 1,76 (m, 2H)
82
831H NMR (400 MHz, CD3OD): δ to 7.35 (s, 1H), 7,26 (s, 1H), 4,60 (m, 1H), 4,51 (m, 1H), 4,15 (s, 3H), 3,85 (m, 2H), and 3.72 (m, 1H)and 3.59 (m, 2H), 3,41 (m, 2H), equal to 2.94 (s, 3H), 2,71 (m, 2H), up to 1.98 (m, 2H), 1,21 (s, 6H)

841H NMR (400 MHz, DMSO-d6): δ 12,15 (s, 1H), of 11.26 (s, 1H), 7,52 (s, 1H), to 7.09 (s, 1H), 4,27 (m, 2H), 4.00 points (s, 3H), 3,40 (m, 2H), up 3.22 (m, 2H), 2,92-2,84 (m, 2H), by 2.55 (m, 2H), 1,90 is 1.86 (m, 2H), 1,75-to 1.67 (m, 5H), 1,35-1,32 (m, 1H)
851H NMR (400 MHz, DMSO-d6): δ 11,82 (s, 1H), to 11.56 (s, 1H), was 7.36 (s, 1H), 7,03 (s, 1H), 4,50-4,47 (m, 1H), or 4.31-4.26 deaths (m, 1H), 4,11 (t, J=6,8 Hz, 2H), 3,98 (s, 3H), of 3.45 (m, 2H), 3,38 (m, 2H), 2,71 (s, 3H), 2,52 (m, 2H), 1.77 in (m, 210
861H NMR (400 MHz, DMSO-d6): δ 11,74 (s, 1H), 11,07 (s, 1H), 7,40 (s, 1H), 7,02 (s, 1H), 4,28 (d, J=5.6 Hz, 2H), of 3.97 (s, 3H), 3,36 (t, J=4,8 Hz, 2H), 3.04 from are 2.98 (m, 2H), of 2.51 (s, 2H), 1,75 (t, J=5.6 Hz, 2H), 1,23 (t, J=7,6 Hz, 6H)
87 1H NMR (400 MHz, DMSO-d6): δ 11,23 (s, 1H), 9,05 (user., 2H), 7,10 (s, 1H), 6,91 (s, 1H), 4,07-of 4.05 (m, 210, of 3.96 (s, 3H), of 3.33 (m, 2H), 2,50 is 2.44 (m, 2H), of 1.75 (m, 2H)
881H NMR (400 MHz, DMSO-d6): δ 11,41 (s, 1H), 9,23 (users, 1H), 7,16 (s, 1H), 6,94 (s, 1H), 4,12-4.09 to (m, 2H), 3.96 points (s, 3H), 3,36 of 3.28 (m, 3H), 2,47 at 2.45 (m, 2H), 1.77 in-1,74 (m, 2H), 1,31 (s, 3H), of 1.29 (s, 3H)
891H NMR (400 MHz, DMSO-d6): δ 11,54 (s, 1H), 9,45 (s, 2H), 7,19 (s, 1H), of 6.96 (s, 1H), 4.09 to (t, J=5,2 Hz, 2H), 3,95 (s, 3H), 3.43 points (s, 1H), 3,34 (t, J=4,8 Hz, 2H), 2,48 (s, 2H), 1,97 (c, 2H), 1,76-1,71 (m, 6H), 1.50 in (s, 2H)
901H NMR (400 MHz, DMSO-d6): δ 11,99 (s, 1H), 11,77 (s, 1H), 7,44 (s, 1H), 7,00 (s, 1H), 4,37 (m, 2H), 4,27-4.26 deaths (m, 1H), 4,10-Android 4.04 (m, 1H), 3,99 (s, 3H), 3,37 (m, 2H), 3,21-3,18 (m, 2H), 2.71 to 2,63 (m, 2H), 2,53 (m, 2H), 1,76 (m, 2H,), of 1.09 (s, 3H), of 1.08 (s, 3H)

911H NMR (400 MHz, DMSO-d6): δ 11,35 (s, 1H), 7,06 (s, 1H), 6,92 (s, 1H), 4,47 (s, 2H), of 3.94 (s, 3H), a 3.87 (t, J=7,6 Hz, 1H), 3.33 and (s, 2H), 2,90 (s, 6H), 2,48 (s, 2H), 1,99 (s, 4H), at 1.73 (s, 4H), and 1.56 (s, 2H)
921H NMR (400 MHz, DMSO-d6): δ 11,51 (s, 1H), 11,06 (s, 1H), 7,27 (s, 1H), of 6.96 (s, 1H), of 4.44 (d, J=9.6 Hz, 2H), 3.96 points (s, 3H), 3,55 (kV, J=7,6 Hz, 1H), 3,34 (t, J=4,8 Hz, 2H), 2,52 (d, J=4,8 Hz, 3H), 2,48 (s, 2H), 2,08-to 2.06 (m, 2H,), 1,94-1,89 (m, 2H), 1,73 (s, 4H), 1,57-1,49 (m, 2H)
931H NMR (400 MHz, DMSO-d6): δ of 11.61 (users, 1H), 10,84 (users, 1H), 7,38 (s, 2H), 7,02 (s, 2H), 4,37-to 4.33 (m, 1H), 4,18 is 4.13 (m, 1H), 3,98 (s, 3H), 3,38-to 3.34 (m, 4H), of 2.53 (s, 3H), 1.77 in is 1.75 (m, 2H), of 1.34 (s, 3H), of 1.29 (s, 3H), 1,22-1,19 (m, 1H)
941H NMR (400 MHz, DMSO-d6): δ 11,46 (s, 1H), 11,21 (s, 1H), 7,20 (s, 1H), 6,93 (s, 1H), 4,98-4,82 (m, 2H), 4,42-is 4.21 (m, 2H), of 3.94 (s, 3H), 3,48 is 3.40 (m, 2H), 3.33 and (m, 2H), 2,70 (s, 3H), 2,46 (m, 2H), 1,74 (m, 2H)

<Example 95> Obtain hydrochloride of 8-[(1H-tetrazol-5-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 2-[6-(methoxymethyl)-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl]acetonitrile

8-(Hydroxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-he (100 mg, 0.36 mmol)obtained in stage 5 of example 41 was dissolved in dichloromethane (105 ml)was added dropwise thionyl chloride (66 μl, of 0.91 mmol) at 0°C. is Obtained in which the result mixture was stirred at room temperature for 4 hours and poured into saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. Then the residue was dissolved in N,N-dimethylformamide (5 ml) was added sodium cyanide (55 mg, of 1.09 mmol). The resulting mixture was stirred at room temperature overnight and poured into ice-cold water. The mixture was extracted with chloroform and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Then the residue was purified flash column-chromatography (chloroform:methanol=30:1) to obtain the specified title compound (70 mg, yield: 69%, white solid).

1H NMR (400 MHz, CDCl3): δ 7,46-7,44 (m, 2H), 7,22 (d, J=8,4 Hz, 1H), 5,72 (s, 2H), 4,87 (s, 1H), 3,86 (s, 2H), 3,47 (m, 2H), 3,42 (s, 3H), 2,69 (t, J=6.4 Hz, 2H), up to 1.98 (m, 2H).

Stage 2: Getting 8-[(1H-tetrazol-5-yl)methyl]-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (65 mg, 0.23 mmol)obtained in stage 1, was dissolved in N,N-dimethylformamide (5 ml)was sequentially added sodium azide (75 mg, 1.15 mmol) and ammonium chloride (61 mg, 1.15 mmol). The resulting mixture was boiled under reflux for 48 hours and cooled to room temperature. The mixture was washed with chloroform and the aqueous layer was concentrated is dry. Then the residue was washed with methanol and filtered. The filtrate was purified flash column-chromatography (chloroform:methanol=5:1) to obtain the specified title compound (34 mg, yield: 45%, yellow solid).

1H NMR (400 MHz, CDCl3): δ of 7.75 (d, J=8.0 Hz, 1H), 7,50 (s, 1H), 7,14 (d, J=8,4 Hz, 1H), 5,67 (s, 2H), to 4.41 (s, 2H), 3,40 (m, 2H), 3.33 and (s, 3H), 2,60 (t, J=6.4 Hz, 2H), 1,92 (m, 2H).

Stage 3: obtain the hydrochloride of 8-[(1H-tetrazol-5-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (34 mg, 0.10 mmol)obtained in stage 2, was dissolved in ethanol (5 ml)was added conc. chloroethanol acid (1.0 ml). The resulting mixture was stirred at 80°C for 10 hours. After completion of the reaction the mixture was concentrated under reduced pressure and filtered to obtain specified in the title compound (28 mg, yield: 84%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,09 (s, 1H), 7,80 (d, J=8,4 Hz, 1H), 7,10 (s, 1H), 7,03 (d, J=8.0 Hz, 1H), 4,33 (s, 2H), 3,30 (m, 2H), 2,45 (m, 2H), 1,78 (m, 2H).

<Example 96> Getting trihydrochloride 10-methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 10-methoxy-6-(methoxymethyl)-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-carbaldehyde

To a stirred solution of compound obtained from the adiya's 8 example 73 (100 mg, 0.32 mmol)in anhydrous dichloromethane (5 ml) was added dropwise periodinane dess-Martin (209 mg, 0.49 mmol) at 0°C. the resulting mixture was stirred at room temperature for 3 hours and poured into ice-cold water. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (95 mg, yield: 96%, yellow solid). The compound obtained was used in the next reaction without further purification.

1H NMR (400 MHz, CDCl3): δ 10,02 (s, 1H), 7,68 (s, 1H), 7,47 (users, 1H), 7,19 (s, 1H), 5,76 (users, 2H), Android 4.04 (s, 3H), 3,44 (s, 3H), 3.43 points is 3.40 (m, 2H), 2,70 (t, J=6.2 Hz, 2H), 1,92 (t, J=5.7 Hz, 2H).

Stage 2: Obtaining (E)-10-methoxy-6-(methoxymethyl)-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (95 mg, 0.31 mmol)obtained in stage 1, was dissolved in toluene (10 ml), was added 4-aminomorpholine (0,031 ml, 0.31 mmol) at room temperature. Then the resulting mixture was heated and boiled under reflux with trap Dean-stark for 5 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was purified flash column-chromatography (dichloromethane:methanol=20:1) to obtain the specified title compound (109 mg, o is d: 89%, yellow solid).

1H NMR (400 MHz, CDCl3): δ 7,58 (s, 1H), 7,45 (users, 1H), 7,19 (s, 1H), 7,15 (s, 1H), 5,72 (users, 2H), 4.00 points (s, 3H), 3,91-to 3.89 (m, 4H), 3.43 points (s, 3H), 3,40-to 3.38 (m, 2H), 3,24-is 3.21 (m, 4H), 2,68 (t, J=6.4 Hz, 2H), 1,94-of 1.88 (m, 2H).

Stage 3: Obtain 10-methoxy-6-(methoxymethyl)-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (50 mg, 0.12 mmol)obtained in stage 2, was dissolved in tetrahydrofuran (2 ml), was slowly added cyanoborohydride sodium (4 mg, 0.06 mmol) and 1.25 N. methanol solution chloroethanol acid (5 ml). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to remove solvent. The residue was podslushivaet 1 N. aqueous sodium hydroxide solution and was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated to dryness. Then the residue was purified flash column-chromatography (dichloromethane:methanol=20:1) to obtain the specified title compound (18 mg, yield: 38%, yellow solid).

1H NMR (400 MHz, CDCl3): δ 7,44 (users, 1H), 7,16 (s, 1H), 6,76 (s, 1H), 5,69 (users, 2H), was 4.02 (s, 2H), 3.96 points (s, 3H), 3.75 to and 3.72 (m, 4H), to 3.41 (s, 3H), 3,41-to 3.38 (m, 2H), 2,74-of 2.66 (m,6H), 1.93 and-1,89 (m, 2H).

Stage 4: Getting trihydrochloride 10-methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[][1,6]naphthiridine-5(6H)-it

The compound (18 mg, 0.046 mmol), obtained in stage 3, was dissolved in ethanol (1 ml), and added 12 N. aqueous solution chloroethanol acid (1.5 ml). The reaction mixture was stirred at 75°C for 2 hours. The solvent was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The precipitate was filtered off, washed with ethyl acetate and dried in vacuum to obtain specified in the connection header (20,1 mg, yield: 96%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,51 (users, 1H), 11,05 (users, 1H), 7,13 (s, 1H), 6,99 (s, 1H), or 4.31 (s, 2H), 3,98-3,71 (m, 6H), 3,36-to 3.34 (m, 2H), 3.15 in (users, 2H), 2,48 is 2.46 (m, 2H), 1.77 in to 1.76 (m, 2H).

<Example 97> Getting trihydrochloride 10-methoxy-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain 10-methoxy-6-(methoxymethyl)-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (40 mg, 0.10 mmol)obtained in stage 3 of example 96, and potassium carbonate (22 mg, 0.15 mmol) was dissolved in acetonitrile (5 ml), was added logmean (0,008 ml, 0.12 mmol). The resulting mixture was boiled under reflux and was stirred for 18 hours. The reaction mixture was poured into ice water and was extracted with chloroform. The organic layer was dried over anhydrous sulfate mage the Oia and concentrated under reduced pressure. Then the residue was purified flash column-chromatography (dichloromethane:methanol=15:1) to obtain the specified title compound (3 mg, yield: 8%, yellow solid).

1H NMR (400 MHz, CDCl3): δ 7,45 (users, 1H), 7,11 (s, 1H), 6,74 (s, 1H), 5,69 (users, 2H), 3,95 (s, 3H), of 3.77 (s, 2H), 3.72 points-3,70 (m, 4H), to 3.41 (s, 3H), 3,39-to 3.38 (m, 2H), 2,78 was 2.76 (m, 4H), to 2.67 (t, J=6.4 Hz, 2H), is 2.37 (s, 3H), 1,92-1,89 (m, 2H).

Stage 2: Getting trihydrochloride 10-methoxy-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

The compound (3 mg, 0,0075 mmol)obtained in stage 1, interacted in the same way as in stage 4 of example 96, obtaining specified in the title compound (2.6 mg, yield: 75%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ 11,05 (users, 1H), 8,88 (users, 1H), was 7.36 (users, 1H), 7,16 (s, 1H), 6.90 to (s, 1H), 4,24 (users, 2H), 3,98-3,71 (m,6H), 3,36-to 3.34 (m, 2H), 3,15 (user., 2H), 2,82-to 2.74 (m, 2H), 1.77 in to 1.76 (m, 2H).

<Example 98> Getting trihydrochloride (E)-10-methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Compound (15 mg, of 0.038 mmol), obtained in stage 2 of example 96, interacted in the same way as in stage 4 of example 96, obtaining specified in the title compound (2.6 mg, yield: 75%, yellow solid).

1H NMR (400 MHz, DMSO-d6): δ of 7.69 (s, 1H), 7,22 (users, 1H), and 7.8 (s, 1H), was 4.02 (s, 3H), 3,89-a 3.87 (m, 4H), 3,42-3,37 (m, 2H), 3,20-3,17 (m, 4H), to 2.66 (t, J=6.4 Hz, 2H), 1,90-1,89 (m, 2H).

<Example 99> Getting dihydrochloride 8-[(dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

Stage 1: Getting 8-[(dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

8-[(Dimethylamino)methyl]-10-methoxy-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-he (28 mg, 0,084 mmol)obtained in example 72 was dissolved in dichloromethane (10 ml) and added dropwise trichromacy boron (0.6 mmol, 152 mg) at 0°C. the Mixture was stirred at room temperature for 2 hours and then carefully added water. The solution was washed with chloroform, the aqueous layer was concentrated under reduced pressure and the residue was purified flash column-chromatography (chloroform:ethanol=1:5) to obtain the specified title compound (14 mg, yield: 58%, white solid).

1H NMR (400 MHz, CD3OD): δ 6,53 (s, 1H), 6,41 (s, 1H), 3,40-to 3.36 (m, 2H), 2,55 of $ 2.53 (m, 4H), and 2.26 (s, 6H), 1,87-of 1.84 (m, 2H).

Stage 2: Getting dihydrochloride 8-[(dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-it

Specified in the header connection (to 13.6 mg, yield: 78%, yellow solid) was obtained using 8-[(dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,naphthyridin-5-(6H)-he (14 mg, 0,051 mol), obtained in stage 1.

1H NMR (400 MHz, DMSO-d6): δ 11,71 (s, 1H), 11,25 (s, 1H), 10,88 (s, 1H), 8,01 (user., 1H), 6,83 (s, 2H), 4,17-4,16 (m, 2H), 3,36-to 3.34 (m, 2H), to 2.67 (d, J=2.4 Hz, 6H), 2,47 at 2.45 (m, 2H), 1,76-of 1.74 (m, 2H).

<Example 100> Getting dihydrochloride 8-[(dimethylamino)methyl]-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Stage 1: Obtain ethyl 3-ethoxy-5-nitrobenzoate

3-Methoxy-5-nitrobenzoic acid (10 g, at 50.7 mmol), obtained in stage 1 of example 72 was dissolved in dichloromethane (200 ml)was added 1 M dichloromethane solution trichromate boron. The reaction mixture was stirred at room temperature for 8 hours. The mixture was poured into ice water and washed with dichloromethane. The aqueous layer was concentrated under reduced pressure and dried in vacuum. The residue was dissolved in N,N-dimethylformamide (150 ml)was added dropwise potassium carbonate (42 g, 304 mmol) and Iodate (20.2 ml, 253 mmol). Then the mixture was stirred for one day at 60°C and poured into ice-cold water. The solution was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified column flash chromatography (hexane:ethyl acetate=5:1) to obtain specified in the connection header (8,49 g, yield: 70%, yellow solid).

1H NMR (00 MHz, CDCl3): δ 8,44 (s, 1H), of 7.90-7,88 (m, 2H), 4,43 (kV, J=3,6 Hz, 2H), 4,16 (kV, J=3,4 Hz, 2H) to 1.48 (t, J=7.2 Hz, 3H), USD 1.43 (t, J=7.2 Hz, 3H).

Stage 2: Obtain ethyl 3-amino-5-ethoxybenzoate

Connection (8,49 g, 35,49 mmol)obtained in stage 1, was dissolved in ethyl acetate, was added 10%-palladium (Pd) (900 mg). The reaction mixture was stirred at room temperature for one day in a gaseous hydrogen. After completion of the reaction the solution was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified column flash chromatography (hexane:ethyl acetate=3:1) to obtain specified in the connection header (6,98 g, yield: 94%, yellow liquid).

1H NMR (400 MHz, CDCl3): δ 6,98 (m, 2H), 6,41 (m, 1H), 4,34 (kV, J=3,6 Hz, 2H), 4,03 (kV, J=3,6 Hz, 2H) 3,76 (user., 2H), 1,42-of 1.36 (m, 6H).

Stage 3: Getting dihydrochloride 8-[(dimethylamino)methyl]-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Specified in the title compound (85 mg, yield: 11.4% (total output), yellow solid) was obtained in the same way as in the stages 4-9 example 72, using ethyl 3-amino-5-ethoxybenzoate (415 mg, to 1.98 mmol), obtained in stage 2.

1H NMR (400 MHz, CDCl3): δ 11,71 (s, 1H), 11,19 (s, 1H), to $ 7.91 (user., 1H), 7,29 (s, 1H) 6,97 (s, 1H), 4,34-4,27 (m, 4H), 3,39 (m, 2H), 2,68 (d, J=2.0 Hz,6H), of 2.51-2.49 USD (m, 2H), 1.77 in (m, 2H), 1,44 (t, J=6.8 Hz, 3H).

Following with the unity received, applying the reaction of example 100.

<Example 101> dihydrochloride 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 102> dihydrochloride 10-ethoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 103> dihydrochloride 10-Ethoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 104> dihydrochloride 10-ethoxy-8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 105> hydrochloride, 8-(hydroxymethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 106> dihydrochloride 10-methoxy-8-(thiomorpholine)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 107> trihydrochloride 10-methoxy-8-[(2-morpholinoethyl)methyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 108> trihydrochloride 10-methoxy-8-[(4-morpholinopropan-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 109> dihydrochloride 8-(aminomethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 110> dihydrochloride 8-[(dimethylamino) methyl)]-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 111> dihydrochloride 8-(morpholinomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 112> dihydrochloride 8-(aminol who yl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 113> dihydrochloride 8-(aminomethyl)-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 114> dihydrochloride 8-(aminomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 115> dihydrochloride 10-methoxy-8-{[methyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 116> dihydrochloride 8-[(dimethylamino)methyl]-10-(2-methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 117> dihydrochloride 10-(2-methoxyethoxy)-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

<Example 118> the dihydrochloride of 1-[(10-methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]-1H-pyrrole-2,5-dione

ExampleChemical structureThese NMR spectrum
1011H NMR (400 MHz, DMSO-d6) δ is 11.39 (user., 1H), 11,35 (s, 1H), to 7.64 (user., 1H), 7,26 (s, 1H), 6,91 (s, 1H) 4,32-4.26 deaths (m, 4H), 3,97-3,82 (m, 4H), 3,39-to 3.34 (m, 2H), 3,22-is 3.08 (m, 4H), 2,47 at 2.45 (m, 2H), 1,78 is 1.75 (m, 2H), 1,44 (t, J=7.2 Hz, 3H),
1021H NMR (400 MHz, DMSO-d-sub> 6) δ 11,41 (s, 1H), a 10.74 (s, 1H), 7,78 (user., 1H), 7,28 (s, 1H), 6,91 (s, 1H) 4,29 (kV, J=6,8 Hz, 2H), 4,23-is 4.21 (m, 2H), 3,36 (m, 2H), 3.25 to up 3.22 (m, 2H), 2,88-to 2.85 (m, 2H), 2,49-2,48 (m, 2H), 1,91 by 1.68 (m, 6H), 1,50 (t, J=6.8 Hz, 3H), of 1.36 and 1.33 (m, 2H)

1031H NMR (400 MHz, DMSO-d6) δ 11,34 (s, 1H), 9,26 (s, 1H), to 7.64 (user., 1H), 7,05 (s, 1H), to 6.88 (s, 1H), 4.26 deaths (kV, J=3,4 Hz, 2H), 4.09 to 4,06 (m, 2H), 3,37-to 3.34 (m, 2H), 2,60-to 2.57 (m, 3H), 2.49 USD at 2.45 (m, 2H), 1,78 is 1.75 (m, 2H), 1,50 (t, J=5,2 Hz, 3H),
1041H NMR (400 MHz, DMSO-d6): δ is 11.39 (s, 1H), 9.28 are (user., 1H), 7,70 (user., 1H), 7,11 (s, 1H), 6,91 (s, 1H), 4,27 (kV, J=3,4 Hz, 2H), 4,08 (user., 2H), 3,36 (user., 1H), 2.95 and (OSiR., 2H), 2,47 (user., 2H), 1.77 in (user., 2H), a 1.45 (t, J=6.4 Hz, 3H), of 1.23 (t, J=7,6 Hz, 3H)
1051H NMR (400 MHz, DMSO-d6): δ 11,77 (s, 1H), 8,23 (user., 1H), 6,99 (s, 1H), 6,74 (s, 1H), 4.53-in (s, 2H), 3,93 (s, 3H), 3,39 (t, J=5.6 Hz, 2H), 2,54-2,52 (m, 2H), 1,78 (t, J=5,2 Hz, 2H)
1061H NMR (400 MHz, DMSO-d6): δ 11,42 (s, 1H), 11,30 (user., 1H), 7,82 (user., 1H), 7,30 (s, 1H), 6,92 (s, 1H), 4,34-to 4.33 (m, 2H), of 3.97 (s, 3H), 3,55-to 3.52 (m, 2H), 3,35-to 3.33 (m, 2H), 3,29 is 3.23 (m, 2H), 3,18-of 3.12 (m, 2H), 1,7 (t, J=5.6 Hz, 2H)
1071H NMR (400 MHz, DMSO-d6): δ 11,83 (s, 1H), is 11.39 (user., 1H), 9,99 (user., 1H), 7,28 (s, 1H), 7,03 (s, 1H), 4,22 (user., 2H), as 4.02-of 3.97 (m, 5H), 3,84-3,81 (m, 2H), 3,56-to 3.52 (m, 6H), 3.43 points-to 3.38 (m, 2H), 3,21-3,10 (m, 2H), 2,53-of 2.50 (m, 2H), 1.77 in (t, J=4.4 Hz, 2H)
1081H NMR (400 MHz, DMSO-d6): δ 11,33 (user., 1H), of 11.29 (s, 1H), 11,14 (user., 1H), 7,71 (user., 1H), 7,19 (s, 1H), 6.89 in (s, 1H), 4,27 (user., 1H), 3,99-of 3.96 (m, 5H), 3,85-of 3.80 (m, 2H), 3,47-to 3.34 (m, 6H), is 3.08 are 2.98 (m, 4H), to 2.55 (m, 1H), 2,48 at 2.45 (m, 2H), 2,33-of 2.30 (m, 2H), 1.77 in-1,74 (m, 2H)
1091H NMR (400 MHz, DMSO-d6): δ 11,44 (s, 1H), 8,48 (user., 3H), 7,01 (s, 1H), 6.90 to (s, 1H), 4.00 points (kV, J=3.2 Hz, 2H), of 3.94 (s, 3H), 3,35 (user., 2H), 2,48 is 2.46 (m, 2H), 1,76 (m, 2H)
1101H NMR (400 MHz, DMSO-d6): δ 11,36 (s, 1H), 10,8 (user., 1H), 7.62mm (user., 1H), 7,16 (s, 1H), 6.89 in (s, 1H), 4,25 (d, J=2,6 Hz, 2H), 4,17 (t, J=6,8 Hz, 2H), 3,36 (user., 2H), 2,70 (s, 3H), 2,69 (s, 3H), 2,48 is 2.46 (m, 2H), 1,86 (kV, J=3,6 Hz, 2H), 1,79-to 1.77 (m, 2H), 1,01 (t, J=7,6 Hz, 3H)
1111H NMR (400 MHz, LCA is-d 6): δ 11,24 (m, 2H), 7,54 (user., 1H), 7,21 (s, 1H), 6.89 in (s, 1H), 4,30-the 4.29 (m, 2H), 4,19-4,16 (m, 2H), 3,94-3,91 (m, 2H), 3,84-of 3.78 (m, 2H), 3,38-to 3.34 (m, 2H), 3,22-3,19 (m, 2H), 3,14-3,10 (m, 2H), 2.49 USD is 2.46 (m, 2H), 1,89 of-1.83 (m, 2H), 1,76-of 1.75 (m, 2H), 1,01 (t, J=7.2 Hz, 3H)
1121H NMR (400 MHz, DMSO-d6): δ of 11.45 (s, 1H), charged 8.52 (user., 3H), of 7.96 (s, 1H), 7,31 (s, 1H), 4,05 (d, J=2,6 Hz, 2H), 3,34-of 3.32 (m, 2H), 2,53-2,48 (m, 2H), 1,81-1, 79 (m, 2H)
1131H NMR (400 MHz, DMSO-d6): δ 11,43 (s, 1H), of 8.47 (user., 3H), 7,72 (user., 1H), 7,01 (s, 1H), 6.89 in (s, 1H), 4.26 deaths (kV, J=3,4 Hz, 2H), 3,99 (d, J=2,8 Hz, 2H), 3,37 (m, 2H), 2.49 USD is 2.46 (m, 2H), 1.77 in (m, 2H), 1,44 (t, J=7.2 Hz, 3H)
1141H NMR (400 MHz, DMSO-d6): δ 11,09 (s, 1H), 8,29 (user., 3H), 7,45 (user., 1H), to 6.88 (s, 1H), for 6.81 (s, 1H), 4,10 (t, J=6,8 Hz, 2H), 3,97-3,95 (m, 2H), 3,32 (m, 2H), 2,46-to 2.41 (m, 2H), 1,86-1, 83 (m, 2H), 1,74 (m, 2H), 0,99 (t, J=7.2 Hz, 3H)
1151H NMR (400 MHz, DMSO-d6): δ at 11.25 (s, 1H), 10,76 (user., 1H), 7,69 (user., 1H), 7,19 (s, 1H), 6,93 (s, 1H), 4,49-of 4.45 (m, 1H), 4,20 (user., 1H), 4,16-to 3.99 (m, 1H), was 4.02-3, 97 (m, 2H), 3.96 points (s, 3H), 3,36 be 3.29 (m, 6H), 2,60-2, 56 (m, 3H), 2.49 USD is 2.46 (m, 2H), 2,12-2,00 (m, 2H), 1.85 to to 1.82 (m, 2H)

1161H NMR (400 MHz, DMSO-d6): δ 11,43 (s, 2H), 10,94 (user., 1H), 7,81 (user., 1H), 7.23 percent (s, 1H), 6,93 (s, 1H), 4,32-4,30 (m, 2H), 4,30-of 4.25 (m, 2H), 3,79-of 3.77 (m, 2H), 3,38 (s, 3H), 3,35-to 3.33 (m, 2H), 2,69 (s, 3H), 2,68 (s, 3H), 2,49-2,47 (m, 2H), 1,79-to 1.77 (m, 2H)
1171H NMR (400 MHz, DMSO-d6): δ 11,25 (user., 2H), 7,71 (user., 1H), 7,24 (s, 1H), 6,91 (s, 1H), or 4.31-the 4.29 (m, 4H), 3,93-3,91 (m, 2H), 3,84-of 3.78 (m, 4H), to 3.38 (s, 3H), 3.33 and (OSiR., 2H), 3,23-3, 20 (m, 2H), 3,12-to 3.09 (m, 2H), 2.49 USD at 2.45 (m, 2H), 1,76 is 1.75 (m, 2H)
1181H NMR (400 MHz, DMSO-d6): δ 11,51-11,36 (m, 1H), br11.01 (user., 1H), 8,12 (user., 1H), 7,05-7, 02 (m, 1H), 6,86-6,85 (m, 1H), 6,74-of 6.71 (m, 1H), 5,10 (t, J=12,4 Hz, 2H), 3,91-3,88 (m, 3H), 3,36-3,30 (m, 2H), 2.49 USD is 2.46 (m, 2H), 2,09-2,05 (m, 3H), 1,76 is 1.75 (m, 2H)

<Example 119> Getting 8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it

Dichloromethane (60 ml) and methanol (60 ml) was added to the dihydrochloride 8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it (13 g, and 31.2 mmol)obtained in example 49, and then was added dropwise at room temperature, triethylamine (of 13.05 ml, 93,6 mmol). After stirring at room temperature for the of 30 minutes the precipitate was collected by filtration, washed with ethyl acetate (20 ml) and dried in vacuum to obtain specified in the title compound (10 g, yield: 93%, white solid).

1H NMR (400 MHz, DMSO-d6): δ 10,77 (s, 1H), 7,72 (d, J=8,4 Hz, 1H), 7,14 (s, 1H), 7,00 (d, J=8,4 Hz, 1H), 6,91 (s, 1H), 3,57-3,55 (m, 4H), 3,44 (s, 2H), or 3.28 (m, 2H), 2,43 (t, J=6.0 Hz, 2H), 2,33 (m, 4H), 1.77 in (t, J=5,2 Hz, 2H,).

The following compounds were obtained, using the reaction of example 119.

<Example 120> 8-[(Methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he

<Example 121> 8-[(Dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he

<Example 122> 10-Methoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he

<Example 123> 10-Ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he

ExampleChemical structureThese NMR spectrum
1201H NMR (400 MHz, DMSO-d6): δ 10,97 (s, 1H), to 7.84 (d, J=4,2 Hz, 1H), 7,26 (d, J=4.0 Hz, 1H), 7,05 (s, 1H), was 4.02 (s, 2H), 3,29 (user., 2H), 2,47 (s, 3H), 2,49-to 2.42 (m, 2H), 1,78 (user., 2H)
1211H NMR (400 MHz, DMSO-d6): δ 10,92 (s,1H), was 7.45 (s, 1H), 7,07 (user., 1H), 6,80 (s, 1H), 4,11 (user., 2H), 3,93 (s, 3H), 3,30 (user., 2H), 2,60 (user., 6H), 2,42 (t, J=6.4 Hz, 2H), 1,73 (user., 2H)
1221H NMR (400 MHz, DMSO-d6): δ is 10.68 (s, 1H), 7,41 (s, 1H), 6,77 (s, 1H), to 6.57 (s, 1H), a 3.87 (s, 3H), to 3.58 (m, 4H), to 3.41 (s, 2H), 3,29 (m, 2H), 2,41 (t, J=6.0 Hz, 2H), 2,35 (m, 4H), 1,72 (t, J=5,2 Hz, 2H)

1231H NMR (400 MHz, CDCl3-d6): δ is 10.68 (s, 1H), was 7.36 (s, 1H), 6,76 (s, 1H), 6,59 (s, 1H), 4,17 (kV, J=3,6 Hz, 2H), 3,59 is 3.57 (m, 4H), to 3.41 (s, 2H), 3,31 (user., 2H), 2,41 (t, J=6.0 Hz, 2H), 2,35 (user., 4H), 1,76-of 1.73 (m, 2H), 1,41 (t, J=6.8 Hz, 3H)

<Experimental example 1> Inhibiting activity of the enzyme poly(ADP-ribose)polymerase [PARP-1]

The active compounds according to the present invention on the inhibition of PARP-1 enzyme was investigated using the PARP assay kit (4671-096-K)was purchased from Trevigen. This analysis was carried out following the modified previously published method of Lee et al [Methods Find Exp. Clin. Pharmacol., 27, 617-622, 2005].

Histone was applied in the form of a coating on a 384-well plate, which is a PS tablet small volume (784101) Greiner Bio-One, and left at 25°C for 2 hours. After that the tablet was washed four times PS (7.5 mm Na 2HPO4, 2.5 mm NaH2PO4, 145 mm NaCl, pH 7,4) and to prevent non-specific reaction, was added Strep-diluent (from a set of Trevigen) and left at 25°C for one hour. After one hour the tablet again washed with PBS four times and connection examples for different concentrations was placed in reactant containing PARP-1 enzyme (0,12 units/well), 2 × PARP cocktail (1,95 mm NAD+, 50 μm biotinylated NAD+and activated DNA in 50 mm Tris pH 8.0, 25 mm MgCl2) and left to react at 25°C for 30 minutes. After 30 minutes, each well was washed in PBS four times and to measure the degree of ribothymidine PARP enzyme was added streptavidin-linked peroxidase (Strep-HRP, 1:1000 diluted) and left to react at 37°C for 30 minutes. The tablet were washed in PBS four times and added army fans the leather-Sapphire substrate and left to react at 25°C for 10 minutes so that proceeded color reaction. Finally, the reaction was stopped by addition of 0.2 N. HCl. The degree of rebaseline of histone made PARP-1 enzyme, which is quantitatively measured at 450 nm using a Wallac EnVision™ (PerkinElmer Oy, Turku, Finland). The results obtained depending on the various concentrations of the compounds of the present invention represent average values obtained from three wells, and the results were analyzed by calculating the IC50amount the compounds using SigmaPlot 10 (Systat Software Inc., USA). Further, commercially available DPQ (Sigma) was used as a control in the comparative experiment.

The results are shown in table 1.

tr>
Table 1
ExamplePARP-1 inhibiting activity IC50(µm)ExamplePARP-1 inhibiting activity IC50(µm)ExamplePARP-1 inhibiting activity IC50(µm)
1>420,6030,50
6>47>48>4
9>410>4111,03
121,07133,8514>4
151,05160,37170,46
181,52191,48201,54
21>4221,16231,43
241,0825>4260,39

td align="center"> 36
272,6428>4292,85
303,11311,07320,23
330,93341,62353,54
3,0237>4380,05
390,1040>4410,04
420,22430,16440,06
450,26460,59470,07
480,13490,62500,32
510,93520,07530,05
540,93551,72560,18
570,48 580,92590,19
600,12610,5462>4
631,02640,54651,54
660,09670,76681,19
69>4701,09713,00
720,08730,10740,23
750,05760,05770,05
780,11790,18 800,14
810,11820,06830,32
840,15850,18860,11
870,61880,11890,27
900,78910,29920,19
930,14940,17950,49
960,77970,90990,75
1000,061010,561020,18
1030,121040,061050,19
1060,091070,071080,14
1090,071100,081110,96
1120,171130,101140,19
1150,411160,181170,61
Control
(DPQ)
of 2.51

As can be seen from table 1 above, the compound according to the present invention showing PARP-1 inhibitory activity of 0.04 to 4 μm and is specific, the compounds of examples 2, 3, 16, 17, 26, 32, 33, 38, 39, 41-54, 56-61, 64, 66, 67, 72-117 show PARP-1 inhibitory act shall want to make, less than 1 µm.Accordingly, compared with the control (for example, DPQ (of 2.51 μm)) of the compounds of the present invention show excellent PARP-1 inhibitory activity. Accordingly, the compounds according to the present invention effectively inhibit PARP-1 and thus can be effectively used for the prevention or treatment of diseases resulting from excessive activation of PARP, including neuropathic pain, neurodegenerative diseases, cardiovascular disease, diabetic neuropathy, inflammatory disease, osteoporosis and cancer.

<Experimental example 2> Intracellular PARP inhibiting activity

In order to test the ability of compounds of the present invention to inhibit PARP-1 enzymatic activity, measured the amount of NAD(P)H accumulated in the medium of cell culture.

The cells of the Chinese hamster ovary (CHO-K1) were grown in RPMI1640 culture medium containing 10% fetal calf serum (FBS). Grown in CHO-K1 cells were planted in 96-hole tablet from 2.9×103cells/well and grown for 16 hours in culture conditions of 37°C, 5% CO2. After growing cells were treated with compounds of examples at various concentrations and were grown at 37°C for 2 hours. After that methylmethanesulfonate (MMS) as Agay is the damaging DNA was treated with 1.5 mm for each, and CCK-8 (Cell count kit-8 solution (CK01-13 DOJINDO) were simultaneously treated with the aim of the degree of color development. The number NND(P)H, released into the culture medium after 3, 4, 5 hours after treatment, MMS, was measured at 450 nm using a Wallac EnVisionTM (PerkinElmer Oy, Turku, Finland). The coefficients of the compounds at various concentrations according to the present invention represent average values obtained in four holes, and the results were calculated using regression analysis. Further, commercially available DPQ (Sigma) was used as a control in the comparative experiment.

The cells of the Chinese hamster ovary (CHO-K1) were treated with compounds at various concentrations according to the present invention and measured the amount of NAD(P)H, released into the culture medium after 4 hours after MMS treatment. The results are shown in table 2 and figure 1.

Table 2
ExamplePARP-1 inhibiting activity IC50(µm)ExamplePARP-1 inhibiting activity IC50(µm)
20,923 0,87
171,63183,71
201,30253,18
323,16374,86
380,14391,56
410,05420,85
431,77440,34
451,16470,25
480,43490,51
520,17530,29
560,47660,32
720,0973 1,39
741,48770,82
870,82880,27
1000,061011,94
1020,501030,82
1041,651051,21
1060,291072,22
1080,111090,94
1100,091111,33
1122,651131,43
1141,921151,22
116 0,521176,32
Control (DPQ)12,40

As can be seen from table 2 and Figure 1, tricyclic derivatives according to the present invention showing PARP-1 inhibitory activity of 0.05-6,32 μm and thus provide excellent PARP-1 inhibitory activity compared to the control compound (e.g., DPQ (12,40 pM)).

<Experimental example 3> Inhibition of cell growth lines of cancer cells

The following tests were carried out to confirm the ability of compounds of the present invention to inhibit cell growth lines of cancer cells.

Tests for inhibitory activity on the growth of cells was against A549 (US, ATCC), SK-OV-3 (Korea Research Institute of Chemical Technology; KRICT), HT-29 (US, ATCC), MCF-7 cell (US, ATCC), using sulforhodamine-B <SRB> analysis (1989, US National Cancer Institute (NCI), which was developed to measure the anticancer activity of the drugin vitro. Cells that were used in the tests was separated from the attached surface of 0.25% trypsin-EDTA solution obtained 1.5×104-7×104cells/ml cell suspension was added to 96-well tablets up to 200 µl per well and grown at 37°C, 5% CO2ulturally environment within 24 hours. Samples of the compounds of examples according to the present invention was used for testing, and to test samples were dissolved in dimethyl sulfoxide and diluted in culture medium (RPMI 1640), which was used. The final concentration of the sample was changed in the range of 0.3 to 100 μm.

After removing the culture medium from the 96-well plates diluted sample was added to 100 μl and were grown at 37°C, 5% CO2culture medium for 72 hours. Tablets with zero time (Tz) were collected at the time of addition of the sample. After completion of the cultivation, the medium was removed from each well together with Tz tablet, then add chilled 10% trichloroacetic acid (TCA), 100 μl per well.

The wells were left at 4°C for 1 hour so that the cells were fixed on the bottom of the tablet. After fixation, cells tablets washed with water 5-6 times to remove the remaining solution of trichloroacetic acid and moisture was completely removed at room temperature. Cells were stained for 30 minutes by adding a dye solution in which 0.4% sulforhodamine-B was dissolved in 1% acetic acid solution, 100 μl of dried wells. The tablets were washed again with 1% solution of acetic acid 5-6 times to ensure the removal of sulforhodamine-B, which was not contacted with the cells. The tablets were again dried at room temperature the re. Then added 100 μl of 10 mm Tris-buffer for dissolving the dye and the optical density (OD) at 520 nm was measured by the reader for microplates. GI50cancer cell sample was measured, as explained below. Received a value of zero moment (Tz), control value (C) and the test value (T), where Tz match the OD value of the point in time at which inflicted the sample and started growing, C corresponds to the OD value of the wells in which cells were grown without processing the sample, and T corresponds to the OD size of the hole, which is treated sample and then grown in her cell. The degree of inhibition of growth of cells of the sample was measured, using:

Mathematical formula 1

If T≤Tz, (T-Tz)/(C-Tz)×100

If T≥Tz, (T-Tz)/Tz×100

Based on the results of the calculations of the mathematical formulas concentration of growth inhibition (GI50), which represents the concentration of pharmaceuticals for inhibition of cancer cell growth by 50%was calculated using a regression analysis of the Lotus program. Next, we determined the ability of the compounds of examples 2, 42, 49, 52, 72, 74, 101 to enhance the effect temosolomida and SN-38 to inhibit growth at 2 microns.

PF50expected:

Mathematical formula 2

GI50processing only temozolomide or SN-38/GI50processing temozolomide or SN-38 + 2 μm soy is emeniem

The results of the calculations are shown in tables 3-6.

Table 3
A549 cell line
ExampleGI50(µm)Temozolomide PF50SN-38 PF50
2592,42,2
42>1002,31,6
29>1002,01,5
52>1001,52,2
72>1003,4the 3.8
74753,22,2
101553,22,6

Table 4 SK-OV-3 cell line
ExampleGI50(µm)Temozolomide PF50SN-38 PF50
250>3,21,2
42>100>2,11,6
29>100>1,71,5
52>100>2,21,4
72>100>10,21,8
7452>5,02,2
10119>a 3.92,8

Table 5
HT-29 Cell line
ExampleGI50(µm) Temozolomide PF50SN-38 PF50
270>1,51,4
4281>1,42,1
2991>1,21,5
5290>1,31,4
72>100>5,22,2
7430>2,83,5
10120>1,94,0

Table 6
MCF-7 Cell line
ExampleGI50(µm)Temozolomide PF50SN-38 PF50
251 1,71,4
42751,61,6
29>1002,12,2
52>1001,51,1
72541,72,6
74456,33,0
101115,93,0

As shown in tables 3-6, adding 2 μm tricyclic derivative according to the present invention, GI50value temosolomida or SN-38 decreased 1.5-3.8 times in the A549 cell line, 1,2-10.2 times in SK-OV-3 cell lines, 1,2-5.2 times in HT-29 cell line and 1.1-6.3-fold in MCF-7 cell line.

<Experimental example 4> Neuroprotective effect in animal model rats with occlusion of the middle cerebral artery (MCAO)

The inventors of the present invention conducted the following test to confirm neuroprotector the th ability of compounds according to the present invention.

The test was performed on male animals rats Sprague, doli (KOATECH Co., Ltd., South Korea), weighing 280-340, the Animals were given food and water adlibitum andadapted to the test conditions for 1 week. A modified method of intravascular filament, as described Zea Longa et al. (Stroke 20:84-91, 1989), was used in order to cause MCAO. Rats were ischemic region as a result of insufficient blood flow in the striatum and temporal lobe, which are the domain area of the middle cerebral artery, and the lack of oxygen and energy sources after occlusion of the middle cerebral artery. For blockage of the middle cerebral artery by way of the intraluminal suture, 4-0 nylon thread cut by 22 mm and 2 mm at the end was zakrugleny heating on the fire. In order to increase the effect of preventing damage and occlusion in the lumen, the samples were covered with a silicon oxide 0.3 mm

Rats were anestesiologi with isoflurane (3% for induction of anaesthesia and 2% for surgery) in a mixture of oxygen/nitrous oxide (30%/70%). The left common carotid artery (CCA) was exposed through a lower midline incision in the neck. The external carotid artery (ECA)and internal carotid artery (ICA) and CCA was carefully separated and gave a Y-shape, using silk thread. The top of the external carotid artery blocked thread and a small hole was bored 1mm below designated, in which the external and internal carotid arteries are separated from the common carotid artery. The probe was inserted in a small hole and fixed by a thread. The incision on the neck closed and each animal was allowed to recover from anesthesia. After 120 minutes after MCA occlusion each animal was re anestesiology and the incision in the neck was opened to remove the thread. Together with reperfusion was injected intravenously compound of example 74. After 22 hours after reperfusion, animals were killed by asphyxiation CO2was beheaded and received six coronary slices of 2 mm thickness, using brain tissue of rodents. Coronal slices were incubated in phosphate-saline buffer solution (PBS)containing 2% chloride, 2,3,5-triphenyltetrazolium (TTC, Sigma), at 37°C for 30 min and then fixed in 4% phosphate-buffered formalin. After fixing the data coronary slices were scanned using a flatbed scanner type. The area of infarction was determined using image J (NIH image version 1,59) and the total volume of infarction was calculated:

Mathematical formula 3

The volume of infarction (mm3) = area of infarction (mm2) × thickness (2 mm)

Statistical analysis of the reduction of heart attack was carried out by test Mann-Whitney (*:p<0,05, **:p<0,01). The test results are shown in table 7 and figure 2.

Table 7
GroupThe number of miceDose (mg/kg)The volume of infarction (mm3)Percent reduction in heart attack (%)p
110- (Control group)263,23--
21010252,3840,65
31220124,68530,003**
41130162,88380,024*

As shown in table 7 and in figure 2, compared with the control group, a group in which mice were administered compound of the present invention with a dose of 10 mg/kg, did not show a significant decline in heart attacks. However, the group in which mice were administered compound of the present invention to the Oh 20 mg/kg and 30 mg/kg, respectively, showed a significant reduction in the area of infarction, 53% and 38%, respectively, compared with the control group.

Accordingly, tricyclic derivatives according to the present invention exhibit excellent inhibitory activity on poly(ADP-ribose)polymerase, in particular excellent PARP-1 inhibitory activity compared with DPQ as a common inhibitor of poly(ADP-ribose)polymerase, increase the inhibitory effect of the growth of cancer cells temosolomida or SN-38 and are preventatively effect in focal ischemia of mice, using the occlusion of middle cerebral artery (MCAO), and thus can be effectively used for preventing or treating diseases caused by excessive activation of PARP, including, in particular, neuropathic pain, neurodegenerative diseases, cardiovascular disease, diabetic neuropathy, inflammatory disease, osteoporosis and cancer.

While tricyclic derivatives according to the present invention can be in various forms depending on the purpose. Accordingly, the idea of the present invention is not limited to a few examples of formulations containing the derivatives as an effective component, described in this invention.

<a Sample recipe 1> Getting farmacevticheskoj the drug

1. Compounding tablets

The compound of chemical formula 1100 mg
Corn starch100 mg
Lactose100 mg
Magnesium stearate2 mg

The above components were mixed with each other and got pills, applying the pressing according to the conventional method of producing tablets.

2. Recipe capsules

The compound of chemical formula 1100 mg
Corn starch100 mg
Lactose100 mg
Magnesium stearate2 mg

The above components were mixed and the capsule was obtained by filling the mixture in gelatin capsules according to the conventional methods of producing capsules.

1. Tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salt
Chemical formula 1

where Y1, Y2and Y 3independently represent H, C1-C10alkyl linear or branched chain, hydroxy, C1-C10alkoxy, -CCOR1, -NR2R3or-A-B;
A represents-O-, -CH2-, -CH(CH3)-, -CH=N -, or-CONH-;
B represents -(CH2n1-Z, -(CH2n2-NR2R3or -(CH2-n3-OR1;
Z represents a C5-C20aryl, unsubstituted or substituted R5and selectively R6C3-C10cycloalkyl, unsubstituted or substituted R5and selectively R6C1-C20heterocyclic compound, unsubstituted or substituted R5and selectively R6;
R1represents H or C1-C10alkyl linear or branched chain;
R2and R3independently represent H, C1-C10alkyl linear or branched chain, or -(CH2n4R7;
R5represents H, C1-C10alkyl linear or branched chain, C5-C20aryl or C1-C20heterocyclic compound;
R6represents H or C1-C10alkyl linear or branched chain;
R7represents-NR8R9, -COOR1, -OR1, -CF3, -CN, halogen, or Z;
R8and R9independently represent FDS is th H or C 1-C10alkyl linear or branched chain;
n1-n4represent respectively an integer from 0 to 15;
Y4represents H or C1-C10alkyl linear or branched chain.

2. Tricyclic derivative or its pharmaceutically acceptable salt according to claim 1, where
Y1and Y2independently represent H, C1-C5alkyl linear or branched chain, hydroxy, C1-C5alkoxy, -COOR1, -NR2R3or-A-B;
where A represents-O-, -CH2-, -CH(CH3)-, -CH=N -, or-CONH-;
In represents -(CH2n1-Z, -(CH2n2-NR2R3or - (CH2n3-OR1;
Z represents one base selected from the group consisting of
,,,,
,,,,
,,,,
,,,,
and,
where R1represents H or C1 -C5alkyl linear or branched chain;
R2and R3independently represent H, C1-C5alkyl linear or branched chain, or -(CH2n4R7;
R5represents H, C1-C5alkyl linear or branched chain, phenyl or morpholino;
R6represents H or C1-C5alkyl linear or branched chain;
R7represents-NR8R9, -COOR1, -OR1, -CF3, -CN, F, Cl, or Z;
R8and R9independently represent H or C1-C5alkyl linear or branched chain;
n1-n4represent an integer from 0 to 10, respectively;
Y3represents H, hydroxy, C1-C5alkoxy or-O(CH2n3-OR1;
Y4represents H or C1-C5alkyl linear or branched chain.

3. Tricyclic derivative or its pharmaceutically acceptable salt according to claim 1, where
Y1and Y2independently represent H, methyl, ethyl, hydroxy, methoxy, ethoxy, -COOR1, -NR2R3or-A-B;
where A represents-O-, -CH2-, -CH(CH3)-, -CH=N -, or-CONH-;
B represents -(CH2n1-Z, -(CH2n2-NR2R3or -(CH2n3-OR1;
Z represents one basis, using the data from the group consisting of
,,,,
,,,,
,,,,
,,,,
and,
R1represents H, methyl, ethyl or isopropyl;
R2and R3independently represent H, methyl, ethyl, propyl, isopropyl, tert-butyl or -(CH2n4R7;
R5represents H, methyl, ethyl, propyl, phenyl or morpholino;
R6represents H, methyl or ethyl;
R7represents-NR8R9, -COOR1, -OR1, -CF3, -CN, F, Cl, or Z;
R8and R9independently represent H or methyl;
n1-n4represent respectively an integer from 0 to 5;
Y3represents H, hydroxy, methoxy, ethoxy, propoxy or methoxyethoxy; and
Y4represents H, methyl, ethyl or propyl.

4. Tricyclic derivative, represented by chemical formula 1, or its pharmaceutically who ielemia salt according to claim 1, selected from the group consisting of:
1) 8-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
2) 10-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
3) 9-Methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
4) 9-Methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
5) Ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate;
6) 9-Methoxy-1-propyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
7) 1-Methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
8) 9-Methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
9) 1-Ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo [h][1,6]naphthiridine-5(6H)-she;
10) 1-Methyl-9-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
11) 9-(1-Propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
12) 9-(1-Methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
13) 1-Methyl-9-(piperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
14) 1-Methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
15) 5-Oxo-N-[2-(piperidine-1-yl)ethyl]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide;
16) 9-[2-(Dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
17) 9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
18) 9-(2-Methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
19) 9-[2-(Piperazine-1-yl)ethoxy]-1,2,3,4-Tetra is drobenko[h][1,6]naphthiridine-5(6H)-it;
20) 9 Ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
21) 9-[3-(piperidine-1-yl)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
22) 9-(2-Aminoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
23) 9-[2-(4-Phenylpiperazin-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
24) 9-(2-Hydroxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
25) 9 Intoxi-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
26) 9-[2-(Diethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
27) 9-(2-Morpholinoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
28) 1,1-Diethyl-4-[2-(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9 yloxy]ethyl)piperazine-1-s;
29) 9-[4-(piperidine-1-yl)butoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
30) 1-Methyl-9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
31) 9-[2-(Dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
32) 8-[2-(Dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
33) 9-[3-(Dimethylamino)propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
34) 8-[2-(Dimethylamino)ethoxy]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide;
35) 8-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h] [1,6]naphthiridine-5(6H)-she;
36) 8-[3-(Dimethylamino)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
37) 8-(Dimethylamino)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-is on;
38) 8-[1-(Dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
39) 8-[1-(Methylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
40) 8-Ethyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
41) 8-[(Dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
42) 8-[(Diethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
43) 8-[(Ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
44) 8-(Pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
45) 8-[(Isopropylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
46) 8-[(Propylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
47) 8-{[Ethyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
48) 8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
49) 8-(Morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
50) 9-[(Dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
51) 8-{[Benzyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
52) 8-[(Methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
53) 8-{[(2-Hydroxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
54) 8-{[(2-(Dimethylaminoethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
55) 8-[(4-Methylpiperazin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
57) Ethyl-3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propionate;
58) 3-{Methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propanoic acid;
59) 8-{[Isopropyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
60) 8-{[(2-Methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
61) Ethyl-3-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]propionate;
62) 8-[(2,2,2-Triptoreline)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
63) 2-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylimino]acetonitrile;
64) 8-[(1H-Imidazol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
65) 8-[(1H-Pyrrol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
66) 8-[(Dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
67) 1-Methyl-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
68) 8-[(Diethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
69) 1-Methyl-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
70) 1-Methyl-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
71) 8-{[Ethyl(methyl)amino]methyl}-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
72) 8-[(Dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
73) 10-Methoxy-8-[(methyl who Mino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
74) 10-Methoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
75) 8-[(Ethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
76) 8-{[Ethyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
77) 10-Methoxy-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
78) 10-Methoxy-8-[(4-oxopiperidin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
79) 8-{[4-(Hydroxyimino)piperidine-1-yl]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
80) 10-Methoxy-8-[(4-(methoxyimino)piperidine-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
81) 10-Methoxy-8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
82) 8-[(2,5-Dihydro-1H-pyrrol-1-yl)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-he;
83) 8-{[(2-Isopropoxyphenyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
84) 10-Methoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
85) 8-{[(2-Chloroethyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
86) 8-[(Diethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
87) 8-[(tert-Butylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
88) 8-[(Isopropylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
9) 8-[(Cyclopentylamine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
90) 8-[(2,6-Dimethylmorpholine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
91) Chloride N-[(10-methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]-N,N-dimethylcyclopentane;
92) 8-{[Cyclopentyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
93) 8-{[Isopropyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
94) 8-{[(2-Foradil)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
95) 8-[(1H-Tetrazol-5-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
96) 10-Methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
97) 10-Methoxy-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
98) (E)-10-Methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
99) 8-[(Dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
100) 8-[(Dimethylamino)methyl]-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
101) 10-Ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
102) 10-Ethoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
103) 10-Ethoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
104) 10-Ethoxy-8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
105) 8-(Hydroxymethyl)-10-methox the -1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
106) 10-Methoxy-8-(thiomorpholine)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
107) 10-Methoxy-8-[(2-morpholinoethyl)methyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
108) 10-Methoxy-8-[(4-morpholinopropan-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
109) 8-(Aminomethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
110) 8-[(Dimethylamino)methyl)]-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
111) 8-(Morpholinomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
112) 8-(Aminomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
113) 8-(Aminomethyl)-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
114) 8-(Aminomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
115) 10-Methoxy-8-{[methyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
116) 8-[(Dimethylamino)methyl]-10-(2-methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
117) 10-(2-Methoxyethoxy)-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
118) 1-[(10-Methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]-1H-pyrrole-2,5-dione;
119) of the Hydrochloride of 8-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
120) Hydrochloride 10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
121) of the Hydrochloride of 9-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
122) G is of drochloride 9-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
123) of the Hydrochloride of ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxylate;
124) of the Hydrochloride of 9-methoxy-1-propyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
125) of the Hydrochloride of 1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
126) of the Hydrochloride of 9-methoxy-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
127) of the Hydrochloride of 1-ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
128) of the Hydrochloride of 1-Methyl-9-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
129) Dihydrochloride 9-(1-propylpiperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
130) Dihydrochloride 9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
131) of the Dihydrochloride of 1-methyl-9-(piperidine-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
132) of the Dihydrochloride of 1-methyl-9-(1-methylpiperidin-4-yloxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
133) Dihydrochloride 5-oxo-N-[2-(piperidine-1-yl)ethyl]-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9-carboxamide;
134) Dihydrochloride 9-[2-(dimethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
135) Dihydrochloride 9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
136) of the Hydrochloride of 9-(2-methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
137) Trihydrochloride 9-[2-(piperazine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-is a;
138) of the Hydrochloride of 9-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
139) Dihydrochloride 9-[3-(piperidine-1-yl)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
140) Dihydrochloride 9-(2-aminoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
141) Dihydrochloride 9-[2-(4-phenylpiperazin-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
142) of the Hydrochloride of 9-(2-Hydroxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
143) of the Hydrochloride of 9-pentoxil-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
144) Dihydrochloride 9-[2-(diethylamino)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
145) Dihydrochloride 9-(2-morpholinoethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
146) Dihydrochloride 1,1-diethyl-4-[2-(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-9 yloxy]ethyl)piperazine-1-s;
147) Dihydrochloride 9-[4-(piperidine-1-yl)butoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
148) of the Dihydrochloride of 1-methyl-9-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
149) Dihydrochloride 9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
150) Dihydrochloride 8-[2-(dimethylamino)ethoxy]-1,2,3,4,-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
151) Dihydrochloride 9-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
152) Dihydrochloride 8-[2-(dimethylamino)ethoxy]-1,2,3,4,5,6-hexahydrobenzo[h][1,naphthyridin-9-carboxamide;
153) Dihydrochloride 8-[2-(piperidine-1-yl)ethoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
154) Dihydrochloride 8-[3-(dimethylamino)propoxy]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
155) Hydrochloride 8-(dimethylamino)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
156) Dihydrochloride 8-[1-(dimethylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
157) Dihydrochloride 8-[1-(Methylamino)ethyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
158) of the Hydrochloride of 8-Ethyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
159) Dihydrochloride 8-[(dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
160) Dihydrochloride 8-[(diethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
161) Dihydrochloride 8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
162) Dihydrochloride 8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
163) Dihydrochloride 8-[(isopropylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
164) Dihydrochloride 8-[(propylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
165) Dihydrochloride 8-{[ethyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
166) Dihydrochloride 8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
167) Dihydrochloride 8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
168) Dihydrochlor the Yes 9-[(dimethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
169) Dihydrochloride 8-{[benzyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
170) Dihydrochloride 8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
171) Dihydrochloride 8-{[(2-hydroxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
172) Trihydrochloride 8-{[(2-(dimethylaminoethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
173) Trihydrochloride 8-[(4-methylpiperazin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
174) Dihydrochloride 8-[(methyl(propyl)amino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
175) Dihydrochloride ethyl-3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propionate;
176) of the Dihydrochloride of 3-{methyl[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]amino}propanoic acid;
177) Dihydrochloride 8-{[isopropyl(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
178) Dihydrochloride 8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
179) Dihydrochloride ethyl-3-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]propionate;
180) Dihydrochloride 8-[(2,2,2-triptoreline)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
181) of the Dihydrochloride of 2-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]acetonitrile;
182) of the Hydrochloride of 8-[(niridazole-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
183) of the Hydrochloride of 8-[(1H-pyrrol-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
184) Dihydrochloride 8-[(dimethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
185) of the Dihydrochloride of 1-methyl-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
186) Dihydrochloride 8-[(diethylamino)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
187) of the Dihydrochloride of 1-methyl-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
188) of the Dihydrochloride of 1-methyl-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
189) Dihydrochloride 8-{[ethyl(methyl)amino]methyl}-1-methyl-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
190) Dihydrochloride 8-[(dimethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
191) Dihydrochloride 10-methoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
192) Dihydrochloride 10-methoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
193) Dihydrochloride 8-[(ethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
194) 8-{[Ethyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
195) Dihydrochloride 10-methoxy-8-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
196) Dihydrochloride 10-methoxy-8-[(4-oxopiperidin-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]natteri the in-5(6H)-it,
197) Trihydrochloride 8-{[4-(hydroxyimino)piperidine-1-yl]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
198) Trihydrochloride 10-methoxy-8-[(4-(methoxyimino)piperidine-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H}-it;
199) Dihydrochloride 10-methoxy-8-{[(2-methoxyethyl)(methyl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
200) Dihydrochloride 8-[(2,5-degidro-1H-pyrrol-1-yl)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
201) Dihydrochloride 8-{[(2-isopropoxyphenyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
202) Dihydrochloride 10-methoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
203) Dihydrochloride 8-{[(2-chloroethyl)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
204) Dihydrochloride 8-[(diethylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
205) Dihydrochloride 8-[(tert-butylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
206) Dihydrochloride 8-[(isopropylamino)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
207) Dihydrochloride 8-[(cyclopentylamine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
208) Dihydrochloride 8-[(2,6-dimethylmorpholine)methyl]-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
209) chloride Hydrochloride N-[(10-methoxy-5-the CSR-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methyl]-N,N-dimethylcyclopentane;
210) Dihydrochloride 8-{[cyclopentyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
211) Dihydrochloride 8-{[isopropyl(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
212) Dihydrochloride 8-{[(2-foradil)(methyl)amino]methyl}-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
213) of the Hydrochloride of 8-[(1H-tetrazol-5-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
214) Trihydrochloride 10-methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
215) Trihydrochloride 10-methoxy-8-{[methyl(morpholino)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
216) Trihydrochloride (E)-10-methoxy-8-[(morpholinothio)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
217) Dihydrochloride 8-[(dimethylamino)methyl]-10-hydroxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5-(6H)-she;
218) Dihydrochloride 8-[(dimethylamino)methyl]-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
219) Dihydrochloride 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
220) Dihydrochloride 10-ethoxy-8-(piperidine-1-ylmethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
221) Dihydrochloride 10-ethoxy-8-[(methylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
222) Dihydrochloride 10-ethoxy-8-[(ethylamino)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
223) Hydrochlori is 8-(hydroxymethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-it;
224) Dihydrochloride 10-methoxy-8-(thiomorpholine)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
225) Trihydrochloride 10-methoxy-8-[(2-morpholinoethyl)methyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
226) Trihydrochloride 10-methoxy-8-[(4-morpholinopropan-1-yl)methyl]-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
227) Dihydrochloride 8-(aminomethyl)-10-methoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
228) Dihydrochloride 8-[(dimethylamino)methyl)]-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
229) Dihydrochloride 8-(morpholinomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
230) Dihydrochloride 8-(aminomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
231) Dihydrochloride 8-(aminomethyl)-10-ethoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
232) Dihydrochloride 8-(aminomethyl)-10-propoxy-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
233) Dihydrochloride 10-methoxy-8-{[methyl(tetrahydro-2H-Piran-4-yl)amino]methyl}-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
234) Dihydrochloride 8-[(dimethylamino)methyl]-10-(2-methoxyethoxy)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she;
235) Dihydrochloride 10-(2-methoxyethoxy)-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthiridine-5(6H)-she; and
236) of the Dihydrochloride of 1-[(10-Methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthiridine-8-yl)methylamino]-1H-pyrrole-2,5-dione.

5. The method according to the teachings of the tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salts according to claim 1, which includes stages:
1) the conversion of carboxylic acid, 2-chloronicotinic acid of formula 2 in the carboxylic acid chloride of the acid of formula 3 (stage 1);
2) obtain the compounds of chemical formula 5 by the amidation reaction of acid chloride of the carboxylic acid of formula 3 obtained in stage 1, the aniline of formula 4, substituted in the meta and/or para-position (stage 2);
3) introduction of a protective group in the compound of formula 5 obtained in stage 2, to obtain the N-protected compounds of formula 6 (stage 3);
4) obtain the compounds of formula 7 by cyclization of the compounds of formula 6 obtained in stage 3, in terms of metal catalyst (T4);
5) obtain the compounds of formula 8 restore aromatic rings of the compounds of formula 7 obtained in stage 4, in terms of the hydrogen-palladium (Pd) catalyst or recovery of the aromatic rings of the compounds of formula 7 obtained in stage 4, in terms of the hydrogen-palladium (Pd) catalyst, and then the reaction alkylhalogenide connection or arylhalides connections and grounds (stage 5); and
6) remove the protection of the compounds of formula 8 is obtained at stage 5, to obtain the tricyclic compounds of formula 1 (stage 6)

where Y1-Y4 are defined in formula 1, and 'pro' is a protective group such as aryl group, benzyl group, benzoyloxymethyl group, para-methoxybenzyl group or methoxymethyl group.

6. A method of obtaining a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salts according to claim 1, which includes stages:
1) demethylation of compound (7a) tribromide boron to obtain hydroxyl compounds (7a-1) (stage 1),
2) interaction of hydroxyl compounds (7a-1)obtained in stage 1, with alkylhalogenide compound in the presence of a base and catalytic amounts of sodium iodide to obtain alkoxysilane (7a-2) (stage 2);
3) get piperidine-lactam (8a) recovering aromatic ring pyridine-lactam compounds (7a-2)obtained in stage 2, the gaseous hydrogen in the presence of palladium (Pd) catalyst (stage 3); and
4) remove the protection compounds (8a), obtained in stage 3, in acidic conditions, such as chloromethane acid, to obtain the compounds of formula (1a) (stage 4)

where 'pro' is methoxymethyl (MOM) group, benzyl group or pair-methoxybenzyloxy (RMB) group, R1defined in chemical formula 1, X represents a leaving group including halogen, methanesulfonyl groups who, p-toluensulfonyl group or trifloromethyl group,
and the chemical formula 1A is included in the chemical formula 1 according to claim 1.

7. A method of obtaining a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salts according to claim 1, which includes stages:
1) hydrolysis of the compound (7b) slowly adding dropwise an aqueous solution of potassium hydroxide or sodium hydroxide to the compound (7b) to obtain the compound (7b-1), which represents a carboxylic acid (stage 1);
2) amidation of the compound (7b-1), which is a carboxylic acid, obtained in stage 1, amines using a condensing agent, to obtain the compounds of formula (7b-2) (stage 2);
3) get piperidine-lactam (8b) recovering aromatic ring pyridine-lactam (7b-2)obtained in stage 2, the gaseous hydrogen in the presence of palladium (Pd) catalyst (stage 3); and
4) remove the protection compounds (8b), obtained in stage 3, in acidic conditions, such as chloromethane acid, to obtain the compounds of formula (1b) (stage 4)

where 'Alk' represents a C1-C10alkyl linear or branched chain, 'pro' is methoxymethyl (MOM) group, benzyl group or pair-methoxybenzyloxy (RMB) group, R2and R3about is defined in chemical formula 1, and the chemical formula 1b included in the chemical formula 1 according to claim 1.

8. A method of obtaining a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salts according to claim 1, which includes stages:
1) recovery of the lactam compound (8c) to the corresponding alcohol (8c-1) using a reducing agent (stage 1);
2) get diamino-lactam compounds (8c-2) halogenoalkanes and aminating the alcohol compound (8c-1)obtained in stage 1 (stage 2); and
3) remove the protection of the compound (8c-2)obtained in stage 2, in acidic conditions, such as chloromethane acid, to obtain the tricyclic compounds of the formula (1c) (stage 3)

where 'Alk' represents a C1-C10alkyl linear or branched chain, 'pro' is methoxymethyl (MOM) group, benzyl group or pair-methoxybenzyloxy (RMB) group, R1-R3defined in chemical formula 1 and chemical formula 1C is included in the chemical formula 1 according to claim 1.

9. A composition comprising a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salt according to one of claims 1 to 4 as an active ingredient, a composition for prevention or treatment of diseases resulting from excessive PARP expr the hurt, which are selected from the group consisting of: neuropathic pain, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, schizophrenia, chronic and acute pain, ischemia, neuronal damage after hypoxia, external damage and neuronal damage.

10. A composition comprising a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salt according to one of claims 1 to 4 as an active ingredient, a composition for prevention or treatment of diseases resulting from excessive PARP expression, which is selected from the group consisting of: atherosclerosis, hyperlipidemia, tissue injury of the heart, coronary artery disease, myocardial infarction, angina or cardiogenic shock.

11. A composition comprising a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salt according to one of claims 1 to 4 as an active ingredient, a composition for prevention or treatment of diseases resulting from excessive PARP expression, which is selected from the group consisting of: diabetic neuropathy, osteoarthritis and osteoporosis.

12. A composition comprising a tricyclic derivative, represented by chemical formula 1, or its formats whitesky acceptable salts according to one of claims 1 to 4 as an active ingredient, composition for prevention or treatment of diabetic neuropathy resulting from excessive PARP expression.

13. A composition comprising a tricyclic derivative, represented by chemical formula 1, or its pharmaceutically acceptable salt according to one of claims 1 to 4 as an active ingredient, a composition for prevention or treatment of cancer, resulting from excessive PARP expression.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel derivatives of hexahydro pyrazino [2,1-c][1,2,4]triazine of general formula (III) (values of radicals are given in invention formula), their pharmaceutically acceptable salts and application of said compounds for obtaining medication for treatment and prevention of acute myeloid leukemia.

EFFECT: obtaining medication for treatment and prevention of acute myeloid leukemia

3 cl, 3 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted tetrahydropyrrolopyrazines of general formula I, wherein R1, R2 and R3 in each case independently mean hydrogen or groups R1 and R2 or R2 and R3 form a common cycle ; R4 and R5 in each case independently mean H; R6 means branched or unbranched saturated, unsubstituted C1-6-alkyl, or unsubstituted heteroaryl wherein heteroaryl is a 5- or 6-member aromatic residue containing 1 heteroatom specified in a group consisting of N, O and S, or means phenyl wherein phenyl is unsubstituted or single-substituted or double-substituted by 1 or 2 substitutes which in each case are independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, and , or means unsubstituted phenyl attached through C1-3-alkyl chain; R4a, R5a and R6a in each case independently mean H; R7 means (CH2)tC(=O)R8, wherein t is equal to 1, (C=O)(CH2)mNR11R12, wherein m is equal to 1 or 2, C(=O)(CH2)n(C=O)R8, wherein n is equal to 1, 2 or 3, (CH2)sNHC(=O)R8, wherein s is equal to 1 or 2; R8 means NR9R10 or saturated, branched or unbranched, unsubstituted C1-6-alkyl; wherein R9 and R10 in each case independently mean H, saturated, branched or unbranched, unsubstituted C1-6-alkyl, or unsubstituted or saturated C3-8-cycloalkyl, or phenyl, or phenyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein phenyl in each case is unsaturated or single or double saturated by 1 or 2 substitutes which independently specified in a group consisting of F, Cl, Br, I, CF3, C1-6-alkyl, O-C1-6-alkyl, pyridyl, and , or unsubstituted heteroaryl attached through C1-3-alkyl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which are specified in a group consisting of O and S, wherein the alkyl chain is saturated, branched or unbranched, or heterocyclyl, or heterocyclyl attached through C1-3-alkyl wherein the alkyl chain is saturated, branched or unbranched, and wherein heterocyclyl in each case is saturated, unsubstituted or single substituted by benzyl, and heterocyclyl contains cycloalkyl containing 5 to 6 atoms in a cycle wherein 1 or 2 carbon atoms are substituted by 1 or 2 heteroatoms which are specified in a group consisting of N; or both groups R9 and R10 mean (CH2)3-6, CH2CH2OCH2CH2 or CH2CH2NR14CH2CH2; wherein R14 means phenyl or phenyl attached through C1-3-alkyl wherein phenyl in each case is unsaturated or single substituted by a substitute whih is specified in a group consisting of F, Cl, Br, I, O-C1-6-alkyl, and , or R14 means C(=O)R13; wherein R13 means saturated and unbranched C1-6-alkyl or means phenyl condensed with heteroaryl wherein heteroaryl is a 6-member aromatic residue 1 heteroatom of which is specified in a group consisting of N; R11 and R12 in each case independently mean H, saturated, branched or unbranched C1-6-alkyl, or unsubstituted, saturated C3-8-cycloalkyl, C(=O)R20 or S(=O)2R13; wherein R20 means NR21NR22, or R20 means saturated, branched or unbranched C1-6-alkyl, or means saturated C3-8-cycloalkyl, unsubstituted or single substituted by phenyl, or means unsaturated heteroaryl wherein heteroaryl is a 5-member aromatic residue 1 heteroatom of which is specified in a group consisting of O, or means phenyl wherein phenyl is unsubstituted or single substituted by C1-6-alkyl or means phenyl attached through C1-6-alkyl which is unsubstituted or single substituted by a substitute specified in a group consisting of F, Cl, Br, I and CF3, wherein the alkyl chain is saturated or unsaturated, branched or unbranched; wherein R21 and R22 in each case independently mean H or saturated, branched or unbranched, unsubstituted C1-6-alkyl; in the form of bases and salts of physiologically acceptable acids. The invention also refers to methods for preparing them, to drug preparations for treating disorders or diseases related with at least partially KCNQ2/3 K+ canals containing such compounds.

EFFECT: there are prepared new compounds and based drug preparations which can find application in medicine for managing pain, epilepsy, migraine, panic conditions and urinary incontinence.

17 cl, 2 tbl, 91 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new bicyclic heterocyclic derivatives of general formula wherein radicals and symbols are specified in the patent claim. Said compounds are FGFR receptor (fibroblast growth factor receptor) inhibitors. The invention also refers to a method for preparing a preferential group of compounds of formula (I), to a pharmaceutical composition containing said compounds, and to the use of said compounds for treating diseases, e.g. cancer.

EFFECT: preparing the new bicyclic heterocyclic derivatives.

22 cl, 16 tbl, 422 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bicyclic heterocyclic derivatives, which are compounds of formula where values of X1-X5, A, B, R1, R2, q are given in claim 1, as well as pharmaceutical compositions containing said compounds, and use of said compounds to treat cancer.

EFFECT: high efficiency of treatment.

22 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: described are novel azolo[1,2,4,5]tetrazine derivatives of general formula I, where Het=3,5-dimethylpyrazol-1-yl, X=N, R=cyclopropylmethylthio or pentylthio; or Het=3,5-dimethylpyrazol-1-yl, X=CH, R=isopropylthil; or Het=imidazol-1-yl, X=CH, R=H, and use of said compounds and additionally compounds of general formula (I), where Het=3,5-dimethylpyrazol-1-yl, X=N, K=cyclopentylthio; or Het=3,5-dimethylpyrazol-1-yl, X=CH, R=H or phenylthio based on disclosed activity as inhibitors of protein kinase PknA, PknB Mycobacterium tuberculosis when treating tuberculosis patients.

EFFECT: high efficiency of treatment.

2 cl, 2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

EFFECT: producing the compounds and compositions for preventing and treating neurological and mental disorders and diseases with involved orexin receptors.

13 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazopyridine compounds of formula (I) and pharmaceutically acceptable salts thereof, which inhibit kinase activity, selected from IGF-1R, IR, EGFR and Erb2 and have cell proliferation inhibitor properties. In formula (I) halogeno denotes a halogen; X1 is H or halogen, R1 is H, halogen or halogen-C1-C4alkyl; R2 is H or O-C1-C4alkyl; each R3 is identical or different and is independently selected from H, halogen, C1-C4alkyl, halogen-C1-C4alkyl and O-C1-C4alkyl; one of R4 and R5 is selected from H, halogen, C1-C4alkyl and O-C1-C4alkyl; and the other is a group selected from: (i), (ii) and (iii) where:(1) each R7 is H; a equals 0, 1, 2 or 3; R8 is selected from NH2, N(H)C1-C4alkyl, N(C1-C4alkyl)2 and a group of formula (iv): (iv), where: ring D is a 5-6-member saturated N-heterocycle, possibly containing 1 or 2 additional heteroatoms selected from N and O. Other values of radicals are given in the claim.

EFFECT: compounds can be used in treating different types of cancer.

4 tbl, 250 ex

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to fluorinated compounds of formula , where: D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more halogen atoms; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: halogen, C1-C10 alkyl; E denotes aryl which can be substituted with one or more fluoro-substitutes or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more fluoro-substitutes, and where Q denotes O; m denotes a number from 1 to 2; under the condition that: R3 is a fluoro-substitute, or group E includes a fluoro-substitute, or group Z includes a fluoro-substitute, with the condition that E does not denote 4-fluorophenyl or a compound of formula , where D, G and L are independently selected from a group consisting of: CH, C and N, and J and M are independently selected from a group consisting of C and N, under the condition that one of J and M denotes C and the other denotes N, wherein at least two of D, G, M, J and L denote N; X denotes CH2; Y is absent; Z denotes NR1R2; R1 and R2 are independently selected from a group consisting of: hydrogen, C1-C10 alkyl, aryl and heteroaryl, which is associated with aromatic radicals having 6 ring atoms, where 1-2 of these ring atoms are N; each of which can be substituted with one or more of the following substitutes: chlorine, bromine, iodine; or R1 and R2, together with nitrogen to which they are bonded, form a heterocyclic ring having 5 ring members; R3 is selected from a group consisting of: chlorine, bromine, iodine, C1-C10 alkyl; E denotes aryl which can be substituted with one or more chlorine, bromine or iodine atoms, and/or one or more of the following substitutes: C1-C6 alkyl, QC1-C10 alkyl, QC2-C10 alkenyl, each of which can be substituted with one or more substitutes selected from chlorine, bromine, iodine or hydroxy, where Q denotes O, wherein when E denotes phenyl, E does not contain, as a substitute, iodine which is directly bonded to it at position 4; m denotes a number from 1 to 2; wherein at least one of Z, E and R3 includes iodine; under the condition that E does not denote 4-iodophenyl and under the condition that said compound is not a compound of formula (Ia), defined in the following table:

The invention also relates to a pharmaceutical composition based on the compound of formula (I) or (Ia), a diagnosis method, a method of treating said disorders, based on use of the compound of formula (I) or (Ia), and use of the compound of formula (I) or (Ia).

EFFECT: obtaining novel compounds useful in treating disorders in mammals, characterised by anomalous density of peripheral benzodiazepine receptors.

24 cl, 13 dwg, 9 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: compounds, which have formula I , in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have values given in description and are inhibitors of receptor tyrosinkinases, useful in treatment of diseases, mediated by class 3 and class 5 receptor tyrosinkinases. It has been also discovered that specific compounds of the claimed invention are Pim-1 inhibitors. Also claimed is method of obtaining formula I compound.

EFFECT: increase of compound efficiency.

27 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of [1,8]naphthyridine, described by formula I(a), where Z represents -NR41-; A represents phenyl; each R10, R17, R31, R33, R35 and R41 in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C1-C6haligenalkyl, phenyl, C3-C6cycloalkyl, -Ls-O-Rs, -Ls-C(O)Rs, -Ls-C(O)ORs and LE-Q-LE-(morpholine); X is selected from group, consisting of bond, -Ls-O-, -Ls-S- and -Ls-C(O)N(Rs)-; R22 is selected from group, consisting of halogen, C1-C6alkyl, phenyl, and phenyl C1-C2alkyl, and, optionally, is substituted with one R26, where R26 in each case is independently selected from group, consisting of halogen, hydroxy, nitro, C1-C6alkyl, -Ls-OSO2Rs; Y is selected from group, consisting of bond, -Ls-O-, -Ls-S(O)-, -Ls-C(O)N(R15) - and -Ls-S-, where R15 represents hydrogen; R50 represents -L1-A1, where A1 is selected from group, consisting of C1-C6alkyl and phenyl and L1 is selected from group, consisting of bond and C1-4alkylene, where A1 is optionally substituted with from one to three R30, and R30 in each case is independently selected from group, consisting of halogen, hydroxy, amino, azido, C1-C6alkyl, -Ls-O-Rs, -Ls-C(O)ORs, -LS-N(RSRS), -Ls-C(=NRs)RS', -Ls-C(O)N(RsRsO, -Ls-N(Rs)C(O)Rs', -LE-Q-LE'- (phenyl or naphthyl) and -LE-Q-LE'-(M5-M6heterocyclyl, which represents pyridine, pyrazine, pyrrolodine, furan, thiophene, piperidine); Ls in each case is independently selected from group, consisting of bond and C1-4alkylene; each RS and Rs' in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C3-6alkenyl, C1-6alkoxy, C1-6alkoxyC1-C6alkyl and C1-6alkoxycarbonylC1-C6alkyl; each LE and LE' in each case is independently selected from group, consisting of bond, C1-4alkylene, -C1-4alkylene-NC(O)-C1-4alkylene-; Q in each case is independently selected from group, consisting of bond, -O-, -N(Rs)C(O)-, -C(O)N(Rs)- and -O-SO2-; each R17 and R30 in each case is optionally independently substituted with from one to three substituent(s), selected from group, consisting of halogen and hydroxy; and each heterocyclyl group in -LE-Q-LE'-(M5-M6heterocyclyl) in each case is optionally independently substituted with at least one or two substituents, selected from group, consisting of hydrogen, hydroxy, C1-C6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, phenyloxy and phenylC1-6alkoxycarbonyl, or to their pharmaceutically acceptable salts. Invention also relates to compounds of formula II(a), pharmaceutical composition based on claimed compounds, application of claimed compounds, method of inhibition of HCV virus replication, method of treating HCV infection.

EFFECT: obtained are novel derivatives, useful in treatment of HCV infection.

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of dihydroquinone and dihydronaphthyridinone of formula (I) or to its pharmaceutically acceptable salts, in which X represents group CR11 or N; Y represents group -C(O)R3, oxazolyl or isoxazolyl; Z represents phenyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, pyridinyl, pyrimidinyl or pyrazolyl, and is substituted with groups R1 and R2; R1 and R2 each independently represents H, halogen, CN group, C1-6alkyl or group -Y1-Y2-Y3-R8, or R1 and R2 together form group -O(CH2)nO-, where n represents 1 or 2; Y1 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O), -S-, -SO2- or bond; Y2 represents heterocycloalkylene, C1-6alkylene or bond, where heterocycloalkylene stands for cycloalkylene group, in which one, two carbon atoms are substituted with heteroatoms O or N, where heterocycloalkylene group also contains, at least, two carbon atoms and cycloalkylene represents ; Y3 represents group -O-, -C(O)-, -C(O)O-, -C(O)NR9-, -NR9C(O)-, -SO2- or bond; R8 represents H, C1-6alkyl, C1-6alkoxy, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, or group -NR9R10, where R8, different from H, is optionally substituted with C1-6alkyl, halogen, group -CF3 or group -OH; R9 and R10 each independently represents H or C1-6alkyl; R3 represents OH, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)-C1-6alkoxy; R4 represents C1-6alkyl, phenyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, tetrahydropyranyl or tetrahydrothiophene 1,1 -dioxide, and is optionally substituted with C1-6alkyl, hydroxyl group, C1-6alkoxy, halogen, nitro group, amino group, cyano group or halo-lower alkyl; R5 and R6 each independently represents H, halogen, C1-6alkyl, group -CF3, C1-6alkoxy; R7 represents H; R11 represents H. Invention also re4lates to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel dihydroquinone and dihydronaphthyridinone derivatives, useful for treatment of disease mediated by JNK kinase.

9 cl, 4 tbl, 38 ex

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel optically active 3-alkyl-4-hydroxy-2-aza-9,10-anthraquinones of formula (Ia-f): R=H, R1=Me (la); R=H, R1=Et (1b); R=H, R1=i-Pr (Ic); R=R1=Me (Id); R=Me, R1=Et (1e); R=Me, R1=i-Pr (If). The invention also relates to the method of obtaining compounds of formula (Ia-f).

EFFECT: novel low-toxicity optically active derivatives of 3-alkyl-4-hydroxy-2-aza-9,10-anthraquinone, having anti-inflammatory activity, are obtained.

2 cl, 3 tbl 8 ex

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