Diaminoheterocyclic carboxamide compound

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

 

The scope of the invention

[0001] the Present invention relates to diaminoguanidinium carboxamide compounds useful as active ingredients in pharmaceutical compositions, in particular pharmaceutical compositions for the treatment of cancer.

Background of the invention

[0002] a Cause of lung cancer is impaired growth of tracheal, bronchial and/or alveolar cells as a result of the loss of their normal functions. The number of people who die from lung cancer, is the largest of the total number of deaths from cancer (17%), and about 1.3 million people die from lung cancer every year.

[0003] lung cancer is divided into three main categories: surgery (surgical treatment), an anti-cancer agent (chemotherapy) and radiation (radiation therapy), but the effectiveness of the treatment varies depending on the tissue type of lung cancer. For example, a definitive diagnosis of lung cancer puts a pathologist on the basis of legistations diagnosis sample for microscopic examination, small cell lung cancer, which accounts for about 20% of cases of lung cancer, often reaches a late stage at the time of its discovery, because he usually has a high degree of malignancy and quickly grows and spreads and often metastasize the other organs. For this reason, often use chemotherapy and/or radiation therapy for treatment of this cancer, but the prognosis is poor because of small cell lung cancer often recurs, although it is relatively sensitive to such therapies. On the other hand, in the case of non-small cell lung cancer, which accounts for roughly 80% of cases, surgical treatment is considered to be useful up to a certain stage, few opportunities for the use of surgery at the subsequent stages, where for the treatment of predominantly use chemotherapy and/or radiation therapy.

[0004] Thus, for any type of lung cancer chemotherapy is an important option for treatment.

[0005] ALK (kinase anaplastic lymphoma) is a receptor receptor and is a protein containing the transmembrane region in the middle part, flanked tyrosinekinase area on carboxykinase and extracellular region in aminocore. Earlier it was reported that full-ALK is expressed in some types of cancer cells of ectodermal origin (e.g., neuroblastoma, glioblastoma, breast cancer, melanoma) (non-patent document 1). In some cases of human malignant lymphoma has also been reported that ALK gene is fused with another gene (e.g., NPM gene, CTCL genome TFG gene, TPM3 gene, ATIC gene and TPM4 gene) as a result of chromosomal translocation, and thus, oncogenic forms hybrid tyrosinekinase (Science, vol.263, p.1281, 1994; Blood, vol.86, p.1954, 1995; Blood, vol.95, p.3204, 2000; Blood, vol.94, p.3265, 1999; Oncogene, vol.20, p.5623, 2001). Also in the case of inflammatory myofibroblastic tumors known that the ALK gene is fused with another gene (e.g., CARS genome, SEC31L1 genome and RanBP2 gene) as a result of chromosomal translocation and, thus, oncogenic forms hybrid tyrosinekinase (Laboratory Investigation a journal of technical methods and pathology, vol.83, p.1255, 2003; International Journal of Cancer, vol.118, p.1181, 2006; Medicinal Research Reviews, vol.28, p.372, 2008). Most molecules partners to merge with ALK contain complexing domain, and, as it turned out, educated hybrid products per se also form complexes. This complexation induces uncontrolled activity of the ALK tyrosine kinase and abnormal activation of intracellular signals, thus causing malignant transformation of Cellular and Molecular Life Science, vol.61, p.2939, 2004; Nature Reviews Cancer, vol.8, p.11, 2008).

[0006] in Addition, recent reports indicate the presence of TPM4-ALK hybrid protein in cancer of the esophagus, defined using procedures proteomic analysis (World Journal of Gastroenterology, vol.12, p.7104, 2006; Journal of Molecular Medicine, vol.85, p.863, 2007). In addition, the slit between gene EML4 (like protein-4, associated the microtubules echinoderms) and ALK was confirmed in samples from patients with lung cancer and it was also reported that the EML4-ALK fused gene has oncogenicity and is a gene that causes cancer, and that inhibitors against its kinase activity inhibit the growth of various cells, where it is expressed EML4-ALK hybrid protein (patent document 1 and non-patent document 2). These documents also show that inhibitors of EML4-ALK hybrid protein are useful as therapeutics for cancer of the lung in patients with EML4-ALK polynucleotide-positive lung cancer. In addition, lung cancer is confirmed by the presence of many variants of EML4-ALK (patent document 1; Annals of surgical oncology, vol.17, p.889, 2010; Molecular Cancer Research, vol.7, p.1466, 2009; Clinical Cancer Research, vol.15, p.3143, 2009; Cancer, vol.115, p.1723, 2009; Clinical Cancer Research, vol.14, p.6618, 2008; Clinical Cancer Research, vol.14, p.4275, 2008), and reported the presence of TFG-ALK (Cell, vol.131, p.1190, 2007) and KIF5B-ALK (Clinical Cancer Research, vol.15, p.3143, 2009). In addition, there are cases when EML4-ALK is expressed in patients with lung cancer, and in patients with colon cancer and patients with breast cancer Molecular Cancer Research, vol.7, p.1466, 2009).

[0007] furthermore, patent document 1 introduces the following compounds A-D (each known as an inhibitor of ALK) as examples of compounds with inhibitory activity against EML4-ALK hybrid protein, and also reveals a valid indicators of their inhibitory activity against EML4-ALK hybrid the tree. However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0008]

[Formula 1]

Their corresponding chemical names of the following: 4-[(3'-bromo-4'-hydroxyphenyl)amino]-6,7-dimethoxyquinazolin (also called WHI-P154) for connection A; N-[2-(3-chlorophenyl)ethyl]-2-[({[4-(triptoreline)phenoxy]acetyl}amino)methyl]-1,3-thiazole-4-carboxamide for connection B; 5-chloro-N4-[2-(isopropylphenyl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}pyrimidine-2,4-diamine (also called TAE684) for connection C; and 2-[(5-bromo-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidine-4-yl)amino]-N-methylbenzenesulfonamide for connection D.

[0009] in Addition, in expressing ALK hybrid protein lymphoma, the compounds having the activity of inhibiting ALK, WHI-P154 (compound A shown above), reportedly inhibits cell growth and induces apoptosis (non-patent document 3). However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0010] similarly, TAE684 (connection C, shown above), the known is how the hybrid protein inhibitor of the fused gene between the NPM gene and ALK gene.

[0011] TAE684 structurally different from the compounds of the present invention that the Central ring between the two-NH groups by type sandwich structure, is a chlorine substituted pyrimidine ring.

[0012] in Addition, TAE684, reportedly inhibits the proliferation of both cell lymphoma (ALCL), due to its inhibitory activity against NPM-ALK hybrid protein (non-patent document 4). On the other hand, although it has been described that the compounds, including TAE684, possess inhibitory activity against focal adhesion kinase (FAK) and are therefore useful for the prevention and/or treatment of non-small cell lung cancer and small-cell lung cancer, there is no information about the actual therapeutic effect on these types of lung cancer (patent document 2). In addition, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0013] Were published and other messages, showing that ELM4-ALK is expressed in cells of non-small cell lung cancer (NCI-H2228)that TFG-ALK is expressed in patients with non-small cell lung cancer and that TAE684 inhibits the growth of cells in non-small cell lung cancer (NCI-H2228) (patent document 1 and non-patent documents 5 and 6).

[0014] in Addition, with whom was Balos about that connection, shown below, has the activity of inhibiting Syk and are useful as an active ingredient in drugs for the prevention or treatment of disease, which involved Syk, such as allergies, inflammation, immune disease, thrombosis and cancer (patent document 3).

[0015]

[Formula 2]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not intended, and there is no specific disclosure regarding therapeutic effects against cancer.

[0016] in Addition, it was reported that the compound below has inhibitory activity against protein kinase C and is useful as an active ingredient in drugs for prevention or treatment of diseases that involve protein kinase C, such as diabetic complications, ischemia, inflammation, and cancer (patent document 4).

[0017]

[Formula 3]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic to rexamine compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not intended, and there is no specific disclosure regarding therapeutic effects against cancer.

[0018] in Addition, it was reported that the compound below has inhibitory activity against the kinase activity of EML4-ALK hybrid protein and mutant EGFR protein, and is useful as an active ingredient in a therapeutic tools for cancer, including lung cancer, and the like (patent document 5).

[0019] [Formula 4]

(In the formula, X represents a 1,3,5-triazine-2,4-diyl or hinzelin-2,4-diyl, which may be substituted. The values of other symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0020] in Addition, it was reported that the compound below has inhibitory activity against various kinases, including ALK, and is useful for treating cellular proliferative diseases (patent document 6).

[0021] [Formula 5]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic CT is oksamitnij compounds in accordance with the present invention.

[0022] in Addition, it was reported that the compound below has inhibitory activity against ALK and/or c-Met and is useful for treatment of proliferative diseases (patent document 7).

[0023]

[Formula 6]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0024] in Addition, it was reported that the compound below has inhibitory activity against various kinases, including ALK, and is useful for the treatment of hyperproliferative diseases and angiogenic diseases (patent document 8).

[0025] [Formula 7]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0026] in Addition, it was reported that the compound below has inhibitory activity against various kinases, including IGF-1R and ALK, and is useful for treatment of cancer (patent document 9).

[0027]

[Formula 8]

(The meaning of the symbols in the formula, see publication).

However, there is no to Kratovo disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0028] in Addition, it was reported that the compound below has activity of inhibiting Syk and are useful for the treatment of allergies, autoimmune diseases, cancer and abnormal myeloid cell growth (patent document 10).

[0029] [Formula 9]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, is not disclosed and is not intended inhibitory activity against the kinase activity of EML4-ALK hybrid protein, and there is no specific disclosure regarding therapeutic effects against cancer.

[0030] in Addition, it was reported that the compound below has inhibitory activity against Aurora-B kinase and is useful for the treatment of cancer, infectious diseases, inflammation and autoimmune diseases (patent document 11).

[0031] [Formula 10]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, is not disclosed and is not intended inhibitory activity against the kinase and the activity of EML4-ALK hybrid protein.

[0032] in Addition, it was reported that the compound below has the activity of inhibiting the activation of STAT6 and activity inhibition of Th2 differentiation and is useful for the treatment of respiratory diseases, asthma and chronic obstructive pulmonary disease (patent document 12).

[0033] [Formula 11]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not intended, and there is no specific disclosure regarding therapeutic effects against cancer.

[0034] in Addition, it was reported that the compound below has activity of inhibiting PKC, and is useful for the treatment of allergies, inflammation, diabetes, cancer and the like (patent document 13).

[0035] [Formula 12]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid is about protein is not disclosed and are not intended to and there is no specific disclosure regarding therapeutic effects against cancer.

[0036] in Addition, it was reported that the compound below has inhibitory activity against PLK-1 and PLK-3 and is useful for the treatment of cancer, cell proliferative disorders, viral infections, autoimmune diseases and neurodegenerative diseases (patent document 14).

[0037] [Formula 13]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not assumed.

[0038] in Addition, it was reported that the compound below has activity inhibition of HSP-90 and is useful for treating cellular proliferative diseases, cancer, inflammation, arthritis and angiogenic diseases (patent document 15).

[0039] [Formula 14]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition to the, inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not assumed.

[0040] in Addition, it was reported that the compound below has activity of inhibiting ALK, c-Met and Mps1 kinases and are useful for the treatment of hyperproliferative diseases, cancer and angiogenic diseases (patent document 16).

[0041] [Formula 15]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0042] in Addition, it was reported that the compound below has inhibitory activity against Syk and Jak and is useful for the treatment of heart disease, inflammation, autoimmune diseases and cell-proliferative diseases (patent document 17).

[0043] [Formula 16]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not assumed.

[0044] in Addition, it was reported that the connection is expressed below, has the activity of inhibiting IKK and is useful for treatment of inflammation, immunopathy, cancer, neurodegenerative diseases, age-related diseases, heart disease and metabolic disorders (Patent document 18).

[0045] [Formula 17]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention. In addition, the inhibitory activity against the kinase activity of EML4-ALK hybrid protein is not disclosed and is not assumed.

[0046] in Addition, it was reported that the compound below has inhibitory activity against various kinases, including ALK, and is useful for treating cellular proliferative diseases and cancer (patent document 19).

[0047]

[Formula 18]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0048] in Addition, it was reported that the compound below has activity of inhibiting ALK, ROS, IGF-1R and InsR kinase and are useful for treating cellular proliferative diseases (patent is the first document 20).

[0049] [Formula 19]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

[0050] in Addition, it was reported that the compound below has activity of inhibiting ALK, ROS, IGF-1R and InsR kinase and are useful for treating cellular proliferative diseases (patent document 21).

[0051] [Formula 20]

(The meaning of the symbols in the formula, see publication).

However, there is no specific disclosure diaminetetracetic carboxamide compounds in accordance with the present invention.

The list of reference documents

Patent documents

[0052] Patent document 1: European patent publication number EP 1914240.

Patent document 2: international publication number WO 2004/080980.

Patent document 3: international publication number WO 00/75113.

Patent document 4: international publication number WO 00/76980.

Patent document 5: international publication number WO 2009/008371.

Patent document 6: international publication number WO 2008/073687.

Patent document 7: international publication number WO 2008/051547.

A patent is a document 8: international publication number WO 2009/032703.

Patent document 9: international publication number WO 2009/020990.

Patent document 10: Japanese patent publication No. 2008-13499.

Patent document 11: international publication number WO 2008/077885.

Patent document 12: international publication number WO 2004/002964.

Patent document 13: international publication number WO 2009/012421.

Patent document 14: international publication number WO 2009/040399.

Patent document 15: international publication number WO 2008/024974.

Patent document 16: international publication number WO 2009/032694.

Patent document 17: international publication number WO 2009/136995.

Patent document 18: international publication number WO 2009/089042.

Patent document 19: the international publication number WO 2009/143389.

Patent document 20: international publication number WO 2009/126514.

Patent document 21: international publication number WO 2009/126515.

Non-patent documents

[0053] non-Patent document 1: International Journal of Cancer, vol.100, p.49, 2002.

Non-patent document 2: Nature, vol.448, No. 2, p.561, 2007.

Non-patent document 3: Laboratory Investigation, vol.85, p.1544, 2005.

Non-patent document 4: Proceedings of the National Academy of Science, vol.104, No. 1, p.270, 2007.

Non-patent document 5: Cell, vol.131, p.1190, 2007.

Non-patent document 6: Proceedings of the National Academy of Science, vol.104, No. 50, p.19936, 2007.

Brief description of the invention

Technical tasks

[0054] the Present invention is to provide the supports connection which is useful as an active ingredient in pharmaceutical compositions, in particular pharmaceutical compositions for the treatment of cancer, and which can be used more safely as an active ingredient in pharmaceutical compositions.

Solving problems

[0055] As a result of a comprehensive and in-depth studies of compounds which are useful as active ingredients in pharmaceutical compositions for the treatment of cancer, the authors of the present invention, it was found that diaminoquinazoline carboxamide connection according to the present invention has excellent inhibitory activity against the kinase activity of EML4-ALK hybrid proteins and is useful as an active ingredient in pharmaceutical compositions for the treatment of cancer. This discovery led to the creation of the present invention.

[0056] Thus, the present invention relates to the compound of formula (I) or salts thereof, and pharmaceutical composition comprising the compound of formula (I) or its salt and excipient.

[0057] [Formula 21]

(where the symbols have the meanings defined below:

[0058] X is a group of formula (II) or (III)

[Formula 22]

;

[0059] A: -H, halogen, lower alkyl, cycloalkyl or lower alkenyl;

[0060] R1:

1and G2(provided that when X represents a group of formula (II) and A represents-H, or when-X - is a group of formula (III), R1represents phenyl, which is substituted by one or more groups selected from the group of G2and may be optionally substituted by one or more groups selected from the groups G1and G2),

(2) an aromatic heterocyclic ring which may be substituted by one or more groups selected from the group of G3or

(3) a bicyclic condensed ring which may be substituted by one or more substituents RZA(provided that the naphthyl or benzodioxolyl, which may be substituted by one or more substituents RZAexcluded);

[0061] the group G1: halogen, R00, -O-R00, -NHSO2-R00, -SO2NH2, -SO2NH-R00, amino, nitro and cyano;

[0062] R00lower alkyl or lower alkenyl, each of which may be substituted by one or more halogen atoms;

[0063] the group G2: -SO2-R00, -SO2N(R00)2, -CONH2, -CONH-R00, -CON(R00)2, -NHCO-R00, -N(R00)CO-R00, -NH-R00, -CONH-(CH2)n-O-R00, -O-(CH2 )n-N(R00)2, -O-(CH2)n-O-R00, -O-(phenyl, substituted aromatic heterocyclic ring), phenyl, aromatic heterocyclic ring, -W-Y-Z and the group of formula (IV)

[Formula 23]

[0064] n is an integer having a value of from 1 to 3.

[0065] L1and L2: L1and L2taken together with the carbon atoms to which they are respectively attached, form

(1) cycloalkyl, which may be condensed with phenyl, or

(2) non-aromatic heterocyclic ring;

[0066] L3: a bond or methylene;

[0067] W: communications, piperidine-1,4-diyl or piperazine-1,4-diyl;

[0068] Y is: a bond, -CO-, -SO2-, -O-(CH2)m- or-N(R00)-(CH2)m-;

[0069] m is an integer having a value of from 0 to 3;

[0070] Z:

(1) RZ0or

(2) non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the group of GA;

[0071] RZ0: cycloalkyl, which may be substituted by one or more substituents R00;

[0072] the group GA: R00which may be substituted by a group selected from the group consisting of OH and RZ0, halogen, -SO2-R00, -CO-R00, -COO-R00, -N(R00)2, oxo, and-OH;

[0073] the group G3: halogen, R00, -O-R00, phenyl, -O-FeNi and W-Z;

[0074] RZA: R00or -(CH2)n-Z;

[0075] R2:

(1) cycloalkyl, which may be substituted by one or more groups selected from the group of G4(it should be noted that cycloalkyl may be condensed with a phenyl or pyrazole, each of which may be substituted by one or more groups-O-lower alkyl),

(2) non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the group of G4,

(3) phenyl which may be substituted by one or more groups selected from the group of G4except oxo,

(4) pyridyl which may be substituted by one or more groups selected from the group of G4except oxo, or

(5) lower alkyl which may be substituted by one or more groups selected from the group of G5(provided that 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl and 2-(dimethylamino)butyl excluded);

[0076] the group G4: lower alkyl which may be substituted by a group selected from group GB, amino, -N(lower alkyl)2, -NH-lower alkyl, -NHCO-lower alkyl, -NHCOO-lower alkyl, -CONH2, -CONH-RZB, -O-lower alkyl, -CO-lower alkyl, -COO-lower alkyl, -OH, -COOH, oxo, -SO2is lower alkyl, RZB, -CO-RZBcycloalkyl and W-Z;

[0077] the group GB: amino, -OH cycloalkyl and R ZB;

[0078] RZB: phenyl which may be substituted by a group selected from the group consisting of halogen and-O-lower alkyl;

[0079] the group G5:

(1) a group selected from group G4,

(2) cycloalkyl, which may be substituted by one or more groups selected from the group of G4,

(3) non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the group of G4,

(4) phenyl which may be substituted by one or more groups selected from the group of G4except oxo, and

(5) pyridyl which may be substituted by one or more groups selected from the group of G4except oxo;

[0080] R3: -H or lower alkyl,

or R2and R3taken together with the nitrogen atoms to which they are linked, may form a cyclic amino which may be substituted by a group selected from group G4).

[0081] it Should be noted that in-SO2N(R00)2, -CON(R00)2, -N(R00)CO-R00, -O-(CH2)n-N(R00)2and-N(R00)2two R00contained in each of these groups may be the same or different from each other. In addition, the group-N(lower alkyl)2two lower alkyl may be the same or different from each other.

[0082] the EU is not specified, when the characters used in the same chemical formula, are also used in a different chemical formula, the same symbols have the same value.

[0083] the Present invention also relates to an inhibitor against the kinase activity of EML4-ALK hybrid protein, which comprises the compound of formula (I) or its salt.

[0084] furthermore, the present invention also relates to pharmaceutical compositions for treating cancer, which comprises a compound of formula (I) or its salt. It should be noted that the pharmaceutical composition comprises a therapeutic tool for treating cancer, which comprises the compound of formula (I) or its salt.

[0085] furthermore, the present invention also relates to the use of compounds of formula (I) or its salt to obtain a pharmaceutical composition for the treatment of cancer, using the compounds of formula (I) or its salts for the treatment of cancer, as well as to a method of treating cancer, which comprises introducing an effective amount of the compounds of formula (I) or salts thereof to a patient.

The beneficial effects of the present invention

[0086] the Compound of formula (I) or its salt has inhibitory activity against the kinase activity of EML4-ALK hybrid protein and inhibitory activity against the growth of EML4-ALK hybrid protein-dependent cells, and it can be used as an active phrases is that in pharmaceutical compositions for the prevention and/or treatment of cancer, such as lung cancer in one variant embodiment of the invention, non-small cell lung cancer or small cell lung cancer in another variant embodiment of the invention, ALK hybrid polynucleotide-positive lung cancer in another variant embodiment of the invention, ALK hybrid polynucleotide-positive lung cancer in another variant embodiment of the invention, ALK hybrid polynucleotide-positive non-small cell lung cancer in yet another variant embodiment of the invention, ALK hybrid protein-positive cancer in another variant embodiment of the invention, ALK hybrid protein-positive lung cancer in another variant embodiment of the invention, ALK hybrid protein-positive non-small cell lung cancer light in another variant embodiment of the invention, EML4-ALK hybrid polynucleotide-positive cancer in another variant embodiment of the invention, EML4-ALK hybrid polynucleotide-positive lung cancer in another variant embodiment of the invention, EML4-ALK hybrid polynucleotide-positive non-small cell lung cancer in yet another variant embodiment of the invention, EML4-ALK hybrid protein-positive cancer in another variant embodiment of the invention, EML4-ALK hybrid protein-positive lung cancer in the next version of the embodiment of the invention, or EML4-ALK hybrid protein-positive nemelka mocny lung cancer in the next variant embodiments of the invention.

Description of the variants of embodiment of the invention

[0087] the Present invention will be described in more detail below.

[0088] As used in this application, the term “halogen” means F, Cl, Br or I.

[0089] the Term “lower alkyl” refers to linear or branched alkyl containing from 1 to 6 carbon atoms (hereinafter abbreviated listed as “C1-6”). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. Another variant embodiment represents a C1-4alkyl, and another variant embodiment represents a methyl, ethyl or isopropyl.

[0090] the Term “lower alkenyl” refers to a monovalent group with a C2-6linear or branched hydrocarbon chain containing at least one double bond. Examples include vinyl, propenyl, Isopropenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl etc. Another variant embodiment is Isopropenyl.

[0091] the Term “cycloalkyl” is not necessarily connected to bridge communication C3-10saturated cyclic hydrocarbon group, consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, adamantyl etc. are Other examples included the t partially unsaturated groups, such as cyclopentenyl, cyclohexenyl, cyclooctadiene, bicyclo[3.1.1]heptenyl etc.

[0092] the Term “cyclic amino” refers to a monovalent group of 3-8-membered monocyclic non-aromatic cyclic amine which contains at least one nitrogen atom and may optionally contain the same or different from each other one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, where at least one nitrogen atom has a connecting branch. Specific examples include aziridinyl, azetidin, pyrrolidinyl, piperidinyl, azepane, atacanli, piperazinil, homopiperazine, morpholine, oxazepines, thiomorpholine, diazepan and the like. Alternatively, another variant embodiment represents a monovalent group, 5 - or 6-membered monocyclic non-aromatic cyclic amine. Another variant embodiment is pyrrolidinyl, piperidinyl, piperazinil or morpholinyl. It should be noted that such a ring may be connected bridge connection, and as an example, you can specify 2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl and the like, or may contain unsaturated bond in the side of the ring, and as an example, you can specify dihydropyrrole, dihydropyridin, tetrahydropyranyl, tetrahydropyranyl or similar.

0093] the Term “non-aromatic heterocyclic ring” refers to a monovalent group 3-10-membered monocyclic non-aromatic heterocyclic ring, which contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples include aziridinyl, azetidin, pyrrolidinyl, piperidinyl, azepane, diazepan, atacanli, piperazinil, homopiperazine, morpholine, oxazepines, thiomorpholine, diazepan, tetrahydropyranyl, tetrahydrofuryl, dioxane, dioxolane, tetrahydrothieno, tetrahydropyranyl and the like. Another variant embodiment represents a monovalent group, 5 - or 6-membered monocyclic non-aromatic heterocyclic ring. It should be noted that such a ring may be connected bridge connection, and as an example, you can specify 2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl or the like, or may contain unsaturated bond in the side of the ring, and as an example, you can specify dihydropyrrole, dihydropyridin, tetrahydropyranyl, tetrahydropyranyl or similar.

[0094] the Term “aromatic heterocyclic ring” refers to a monovalent group of 5-10-membered monocyclic aromatic heterocyclic ring, which contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, thienyl, furyl, 1,2,4-oxadiazolyl and the such. Another variant embodiment represents pyridyl, imidazolyl or pyrazolyl. Another variant embodiment represents pyridyl.

[0095] the Term “bicyclic condensed ring” refers to (a) a monovalent group 9-11-membered bicyclic condensed rings, in which one of the two rings in a 9-11-membered bicyclic condensed ring is a 5-7-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and the other of the two rings is a benzene ring (provided that benzodioxolyl excluded), (b) a monovalent group 9-11-membered bicyclic condensed rings, in which one of the two rings in 9-11-membered bicyclic condensed ring represents a C5-7cycloalkyl, and the other of the two rings is a benzene ring, or (c) azulejo. Another variant embodiment represents a monovalent group 9-11-membered bicyclic condensed rings, in which one of the two rings in a 9-11-membered bicyclic condensed ring is a 5-7-membered monocyclic heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and the other of e the two rings is a benzene ring (provided what benzodioxolyl excluded), and examples include chenail, benzothiazolyl, benzoimidazolyl, indolyl, indazoles, benzothiazyl, benzofuran, tetrahydroisoquinoline, 2,3-dihydro-1,4-benzodioxin, 1,2,3-benzothiadiazoles, 2,1,3-benzothiadiazole, 3,4-dihydro-1,4-benzoxazine etc. Another variant embodiment is azulenes. It should be noted that when one of these rings represents a monocyclic heterocyclic ring containing a saturated carbon atom, these rings may be substituted by oxo, and as an example, you can specify 3-oxo-3,4-dihydro-1,4-benzoxazines and 1-oxo-1,2,3,4-tetrahydroisoquinoline.

[0096] the Term “ALK hybrid polynucleotide” refers to hybrid polynucleotide in which ALK gene fused to another gene and, consequently, expresses oncogenic hybrid tyrosinekinase. Examples include EML4-ALK hybrid polynucleotide, TFG-ALK hybrid polynucleotide, KIF5-ALK hybrid polynucleotide, NPM-ALK hybrid polynucleotide, CLTCL-ALK hybrid polynucleotide, TPM3-ALK hybrid polynucleotide, TPM4-ALK hybrid polynucleotide, ATIC-ALK hybrid polynucleotide, CARS-ALK hybrid polynucleotide, SEC31L1-ALK hybrid polynucleotide, RanBP2-ALK hybrid polynucleotide and the like.

[0097] the Term “ALK hybrid protein” refers to a hybrid tyrosinekinase produced by the expression of ALK hybrid polynucleotide./p>

[0098] the Term “EML4-ALK hybrid polynucleotide” refers to hybrid polynucleotide in which ALK gene fused with EML4 gene and, consequently, expresses oncogenic ALK hybrid protein, including its variants, such as EML4-ALK hybrid polynucleotide v1 (polynucleotide SEQ ID NO:1 of the patent document 1), EML4-ALK hybrid polynucleotide v2 (polynucleotide SEQ ID NO:6 the patent document 1) and EML4-ALK hybrid polynucleotide v3 (polynucleotide SEQ ID NO:129 patent document 1), as well as different ways (Annals of surgical oncology, vol.17, p.889, 2010, Molecular Cancer Research, vol.7, p.1466, 2009, Clinical Cancer Research, vol.15, p.3143, 2009, Cancer, vol.115, p.1723, 2009, Clinical Cancer Research, vol.14, p.6618, 2008, Clinical Cancer Research, vol.14, p.4275, 2008 etc).

[0099] the Term “EML4-ALK hybrid protein” refers to a hybrid tyrosinekinase produced by the expression of EML4-ALK hybrid polynucleotide.

The compound of formula (I) or its salt, where-X - in the formula (I) represents a group of formula (II), means a compound of the formula (V) or its salt.

[0100] [Formula 24]

The compound of formula (I) or its salt, where-X - in the formula (I) represents a group of formula (III), means a compound of the formula (VI) or its salt.

[0101]

[Formula 25]

The phrase “may be substituted” means unsubstituted or containing from 1 to 5 substituents”. In the presence of several groups to cover the oil these groups may be the same or different from each other.

[0102] the Phrase “is (are) substituted” or “substituted” means “containing from 1 to 5 substituents”. In the presence of several groups of substituents of these groups may be the same or different from each other.

[0103] the Phrase “lower alkyl which may be substituted by one or more halogen atoms” includes, for example, lower alkyl which may be substituted by the same or different from each other 1-7 halogen atoms. Another variant embodiment represents a lower alkyl which may be substituted by 1-5 halogen atoms. Another variant embodiment represents a lower alkyl which may be substituted by 1-3 halogen atoms.

[0104] the Phrase “lower alkenyl, which may be substituted by one or more halogen atoms” include, for example, to lower alkenyl, which can be substituted by 1-3 halogen atoms.

[0105] Some variants of the embodiment of the compounds of formula (I) or their salts are presented below.

(1) the compounds of formula (I) or a salt of such a compound, where

(1-1) -X - represents a group of formula (II), and a is a halogen or lower alkyl,

(1-2) -X - represents a group of formula (II), and a represents a halogen,

(1-3) -X - represents a group of formula (II), and a represents a lower alkyl,

(1-4) -X - represents a group of formula is (II), and a represents a chlorine, ethyl or isopropyl,

(1-5) -X - represents a group of formula (II), and represents chlorine,

(1-6) -X - represents a group of formula (II), and represents an ethyl or isopropyl,

(1-7) -X - represents a group of formula (II), and represents ethyl, or

(1-8) -X - represents a group of formula (II), and represents isopropyl.

(2) the compounds of formula (I) or a salt of such a compound, where

(2-1) R1represents phenyl, which is substituted by a group-W-Y-Z, and may be optionally substituted by a group selected from the group consisting of halogen, R00, -O-R00, -NHSO2-R00, -SO2NH-R00, cyano, -SO2-R00, -SO2N(R00)2, -CONH-R00, -CON(R00)2, -NHCO-R00, -N(R00)CO-R00, -O-(CH2)n-O-R00and cycloalkyl, R00represents lower alkyl which may be substituted by one or more halogen atoms, Y represents a bond, and Z represents a non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the group of GA,

(2-2) R1represents phenyl, in which the carbon at the 4-position is substituted by a group-W-Y-Z, and the carbon at the 3-position may be substituted by a group selected from the group consisting of halogen is, R00and-O-R00, R00represents lower alkyl which may be substituted by one or more halogen atoms, Y represents a bond, and Z represents a non-aromatic heterocyclic ring which may be substituted by one or more substituents R00,

(2-3) R1represents phenyl, in which the carbon at the 4-position is substituted by a group selected from the group consisting of 4-(4-methylpiperazin-1-yl)piperidine-1-yl, 4-(1-methylpiperidin-4-yl)piperazine-1-yl, 4-methylpiperazin-1-yl and 4-isopropylpiperazine-1-yl, and the carbon at the 3-position may be substituted by a group selected from the group consisting of fluorine, methyl, trifloromethyl and methoxy,

(2-4) R1represents phenyl, in which the carbon at the 4-position is substituted by a group of 4-(4-methylpiperazin-1-yl)piperidine-1-yl, and the carbon at the 3-position may be substituted by a group selected from the group consisting of methyl, trifloromethyl and methoxy,

(2-5) R1represents phenyl, in which the carbon at the 4-position is substituted by a group of 4-methylpiperazin-1-yl, and the carbon at the 3-position may be substituted by a group selected from the group consisting of fluorine and methoxy,

(2-6) R1represents 4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(2-7) R1represents a 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(2-8)R 1represents 4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}-3-(trifluoromethyl)phenyl,

(2-9) R1is a 3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(2-10) R1represents a 4-(4-methylpiperazin-1-yl)phenyl,

(2-11) R1represents 3-fluoro-4-(4-methylpiperazin-1-yl)phenyl,

(2-12) R1is a 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl,

(2-13) R1represents a 3-methyl-4-{4-(1-methylpiperidin-4-yl)piperazine-1-yl}phenyl, or

(2-14) R1represents a 4-(4-isopropylpiperazine-1-yl)-3-were.

(3) the compounds of formula (I) or a salt of such a compound, where

(3-1) R2represents a

(i) cycloalkyl, which may be substituted by one or more groups selected from the group consisting of-N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZBand morpholinyl, or

(ii) non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZBand benzyl,

(3-2) R2is cycloalkyl, which may be substituted by one or more groups selected from the group consisting of-N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZBand morpholinyl,

2represents a non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZBand benzyl,

(3-4) R2represents a

(i) cyclohexyl which may be substituted by one or more groups selected from the group consisting of-N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZBand morpholinyl,

(ii) piperidinyl, which may be substituted by one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZBand benzyl, or

(iii) tetrahydropyranyl,

(3-5) R2represents cyclohexyl which may be substituted by one or more groups selected from the group consisting of-N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZBand morpholinyl,

(3-6) R2is piperidinyl, which may be substituted by one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZBand benzyl,

(3-7) R2is tetrahydropyranyl,

(3-8) R2is a 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl or tetrahydropyran-4-yl,

(3-9) R2the stand is made by a 4-hydroxycyclohexyl,

(3-10) R2represents a 4-hydroxy-4-methylcyclohexyl, or

(3-11) R2represents tetrahydropyran-4-yl.

(4) the compounds of formula (I) or a salt of such a compound, where R3is a-H.

(5) Compounds, where applicable, any combination of two or more of (1)to(4)described above. Examples of embodiments of such combinations include

(5-1) Compound or salt of such a compound, where applicable, the combination of (1) and (4)above,

(5-2) the Compound or salt of such a compound, where applicable, the combination of (1), (2) and (4)above,

(5-3) the Compound or salt of such a compound, where applicable combination(1), (2), (3) and (4)above,

(5-4) the Compound or salt of such a compound, where applicable, the combination of (1-1), (2-1), (3-1) and (4)above,

(5-5) the Compound or salt of such a compound, where applicable combination (1-4), (2-1), (3-1) and (4)above,

(5-6) the Compound or salt of such a compound, where applicable combination (1-4), (2-2), (3-1) and (4)above,

(5-7) the Compound or salt of such a compound, where applicable combination (1-4), (2-3), (3-1) and (4)above,

(5-8) the Compound or salt of such a compound, where applicable combination (1-4), (2-3), (3-8) and (4)described above and

(5-9) the Compound or salt of such a compound, where applicable, any compatible combination on the ear or over, selected from the group consisting of (1-5), (1-7), (1-8), (2-6), (2-7), (2-8), (2-9), (2-10), (2-11), (2-12), (2-13), (2-14), (3-9), (3-10), (3-11) and (4)above.

Other variants of embodiment of the compounds of formula (I) or salts thereof are presented below.

(6) the compounds of formula (I) or a salt of such a compound, where

(6-1) -X - represents a group of formula (II), and a represents a lower alkyl,

(6-2) -X - represents a group of formula (II), and represents an ethyl or isopropyl,

(6-3) -X - represents a group of formula (II), and represents ethyl, or

(6-4) -X - represents a group of formula (II), and represents isopropyl.

(7) the compounds of formula (I) or a salt of such a compound, where

(7-1) R1represents phenyl, in which the carbon at the 4-position is substituted by a group-W-Y-Z, and as another substituent, the carbon in the 2 - or 3-position may be substituted by a group R00or-O-R00and Y represents a bond,

(7-2) R1represents phenyl, in which the carbon at the 4-position is substituted by a group-W-Y-Z, and as another substituent, the carbon on the carbon at the 3-position may be substituted by a group R00or-O-R00, -W - is a piperidine-1,4-diyl (attached via a nitrogen atom to the phenyl to which is attached-W-) or a bond, Y is a bond , and Z represents piperazine-1-yl, in which the atoms is nitrogen in 4-position may be substituted by lower alkyl,

(7-3) R1represents phenyl, in which the carbon at the 4-position is substituted by a group of 4-(4-methylpiperazin-1-yl)piperidine-1-yl, and as another substituent, the carbon at the 3-position may be replaced by stands, trifluoromethyl, methoxy or ethoxy,

(7-4) R1represents a 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(7-5) R1represents 4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}-3-(trifluoromethyl)phenyl,

(7-6) R1is a 3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(7-7) R1is a 3 ethoxy-4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(7-8) R1represents 4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(7-9) R1represents phenyl, in which the carbon at the 4-position is substituted by a group of 4-methylpiperazin-1-yl or 4-isopropylpiperazine-1-yl, and as another substituent, the carbon at the 3-position may be substituted by a methyl group, a trifluoromethyl or methoxy,

(7-10) R1represents a 3-methyl-4-(4-methylpiperazin-1-yl)phenyl,

(7-11) R1represents a 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl,

(7-12) R1is a 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl,

(7-13) R1represents a 4-(4-methylpiperazin-1-yl)phenyl,

(7-14) R1represents a 4-(4-isopropylpiperazine-1-yl)-3-methylp the Nile

(7-15) R1represents phenyl, in which the carbon at the 3-position is substituted by a group-SO2-R00,

(7-16) R1represents a 3-(methylsulphonyl)phenyl,

(7-17) R1represents phenyl, in which the carbon at the 3-position is substituted by a group-W-Y-Z, and as another substituent, the carbon at the 4-position may be substituted by a group-O-R00, W is a bond and Y represents a bond,

(7-18) R1represents phenyl, in which the carbon at the 3-position substituted group 4-methylpiperazin-1-yl, and as another substituent, the carbon at the 4-position may be substituted by a methoxy group,

(7-19) R1represents 4-methoxy-3-(4-methylpiperazin-1-yl)phenyl,

(7-20) R1represents a 3-(4-methylpiperazin-1-yl)phenyl,

(7-21) R1represents 2-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidine-1-yl}phenyl,

(7-22) R1is a 1-methylindol-6-yl,

(7-23) R1is a 4-morpholine-4-ylphenyl,

(7-24) R1represents a 4-(1-methylpiperidin-4-yl)phenyl,

(7-25) R1represents 4-{4-(cyclopropylmethyl)piperazine-1-yl}-3-(trifluoromethyl)phenyl, or

(7-26) R1represents 4-{3-(dimethylamino)pyrrolidin-1-yl}-3-(trifluoromethyl)phenyl.

(8) the compounds of formula (I) or a salt of such a compound, where

(8-1) R2is the nd cycloalkyl, substituted by-OH and the lower alkyl,

(8-2) R2represents cyclohexyl, substituted by-OH and the lower alkyl,

(8-3) R2represents cyclohexyl, in which the carbon at the 4-position is substituted by-OH and the lower alkyl,

(8-4) R2represents cyclohexyl, in which the carbon at the 4-position is substituted by-OH and stands,

(8-5) R2is cycloalkyl substituted by a group-OH,

(8-6) R2represents cyclohexyl, substituted by a group-OH,

(8-7) R2is a 4-hydroxycyclohexyl,

(8-8) R2represents a non-aromatic heterocyclic ring which may be substituted by lower alkyl,

(8-9) R2is tetrahydropyranyl, which may be substituted by lower alkyl, or piperidinyl, which may be substituted by lower alkyl,

(8-10) R2represents tetrahydropyran-4-yl,

(8-11) R2represents piperidine-4-yl, in which the nitrogen atom in the 1-position may be substituted by lower alkyl,

(8-12) R2is a 1-methylpiperidin-4-yl or

(8-13) R2represents piperidine-4-yl.

(9) the compounds of formula (I) or a salt of such a compound, where R3is a-H.

(10) Compounds in accordance with paragraph (6-3)above, or a salt of such compounds.

(11) Compounds in accordance with the tvii paragraphs (7-4), (7-5), (7-6), (7-7)and (7-8), (7-10), (7-13) and (7-14)above, or a salt of such compounds.

(12) Compounds in accordance with paragraphs (8-4), (8-7), (8-10) or (8-13)above, or a salt of such compounds.

(13) Compounds in which

(13-1) apply any combination of two or more of (6)-(9)above, or a salt of such a compound, or

(13-2) apply any combination of two or more of (9)to(12)above, or a salt of such compounds.

[0106] Examples of specific compounds covered by the scope of the present invention include the following compounds:

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamid,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,

5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamid,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamid,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,

5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamid is,

6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazine-1-yl)-3-were]amino}pyrazin-2-carboxamid,

6-ethyl-5-[(TRANS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,

6-chloro-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,

6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,

6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,

6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,

6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,

6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,

6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)Piras is n-2-carboxamid, or

6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide, or salt of such compounds.

[0107] Examples of specific compounds covered by the scope of the present invention include compounds selected from compounds of the groups P and Q, are presented below.

Connection group P:

group consisting of 6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazine-1-yl)-3-were]amino}pyrazin-2-carboxamide,

3-({3-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}am the but)-6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide,

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(piperidine-4-ylamino)pyrazin-2-carboxamide,

6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide,

6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide and

6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide and salts of these compounds.

Connection group Q:

group consisting of 6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-[(1-methyl-1H-ind is evil-6-yl)amino]pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-[(4-morpholine-4-ylphenyl)amino]pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazin-2-carboxamide,

5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide,

3-({4-[4-(cyclopropylmethyl)piperazine-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin-2-carboxamide,

3-({4-[3-(dimethylamino)pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin--carboxamide,

6-ethyl-5-[(CIS-4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(CIS-4-hydroxy-4-isopropylcyclohexane)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide,

6-ethyl-5-[(TRANS-4-hydroxy-4-isopropylcyclohexane)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide and

6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-[(1-methylpiperidin-4-yl)amino]pyrazin-2-carboxamide and salts of these compounds.

[0108] the compounds of formula (I) may contain tautomers and/or geometric isomers (including CIS-TRANS isomers of compounds containing saturated ring group, such as cycloalkyl group), depending on the type of their substituents. Even when the compounds of formula (I) provided in this application only one isomeric form, the present invention encompasses other isomers and also covers the individual isomers or a mixture thereof.

[0109] in Addition, since some of the compounds of formula (I) contain an asymmetric carbon atom or axial asymmetry, there may also be optical out is a career based on this asymmetry. The present invention also covers the individual optical isomers of compounds of formula (I) or mixtures thereof.

[0110] furthermore, the present invention encompasses pharmaceutically acceptable prodrugs of compounds represented by formula (I). The term “pharmaceutically acceptable prodrug” refers to a compound containing a group which can be converted into the amino group, hydroxyl group, carboxyl group or the like by solvolysis or under physiological conditions. Examples of forming the prodrug groups include groups described in Prog. Med., 5, 2157-2161 (1985), or group described in “Development of Pharmaceuticals” (Hirokawa Publishing, 1990) vol.7, Molecular Design, 163-198.

[0111] similarly salts of compounds of formula (I) are pharmaceutically acceptable salts of compounds of formula (I). The compounds of formula (I) can form acid or basic additive salt, depending on the type of their substituents. Specific examples include acid additive salts with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid, phosphoric acid and the like) or organic acids (e.g. formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic Ki is lotay, fumaric acid, maleic acid, lactic acid, malic acid, almond acid, tartaric acid, dibenzoyltartaric acid, litoloogiline acid, citric acid, methanesulfonic acid, econsultancy acid, benzosulfimide acid, p-toluensulfonate acid, aspartic acid, glutamic acid and the like), salts with inorganic bases (for example, salts of sodium, potassium, magnesium, calcium, aluminum and the like) or organic bases (for example, methylamine, ethylamine, ethanolamine, lysine, ornithine and the like), salts with various amino acids and amino acid derivatives (for example, acetylleucine and the like), as well as ammonium salts, etc.

[0112] furthermore, the present invention also encompasses the compounds of formula (I) and their salts in the form of various hydrates, solvate and crystalline polymorphic substances. The present invention also encompasses compounds labeled with various radioactive or non-radioactive isotopes.

[0113] the compounds of formula (I) and their pharmaceutically acceptable salts can be obtained by applying various known synthesis methods based on the characteristics that depend on the structure of their skeleton or type of their substituents. In some cases, depending on the type of functional group, with technical the point of view is an effective replacement of such a functional group suitable protecting group (group which can be easily transformed into the original functional group) at the stage of initial substance or being received intermediate compounds. Examples of such protective groups are described in Greene and Wuts, “Greene's Protective Groups in Organic Synthesis (fourth edition, 2007), and the like, which can be selected and used as appropriate, depending on the reaction conditions. In this way, after the introduction of the protective group and subsequent interaction of the protective group may be removed, if necessary, to give the desired compound.

[0114] similarly, the prodrug compounds of the formula (I) can be obtained by introducing a specific group at the stage of initial substance or being received intermediate compounds, as in the case described above protective group, or by the subsequent interaction of the compounds of formula (I). The interaction can be performed using conventional methods of esterification, amidation, dehydration, or other well-known experts in this field.

[0115] Below is an explanation of typical ways to obtain compounds of formula (I). Each method can also be carried out with reference to the documents referred to in this explanation. It should be noted that the methods of the present invention is not limited to the examples illustrated n the same.

(Method of obtaining 1)

[0116] [Formula 26]

(In the formula-LArepresents a removable group and examples include the lowest alkylsulfanyl).

This method is designed to produce compounds of the present invention (I-a) by reacting the compound (1a) with the compound (2).

[0117] In this reaction, the compounds (1a) and (2) are used in equal amounts or one of them is used in excessive quantities. The mixture of these compounds is stirred in a solvent inert to the reaction or without solvent, in the conditions of cooling to the boiling temperature under reflux, preferably at a temperature ranging from 0°C to 200°C, usually in a period of time from 0.1 hour to 5 days. The reaction may be carried out using a microwave reaction system, as it is beneficial for smooth reaction in some cases. The solvent used is not specifically limited, provided that it is inert to the reaction, and examples include aromatic hydrocarbons (e.g. benzene, toluene, xylene), ethers (e.g. diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane), halogenated hydrocarbons (for example, 1,2-dichloroethane, chloroform), alcohols (e.g. methanol, ethanol, 2-propanol), 1-methyl-2-pyrrolidinone (NMP), N,N-dim is telharmonic (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI), dimethylsulfoxide (DMSO), acetonitrile and mixtures thereof. The reaction can be performed in the presence of organic bases (e.g. triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or the like) or inorganic bases (e.g. potassium carbonate, sodium carbonate, potassium hydroxide or the like), as it is beneficial for smooth reaction in some cases.

[0118] When the reaction is carried out in the presence of such grounds, as specified above, depending on the properties or the like of the parent compounds, the desired response is impossible or difficult to implement, for example, due to decomposition or the like of the parent compounds. In this case, the reaction can be performed in the presence of a mineral acid (e.g. hydrochloric acid, Hydrobromic acid and the like), organic acids (e.g. acetic acid, propionic acid and the like) or sulfonic acid (for example, methanesulfonic acid, p-toluensulfonate acid and the like), as it is beneficial for smooth reaction in some cases. In addition, when LArepresents the lowest alkylsulfanyl, S atom may be oxidized using various oxidants, such as Oxone®, m-chloroperbenzoic acid (mCPBA) and peracetic acid is, for conversion of lower alkylsulfanyl in the lower alkylsulfonyl or lower alkylsulfonyl, and then lower alkylsulfonyl or lower alkylsulfonyl can be subjected to interaction with compound (2), as it is beneficial for smooth reaction in some cases.

[0119] [Docs]

S. R. Sandler and W. Karo, “Organic Functional Group Preparations,second edition, vol.1, Academic Press Inc., 1991.

The Chemical Society of Japan, “Fifth Series of Experimental Chemistry”, vol.14 (2005) (MARUZEN Co., Ltd., Japan)

(Method of obtaining 2)

[0120] [Formula 27]

(In the formula-LBrepresents a removable group, and examples include a halogen (for example F, Cl), sulfonyloxy (for example, methanesulfonate, p-toluensulfonate, tripterocalyx), the lowest alkylsulfonyl and lower alkylsulfonyl).

This method is designed to produce compounds of the present invention (I-b) by reacting compound (1b) with the compound (2).

[0121] In this reaction, you can use the procedure of the method of obtaining 1.

(Synthesis of the starting compounds 1)

[0122] [Formula 28]

(In the formula-LCrepresents a removable group, and examples include a halogen (for example F, Cl) and sulfonyloxy (for example, methanesulfonate, p-toluensulfonate, tripterocalyx); RArepresents and the sludge benzyl, lower alkyl or-H; and M represents an alkali metal).

This method is intended to obtain compound (1a) by reacting compound (5), which is obtained by reacting compound (3) with compound (4)with compound (6) and then the implementation of the reaction remove the protection for the removal of RA.

[0123] In the reaction, which gives the compound (5), you can use the procedure of the method of obtaining 1. In the reaction, which gives compound (1a), you can use the procedure of the method of obtaining 1, and the reaction may be carried out using the compound (6) or reagent, which provides obtaining the compound (6) in the system, and you can then carry out the reaction of removal of protection under reaction conditions that are selected as appropriate, for example, from the reaction conditions described in Greene and Wuts, “Greene's Protective Groups in Organic Synthesis (fourth edition, 2007)”. Examples of the compound (6) include sodium acetate and sodium methoxide. It should be noted that the compound (1a) can also be obtained by performing the reaction using hydrogen peroxide solution instead of the compound (6) with the subsequent implementation of the acid treatment using hydrochloric acid or the like

(Synthesis of the starting compounds 2)

[0124] [Formula 29]

This method is intended to obtain compound (1b) by vzaimode istia compound (7) with compound (4).

[0125] In this reaction, you can use the procedure of the method of obtaining 1.

[0126] the Compound of formula (I) is isolated and purified as a free compound or its pharmaceutically acceptable salt, hydrate, MES or crystalline polymorphic substances. Pharmaceutically acceptable salt of the compounds of formula (I) also can be obtained by subjecting compound traditional salt formation reaction.

[0127] the isolation and purification can be performed using conventional chemical procedures such as extraction, fractional crystallization, various types of fractional chromatography, etc.

[0128] Various isomers can be obtained by selecting suitable starting compounds or they can be separated based on differences in physical and chemical properties of the isomers. For example, optical isomers divided into optically pure isomers using traditional methods of optical separation (e.g., fractionated crystallization, which gives diastereomer salt with an optically active base or acid, chromatography on a column with a chiral phase or etc. etc.). They can also be obtained from the appropriate optically active starting compounds.

[0129] the compounds of formula (I) were tested for their pharmacological activity in the following tests. Unless otherwise stated, when the career tests below, you can implement the method described in EP 1914240, or any well-known way, and in the case of using commercially available reagents, kits, or the like can be carried out in accordance with the instructions accompanying these commercially available products. It should be noted that the term “EML4-ALK hybrid protein v1” refers to a polypeptide having the amino acid sequence presented as SEQ ID NO:2 in patent document 1, and the term “EML4-ALK v3 hybrid protein” refers to a polypeptide having the amino acid sequence presented as SEQ ID NO:130 in patent document 1.

[0130] Example test 1: evaluation of inhibitory activity against the kinase activity of EML4-ALK hybrid protein

Recombinant retrovirus was obtained from a plasmid for the expression of FLAG-EML4-ALKv1/pMX-iresCD8, which was integrated cDNA for EML4-ALK hybrid protein v1, and was administered by injection into BA/F3 cells of lymphoid cell lines of the mouse. Using the reagent in the form of magnetic beads for cell division and cleanup columns (anti-CD8 monoclonal antibody immobilized on magnetic beads, and the column for cleaning MiniMACS; both products of the company Miltenyi Biotec Inc.), cells expressing cell-surface CD8, was purified to obtain BA/F3 cells expressing EML4-ALK hybrid protein v1. Of these cells is to, EML4-ALK hybrid protein v1 was purified and subjected to evaluation of kinase activity. EML4-ALK hybrid protein v1 investigated on its phosphorylation activity against peptide substrate using a kit for determining kinase activity (HTRF KinEASE-TK; Cisbio Inc.). The test compounds, each, was added to the reaction solution containing the enzyme protein with getting 8 final concentrations of 1000 nm to 0.3 nm, followed by the addition of ATP and interaction within 1 hour. Used the ATP concentration was 100 μm. Another reaction solution was received as containing enzyme protein, but without the test compound (added only the solvent DMSO at a concentration of 0.4% instead of the test compound), followed by the interaction in the same way with or without the addition of ATP. In the absence of the test compound to the amount of phosphorylation without the addition of ATP and with the addition of ATP was taken as 100% inhibition and 0% inhibition, respectively. The concentration providing 50% inhibition (IC50), was calculated for each test compound using the method of logarithmic regression.

[0131] As a result, it was found that some compounds of the present invention have inhibitory activity against the kinase activity of EML4-ALK hybrid protein v1. 1 represents values IR 50obtained for some compounds of the present invention. The example indicates the example number. The following table connection X is the racemic form of the compound of example 174, presented in international publication no WO 2009/136995 (rac-2-{[(1R,2S)-2-aminocyclohexanol]amino}-4-{[4'-(morpholine-4-yl)biphenyl-4-yl]amino}pyrimidine-5-carboxamide), and the Y connection means connection examples 26-22, presented in international publication no WO 00/76980 (5-{[2-(dimethylamino)ethyl]amino}-6-ethyl-3-[(3-were)amino]pyrazin-2-carboxamide).

[0132]

[0133] test Example 2: evaluation of the activity of growth inhibition against EML4-ALK hybrid protein-dependent cells

BA/F3 cells expressing EML4-ALK hybrid protein v1, can be grown in the absence of IL-3. In other words, they are cells whose growth depends on EML4-ALK hybrid protein v1.

[0134] In a 96-well plate (Iwaki) were sown BA/F3 cells expressing EML4-ALK hybrid protein v1, with a density of 500 cells/well in RPMI1640 medium (Invitrogen)containing 10% fetal bovine serum, followed by the addition of the test compound (final concentration: 10 μm to 0.1 nm). As a negative control, was added DMSO used as solvent for test compounds. Then cells were cultured in 5% CO2at 3°C for 2 days. Added reagent for counting cells (AlmarBlue; Biosource) and cells were cultured for 150 minutes followed by measuring fluorescence intensity using a luminometer (Safire; Tecan) in accordance with the instructions supplied with the reagent. Taking the value measured when only the environment and the value measured for the negative control, 100% inhibition and 0% inhibition, respectively, used to calculate the degree of inhibition for each compound to determine thus the concentration providing 50% inhibition (value IR50), using the method of logarithmic regression.

[0135] As a result, some compounds of the present invention showed activity of growth inhibition against BA/F3 cells expressing EML4-ALK hybrid protein v1. Table 2 tabulates the values of IR50obtained for some compounds of the present invention. The example indicates the example number in the table below, compound X and compound Y, respectively, denote compounds described in test example 1.

[0136]

On the basis of results examples tests 1 and 2 shown above, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of EML4-ALK hybrid protein v1 the activity of growth inhibition against BA/F3 cells, expressing EML4-ALK hybrid protein v1. On the other hand, it was confirmed that the Compounds X and Y, described in test example 1, have an extremely weak inhibitory activity against the kinase activity of EML4-ALK hybrid protein v1 and activity of growth inhibition against BA/F3 cells expressing EML4-ALK hybrid protein, compared with the compounds of the present invention.

[0137] test Example 3: anti-tumor test (in vivo) EML4-ALK hybrid protein-dependent cells

Plasmid expression of EML4-ALKv1/pMXS with integrated cDNA for EML4-ALK hybrid protein v1 was transfusional in 3T3 fibroblast cells calcium phosphate method to obtain this way of 3T3 cells expressing EML4-ALK hybrid protein v1. 3×106the 3T3 cells expressing EML4-ALK hybrid protein v1, suspended in PBS, were inoculable subcutaneously injected into the back of a 5-week old male Balb/c Nude" mice (Charles River Japan, Inc.). 7 days after inoculation began the introduction of the test compounds. The test was carried out in the group the introduction of the solvent and the group introducing compound, 4 animals in each group. The test compound suspended in a solvent consisting of 0.5% methylcellulose and administered orally at the dose of 10 mg/kg Injection was carried out once a day for 5 days, and body weight and tumor size metering is whether constantly through the day. Tumor volume was calculated using the following formula.

[Tumor volume (mm3)]=[Major axis of the tumor (mm)]×[the minor axis of the tumor (mm)]2× 0,5

[0138] Taking tumor volume in the group of introduction of the solvent in the start day and end day of the introduction of the test compounds in 100% inhibition and 0% inhibition, respectively, used to calculate the degree of inhibition for the tested compounds. When induced regression of tumor volume from the start of injection, the tumor volume on the first day of administration and the state in which the tumor was gone, took 0% regression and 100% regression, respectively, and used to calculate the degree of regression to test the connection.

[0139] As a result, it was confirmed that among the compounds of the present invention include compounds that inhibit tumor growth of 3T3 cells expressing EML4-ALK hybrid protein v1, and compounds that induce regression of tumors 3T3 cells expressing EML4-ALK hybrid protein v1. Table 3 represents the degree of inhibition for some compounds of the present invention. It should be noted that the following table of digital values that specify the word “(regression)”each indicates the degree of regression. The example indicates the example number.

[0140]

Table 3
Example(%)
37081
37892
39228 (regression)
42681
46654 (regression)
54679
54967 (regression)
55363
55837 (regression)

Thus, when administered orally, the compounds of the present invention inhibit tumor growth in mice inoculated with expressing EML4-ALK hybrid protein v1 3T3 cells, or induce regression of tumors, thus confirming that the compounds of the present invention have oral activity.

[0141] test Example 4: anti-tumor test (in vivo) EML4-ALK hybrid protein-dependent cells

Antitumor effects on EML4-ALK hybrid protein-dependent cells can be confirmed using cells of human cell lines is non-small cell lung cancer NCI-H2228 cells were isolated from EML4-ALK hybrid polynucleotide-positive patients with lung cancer (EML4-ALK v3 hybrid protein-dependent cell)) instead of expressing EML4-ALK hybrid protein v1 cells 3T3 example, test 3, as shown below.

[0142] 3×106cells NCI-H2228, suspended in 50% Matrigel (Invitrogen), was inoculable subcutaneously injected into the back area 5-week old male NOD/SCID mice (Charles River Japan, Inc.). 3 weeks after inoculation began the introduction of the test compounds. The test was carried out in the group the introduction of the solvent and groups injection of the test compounds for 6 animals in each group. The test compounds, each dissolved in a solvent consisting of 10% 1-methyl-2-pyrrolidinone (SIGMA-ALDRICH Inc.)/90% of polyethylene glycol 300 (Fluka Inc.), and is administered orally at a dose of 1 mg/kg Injection was carried out once a day for 14 days, and body weight and tumor size were measured continuously through the day. Tumor volume was calculated using the following formula.

[Tumor volume (mm3)]=[Major axis of the tumor (mm)]×[the minor axis of the tumor (mm)]2× 0,5

[0143] Taking tumor volume in the group of introduction of the solvent in the start day and end day of the introduction of the test compounds in 100% inhibition and 0% inhibition, respectively, used to calculate the degree of inhibition for the test connection.

[0144] As a result, it was confirmed that among the compounds of the present invention include compounds that inhibit the growth of tumors NCI-H2228 cells. For example, the compound of example 549 inhibits ROS the tumor NCI-H2228 cells by 69%.

[0145] Thus, by oral administration of the compounds of the present invention inhibit tumor growth in mice inoculated with cells of the human cell line non-small cell lung cancer NCI-H2228, thus confirming that the compounds of the present invention have oral activity.

[0146] on the other hand, when he introduced the compounds X and Y, described in test example 1, was not shown any significant growth inhibition against NCI-H2228 cells (tumor), compared to group the introduction of the solvent. The criterion of significance was determined using t-student test.

[0147] given the above, the examples in tests 1 and 2, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of EML4-ALK hybrid protein, and activity of growth inhibition against EML4-ALK hybrid protein-dependent cells. In addition, examples of tests 3 and 4 was confirmed that the compounds of the present invention have anti-tumor effect on EML4-ALK hybrid protein-dependent cells (tumor)based on the above actions. This indicates that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for the profile is ctice and/or treatment of cancer, such as lung cancer in one variant embodiment of the invention, non-small cell lung cancer or small cell lung cancer in another variant embodiment of the invention, ALK hybrid polynucleotide-positive cancer in another variant embodiment of the invention, ALK hybrid polynucleotide-positive lung cancer in another variant embodiment of the invention, ALK hybrid polynucleotide-positive non-small cell lung cancer in yet another variant embodiment of the invention, ALK hybrid protein-positive cancer in another variant embodiment of the invention, ALK hybrid protein-positive lung cancer in another variant embodiment of the invention, ALK hybrid protein-positive non-small cell lung cancer in another variant embodiment of the invention, EML4-ALK hybrid polynucleotide-positive cancer in another variant embodiment of the invention, EML4-ALK hybrid polynucleotide-positive lung cancer in another variant embodiment of the invention, EML4-ALK hybrid polynucleotide-positive non-small cell lung cancer in yet another variant embodiment of the invention, EML4-ALK hybrid protein-positive cancer in another variant embodiment of the invention, EML4-ALK hybrid protein-positive lung cancer in the next version of the incarnation, or EML4-ALK hybrid protein-positive non-small cell lung cancer is the next version of the incarnation.

[0148] Thus, as for the ALK gene, the presence of different types of active point mutations and overexpression associated with gene amplification was confirmed in cells isolated from patients with neuroblastoma (Nature, vol.455, p.971, 2008; Cancer Research, vol.68, p.3389, 2008). In addition, it is known that compounds having inhibitory activity against the kinase activity of ALK protein, demonstrates anti-tumor effects on cells isolated from mutant ALK polynucleotide-positive cancer patients, and cells isolated from cancer patients with overexpression of ALK polynucleotide (Cancer Research, vol.68, p.3389, 2008). This shows that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for the prevention and/or treatment of neuroblastoma, such as mutant ALK polynucleotide-positive cancer in one variant embodiment of the invention, the cancer with overexpression of ALK polynucleotide in another variant embodiment of the invention, the mutant ALK polynucleotide-positive neuroblastoma in the next version of the incarnation or neuroblastoma with overexpression of ALK polynucleotide in the next version of the implementation.

[0149] the compounds of formula (I) were also tested to confirm their pharmacological activity in the following tests. Unless otherwise specified, the tests described the data in the examples below, can be carried out in a known way, and when using commercially available reagents and/or kits can be implemented in accordance with the instructions accompanying these commercially available products.

[0150] test Example 5: evaluation of inhibitory activity against the kinase activity of RET protein

Incomplete protein consisting only of the kinase domain of the RET protein, bought the company Carna Biosciences Inc., Japan. The phosphorylation activity against peptide substrates was investigated using the EZ reader (Caliper). The test compounds, each, were mixed with the protein solution with obtaining 8 final concentrations from 100 nm to 0.03 nm, then add liquid mixture of ATP and peptide substrate (Caliper) and interaction within 30 minutes. Used the ATP concentration was 100 μm. Got the reaction liquid, which contained protein, but without the test compound (which was only added with the solvent DMSO at a concentration of 0.8% instead of the test compound), followed by the interaction in the same way, with or without the addition of ATP. In the absence of the test compound, the peak of phosphorylation of the peptide without the addition of ATP and with the addition of ATP was taken as 100% inhibition and 0% inhibition, respectively. The concentration of the test compound providing 50% and generowanie (value IR 50), was calculated using the method of logarithmic regression.

[0151] As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of RET protein. Table 4 presents the values IR50obtained for some compounds of the present invention. The example indicates the example number.

[0152]

RET (rebuilt during transfection) is a receptor receptor and is a protein containing the transmembrane region in the middle part, flanked tyrosinekinase area on carboxykinase and extracellular region in aminocore.

[0153] Based on the results of test example 5, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of RET protein. Thus, as for the RET gene, the active presence of the point mutation was confirmed in cells or cancer tissue samples, isolated from non-small cell lung cancer, small-cell lung cancer, thyroid cancer, programatically adrenal, colon cancer and pancreatic cancer, and merge with H4, H4L, PRKAR1A, NCOA4, GOLGA5, HTIF1, TIF1G, TKTN1, RFG9, ELKS, PCM1, RFP and HOOK3 genes was confirmed in cells or cancer tissue samples, isolated from thyroid cancer, the aka ovarian cancer and mesothelioma (a point mutation in non-small cell lung lung cancer: Nature Genetics, 2007, 39, 347-351; point mutation in small cell lung cancer: Japanese Journal of Cancer Research, 1995, 86, 1127-1130; mergers and point mutation in thyroid cancer: Endocrine Reviews, 2006, 27, 535-560; point mutation in the tumor adrenal: Journal of Clinical Endocrinology and Metabolism, 1996, 81, 2041-2046; point mutation in colon cancer: Science, 2006, 314, 268-274; point mutation in pancreas cancer: Cancer Research, 2005, 65, 11536-11544; merge in ovarian cancer: the International Journal of Surgical Pathology, 2009, 17, 107-110; merge in mesothelioma: Cancer letters, 2008, 265, 55-66). In addition, it is known that compounds having inhibitory activity against the kinase activity of RET protein, demonstrates anti-tumor effects on cells isolated from mutant RET polynucleotide-positive cancer patients, and cells isolated from hybrid RET polynucleotide-positive cancer patients (Endocrine Reviews, 2006, 27, 535-560). This shows that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and/or treating cancer of the thyroid gland, such as freepromotion adrenal in one variant embodiment of the invention, colon cancer in another variant embodiment of the invention, cancer of the pancreas in another variant embodiment of the invention, ovarian cancer in another variant embodiment of the invention, mesothelioma is still in odnawiane embodiment of the invention, mutant RET polynucleotide-positive cancer in another variant embodiment of the invention, the mutant RET polynucleotide-positive lung cancer in another variant embodiment of the invention, the mutant RET polynucleotide-positive non-small cell lung cancer in yet another variant embodiment of the invention, the mutant RET polynucleotide-positive small cell lung cancer in yet another variant embodiment of the invention, the mutant RET polynucleotide-positive thyroid cancer in another variant embodiment of the invention, the mutant RET polynucleotide-positive freepromotion adrenal in another variant embodiment of the invention, the mutant RET polynucleotide-positive colon cancer in another variant embodiment of the invention, mutant RET polynucleotide-positive pancreatic cancer in another variant embodiment of the invention, RET hybrid polynucleotide-positive cancer in another variant embodiment of the invention, RET hybrid polynucleotide-positive thyroid cancer in another variant embodiment of the invention, RET hybrid polynucleotide-positive ovarian cancer in the next version of the incarnation or RET hybrid polynucleotide-positive mesothelioma in the next version of the implementation.

[0154] test Example 6: evaluation of the inhibitory activity of Rotel kinase activity of the ROS protein

Incomplete protein consisting only of the kinase domain of ROS protein, bought the company Carna Biosciences Inc., Japan and the tests were carried out as in test example 5, except that the concentration of ATP in the mixed solution of ATP and peptide substrate (Caliper) was 50 μm.

[0155] As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of the ROS protein. Table 5 presents the values IR50obtained for some compounds of the present invention. The example indicates the example number.

[0156]

ROS (oncogenic homolog 1 v-Ros bird UR2 sarcoma virus) receptor is a receptor and is a protein containing the transmembrane region in the middle part, flanked tyrosinekinase area on carboxykinase and extracellular region in aminocore.

[0157] Based on the results of test example 6, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of the ROS protein. Thus, as for the ROS gene fusion with FIG genome, SLC34A2 gene and CD74 gene was confirmed in cells or cancer tissue samples, isolated from cell lung carcinoma and glioblastomas (Biochimica et Biophysica Acta (BBA) Reviews on Cancer, 2009, 1795, 37-52). In addition, since it is known that h is of siRNAs, which inhibits molecular expression cell lines isolated from patients with SLC34A2-ROS hybrid polynucleotide-positive cancer, demonstrates anti-tumor effect on these cell lines (Cell, 2007, 131, 1190-1203), it can be expected that the compounds having inhibitory activity against the kinase activity of the ROS protein, has anti-tumor effects against ROS hybrid polynucleotide-positive cancer. This shows that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for the prevention and/or treatment of glioblastoma, for example, ROS hybrid polynucleotide-positive cancer in one variant embodiment of the invention, ROS hybrid polynucleotide-positive lung cancer in another variant embodiment of the invention, ROS hybrid polynucleotide-positive non-small cell lung cancer in the next version of the incarnation or ROS hybrid polynucleotide-positive glioblastoma in the next version of the implementation.

[0158] the test Example 7: evaluation of inhibitory activity against the kinase activity of FLT3 protein

Incomplete protein consisting only of the kinase domain of FLT3 protein, bought the company Carna Biosciences Inc., Japan, and the tests were carried out as in test example 5.

[0159] As a result, some compounds is of the present invention showed inhibitory activity against the kinase activity of FLT3 protein. Table 6 presents the values IR50obtained for some compounds of the present invention. The example indicates the example number.

[0160]

FLT3 (Fms-like tyrosinekinase 3) receptor is a receptor and is a protein containing the transmembrane region in the middle part, flanked tyrosinekinase area on carboxykinase and extracellular region in aminocore.

[0161] Based on the results of test example 7, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of FLT3 protein. Thus, as for the FLT3 gene, the presence of active point mutations and mutations of internal tandem duplications in ikolomani region (FLT3-ITD) was confirmed in cells isolated from patients with acute miliitary leukemia, and merge with SPTBN1 gene was confirmed in cells isolated from patients with atypical chronic miliitary leukemia (active point mutation and internal tandem duplication in ikolomani region in acute malacitana leukemia: Current Pharmaceutical Design, 2005, 11, 3449-3457; merge in atypical chronic malacitana leukemia: Experimental Hematology, 2007, 35, 1723-1727). In addition, it is known that compounds having inhibitory activity against the kinase activity of FLT3 b is the left main coronary artery demonstrates anti-tumor effects on cells isolated from patients with mutant FLT3 polynucleotide-positive cancer, and cells isolated from patients with SPTBN1-FLT3 hybrid polynucleotide-positive cancer Current Pharmaceutical Design, 2005, 11, 3449-3457; Experimental Hematology, 2007, 35, 1723-1727). This shows that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for the prevention and/or treatment of acute malacitana leukemia, such as atypical chronic miliitary leukemia in one variant embodiment of the invention, mutant FLT3 polynucleotide-positive cancer in another variant embodiment of the invention, mutant FLT3 polynucleotide-positive acute military leukemia in another variant embodiment of the invention, FLT3 hybrid polynucleotide-positive cancer in the next version of the incarnation or FLT3 hybrid polynucleotide-positive atypical chronic miliitary leukemia in the next version of the implementation.

[0162] the test Example 8: analysis of the profile of inhibition of kinase activity

The degree of inhibition against 78 types tyrosinekinase (ABL, ARG, BTK, BMX, ITK, TEC, TXK, FRK, BLK, LCK, HCK, LYN, FGR, FYN, SRC, YES, BRK, SRM, CSK, CTK, FER, FES, ACK, TNK1, HER4, EGFR, HER2, JAK1, TYK2, JAK2, JAK3, ROS, ALK, LTK, IRR, INSR, IGF1R, DDR1, DDR2, MUSK, TRKA, TRKB, TRKC, TYRO3, AXL, MER, MET, RON, RET, FGFR4, FGFR1, FGFR2, FGFR3, FLT4, KDR, FLT1, FLT3, FMS, KIT, PDGFRa, PDGFRb, TIE2, EphA1, EphA2, EphA8, EphA7, Eph6, EphA4, EphA3, EphA5, EphB4, EphB3, EphB1, EphB2, FAK, PYK2, SYK, ZAP70) was calculated for each test compound at a concentration of 5 nm. Measurement of the activity carried out by the company Carna Biosciences Inc., Japan, and the data were analysed as follows: assuming an average signal in the control wells, containing all of the interacting components, for 0% inhibition and the average signal in the absence of the enzyme for 100% inhibition, the degree of inhibition was calculated for each test substance from the average signal from the two holes for testing.

[0163] As a result, at a concentration of 5 nm some compounds of the present invention showed inhibitory activity of 50% or more against 7 types of kinases, including ALK, RET, ROS, and FLT3, and, therefore, they are highly selective for certain kinases and cause less concern about their safety, because these concerns are related to the inhibition of non-target kinases responsible for side effects.

[0164] the Pharmaceutical composition that includes one or more compounds of the formula (I) or their pharmaceutically acceptable salts as an active ingredient, can be obtained in the traditional way using pharmaceutical excipients, pharmaceutical carrier or other additives commonly used in this field.

[0165] it is Possible and in order to use any method of administration, or oral administration in the dosage form such as tablets, pills, capsules, granules, powders, solutions or the like, or parenteral administration in the dosage form, such as injections (e.g., intra-articular, intravenous, intramuscular and the like), suppositories, eye drops, eye ointments, percutaneous solutions, ointments, transdermal patches, solutions for injection through the mucous membrane, patches for insertion through the mucous membrane, preparations for inhalation or similar.

[0166] the Solid composition used for oral administration include tablets, powders, granules and the like. In such solid compositions one or more active ingredients are mixed with at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or alumosilicate magnesium or the like. The composition can also include inert additives such as lubricants (e.g. magnesium stearate), disintegrating agents (e.g. sodium carboximetilkrahmal and the like), stabilizers and/or solubilizing agents, as it happens in normal cases. Tablets or pills may have put on them a coating of sugar or gastro - or intersolubility film, if necessary.

[0167] the Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs or the like, and include traditionally used inert diluent such as purified water or ethanol. These liquid compositions may include, in addition to inert diluents, excipients (for example, solubilizing agents, wetting agents, suspendresume substances and the like), sweeteners, fragrances, flavorings and/or antiseptics.

[0168] Preparations for parenteral administration by injection include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of aqueous solvents include distilled water or physiological saline for injection. Examples of nonaqueous solvents include propylene glycol, polyethylene glycol or vegetable oils (such as olive oil and the like), and alcohols (e.g. ethanol and the like) or Polysorbate 80 (the name used in the Pharmacopoeia) and the like. These compositions may also include isotonicity agents, antiseptics, wetting agents, emulsifiers, dispersing agents, stabilizers and / or solubilizing agents. They are sterilized, for example, by filtration through a bacterial filter, by introducing a disinfectant or by irradiation. Al is ernative, they can be formulated into a sterile solid composition and restructure for use by dissolution or suspension in sterile water or a sterile solvent for injection before use.

[0169] the agents for external use include ointments, plasters, creams, jellies, douches, sprays, lotions, eye drops, eye ointments and the like. These include traditionally used bases for ointments, foundations for lotion, aqueous or non-aqueous solutions, suspensions, emulsions or the like, Examples of the base for the ointment or lotion include polyethylene glycol, propylene glycol, petrolatum, white beeswax, polyoxyethylene-gidrirovannoe castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, Lauromacrogol, servicesecurity and the like.

[0170] the Preparations for the introduction through the mucous membrane, such as preparations for inhalation or drugs for insertion through the nose, used in solid, liquid or semi-solid form, and you can get the usual well known way. For example, such compositions can be supplemented, if it is suitable, known excipients and, in addition, pH control agents, antiseptics, surfactants, lubricating agents, stabilizers, thickeners, etc. For their introduction you can use a suitable device for ingal the tion or insufflation. For example, using a known device (for example, a measuring device for inhalation and the like) or atomizer, the compound(I) can be introduced as such or in a mixture, formulated in the form of powder or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier. Inhalers dry powder or the like can be designed for single or multiple injections, in such devices, you can use dry powder or containing powder capsules. Alternatively, they can be in the form of a pressurized aerosol sprays or the like, using suitable propellant, for example, the preferred gas, such as chlorphenesin, hydroforce, carbon dioxide or the like.

[0171] typically, for oral administration, the daily dose is desirable in the range from about 0.001 to 100 mg/kg, preferably 0.005 to 30 mg/kg, and more preferably from 0.01 to 10 mg/kg body mass, which is injected as a single dose or in 2-4 separate doses. For intravenous administration, the daily dose is desirable in the range from about 0.0001 to 10 mg/kg body mass, which is injected as a single dose or as multiple doses per day. Similarly, for preparations for insertion through the mucous membrane of the daily dose is from about 0.001 to 100 mg/kg body mass, which is injected in the form of pay dozily as multiple doses per day. A suitable dose for each case can be determined in consideration of the symptom, age, sex etc

[0172] the compounds of formula (I) can be used in combination with various therapeutic or preventive agents from diseases against which the compounds of formula (I) are effective. Typically, when the antitumor agent is administered separately as a chemotherapy of tumors, in particular malignant tumors, such antitumor agent has a limitation of its effect associated with side effects, etc. and, therefore, often cannot provide sufficient anti-tumor effect. For this reason, in clinical cases use multilocational therapy, which combine two or more drugs with different mechanisms of action. Through a combination of anticancer agents with different mechanisms of action of this combination therapy aimed at reducing the side effects and/or enhancement of the desired anticancer effect, for example, 1) to reduce the number of insensitive cell population, 2) to prevent or slow the development of drug resistance, (3) dispersion of toxicity by combining drugs with different levels of toxicity, etc. In such combination therapy drugs, monomodal simultaneously or separately, sequentially or with the desired time intervals. Composition for simultaneous administration can be either mixed or in separate form.

[0173] Drugs that can be combined include chemotherapeutic agents (e.g., an alkylating agent, an antimetabolite, and the like), immunotherapy, hormonal therapeutic agents and inhibitors of cell growth factor, more specifically, drugs, such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, irinotecan, vinorelbine, bevacizumab, pemetrexed and the like.

EXAMPLES

[0174] Hereinafter explained in more detail how to obtain the compounds of formula (I) using the following examples. It should be noted that the present invention is not limited to the compounds represented in the following examples. In addition, the receiving parent compounds described in the examples received. Methods for obtaining compounds of formula (I) are not limited to those described in the following examples, and the compounds of formula (I) can also be obtained using any combination of these means or in any manner that is obvious to a person skilled in this field.

[0175] In the examples, the examples of the preparation and the tables below use the following abbreviations, as necessary.

Ave. gender: P the emer receipt no. PR.: Example no. Structure: chemical structural formula. Data: physical and chemical data (FAB+: FAB-MS[M+H]+, ESI+: ESI-MS[M+H]+, APCI/ESI+: APCI/ESI-MS[M+H]+(APCI/ESI means simultaneously measuring APCI and ESI), FAB: FAB-MS[M-H]-, ESI-: ESI-MS[M-H]-, APCI-: APCI-MS[M-H]-,1H-NMR (CDCl3): δ (ppm)1H-NMR peaks in chloroform-d,1H-NMR (CD3OD): δ (ppm)1H-NMR peaks in methanol-d,1H-NMR (CDCl3+CD3OD): δ (ppm)1H-NMR peaks in the mixed solution of chloroform-d and methanol-d,1H-NMR (DMSO-d6): δ (ppm)1H-NMR peaks in DMSO-d6, XRD: the diffraction angle 2θ(°) of the main peak when measured by powder x-ray diffraction, HCl: means that the desired product was obtained as hydrochloride, 2HCl: means that the desired product was obtained in the form of the dihydrochloride, TsOH: means that the desired product was obtained in the form of a salt of p-toluensulfonate acid, HFM: means that the desired product was obtained as a salt hemifumarate acid, FM: indicates that the desired product was obtained in the form of salts of fumaric acid, Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, cPr: cyclopropyl, cHex: cyclohexyl, Ph: phenyl, Bn: benzyl, Boc: tert-butyloxycarbonyl, Ac: acetyl. SYN.: the method of obtaining (indicating that the requested connection is received from the appropriate starting compounds, as specified in pierpoline or example). In the tables presented in the examples is received or examples are CIS-TRANS isomers, and their configuration is not defined, but as far as compounds that contain one configuration is CIS or TRANS, there is no indication configuration in their chemical structural formulas, but instead the number of samples received and the number of examples is indicated by the symbol “*”. Connections with the same number after the symbol “*” means that one of these compounds represents a CIS-form and the other is a TRANS-form.

[0176] the Measurement by powder x-ray diffraction was performed using RINT-TTR II under the following conditions; tube: Cu, tube current: 300 mA, tube voltage: 50 kV, the width of the sample: 0,020°, scanning speed: 4°/min, wavelength: 1,54056 Å, the measurement range of the diffraction angle (2θ)from 2.5 to 40°. It should be noted that the powder x-ray diffraction should not be regarded as absolutely accurate method, because, given the nature of the data obtained by powder x-ray diffraction, the step of crystal lattice and the overall picture is important to determine the identity of the crystal, and the relative intensity may vary to some extent depending on the direction of crystal growth, particle size, and the measurement conditions.

[0177] Note the p 4

A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and thionyl chloride (6 ml) was heated at the boiling point under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure, followed by azeotropic distillation with toluene to obtain a red-brown oil. To a mixture of red-brown oil and THF (25 ml) was added diethylamine (2,6 ml) under cooling with ice and stirred at room temperature for 5 hours. The reaction liquid was poured into water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to obtain N,N-diethyl-4-methyl-3-nitrobenzamide (2,61 g) as a brown oil.

[0178] an Example of retrieving 41

To a mixture of 2-methoxy-4-nitrobenzenesulfonamide (600 mg) and THF (5 ml) was added to a mixture of piperidine (406 mg) and THF (1 ml) and stirred at room temperature for 12 hours. After adding 10% hydrochloric acid, the reaction liquid was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to obtain 1-[(2-methoxy-4-nitrophenyl)sulfonyl]piperidine (714 mg) as yellow is th solids.

[0179] an Example of retrieving 48

A mixture of 2-fluoro-5-nitrobenzoic acid (600 mg) and thionyl chloride (2 ml) was heated at the boiling point under reflux for 15 hours. The reaction liquid was concentrated under reduced pressure, followed by azeotropic distillation with toluene to obtain a yellow crystalline substance. To a mixture of yellow crystalline substance and THF (11 ml) was added triethylamine (0,47 ml) and Isopropylamine (0,29 ml) under cooling with ice and stirred at room temperature for 5 hours. The reaction liquid was poured into water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent drove under reduced pressure to obtain a yellow crystalline substance. To a mixture of yellow crystalline substance (723 mg) and methanol (8 ml) and water (3 ml) was added ammonium chloride (2,05 g) and zinc powder (2,09 g) and the mixture was heated at the boiling point under reflux for 3 hours. After filtration of the reaction suspension through celite, the filtrate was concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate solution and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and the eat was dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol) to give 5-amino-2-fluoro-N-isopropylbenzene (527 mg) as a light brown crystalline substance.

[0180] an Example of retrieving 160

To a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.0 g) and DMF (15 ml) was added thionyl chloride (1 ml) at room temperature and was stirred for 20 minutes. The reaction liquid was poured into ice water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: ethyl acetate:n-hexane) to give 3,5-dichloro-6-ethylpyrazine-2-carbonitrile (608 mg) in the form of a slightly yellowish oil.

[0181] an Example of retrieving 194

To a solution mixture of methyl 5-chloro-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxylate (example getting 193) (20 mg) and THF (2 ml) were added hydrochloride O-methylhydroxylamine (14 mg). To the reaction liquid were added hexamethyldisilazide lithium (of 0.39 ml, 1M THF solution) under ice cooling and stirred for 20 minutes. The reaction liquid was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate and then the organic layer was washed with saturated aqueous what astora sodium chloride. After drying over anhydrous sodium sulfate, the solvent is kept at reduced pressure to obtain 5-chloro-N-methoxy-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (21 mg) as a yellow powder.

[0182] an Example of retrieving 240

To a mixture of 1-(2-iodine-4-nitrophenyl)-4-methylpiperazine (example getting 241) (406 mg), toluene (3 ml) and water (3 ml) was added sodium carbonate (496 mg), phenylboronic acid (157 mg) and tetrakis(triphenylphosphine)palladium (68 mg) in an argon atmosphere and stirred overnight at 110°C. the Reaction liquid was poured into water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform/methanol) to give 1-methyl-4-(5-nitrobiphenyl-2-yl)piperazine (348 mg) as a yellow brown oil.

[0183] an Example of retrieving 244

To a mixture of N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]ndimethylacetamide (433 mg) and DMF (5 ml) was added 63% sodium hydride in oil (66 mg) under ice cooling and stirred at room temperature for 1 hour. The reaction liquid was again cooled with ice was added methyliodide (0,11 ml) and stirred at room temperature for 4 hours. The reaction liquid was poured into the feast upon the aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]ndimethylacetamide (200 mg) as an orange solid.

[0184] an Example of retrieving 246

To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (totaling 3.04 g) and THF (100 ml) was added utility (0.5 M solution in benzene-cyclohexane) (56,8 ml) at -78°C and was stirred for 4 hours until a temperature of -50°C. After addition of water (150 ml), the reaction liquid was heated to room temperature and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over sodium sulfate and the solvent drove away. The obtained residue was purified column chromatography on silica gel (eluent: chloroform:methanol=30:1) and further purified (eluent: n-hexane:ethyl acetate=2:1 to 1:1) to give tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (example getting 246) (0,202 g), which was iskopaemye product, in the form of a white solid substance and tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (example getting 248), which was a highly polar product, in VI is e colorless syrup.

[0185] an Example of retrieving 247

To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (example getting 246) (0,202 g) and dioxane (2 ml) was added a 26% solution of hydrogen chloride-dioxane (1.1 ml) under cooling with ice and stirred at room temperature for 12 hours. The solvent drove with obtaining hydrochloride 4-amino-1-ethylcyclohexane (0,140 g) as a white viscous solid.

[0186] an Example of retrieving 249

To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate (example getting 248) (0,256 g) and dioxane (2 ml) was added a 26% solution of hydrogen chloride-dioxane (1.4 ml) under ice cooling and stirred at room temperature for 17 hours. The precipitated solid was collected by filtration to obtain hydrochloride of 4-amino-1-ethylcyclohexane (0.152 g) in the form of a white solid.

[0187] an Example of retrieving 250

To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (totaling 3.04 g) and THF (100 ml) was added isopropylate (0,7 M solution in pentane) (40,3 ml) at -78°C and was stirred for 4 hours until a temperature of -50°C. After addition of water (150 ml), the reaction liquid was heated to room temperature and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and then dried over sodium sulfate and the solvent drove away. The remainder of cleansing and column chromatography on silica gel (eluent: n-hexane:ethyl acetate=3:1) and further purified (eluent: chloroform:methanol=30:1) to give tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (example receive 250) (0,854 g), which was iskopaemye product, in the form of a white solid substance and tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (example getting 252) (0,179 g), which was a highly polar product as a yellow oil.

[0188] an Example of retrieving 251

To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (example receive 250) (0,392 g) and dioxane (3 ml) was added a 26% solution of hydrogen chloride-dioxane (2.0 ml) under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to obtain hydrochloride of 4-amino-1-isopropylcyclohexane (0,190 g) as a white solid.

[0189] an Example of retrieving 253

To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (example getting 252) (0,179 g) and dioxane (1.5 ml) was added a 26% solution of hydrogen chloride-dioxane (0.9 ml) under cooling with ice and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to obtain hydrochloride of 4-amino-1-isopropylcyclohexane (0,086 g) as a white solid.

[0190] an Example of retrieving 287

To a mixture of propane-2-thiol (3,30 ml), potassium carbonate (6.60 g) and DMF (40 ml) was added 1-fluoro-4-methyl-2-nitrobenzene (4,85 g) and stirred at room temperature for 5 hours. After you add the value of water, the reaction liquid was extracted with ethyl acetate and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent is kept at reduced pressure to obtain 1-(isopropylphenyl)-4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.

[0191] an Example of retrieving 291

To a mixture of 1-(isopropylphenyl)-4-methyl-2-nitrobenzene (example getting 287) (6.60 g) and chloroform (150 ml) was added m-chloroperbenzoic acid (18.0 g) and stirred at 50°C for 12 hours. After cooling the reaction liquid was added a saturated aqueous solution of sodium bicarbonate and 5% aqueous solution of sodium sulfite and the reaction liquid was extracted with chloroform. After drying the organic layer over anhydrous sodium sulfate, the solvent is kept at reduced pressure to obtain 2-(isopropylphenyl)-4-methyl-1-nitrobenzene (7,41 g) as a yellow solid.

[0192] an Example of retrieving 292

To a mixture of 2-(isopropylphenyl)-4-methyl-1-nitrobenzene (example getting 291) (7,41 g) and acetic acid (70 ml) was added iron powder (5,43 g) and stirred at 80°C for 3 hours. Then insoluble substances were removed from the reaction liquid and the solvent drove away under reduced pressure. After adding ethyl acetate (150 ml) and removal of insoluble substances, the residue was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent thorelii reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to obtain 2-(isopropylphenyl)-4-methylaniline (3,86 g) as a pale yellow solid.

[0193] an Example of retrieving 298

To a mixture of 55% sodium hydride in oil (733 mg) and DMF (20 ml) was added a mixture of 3-(methylsulphonyl)aniline (1.44 g) and THF (20 ml) under cooling with ice and stirred for 30 minutes under ice cooling. After adding dropwise a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxamide (2.0 g) and DMF (30 ml) for 15 minutes, the reaction liquid was again stirred under ice cooling for 15 minutes. After adding 10% aqueous citric acid solution (300 ml) and extraction with ethyl acetate the organic layer was washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was concentrated and the precipitated solid substance was collected by filtration and dried to obtain 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulphonyl)phenyl]amino}pyrimidine-5-carboxamide (1,95 g) as a pale yellow solid.

[0194] an Example of retrieving 299

To a mixture of 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulphonyl)phenyl]amino}pyrimidine-5-carboxamide (example getting 298) (1,95 g) and DMSO (30 ml) was added potassium carbonate (1.81 in) and 30% hydrogen peroxide solution (2.65 ml) and stirred at 50°C for 1.5 hours. The reaction liquid cooling gap is Ali and ice was added 1M hydrochloric acid solution (25 ml) and then water (150 ml) and was stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water to obtain 2-(methylsulfanyl)-4-{[3-(methylsulphonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidin-5-carboxamide (1.40 g) as a pale yellow solid.

[0195] an Example of retrieving 304

To a mixture of 4-chloro-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (example getting 303) (51 mg) and methanol (1 ml) was added sodium methoxide (11 mg) under ice cooling and stirred overnight at room temperature. To the reaction liquid were added water and the solid collected by filtration to obtain 4-methoxy-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (41 mg).

[0196] an Example of retrieving 311

To a mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (example getting 306) (500 mg), dichloromethane (40 ml) and methanol (40 ml) was added a mixture of Oxone® (922 mg) and water (10 ml) and stirred at room temperature for 18 hours. To the reaction liquid were added chloroform and water and the precipitated solid substance was collected by filtration and washed with water to obtain 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (234 mg) as a pale yellow solid.

[0197] an Example of retrieving 339

To a mixture of 4-methoxy-6-[(6-labels is piperidin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (example getting 337) (0.35 g) and water (2.2 ml) was added concentrated hydrochloric acid (2.2 ml) and stirred at 80°C for 1.5 hours. After cooling the reaction liquid was added 1M aqueous sodium hydroxide solution so that the reaction liquid became almost neutral and then the resulting solid was collected by filtration to obtain 4-[(6-methoxypyridine-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (0.34 g).

[0198] an Example of retrieving 342

To a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid (1.50 g) and dichloromethane (15 ml) was added oxalicacid (1.20 ml) and DMF (0,015 ml) under cooling with ice and stirred for 30 minutes under ice cooling and for 2 hours at room temperature. The solvent is kept under reduced pressure, followed by azeotropic distillation with toluene. The obtained residue was dissolved in THF, followed by adding dropwise a 40% aqueous solution of methylamine at -10°C. After completion of adding dropwise, the reaction liquid was concentrated and added water. The formed solid substance was collected by filtration and washed with water to obtain white solids. The solid was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent drove away. To a mixture of the obtained residue and dioxane (20 ml) were added hydrochloride 3-(methylsulphonyl)aniline (432 mg) and N,N-disop operationin (0,73 ml) and stirred at 100°C for 4 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 30:1) to obtain 4-chloro-N-methyl-2-(methylsulfanyl)-6-{[3-(methylsulphonyl)phenyl]amino}pyrimidine-5-carboxamide (445 mg) as a white solid.

[0199] an Example of retrieving 346

To a mixture of 4-chloro-2-(methylsulfanyl)-6-(quinoline-3-ylamino)pyrimidine-5-carboxamide (example getting 344) (0.68 g) and sodium acetate (0,80 g) was added DMF (7 ml) and stirred at 100°C for 6 hours. After the reaction liquid was again reached room temperature, was added water and the resulting solid was collected by filtration to obtain 5-carbarnoyl-2-(methylsulfanyl)-6-(quinoline-3-ylamino)pyrimidine-4-ilaclama (0.71 g).

[0200] an Example of retrieving 349

To 5-carbarnoyl-2-(methylsulfanyl)-6-(quinoline-3-ylamino)pyrimidine-4-racette (example getting 346) (0.71 g) was added ethanol (14 ml) and THF (14 ml) was added 1M aqueous sodium hydroxide solution (6 ml) and stirred at room temperature for 1 hour. Then was added a 1M solution of hydrochloric acid (6 ml) and the precipitated solid substance was collected by filtration and dried to obtain 2-(matilal panel)-6-oxo-4-(quinoline-3-ylamino)-1,6-dihydropyrimidin-5-carboxamide (0,63 g).

[0201] an Example of retrieving 353

A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg), 3-(methylsulphonyl)aniline (467 mg), N,N-diisopropylethylamine (0,48 ml) and dioxane (18 ml) was stirred in a sealed tube at 170°C for 17 hours. After cooling, the mixture was separated using ethyl acetate and water and the organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was washed with chloroform and the solid substance was collected by filtration and dried to obtain 5-chloro-6-ethyl-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (412 mg) as a yellow solid.

[0202] an Example of retrieving 364

To a mixture of 4-chloro-6-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide (example getting 359) (194 mg) and DMF (5 ml) was added sodium acetate (257 mg) and stirred at 100°C for 5 hours. After cooling the reaction liquid was added ethyl acetate and water and the precipitated powdery substance was collected by filtration and dried to obtain a light-yellow solid. To a mixture of this solid substance ethanol (5 ml), methanol (20 ml) and THF (5 ml) was added 1M aqueous sodium hydroxide solution (3 ml) and stirred at room temperature for 1 hour, at 60°C for 1 hour and at 80°C for 1 hour. After cooling the Oia, the reaction liquid was added a 1M solution of hydrochloric acid (3 ml) and the reaction liquid was extracted with chloroform-isopropanol. To the organic layer was added silica gel and the solvent drove away, followed by purification column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 20:1) to give the crude product. This crude product was washed with a small amount of methanol to obtain 4-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (27 mg) as a yellow solid.

[0203] an Example of retrieving 397

To a mixture of 5-chloro-6-ethyl-3-{[4-(methylsulfanyl)phenyl]amino}pyrazin-2-carboxamide (example getting 394) (92 mg) and acetic acid (2.5 ml) was added sodium tungstate dihydrate (29 mg) and 30% hydrogen peroxide solution (0.15 ml) and stirred at room temperature for 30 minutes. After adding water and ethyl acetate to the reaction liquid was added 1M aqueous sodium hydroxide solution and was stirred for 30 minutes and the reaction liquid was separated. After drying over anhydrous sodium sulfate the organic layer was filtered and concentrated. The obtained residue was washed with ethyl acetate to obtain 5-chloro-6-ethyl-3-{[4-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (103 mg).

[0204] an Example of retrieving 398

To a mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazin-2-carboxamide (2.64 g) and pyridine (30 ml) was added methylchloride (2,45 ml) under cooling with ice. After stirring at room the temperature for 5 hours the pyridine drove under reduced pressure and the resulting residue was separated using ethyl acetate and water. The obtained organic layer is washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent drove away with getting a light brown syrup. This light brown syrup was added ethanol (60 ml) and THF (30 ml) and then was added 10% palladium-on-carbon (0.7 g) and stirred at room temperature for 14 hours under hydrogen pressure of 3 atmospheres. After filtration through celite the filtrate is kept under reduced pressure and the residue was diluted with ethyl acetate and then washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 40:1). The crude product washed with diisopropyl ether to obtain 3,5-dichloro-6-isopropylpyridine-2-carboxamide (632 mg) as a white solid.

[0205] an Example of retrieving 399

To a mixture of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (4,00 g) and methanol (50 ml) was added ammonium formate (10.2 g) and water (5 ml) and was stirred for 1 hour until complete dissolution. Then was added 10% palladium-on-carbon (2.0 g) and stirred at room temperature for 65 hours is. After separation of insoluble substances by filtration through celite the solvent and drove to the obtained residue was added chloroform, followed by drying over anhydrous magnesium sulfate. The solvent drove to obtain tert-butyl (4-amino-1-methylcyclohexyl)carbamate (of 3.73 g) as a colourless syrup.

[0206] an Example of retrieving 400

To a mixture of tert-butyl (4-amino-1-methylcyclohexyl)carbamate (example getting 399) (of 3.73 g) and ethanol (30 ml) was added 4M solution of hydrogen chloride in ethyl acetate (30 ml) under cooling with ice and stirred at room temperature for 20 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to obtain the dihydrochloride of 1-methylcyclohexane-1,4-diamine (2.10 g) as a white solid.

[0207] an Example of retrieving 412

To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridines-1(2H)-carboxylate (3,16 g), 4-bromo-3-methoxy-1-nitrobenzene (2,63 g) and DMF (31,6 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in the form of a product join with dichloromethane (0.50 g) and potassium carbonate (4,24 g) and stirred at 80°C for 4 hours. After concentrating the mixture under reduced pressure was added water and ethyl acetate and insoluble materials were filtered through celite. The organic layer was washed with a saturated aqueous solution x is orida sodium. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: n-hexane:ethyl acetate=1:0 to 2:1) to obtain tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridines-1(2H)-carboxylate (of 2.21 g) as a yellow solid.

[0208] an Example of retrieving 413

To a mixture of tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridines-1(2H)-carboxylate (example getting 412) (2,21 g), ethanol (40 ml) and THF (20 ml) was added 10% palladium-on-carbon (1.0 g) and stirred at room temperature for 3 hours in hydrogen atmosphere at normal pressure. After filtration through celite the filtrate is kept under reduced pressure to obtain tert-butyl 4-(4-amino-2-methoxyphenyl)piperidine-1-carboxylate (1.97 g) as a gray solid.

[0209] an Example of retrieving 417

A mixture of 5-chloro-6-(1-hydroxy-1-methylethyl)-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (example getting 416) (430 mg) and acetic acid (10 ml) was stirred at 120°C for 5 hours. After cooling the reaction liquid solvent drove and were added water and saturated aqueous solution of sodium bicarbonate for neutralization. After extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride and dried over be the aqueous magnesium sulfate. The solvent is kept off and the residue is washed with diisopropyl ether to obtain 5-chloro-6-Isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (265 mg) as an orange solid.

[0210] an Example of retrieving 430

To a mixture of 7-nitro-2H-1,4-benzoxazin-3(4H)-she (2.0 g), benzyltriethylammonium ammonium (470 mg), potassium carbonate (4,27 g) and acetonitrile (60 ml) was added 1-bromo-2-chlorate (1,28 ml) and stirred at 75°C for 3 hours. After cooling the reaction liquid was added a saturated aqueous solution of sodium bicarbonate and the reaction liquid was extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform) to give 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazin-3(4H)-she (1.92 g) as a yellow powder.

[0211] an Example of retrieving 432

To a mixture of 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazin-3(4H)-it (Example of getting 430) (1.08 g), potassium carbonate (0.87 g) and acetonitrile (10,8 ml) was added 1-methylpiperazine (1.39 ml) and stirred at 80°C for 48 hours. After cooling the reaction liquid was added a saturated aqueous solution of sodium bicarbonate and the reaction liquid was extracted with ethyl acetate and the extract washed nasy the n aqueous solution of sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 20:1) to obtain 4-[2-(4-methylpiperazin-1-yl)ethyl]-7-nitro-2H-1,4-benzoxazin-3(4H)-she (690 mg) as a yellow liquid.

[0212] an Example of retrieving 440

A mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazin-2-carboxamide (1.10 g), 4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)aniline (example getting 436) (1,58 g), N,N-diisopropylethylamine (0,80 ml) and dioxane (31 ml) was stirred at 100°C for 135 hours. After cooling, was added water, followed by extraction with ethyl acetate. Then the insoluble matter was separated by filtration, and the insoluble substance was dissolved in methanol and then mixed with the organic layer. The solvent is kept under reduced pressure, followed by drying to obtain a brown solid. A mixture of this brown solid and acetic acid (30 ml) was stirred at 120°C for 5 hours. After removal of the solvent was added saturated aqueous sodium hydrogen carbonate solution and the precipitated solid substance was collected by filtration and washed with water. The resulting solid was purified column chromatography on basic silica gel (eluent: chloroform) to obtain 5-chloro-6-and propenyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamide (0,99 g) as a yellow solid.

[0213] an Example of retrieving 444

After stirring a mixture of palladium acetate (188 mg), 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine) (781 mg), cesium carbonate (4.09 g) and THF (20 ml) for 30 minutes was added a mixture of 1-bromo-3-methoxy-5-nitrobenzene (1,94 g), 1-methylpiperazine (2.76 ml) and THF (20 ml) and was heated at the boiling point under reflux for 14 hours. After cooling, the reaction liquid was diluted with ethyl acetate and the insoluble matter was separated by filtration. After extraction of the filtrate 2M solution of hydrochloric acid the resulting aqueous layer was podslushivaet 50% aqueous potassium hydroxide solution and then was extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 20:1) to give 1-(3-methoxy-5-nitrophenyl)-4-methylpiperazine (1.01 g) as an orange syrup.

[0214] an Example of retrieving 454

To a mixture of tert-butyl 4-(4-amino-2-methoxyphenyl)piperidine-1-carboxylate (example getting 413) (4,25 g) and THF (100 ml) was added sodium hydrogen carbonate (1.28 g) and water (30 ml) followed by the addition dropwise of benzylchloride (1,98 ml) under ice cooling and stirring over night. After the addition of water and extraction with ethyl acetate, the extract was washed with saturated is one solution of sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: n-hexane:ethyl acetate=2:1) to obtain tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (4,92 g) as a colorless amorphous substance.

[0215] an Example of retrieving 455

A mixture of tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (example getting 454) (4,92 g), triperoxonane acid (10 ml) and 1,2-dichloroethane (50 ml) was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure and after adding saturated aqueous sodium hydrogen carbonate solution, the residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was utverjdali by adding diethyl ether to obtain benzyl (3-methoxy-4-piperidine-4-ylphenyl)carbamate (3,24 g) as a white solid.

[0216] an Example of retrieving 464

To a mixture of benzyl (3-methoxy-4-piperidine-4-ylphenyl)carbamate (example getting 455) (1.52 g) and 1,2-dichloroethane (70 ml) was added formalin (3,62 ml) and triacetoxyborohydride sodium (1.42 g) and was stirred over night at room temperature. After adding water and a saturated aqueous solution of sodium bicarbonate, the reaction liquid e which was strayaway chloroform and the organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure the residue was purified column chromatography on silica gel (eluent: chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0,1) to obtain benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (1.26 g) as a white solid.

[0217] an Example of retrieving 467

To a mixture of 7-amino-4-[3-(4-methylpiperazin-1-yl)propyl]-2H-1,4-benzoxazin-3(4H)-it (Example of getting 435) (300 mg) and THF (9 ml) was gradually added dropwise a complex of borane-tetrahydrofuran (3.0 ml, 1M solution in THF) under ice cooling in an argon atmosphere. After completion of adding dropwise, the mixture was stirred at room temperature for 1 hour and then stirred at 70°C for 3 hours. After the gradual addition of methanol (10 ml) to the reaction liquid while cooling with ice, was added 1M hydrochloric acid solution (5 ml) and then 1M aqueous sodium hydroxide solution (10 ml) and stirred at room temperature for 1 hour. After dilution with water the reaction liquid was extracted with ethyl acetate. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 20:1) to obtain 4-[3-(4-methylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-amine (120 mg).

[0218] an Example of retrieving 468

To a mixture of benzyl [3-methoxy-4-(1-methylpiperid the DIN-4-yl)phenyl]carbamate (example getting 464) (1.26 g), ethanol (20 ml) and THF (10 ml) was added 5% palladium-on-carbon (0,38 g) and was stirred over night at room temperature in hydrogen atmosphere under normal pressure. After filtration through celite the filtrate is kept under reduced pressure to obtain 3-methoxy-4-(1-methylpiperidin-4-yl)aniline (0,80 g) as a pink solid.

[0219] an Example of retrieving 472

To a mixture of 2-[methyl(3-nitrophenyl)amino]ethanol (780 mg) and dichloromethane (20 ml) was sequentially added triethylamine (0,66 ml) and methylchloride (0,37 ml) under ice cooling and stirred for 3 hours. To the reaction liquid were added water and the organic layer was separated and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent drove to obtain 2-[methyl(3-nitrophenyl)amino]ethylmethanesulfonate (1.0 g) as a yellow solid.

[0220] an Example of retrieving 473

A mixture of 2-[methyl(3-nitrophenyl)amino]ethylmethanesulfonate (example getting 472) (1.0 g), 1-methylpiperazine (1,61 ml) and NMP (5 ml) was subjected to interaction at 130°C for 30 minutes using a microwave reaction system. The reaction liquid was diluted with water, was extracted with a mixed solvent consisting of chloroform and methanol (10:1), and then washed with a saturated aqueous solution of sodium chloride. After drying over betwedn the m magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol:saturated aqueous ammonia = 10:1:0,1) to obtain N-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) as a yellow oil.

[0221] an Example of retrieving 502

To a mixture of 8-(2-methoxy-5-nitrophenyl)-1,4-dioxa-8 azaspiro[4,5]decane (example getting 495) (795 mg) and dioxane (16 ml) was added 4M solution of hydrochloric acid (6.8 ml) and was stirred over night at 80°C. the Reaction liquid was concentrated under reduced pressure and the concentrate was added a saturated aqueous solution of sodium bicarbonate. The concentrate was extracted with chloroform and then washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: ethyl acetate:n-hexane) to obtain 1-(2-methoxy-5-nitrophenyl)piperidine-4-it (296 mg).

[0222] an Example of retrieving 503

To a mixture of 1-(2-methoxy-5-nitrophenyl)piperidine-4-it (example of getting 502) (296 mg), 1-methylpiperazine (0,20 ml) and 1,2-dichloroethane (11 ml) was added triacetoxyborohydride sodium (385 mg) and was stirred over night at room temperature. After adding water and a saturated aqueous solution of sodium bicarbonate, the reaction liquid was extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methane is=100:0 to 10:1) to give 1-[1-(2-methoxy-5-nitrophenyl)piperidine-4-yl]-4-methylpiperazine (0.40 g) as a brown oil.

[0223] an Example of retrieving 516

To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 ml) was added 1,4-dioxa-8 azaspiro[4,5]decane (4.15 g) and stirred at 80°C for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol=100:0 to 100:1) to give 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8 azaspiro[4,5]decane (5,13 g) as a yellow solid.

[0224] an Example of retrieving 545

To a mixture of 5-chloro-6-(2-hydroxypropan-2-yl)-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (example getting 544) (300 mg) and triperoxonane acid (3 ml) was added triethylsilane (0,55 ml) under cooling with ice and stirred under ice cooling for 10 minutes and at room temperature for 22 hours. After concentration of the reaction liquor, the residue was diluted with chloroform and washed with a saturated aqueous solution of sodium bicarbonate. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0,1) to obtain the crude product. N is the purified product washed with diisopropyl ether to obtain 5-chloro-6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (219 mg) as an orange solid.

[0225] Table 7-47 represent chemical structures of the compounds obtained in the examples described above obtain, and the chemical structure of the compounds of examples of the preparation obtained in the same manner as described above in the examples of obtaining, using the appropriate starting materials. Table 48-84 present methods of preparation and physical and chemical data of the compounds of these examples is received.

[0226] Example 4

A mixture of 4-{[2-(isopropylphenyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (Example getting 294) (200 mg), 1-(aminomethyl)-N,N-dimethylcyclohexylamine (409 mg) and NMP (1 ml) was heated at 180°C for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate and the precipitated crystalline substance was collected by filtration and washed with ethyl acetate to obtain white solids. To the white solid substance was added to a mixed solvent consisting of ethanol and water was heated and then cooled, and the precipitated solid substance was collected by filtration to obtain 2-({[1-(dimethylamino)cyclohexyl]methyl}amino)-4-{[2-(isopropylphenyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidin-5-carboxamide (136 mg) as a white solid.

[0227] Example 19

A mixture of 4-{[2-(isopropylphenyl)phenyl]amino}2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (example getting 294) (200 mg), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (1.12 g) and NMP (1 ml) was heated at 180°C for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column chromatography on silica gel (chloroform:methanol=100:0 to 20:1) to give a white amorphous substance. To a mixture of white amorphous substance, ethyl acetate (10 ml) and ethanol (5 ml) was added 4M solution of hydrogen chloride in ethyl acetate (5 ml) under ice cooling and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and dried to obtain hydrochloride of 4-{[2-(isopropylphenyl)phenyl]amino}-6-oxo-2-[(piperidine-2-ylmethyl)amino]-1,6-dihydropyrimidin-5-carboxamide (126 mg) as a white solid.

[0228] Example 29

To a mixture of tert-butyl 3-[(5-carbarnoyl-4-{[2-(isopropylphenyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidin-2-yl)amino]piperidine-1-carboxylate (example 28) (299 mg) and ethyl acetate (3 ml) was added 4M solution of hydrogen chloride in ethyl acetate (2.7 ml) under cooling with ice and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and is sewed with getting dihydrochloride 4-{[2-(isopropylphenyl)phenyl]amino}-6-oxo-2-(piperidine-3-ylamino)-1,6-dihydropyrimidin-5-carboxamide (194 mg) as a white solid.

[0229] Example 31

To a mixture of the dihydrochloride of 4-{[2-(isopropylphenyl)phenyl]amino}-6-oxo-2-(piperidine-3-ylamino)-1,6-dihydropyrimidin-5-carboxamide (example 29) (67 mg) and pyridine (1.3 ml) was added methylchloride (0.10 ml) under cooling with ice and stirred for 1 hour. After adding ethanol to the reaction system, the reaction mixture was concentrated. The resulting residue was separated using chloroform and a saturated aqueous solution of sodium bicarbonate and the organic layer was dried. The organic layer was concentrated, followed by azeotropic distillation with toluene. The obtained residue was utverjdali with ethyl acetate-hexane. The resulting solid is recrystallized from ethanol to obtain 4-{[2-(isopropylphenyl)phenyl]amino}-2-{[1-(methylsulphonyl)piperidine-3-yl]amino}-6-oxo-1,6-dihydropyrimidin-5-carboxamide (43 mg).

[0230] Example 37

A mixture of 4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidin-5-carboxamide (example getting 311) (234 mg), 1-(aminomethyl)cyclohexanamine (172 mg) and NMP (2 ml) was stirred at 80°C for 30 minutes. After cooling, the reaction liquid was diluted with ethyl acetate and the precipitated solid substance was collected by filtration. This solid was heated with ethanol-water and washed with obtaining 2-{[(1-aminocyclohexane)methyl]amino}-4-{[3-(methylcarbamoyl)is enyl]amino}-6-oxo-1,6-dihydropyrimidin-5-carboxamide (215 mg) as a white solid.

[0231] Example 84

A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (example getting 353) (150 mg), 1-(aminomethyl)cyclohexanamine (163 mg) and NMP (1 ml) was heated at 180°C for 20 minutes using a microwave reaction system. The reaction liquid was cooled and was added ethyl acetate and water and was stirred for 30 minutes. Then the precipitated powdery substance was collected by filtration. This powder was heated with ethanol-water (1:1) and washed with obtaining 5-{[(1-aminocyclohexane)methyl]amino}-6-ethyl-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (112 mg) as a white solid.

[0232] Example 146

A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylamino (374 mg) and NMP (1 ml) was stirred at 230°C for 1 hour using a microwave reaction system. Then to the reaction liquid was added TRANS-4-aminocyclohexanol (524 mg) and stirred at 190°C for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was separated using ethyl acetate and water and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is kept off and the residue was purified column is a chromatography on silica gel (eluent: chloroform:methanol=10:0 to 30:1) to give the crude product. This product was heated with ethanol and washed with obtaining a light yellow solid. This light yellow solid substance was added ethyl acetate and heated and the insoluble matter was separated by filtration and the filtrate was concentrated. After concentration of the filtrate the residue was heated and washed with ethanol to obtain 3-{[3-chloro-4-(methylsulphonyl)phenyl]amino}-6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin-2-carboxamide (39 mg) as a pale yellow solid.

[0233] Example 159

To a mixture of 5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (example 111) (298 mg), chloroform (40 ml) and acetonitrile (10 ml) was added N-chlorosuccinimide (108 mg) and stirred at 70°C for 8 hours. After cooling the reaction liquid was added silica gel and the solvent drove away, followed by purification column chromatography on silica gel (eluent: chloroform:methanol=10:0 to 10:1). The crude product was utverjdali of chloroform and collected by filtration. The obtained solid was heated with ethyl acetate and washed with ethyl acetate to obtain 6-chloro-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (189 mg) as a white solid.

[0234] Example 181

To a mixture of 5-[(TRANS-4-hydroxycyclohexyl)amino]3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (example 111) (150 mg), chloroform (40 ml) and acetonitrile (20 ml) was added N-bromosuccinimide (69 mg) and stirred at room temperature for 2 hours. To the reaction liquid was added silica gel and the solvent drove away, followed by purification column chromatography on silica gel (eluent: chloroform:methanol=10:0-10:1). The crude product was utverjdali using ethyl acetate and washed with ethyl acetate to obtain 6-bromo-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (130 mg) as a pale yellow solid.

[0235] Example 190

To a mixture of 5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (example 111) (150 mg), chloroform (40 ml) and acetonitrile (20 ml) was added N-jodatime (87 mg) and stirred at room temperature for 2 hours. To the reaction liquid was added silica gel and the solvent drove away, followed by purification column chromatography on silica gel (eluent: chloroform:methanol=10:0 to 10:1). The crude product was utverjdali using ethyl acetate and washed with ethyl acetate to obtain 5-[(TRANS-4-hydroxycyclohexyl)amino]-6-iodine-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (153 mg) as a pale yellow solid.

[0236] Example 196

A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulphonyl)phenyl]amino}PI is Azin-2-carboxamide (example getting 353) (8,8 mg), 1 methylpiperidin-3-ylamine (8.0 mg) and NMP (0.5 ml) was heated at 190°C for 30 minutes using a microwave reaction system. After cooling the reaction liquid organic layer is kept under reduced pressure and the residue was separated and purified using HPLC (column: SunFire® C18, 5 microns, 19 mm × 100 mm, solvent: MeOH/0.1% of HCOOH-H2O = 10/90 (0 min)-10/90 (1 min)-95/5 (9 min)-95/5 (12 min), flow rate: 25 ml/min) to give (6-ethyl-5-[(1-methylpiperidin-3-yl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (2.4 mg).

[0237] Example 302

To a mixture of 5-[(4-amino-4-methylcyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}-6-propylpyrazine-2-carboxamide (example 301) (89 mg) and dichloromethane (5 ml) was added formalin (0,30 ml) and triacetoxyborohydride sodium (82 mg) and stirred at room temperature for 1.5 hours. After dilution of the reaction liquid chloroform was washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. After removal of the desiccant by filtration was added silica gel and the solvent drove away, followed by purification of the residue column chromatography on silica gel (eluent: chloroform:methanol:saturated aqueous ammonia=10:0:0 to 10:1:0,1). The obtained residue was washed with ethyl acetate to obtain 5-{[4-(dimethylamino)-4-methylcyclohexyl]amino}-3-{[3-(methylsulfone the l)phenyl]amino}-6-propylpyrazine-2-carboxamide (31 mg) as a pale yellow solid.

[0238] Example 309

To a mixture of 6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]-3-[(4-methyl-3-nitrophenyl)amino]pyrazin-2-carboxamide (example 308) (242 mg) and methanol (10 ml) was added 5% palladium-on-carbon (25 mg) was stirred in hydrogen atmosphere at room temperature for 4 hours. After filtration of the reaction liquid, the filtrate was concentrated under reduced pressure to obtain 3-[(3-amino-4-were)amino]-6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]pyrazin-2-carboxamide (162 mg) as a green solid.

[0239] Example 310

To a mixture of 3-[(3-amino-4-were)amino]-6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]pyrazin-2-carboxamide (example 309) (150 mg), THF (2 ml) and DMF (2 ml) was added N,N-diisopropylethylamine (49 mg) and the acid chloride of acrylic acid (34 mg) under ice cooling and stirred for 30 minutes. The reaction liquid was poured into water and was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol) to give 3-{[3-(acrylamido)-4-were]amino}-6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]pyrazin-2-carboxamide (48 mg) as a pale W is LEGO powder.

[0240] Example 343

To a mixture of 5-[(TRANS-4-hydroxycyclohexyl)amino]-6-Isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (example 342) (205 mg), ethanol (20 ml) and THF (10 ml) was added 10% palladium-on-carbon (100 mg) in an atmosphere of hydrogen and stirred at room temperature for 18 hours. After removal of catalyst by filtration, the solvent is kept off and the residue was purified column chromatography on basic silica gel (eluent: chloroform). The obtained yellow solid was washed with ethyl acetate to obtain 5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamide (136 mg) as a yellow solid.

[0241] Example 381

To a mixture of tert-butyl 4-[4-({3-carbarnoyl-5-ethyl-6-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin-2-yl}amino)-2-methoxyphenyl]piperidine-1-carboxylate (example 382) (270 mg) and ethyl acetate (10 ml) was added 4M solution of hydrogen chloride in ethyl acetate (4 ml) under ice cooling and stirred at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure and to the residue was added saturated aqueous sodium hydrogen carbonate solution and chloroform. The precipitated solid was collected by filtration and dried to obtain 6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-[(3-methoxy-4-piperidine-4-and what phenyl)amino]pyrazin-2-carboxamide (85 mg) as a pale yellow solid.

[0242] Example 405

To a mixture of 6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-[(4-piperidine-4-ylphenyl)amino]pyrazin-2-carboxamide (example 358) (43 mg) and dichloroethane (1 ml) was added pyridine (0.01 ml) and acetic anhydride (0.01 ml) under cooling with ice and stirred at room temperature for 20 minutes. After adding a saturated aqueous solution of sodium bicarbonate, the reaction liquid was separated using chloroform and a saturated aqueous solution of sodium bicarbonate. After drying over anhydrous sodium sulfate the organic layer was concentrated and the obtained residue was utverjdali using ethyl acetate-hexane to obtain 3-{[4-(1-acetylpiperidine-4-yl)phenyl]amino}-6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin-2-carboxamide (26 mg) as a white solid.

[0243] Example 436

To a mixture of methyl 4-[(5-carbarnoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylate (example 435) (126 mg), THF (2 ml) and methanol (2 ml) was added 10% aqueous sodium hydroxide solution (1 ml) and was heated at the boiling point under reflux for 2 hours. To the reaction liquid was added 10% hydrochloric acid solution to bring the pH to about 7 and the formed solid substance was collected by filtration. This solid was purified column chromate what graphy on silica gel (eluent: chloroform:methanol) to give 4-[(5-carbarnoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (example 436) (47 mg), which was iskopaemye product, in the form of light yellow to white powder and 4-[(5-carbarnoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (example 437) (59 mg), which was a highly polar product as a pale yellow powder.

[0244] Example 438

To a mixture of 4-[(5-carbarnoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (example 436) (62 mg), o-anisidine (42 mg) and DMF (2 ml) was added 1-hydroxy-1H-benzotriazole monohydrate (46 mg), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (65 mg) and stirred at room temperature for 7 hours. The reaction liquid was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate and the solvent is kept at reduced pressure. The residue was purified column chromatography on silica gel (eluent: chloroform:methanol) to give 6-ethyl-5-({4-[(2-methoxy-phenyl)carbarnoyl]cyclohexyl}amino)-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-carboxamide (33 mg) as a yellow powder.

[0245] Example 495

A mixture of 6-chloro-3-{[3-(1,4-dioxa-8 azaspiro[4,5]DECA-8-is l)-4-methoxyphenyl]amino}-5-[(TRANS-4-hydroxycyclohexyl)amino]pyrazin-2-carboxamide (example 482) (0,80 g), acetic acid (4 ml) and water (4 ml) was stirred at 80°C for 3 hours. To the reaction liquid was added concentrated hydrochloric acid (1 ml) and stirred at 80°C for 2 hours. The reaction liquid was cooled and concentrated under reduced pressure and then was added chloroform, followed by washing with a saturated aqueous solution of sodium bicarbonate. After drying the organic layer over anhydrous magnesium sulfate, the solvent drove away, followed by purification column chromatography on silica gel (eluent: chloroform:methanol=10:1 to 30:1) to obtain 6-chloro-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazin-2-carboxamide (0.74 g) as a yellow amorphous substance.

[0246] Example 499

To a mixture of 6-chloro-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazin-2-carboxamide (example 495) (0,346 mg), N-methylpiperazine (0,12 ml) and 1,2-dichloroethane (10 ml) was added triacetoxyborohydride sodium (225 mg) and stirred at room temperature for 5 hours. After adding a saturated aqueous solution of sodium bicarbonate, the reaction liquid was extracted with chloroform and the organic layer was washed with a saturated aqueous solution of sodium chloride. After drying over anhydrous sodium sulfate, the solvent is kept at Pont the leaders introduce pressure and the residue was purified column chromatography on silica gel (eluent: chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0,1) to obtain the crude product. The crude product was utverjdali using ethyl acetate-diisopropyl ether and then washed with ethyl acetate to obtain 6-chloro-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-methoxy-3-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide (39 mg) as a pale yellow solid.

[0247] Example 508

A mixture of 6-bromo-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (example 181) (50 mg), cyclopropylboronic acid (18 mg), tetranitroaniline (24 mg), potassium carbonate (71 mg), dioxane (2.5 ml) and water (0.5 ml) was stirred at 115°C during the night. After cooling, the reaction liquid was separated using chloroform, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. After drying the organic layer was concentrated and the obtained residue was purified column chromatography on silica gel (eluent: chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0,1). The obtained residue was utverjdali using ethyl acetate-hexane to obtain 6-cyclopropyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulphonyl)phenyl]amino}pyrazin-2-carboxamide (10 mg) as a yellow solid.

[0248] Example 534

To a mixture of 5-[(1-benzylpiperidine-4-yl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]enyl}amino)pyrazin-2-carboxamide (example 507) (1.31 g), ethanol (26 ml) and acetic acid (13 ml) was added palladium hydroxide (0.65 g) and stirred in a hydrogen atmosphere at room temperature for 3 days. After separation of the catalyst by filtration, the solvent was concentrated and separated using chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was concentrated to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(piperidine-4-ylamino)pyrazin-2-carboxamide (0.73 g) as a pale yellow solid.

[0249] Table 85-164 represent chemical structures of the compounds obtained in the examples described above, and the chemical structure of the compounds of examples obtained in the same manner as described above in the examples, using appropriate starting materials. Table 165-183 present methods of preparation and physical and chemical data of the compounds of these examples.

[0250]

2
Table 48
Example recip.SYN.Data
1Example of getting 299ESI-: 402
Example of getting 298ESI-: 420
3Example of getting 2921H-NMR (CDCl3): a 1.11 (3H, users), to 1.21 (3H, users), 2,17 (3H, s), or 3.28 (2H, users), 3,51 (2H, users), 3,66 (2H, users), 6,66 of 6.68 (2H, m), 7,03 (1H, DD, J=0.8 Hz, 8.0 Hz).
4Example 4EI: 236
5Example of getting 299ESI-: 388
6Example of getting 298ESI-: 406
7Example of getting 2921H-NMR (CDCl3): 1,50-of 1.65 (6H, m)of 2.16 (3H, s)to 3.36 (2H, users), 3,71 (4H, m), 6,66-6,69 (2H, m), 7,02 (1H, d, J=7,6 Hz).
8Example 4EI: 248
9Example of getting 2991H-NMR (DMSO-d6): 1,48-to 1.59 (6H, m), is 2.30 (3H, s)to 2.41 (3H, s)to 3.33 (2H, users), of 3.54 (2H, users), 7,02 (1H, DD, J=1.2 Hz, 8.0 Hz), 7,28 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=4.0 Hz), to 7.99 (1H, d, J=1.2 Hz), 9,16 (1H, d, J=4.4 Hz), 12,68 (1H, s), 12,84 (1H, s).
10ESI-: 418
11Example of getting 2921H-NMR (CDCl3): of 1.24 (6H, d, J=6.8 Hz), 2,19 (3H, s), 3,70 (2H, users), 4,23-the 4.29 (1H, m), of 5.85 (1H, users), 6,97 (1H, DD, J=1.6 Hz and 7.6 Hz), 7,06 (1H, d, J=7,6 Hz), 7,13 (1H, d, J=1.6 Hz).
12Example 41H-NMR (CDCl3): of 1.29 (6H, d, J=6.4 Hz), 2,65 (3H, s), 4,25-4,34 (1H, m), of 5.99 (1H, users), 7,42 (1H, d, J=8.0 Hz), 7,94 (1H, DD, J=2.0 Hz, 8.0 Hz), 8,30 (1H, d, J=1.6 Hz).

Table 49
Example recip.SYN.Data
13Example of getting 2991H-NMR (DMSO-d6): to 1.14 (6H, d, J=6.4 Hz), 2,31 (3H, s), 2,43 (3H, s), 4,06-4,11 (1H, m), 7,31 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=4.4 Hz), 7,54 (1H, DD, J=1.6 Hz, 8.0 Hz), 8,14 (1H, d, J=7,6 Hz), of 8.47 (1H, d, J=1.6 Hz), 9,17 (1H, d, J=4.4 Hz), 12,69 (1H, s), 12,84 (1H, s).
14Example of getting 298ESI-: 392
15Example of getting 2991H-NMR (DMSO-d6): 2,31 (3H, s), 244 (3H, C)was 2.76 (3H, d, J=4.4 Hz), 7,31 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=4.4 Hz), 7,52 (1H, DD, J=1.6 Hz, 8.0 Hz), at 8.36 (1H, d, J=4,8 Hz), 8,49 (1H, d, J=1.6 Hz), 9,19 (1H, d, J=4.4 Hz), 12,70 (1H, s), is 12.85 (1H with).
16Example of getting 298ESI-: 364
17Example of getting 299ESI-: 424
18Example of getting 298ESI-: 442
19Example of getting 299ESI-: 436
20Example of getting 298ESI-: 454
21Example of getting 2921H-NMR (CDCl3): 3,00 (3H, d, J=4.9 Hz), of 3.94 (2H, m), 6,44 (1H, m), to 6.58 (1H, DD, J=2,4 Hz, 8.5 Hz), only 6.64 (1H, d, J=2.4 Hz), to 7.67 (1H, d, J=8,5 Hz).
22Example 41H-NMR (CDCl3): of 3.07 (3H, d, J=4.9 Hz), x 6.15 (1H, m), 7,82 (1H, d, J=8,3 Hz), 8,17 (1H, DD, J=2.2 Hz, 8,3 Hz), 8,29 (1H, d, J=2.2 Hz).
23Example of getting 299ESI-: 366
24Example of getting 28 ESI-: 384
25Example of getting 2921H-NMR (CDCl3): of 1.05 (3H, t, J=7,1 Hz)of 1.24 (3H, t, J=7,1 Hz), 3,18 (2H, q, J=7,1 Hz), the 3.35 (1H, m), 3,83 (3H, m), 6,56 (1H, DD, J=2.2 Hz, 8.1 Hz), to 6.67 (1H, d, J=2.2 Hz), 7,03 (1H, d, J=8,1 Hz).

Table 50
Example recip.SYN.Data
26Example 41H-NMR (CDCl3): of 1.09 (3H, t, J=7,1 Hz)of 1.29 (3H, t, J=7,1 Hz), 3,06-is 3.21 (2H, m), 3,35-3,44 (1H, m), 3,76-of 3.85 (1H, m), 7,74 (1H, d, J=8,3 Hz), 8,18 (1H, DD, J=2.2 Hz, 8,3 Hz), 8,29 (1H, d, J=2.2 Hz).
27Example of getting 299ESI-: 408
28Example of getting 298ESI-: 426
29Example of getting 2921H-NMR (CDCl3): a 1.08 (6H, d, J=6.4 Hz), of 2.21 (1H, s), 3,40-3,47 (1H, m), is 4.21 (1H, d, J=6.8 Hz), 7,14-to 7.18 (1H, m).
30Example of getting 2991H-NMR (DMSO-d6 ): 0,86-to 0.96 (6H, m), 2,43 (1H, s), 3,15-3,20 (1H, m)to 3.35 (3H, s), 7,43-of 7.70 (4H, m), 8,23 (1H, s), 9,18 (1H, s), 12,79 (1H, s), 13,06 (1H, s).
31Example of getting 298ESI-: 428
32Example of getting 2991H-NMR (DMSO-d6): 2,32-2,54 (9H, m), 7,33-of 7.70 (4H, m), charged 8.52 (1H, s), 9,18 (1H, s), 12,81 (1H, s), to 13.09 (1H, s).
33Example of getting 298ESI-: 400
34Example of getting 2991H-NMR (DMSO-d6): 1,45-to 1.59 (6H, m), of 2.54 (3H, s), of 3.12 (2H, m), 3,56-3,63 (2H, m), 7,28-7,30 (1H, m), 7,38-7,41 (1H, m), 7,58-to 7.59 (1H, m), 7,99-to 7.99 (1H, m), 9,16-9,17 (1H, m), is 12.85 (1H, users), 13,13 (1H, users).
35Example of getting 298ESI-: 438
36Example of getting 2921H-NMR (CDCl3): a 1.25 (6H, d, J=6.6 Hz), of 3.94 (2H, m), 4,20-4,32 (1H, m), from 6.22 (1H, m), 6,55 return of 6.58 (1H, m), 6,63 (1H, d, J=2.2 Hz), to 7.61 (1H, DD, J=1.2 Hz, 8,3 Hz).

Table 51
Example recip.SYN. Data
37Example 41H-NMR (CDCl3): of 1.30 (6H, d, J=6.6 Hz), 4,28 is 4.36 (1H, m), 5,90 (1H, m), 7,78 (1H, d, J=8.5 Hz), 8,16 (1H, DD, J=2.2 Hz, 8,3 Hz), of 8.28 (1H, d, J=2.2 Hz).
38Example of getting 2991H-NMR (DMSO-d6): to 1.14 (6H, d, J=6.6 Hz), of 2.56 (3H, c), 4,01-was 4.02 (1H, m), of 7.36-7,37 (2H, m), 7,58-to 7.59 (1H, m), 7,94-of 7.95 (1H, m), 8,24 compared to 8.26 (1H, m), 9,17 (1H, m), is 12.85 (1H, users), 13,14 (1H, users).
39Example of getting 298ESI-: 412
40Example of getting 2921H-NMR (CDCl3): 1,43 of 1.50 (2H, m), 1,57-to 1.63 (4H, m), 3,11-3,13 (4H, m), a-3.84 (1H, c), 6,16 and 6.25 (2H, m), 7,62-7,66 (1H, m).
41An example of retrieving 411H-NMR (CDCl3): 1,54-to 1.63 (6H, m)of 3.25 (4H, t, J=5.6 Hz), Android 4.04 (1H, c), 7,83 (1H, d, J=0.2 Hz), 7,88 (1H, DD, J=0.2 Hz, 8,8 Hz), 8,07 (1H, d, J=8,8 Hz).
42Example of getting 299ESI-: 452
43Example of getting 2981H-NMR (DMSO-d6): 1,44 of 1.50 (6H, m), 3,30 totaling 3.04 (4H, m), 3,10 (1H, c), 3,85 (1H, c), 7,46-of 7.48 (1H, m), 7,55-7,56 (1H, m), 7,6-7,66 (1H, m), to 7.93 (1H, users), at 9.53 (1H, users).
44Example of getting 2921H-NMR (CDCl3): of 1.09 (6H, t, J=7.2 Hz), 2,28 (4H, q, J=7.2 Hz), a-3.84 (1H, c), 6,17-6,23 (2H, m), to 7.67-7,71 (1H, m).
45An example of retrieving 411H-NMR (CDCl3): of 1.13 (6H, t, J=7.2 Hz), 3,37 (4H, q, J=7.2 Hz), Android 4.04 (3H, c), of 7.82 (1H, d, J=2,8 Hz), 7,87 (1H, DD, J=2,8 Hz and 8.8 Hz), to 8.12 (1H, d, J=8,8 Hz).
46Example of getting 299ESI-: 440
47Example of getting 298ESI-: 458

Table 52
Example recip.SYN.Data
48Example obtain 481H-NMR (CDCl3): of 1.26 (6H, d, J=6.4 Hz), 3,66 (2H, users), 4,25-or 4.31 (1H, m), to 6.57 (1H, users), 6,69-of 6.73 (1H, m), 6.89 in (1H, DD, J=8,4 Hz and 11.6 Hz), 7,35 (1H, DD, J=3.2 Hz, 6.8 Hz).
49Example of getting 2991H-NMR (DMSO-d6): to 1.14 (6H, d, J=6.4 Hz), 2,39 (3H, s), 4,01-4,06 (1, m), from 7.24 (1H, t, J=9,2 Hz), 7,49-7,53 (2H, m), 7,88 (1H, DD, J=2,8 Hz, 6.4 Hz), 8,18 (1H, d, J=8.0 Hz), 9,16 (1H, d, J=4.4 Hz), 12,74 (1H, s), 12,96 (1H, s).
50Example of getting 2981H-NMR (DMSO-d6): to 1.14 (6H, d, J=6,8 Hz)to 2.41 (3H, s), 4,01-4,07 (1H, m), 7,24 (1H, t, J=9,2 Hz), 7,62-7,66 (1H, m), 7,82-to 7.84 (1H, m), 7,87 (1H, s)to 8.14 (1H, s), 8,15 (1H, m), 9,38 (1H, s).
51Example obtain 481H-NMR (CDCl3): 1,50-of 1.65 (6H, m), or 3.28 (2H, users), 3,63 (2H, users), 3,71 (2H, users), 6,61-of 6.65 (2H, m)6,86 (1H, t, J=7,6 Hz).
52Example of getting 2991H-NMR (DMSO-d6): 1,44-to 1.61 (6H, m), of 2.45 (3H, s), 3,21 (2H, users)and 3.59 (2H, users), 7,26 (1H, t, J=8,8 Hz), 7,49-7,53 (2H, m), 7,63 (1H, DD, J=2,4 Hz, 6.4 Hz), 9,14 (1H, d, J=4.4 Hz), 12,72 (1H, s), 12,89 (1H, s).
53Example of getting 2981H-NMR (DMSO-d6): 1,45-of 1.62 (6H, m), of 2.33 (3H, s), up 3.22 (2H, m)and 3.59 (2H, users), 7,26 (1H, t, J=8,8 Hz), EUR 7.57 to 7.62 (2H, m), 7,86 (1H, s), 8,13 (1H, s), a 9.35 (1H, s).
54Example of getting 2991H-NMR (DMSO-d6): of 2.45 (3H, s), 3,26 (2H, users), 3,53 (2H, t, J=4,8 Hz), 3,63 (4H, users), 7,28 (1H, t, J=8,8 Hz), 7,51-EUR 7.57 (2H, m), the 7.65 (1H, DD, J=2,8 Hz, 6.0 Hz), 9,14 (1H, d, J=4.4 Hz)of 12.73 (1H, s), 12,89 (1H, s).

Table 53
Example recip.SYN.Data
55Example of getting 2981H-NMR (DMSO-d6): to 2.41 (3H, s), with 3.27 (2H, m), of 3.54 (2H, t, J=4,8 Hz)to 3.64 (4H, users), 7,28 (1H, t, J=8,8 Hz), to 7.61-to 7.64 (2H, m), 7,88 (1H, users), 8,14 (1H, users), 9,38 (1H, s).
56Example of getting 2921H-NMR (CDCl3): a 1.08 (3H, t, J=7.2 Hz), of 1.23 (3H, t, J=7.2 Hz), 3,24 (2H, q, J=7.2 Hz), 3,55 (2H, m), 3,70 (2H, users), 6,56 (1H, DD, J=3.2 Hz, 5.6 Hz), 6,62 (1H, m), 6,85 (1H, t, J=8,8 Hz).
57Example of getting 2991H-NMR (DMSO-d6): a 1.01 (3H, t, J=7.2 Hz), of 1.13 (3H, t, J=7.2 Hz), a 2.45 (3H, s), 3,17 (2H, q, J=7.2 Hz), 3,44 (2H, m), 7,26 (1H, t, J=8,8 Hz), 7,46 (1H, m), 7,52 (1H, d, J=4.4 Hz), to 7.67 (1H, DD, J=2,8 Hz, 6.0 Hz), 9,15 (1H, d, J=4.4 Hz)of 12.73 (1H, s), 12,94 (1H, s).
58Example of getting 2981H-NMR (DMSO-d6): of 1.02 (3H, t, J=7.2 Hz), of 1.13 (3H, t, J=7.2 Hz), 2.40 a (3H, s)3,18 (2H, q, J=7.2 Hz), of 3.45 (2H, q, J=7.2 Hz), 7,27 (1H, t, J=9,2 Hz), 7,58-to 7.61 (2H, m), 7,87 (1H, users), 8,14 (1H, users), a 9.35 (1H, s).
59Example of getting 292 1H-NMR (CDCl3): of 1.05 (6H, d, J=6.4 Hz), 3.27 to to 3.49 (1H, m), 3,90 (1H, s)4,55 (1H, d, J=6.4 Hz), 6,62-6,28 (2H, m), 7,65-of 7.69 (1H, m).
60An example of retrieving 411H-NMR (CDCl3): a 1.08 (6H, t, J=6.8 Hz), 3,48 (1H, q, J=7,6 Hz), 4,11 (1H, s), and 4.75 (1H, d, J=7,6 Hz), 7,88 (1H, d, J=2.0 Hz), 7,94 (1H, DD, J=2.0 Hz, 8,4 Hz)to 8.12 (1H, d, J=8,4 Hz).
61Example of getting 2991H-NMR (DMSO-d6): 0,94 is 0.99 (6H, m), 3,18-3,24 (1H, m), 2.49 USD (1H, s), 3,92 (1H, s), 7,06-was 7.08 (1H, m), 7,20-of 7.23 (1H, m), 7,39-7,40 (1H, m), to 7.61-of 7.69 (2H, m), 9,20 (1H, users), 12,88 (1H, users), 13,28 (1H, users).

Table 54
Example recip.SYN.Data
62Example of getting 298ESI-: 444
63Example of getting 2921H-NMR (CDCl3): 1,40-of 1.46 (2H, m), 1,62-to 1.67 (4H, m), 2,96-to 2.99 (4H, m), of 3.97 (1H, users), 7,06-7,10 (2H, m), 7,15-to 7.18 (1H, m).
64An example of retrieving 411H-NMR (CDCl3): 1,45-1,71 (7H, m), 3,06 (4H, t, J=5.6 Hz), 7,46-7,52 (1H, m), 00-8,04 (1H, m), 8,43-8,46 (1H, m).
65Example of getting 299ESI-: 440
66Example of getting 2981H-NMR (DMSO-d6): 1,31-to 1.38 (4H, m)and 1.51-of 1.55 (7H, m)2,44 (1H, s), 2,83-2,92 (7H, m), 7,56-7,58 (2H, m), 8,14 compared to 8.26 (3H, m), 9,77 (1H, users).
67Example of getting 2921H-NMR (CDCl3): 1,43-to 1.45 (2H, m)of 1.64 (4H, m), 2,22 (1H, s), 3,21 (2H, m), 3,66 is 3.76 (4H, m), 6.48 in-6,51 (2H, m)6,94 (1H, d, J=8.0 Hz).
68Example 41H-NMR (CDCl3): 1,43-to 1.87 (6H, m), 2,42 (3H, s), 3,13 is 3.15 (2H, m), 3,69-a 3.83 (2H, m), 7,32 (1H, d, J=8,4 Hz), 8.07-a 8,11 (2H, m).
69Example of getting 299ESI-: 400
70Example of getting 298ESI-: 418
71Example of getting 2921H-NMR (CD3OD): of 2.23 (3H, s)2,84 (3H, s), 6,50-6,55 (2H, m), 7,14 (1H, d, J=8,4 Hz).
72Example 41H-NMR (CDCl3): of 2.54 (3H, s), 3.04 from (3H, d, J=4,8 Hz), 5,80 (1H, users) 7,49 (1H, d, J=8,4 Hz), 8,04-to 8.12 (1H, m).
73Example of getting 299ESI-: 346
74Example of getting 298ESI-: 364
75Example of getting 2921H-NMR (CDCl3): 1,54-of 1.62 (6H, m), 3,20 is 3.23 (2H, m), 3,62-of 3.64 (1H, m), of 3.77 (5H, m), of 6.20 (1H, d, J=2.0 Hz), 6,27 (1H, DD, J=2.0 Hz, 8,1 Hz), 7,02 (1H, dJ=8,1 Hz).
76Example of getting 299ESI-: 416

Table 55
Example recip.SYN.Data
77Example of getting 298ESI-: 434
78Example of getting 2921H-NMR (CDCl3): of 1.45 to 1.47 (2H, m), of 1.65 (4H, m), 2,17 (3H, s), 3,18-is 3.21 (2H, m), 3,59-3,66 (3H, m), 3,78-3,82 (1H, m), of 6.49 (1H, d, J=2.7 Hz), 6,60 (1H, DD, J=2.7 Hz, 8,3 Hz), 6,97 (1H, d, J=8,3 Hz).
79Example 41H is the Mr (CDCl 3): 1,48-and 1.54 (2H, m)to 1.70 (4H, m), 2,42 (3H, s), 3,16-3,20 (2H, m), of 3.73-of 3.80 (2H, m), 7,39 (1H, d, J=8.5 Hz), with 8.05 (1H, d, J=2.2 Hz), to 8.12 (1H, DD, J=2.2 Hz, 8.5 Hz).
80Example of getting 299ESI-: 400
81Example of getting 298ESI-: 418
82Example of getting 2921H-NMR (CDCl3): 2,31 (3H, s), 2,98 (3H, d, J=4.9 Hz), 3,60 (2H, m), 5,69 (1H, m), only 6.64 (1H, DD, J=2.7 Hz, 8.1 Hz), 6,70 (1H, d, J=2.7 Hz), 6,98 (1H, d, J=8,1 Hz).
83Example of getting 299ESI-: 346
84Example of getting 298ESI-: 364
85Example obtain 481H-NMR (CDCl3): of 2.97 (3H, d, J=4,8 Hz), a 4.03 (2H, users), USD 5.76 (1H, users), 6,77 (1H, DD, J=2,4 Hz, 8.0 Hz), 6.90 to (1H, d, J=2.4 Hz), 7,33 (1H, d, J=8.0 Hz).
86Example of getting 2991H-NMR (DMSO-d6): of 2.51 (3H, s), 2,73 (3H, d, J=4.4 Hz), of 7.48 (1H, d, J=8,4 Hz), 7,63-the 7.65 (2H, m), by 8.22 (1H, d, J=1.6 Hz), scored 8.38 (1H, d, J=4,8 Hz), 9,18 (1H, d, J=4.4 Hz), 12,89 (1H, s), of 13.27 (1H, s).
87 Example of getting 2981H-NMR (DMSO-d6): of 2.45 (3H, s), 2,73 (3H, d, J=4,8 Hz), of 7.48 (1H, d, J=8,4 Hz), 7,88 (1H, d, J=8,8 Hz), 7,89 (1H, s)to 8.12 (1H, d, J=2.0 Hz), 8,17 (1H, s), scored 8.38 (1H, m), 9,62 (1H, s).

Table 56
Example recip.SYN.Data
88Example obtain 481H-NMR (CDCl3): a 3.01 (3H, DD, J=1.2 Hz, 5.2 Hz), of 3.69 (2H, users), 6,70-6,74 (1H, m), 6,77 (1H, users), of 6.90 (1H, DD, J=8,4 Hz and 11.6 Hz), 7,38 (1H, DD, J=3.2 Hz, 6.4 Hz).
89Example of getting 2991H-NMR (DMSO-d6): 2,49 (3H, s), 2,77 (3H, d, J=4.4 Hz), 7,26 (1H, t, J=8,8 Hz), 7,53-7,58 (2H, m), 7,95 (1H, DD, J=2,8 Hz, 6.4 Hz), 8,24 (1H, users), 9,16 (1H, d, J=4.4 Hz), was 12.75 (1H, s), 12,96 (1H, s).
90Example of getting 2981H-NMR (DMSO-d6): is 2.40 (3H, s), 2,77 (3H, d, J=4,8 Hz), 7,26 (1H, t, J=10.0 Hz), of 7.64-7.68 per (1H, m), 7,87 (1H, users), 7,92 (1H, DD, J=2,4 Hz, 6.4 Hz), 8,14 (1H, users), 8,21 (1H, users), 9,39 (1H, users).
91Example of getting 2921H-NMR (CDCl3): to 2.55 (3H, s), 3,91 (3H, s), 6.22 per 6,30(2H, m), 7,65-of 7.69 (1H, m).
92An example of retrieving 411H-NMR (CDCl3): of 2.66 (3H, d, J=5,2 Hz), 4,11 (3H, s), 4,84 (1H, d, J=5,2 Hz), 7,89 (1H, d, J=2.0 Hz), 7,94 (1H, DD, J=2.0 Hz, 8,8 Hz)to 8.12 (1H, d, J=8,8 Hz).
93Example of getting 299ESI-: 398
94Example of getting 298ESI-: 416
95Example of getting 2921H-NMR (CDCl3): of 2.97 (3H, d, J=4.6 Hz), 3,90 (3H, s), of 3.96 (2H, m), of 6.20 (1H, d, J=2.2 Hz), 6,34 (1H, DD, J=2.2 Hz, 8.5 Hz), 7,66 (1H, m), of 8.04 (1H, d, J=8,5 Hz).
96Example 41H-NMR (CDCl3): 3.04 from (3H, d, J=4.9 Hz), 4.09 to (3H, s), 7,74 (1H, m), to 7.84 (1H, d, J=2.2 Hz), to 7.93 (1H, DD, J=2.2 Hz, 8.5 Hz), 8,39 (1H, d, J=8,5 Hz).
97Example of getting 299ESI-: 362

Table 57
Example recip.SYN.Data
98the example of obtaining 298 ESI-: 380
99Example obtain 481H-NMR (CDCl3): 0,83-0,88 (1H, m), 1,42-of 1.65 (5H, m)and 3.15 (2H, DD, J=9,2 Hz, 15.2 Hz), 3,64 is 3.76 (2H, m)to 4.01 (2H, users), is 6.78 (1H, DD, J=2,4 Hz and 8.4 Hz), 6.90 to (1H, d, J=2,8 Hz), 7,05 (1H, d, J=8,4 Hz).
100Example of getting 2991H-NMR (DMSO-d6): 1,37-to 1.59 (6H, m), of 2.54 (3H, s), 3,06-3,11 (2H, m), 3,51-3,62 (2H, m), 7,40 (1H, d, J=8,4 Hz), to 7.61-7,66 (2H, m), of 8.27 (1H, d, J=2.0 Hz), 9,18 (1H, d, J=4.0 Hz), 12,89 (1H, s), 13,28 (1H, s).
101Example of getting 2981H-NMR (DMSO-d6): 1,37-to 1.59 (6H, m), of 2.45 (3H, s), 3,06-3,11 (2H, m), 3,52-3,62 (2H, m), 7,40 (1H, d, J=8.0 Hz), of 7.90 (1H, users), 7,92 (1H, m), 8,16 (1H, users), 8,19 (1H, d, J=2.0 Hz), 9,62 (1H, s).
102Example of getting 353ESI-: 346
103Example of getting 353ESI-: 454
104Example of getting 353ESI-: 346
105Example of getting 353ESI-: 346
106Example the floor is placed 299 1H-NMR (DMSO-d6): of 2.53 (3H, s), of 2.72 (3H, d, J=4.4 Hz), 7,41 (1H, d, J=8,8 Hz), of 7.48-7,56 (2H, m), at 8.36 (1H, d, J=4.6 Hz), 9,16 (1H, d, J=3,7 Hz), 12,80 (1H, s), 13,10 (1H, s).
107Example of getting 2981H-NMR (DMSO-d6): 2,43 (3H, s), 2,73 (3H, d, J=4.6 Hz), 7,41 (1H, d, J=8.5 Hz), the 7.65 (1H, DD, J=2.7 Hz, 8,8 Hz), to 7.77 (1H, d, J=2.4 Hz), 7,88 (1H, s)to 8.14 (1H, s), 8,35 (1H, d, J=4.6 Hz), 9,43 (1H, s).

Table 58
Example recip.SYN.Data
108Example of getting 3531H-NMR (CDCl3): of 1.29 (3H, t, J=7,6 Hz), 2,87 (2H, q, J=7,3 Hz), 3.04 from (3H, s)to 5.56 (1H, users), and 6.25 (1H, users), 7,34 (1H, d, J=8,8 Hz), 7,74 (1H, users), 7,81 (1H, DD, J=2,9 Hz and 8.8 Hz), to 7.93 (1H, d, J=2.7 Hz), 10,95 (1H, users).
109Example of getting 3531H-NMR (CDCl3): of 1.31 (3H, t, J=7,6 Hz), 2,89 (2H, q, J=7,3 Hz), 3,03 (3H, d, J=4.9 Hz), Android 4.04 (3H, s), of 5.53 (1H, users), 6,12 (1H, users), 7,28 (1H, m), 7,49 (1H, s), 7,74 (1H, users), 8,58 (1H, d, J=8,3 Hz), 11,43 (1H, users).
110Example of getting 2921H-NMR (CDCl3/sub> ): to 2.18 (3H, s), 2,98 (3H, d, J=4.9 Hz), 3,88 (2H, m), 5,97 (1H, m), only 6.64 (1H, d, J=8.1 Hz), 7,44 (1H, DD, J=2.0 Hz, 8,3 Hz), 7,51 (1H, m).
111Example 41H-NMR (CDCl3): of 2.64 (3H, s), 3,05 (3H, d, J=4.9 Hz), 6,17 (1H, m), to 7.67 (1H, DD, J=2.0 Hz, 8,3 Hz), 7,76 (1H, d, J=2.0 Hz), 8,00 (1H, d, J=8,3 Hz).
112Example of getting 353ESI-: 346
113Example of getting 353ESI-: 400
114Example of getting 2921H-NMR (CDCl3): of 2.21 (3H, s)to 2.99 (3H, d, J=4.9 Hz), 3,70 (2H, m), 5,72 (1H, m), of 6.71-6,77 (2H, m), 7,00? 7.04 baby mortality (1H, m).
115Example of getting 3531H-NMR (CDCl3): of 1.30 (3H, t, J=7,3 Hz), 2,42 (3H, s), 2,87 (2H, q, J=7,3 Hz), to 3.02 (3H, d, J=4.9 Hz), of 5.50 (1H, m), of 5.75 (1H, m), 7,09-7,11 (1H, m), of 7.75 (1H, m), 8,16-8,18 (1H, m), a 10.74 (1H, m).
116Example of getting 353ESI-: 366
117Example of getting 353ESI-: 325

Table 59
Example recip.SYN.Data
118Example of getting 2921H-NMR (CDCl3): 2,98 (3H, d, J=4.9 Hz), 3,85 (2H, users), the 6.06 (1H, users), 6,98-7,01 (2H, m), 7,25-7,29 (1H, m).
119Example of getting 3531H-NMR (CDCl3): of 1.31 (3H, t, J=7,6 Hz), of 2.92 (2H, q, J=7,3 Hz), 3,05 (3H, d, J=4.9 Hz), to 5.57 (1H, users), 6,13 (1H, users), 7,18 (1H, m), 7,52 (1H, m), 7,73 (1H, s), 8,87 (1H, d, J=8.5 Hz), of 11.15 (1H, users).
120Example of getting 2921H-NMR (CDCl3): 3,00 (3H, d, J=4.9 Hz), 4,19 (2H, users), of 5.92 (1H, users), to 6.80 (1H, DD, J=1.7 Hz and 7.6 Hz), 6.87 in (1H, DD, J=1.7 Hz and 7.6 Hz), was 7.08 (1H, d, J=7,6 Hz).
121Example 41H-NMR (CDCl3): a 3.06 (3H, s), to 5.57 (1H, users), 6,04 (1H, users), 7,42 (1H, d, J=8.1 Hz), 7,74 (1H, DD, J=1.5 Hz and 7.6 Hz), 7,83 (1H, DD, J=2.0 Hz, 8.1 Hz).
122Example of getting 3531H-NMR (CDCl3): of 1.31 (3H, t, J=7,6 Hz), only 2.91 (2H, q, J=7,3 Hz), 3.04 from (3H, d, J=4,9 Hz)to 5.56 (1H, users), 5,95 (1H, users), 7,21 (1H, m), 7,34 (1H, m), 7,74 (1H, users), 8,56 (1H, m), 11,40 (1H, users).
123Example of getting 2991H-NMR (DMSO-d6): 2,84 (3H, s), 7,21 (2H, t, J=9.6 Hz), 7,52 (1H, t, J=9.6 Hz), 7,53 (2H, s), to 7.64 (1H, d, J=4.0 Hz), by 8.22 (2H, d, J=9,2 Hz), 9,24 (1H, d, J=4.0 Hz), 12,92 (1H, users), 13,73 (1H, s).
124Example of getting 298ESI-: 343
125Example of getting 353ESI-: 325
126Example of getting 353ESI-: 398
127Example of getting 353ESI+: 334

Table 60
Example recip.SYN.Data
128Example of getting 3531H-NMR (DMSO-d6): of 1.24 (3H, t, J=7,6 Hz), 2,89 (2H, q, J=7,3 Hz), a 4.53 (2H, s), 6,92 (1H, d, J=8.5 Hz), 7,11-7,16 (2H, m), 8,02 (1H, users), to 8.25 (1H, users), 10,78 (1H, users), 11,06 (1H, users).
129Example of getting 353ESI-: 265
Example of getting 353ESI-: 350
131Example of getting 353ESI-: 289
132Example of getting 353ESI+: 488
133Example of getting 3531H-NMR (CDCl3): of 1.31 (3H, t, J=7.2 Hz), 2,64 (6H, s), 2.91 in (2H, q, J=7.2 Hz), 4,30 (1H, users), the ceiling of 5.60 (1H, users), 7,56 (1H, users), to 7.77 (1H, m), 7,95 (1H, d, J=8.0 Hz), 11,12 (1H, users).
134Example of getting 3531H-NMR (CDCl3): of 1.30 (3H, t, J=7.2 Hz), 2,89 (2H, q, J=7,6 Hz), 2,99 (3H, s)5,59 (1H, users), 6,60 (1H, users), 7,53 (1H, DD, J=2,4 Hz and 9.2 Hz), 7,60 (1H, d, J=8,8 Hz), of 7.75 (1H, users), of 7.96 (1H, d, J=2.4 Hz), 10,95 (1H, s).
135Example of getting 353ESI+: 368
136Example of getting 353ESI+: 364
137Example of getting 2921H-NMR (CDCl3): of 2.44 (3H, s)of 2.50 (3H, s), 6,79 (1H, DD, J=2,4 Hz and 8.4 Hz), 7,06 (1H, d, J=8,4 Hz), 7,25 (1H, d, J=2,4 Hz).
138ESI-: 382
139Example of getting 2921H-NMR (CDCl3): 3,15-3,17 (4H, m), 3,70-and 3.72 (4H, m), 3,85 (3H, s), of 4.13 (2H, users), to 6.19 (1H, d, J=2.0 Hz), 6,23 (1H, DD, J=2.0 Hz, 8,4 Hz), 7,01 (1H, d, J=8,4 Hz).
140An example of retrieving 411H-NMR (CDCl3): 3,28-3,30 (4H, m), 3.72 points-3,74 (4H, m)4,06 (3H, s), 7,86 (1H, d, J=2.0 Hz), 7,89 (1H, DD, J=2.0 Hz, 8,4 Hz), 8,80 (1H, d, J=8,4 Hz).

Table 61
Example recip.SYN.Data
141Example of getting 353ESI-: 454
142Example of getting 3531H-NMR (DMSO-d6): of 1.24 (3H, t, J=7,6 Hz), and 2.79 (2H, q, J=7,3 Hz), 4,56 (2H, s), at 6.84 (1H, d, J=8.5 Hz), 6,98 (1H, DD, J=2,4 Hz, 8.5 Hz), 7,46 (1H, d, J=2.2 Hz), 8,01 (1H, users), 8,24 (1H, users), 10,65 (1H, users), of 11.11 (1H, users).
143Example of getting 353ESI+: 317
144The example on the teachings 353 1H-NMR (DMSO-d6): of 1.24 (3H, t, J=7,6 Hz), 2,78 (2H, q, J=7,3 Hz), 4,20-4,24 (4H, m), for 6.81-6.89 in (2H, m), 7,29 (1H, d, J=2.4 Hz), 7,98 (1H, users), 8,21 (1H, users), 10,98 (1H, users).
145Example obtain 481H-NMR (CDCl3): to 3.36 (3H, s), 3,53 (2H, t, J=5,1 Hz), 3,61 (2H, m)to 4.01 (2H, users), 6,14 (1H, users), 6,76 (1H, DD, J=2.0 Hz, 8,3 Hz)6,91 (1H, d, J=2.2 Hz), 7,33 (1H, d, J=8,3 Hz).
146Example of getting 3531H-NMR (CDCl3): of 1.31 (3H, t, J=7,6 Hz), 2,90 (2H, q, J=7,3 Hz), 3,39 (3H, s)to 3.58 (2H, m)to 3.64 (2H, m), 5,79 (1H, users), 6,38 (1H, users), 7,52 (1H, d, J=3,7 Hz), of 7.75 (1H, users), 7,87 (1H, DD, J=2.0 Hz, 8,3 Hz)11,05 (1H, users).
147Example of getting 3531H-NMR (CDCl3): 1,24-to 1.59 (9H, m), 2,90 (2H, q, J=7,6 Hz), 3,10-3,17 (4H, m), of 3.95 (3H, s)5,59 (1H, users), 7,13 (1H, d, J=8,8 Hz), 7,63 (1H, d, J=8,4 Hz), 7,75-7,81 (3H, m), 11,16 (1H, users).
148Example of getting 3531H-NMR (CDCl3): a 1.25 (3H, t, J=7,6 Hz), 2,60 (3H, s), of 2.92 (2H, q, J=7,6 Hz), 5,59 (1H, users), 7,28 (1H, m), 7,73 (1H, users), of 7.75 (1H, m), 8,44 (1H, d, J=2.0 Hz), 10,99 (1H, users).
149Example of getting 3531H-NMR (CDCl3): to 1.21 to 1.34 (3H, m) 2,82 of 2.92 (5H, m), 5,61 (1H, users), 7,51 (1H, d, J=6.8 Hz), 7,72 to 7.75 (1H, m), 7,87 (1H, d, J=6.8 Hz), 8,42 (1H, d, J=2,8 Hz), 10,99 (1H, users).

Table 62
Example recip.SYN.Data
150Example of getting 353ESI+: 364
151Example of getting 3531H-NMR (CDCl3): a 1.25 (3H, t, J=7,6 Hz), 2,92 (3H, q, J=7,6 Hz), 5,63 (1H, users), 7,53 (1H, DD, J=3,6 Hz, 6.9 Hz), 7,76 (1H, users), of 7.90 (1H, d, J=6.0 Hz), 8,78 (1H, d, J=3.6 Hz), 11,27 (1H, users).
152Example of getting 353ESI+: 329
153Example of getting 3531H-NMR (CDCl3): of 1.34 (3H, t, J=7,6 Hz), 2,95 (2H, q, J=7,6 Hz), the 5.65 (1H, users), 7,74 (1H, DD, J=2.0 Hz, 9,2 Hz), 7,79 (1H, users), 8,02 (1H, d, J=9,2 Hz), 9.28 are (1H, d, J=2.0 Hz), 11,25 (1H, users).
154Example of getting 3531H-NMR (CDCl3): of 1.30 (3H, t, J=7,6 Hz), of 2.86 (2H, q, J=7,6 Hz), with 3.79 (3H, s)5,49 (1H, m), 6,44 (1H, d, J=3.2 Hz), 7,01 (1H, d, J=3.2 Hz), to 7.15 (1H, DD, J=0.2 Hz, and 8.4 Hz), 7,54 (1H, d, J=8,4 Hz), 7,74 (1H,m), 7,98 (1H, s), 10,84 (1H, m).
155Example of getting 2921H-NMR (CDCl3): 2,84 (3H, s), 3,37 (2H, users), 3,99 (1H, users), 6,62 (1H, d, J=8,4 Hz), PC 6.82 (1H, DD, J=2,8 Hz and 8.4 Hz), 6,86 (1H, d, J=2,8 Hz).
156Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,6 Hz), 2,85 (2H, q, J=7,6 Hz), 2.91 in (3H, d, J=4,8 Hz), 4,32 (1H, users), the 5.51 (1H, users), was 6.73 (1H, d, J=8,4 Hz), 7,66-of 7.70 (3H, m), 10,50 (1H, users).
157Example of getting 2921H-NMR (DMSO-d6): 1,67-of 1.78 (2H, m)2,07 (2H, m), 3,03-3,27 (8H, m), of 3.73 (3H, s), 3,90-4,16 (3H, m), 5,79 (2H, users), of 6.29 (1H, d, J=8.5 Hz), 6,50-is 6.54 (2H, m).
158Example of getting 503ESI+: 338
159Example of getting 353ESI+: 491
160Example of getting 1601H-NMR (CDCl3): of 1.35 (3H, t, J=7,6 Hz), to 3.02 (2H, q, J=7,6 Hz).
161Example of getting 353ESI+: 375

the figure 63
Example recip.SYN.Data
162Example of getting 292ESI+: 276
163Example of getting 444ESI+: 306
164Example of getting 353ESI+: 459
165Example of getting 353ESI+: 376
166Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,6 Hz), 2,84 (2H, q, J=7,6 Hz), 3.46 in-of 3.48 (4H, m), 3,83-of 3.85 (4H, m), of 5.55 (1H, users), to 6.67 (1H, d, J=8,8 Hz), 8,43 (1H, d, J=2.4 Hz), 10,45 (1H, users).
167Example of getting 292ESI+:276
168Example of getting 444ESI+: 306
169Example of getting 353ESI+: 459
170Example of getting 353ESI+: 552
171Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7.2 Hz), 2,84 (2H, q, J=7.2 Hz), 3,12-3,14 (4H, m), 3,86-3,88 (4H, m), the 5.51 (1H, users), 6,91 (1H, DD, J=2,4 Hz, 7.2 Hz), 7,55 (1H, DD, J=2,4 Hz, 7.2 Hz), 7,71 (1H, users), of 10.58 (1H, users).
172Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,6 Hz), 2,31 (3H, s), a 2.36 (3H, s)2,84 (2H, q, J=7,6 Hz), 2,92-to 2.94 (4H, m), of 5.48 (1H, users), 7,02 (1H, d, J=8,8 Hz), 7,34 (1H, d, J=2.4 Hz), 7,55 (1H, DD, J=2.7 Hz, 8.5 Hz), 7,71 (1H, users), or 10.60 (1H, users).
173Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,6 Hz), 1,68-of 1.74 (6H, m), 1,92-of 1.95 (2H, m), 2,29-2,36 (7H, m), 2,50-to 2.65 (8H, m), 2,84 (2H, q, J=7,6 Hz), 3,13-and 3.16 (2H, m)5,54 (1H, users), 6,98 (1H, d, J=6.5 Hz), 7,33 (1H, d, J=2,6 Hz), 7,51 (1H, d, J=2.7 Hz), 7,71 (1H, users), of 10.58 (1H, users).

Table 64
Example recip.SYN.Data
174Example of getting 3531H-NMR (CDCl3): of 1.29 (3H, t, J=7,3 Hz), is 2.37 (3H, s), 2,62 (4H, m), 2,85 (2H, q, J=7,3 Hz), 3,03 (4H, m), of 5.53 (1H, users), 7,05 (1H, d, J=8,8 Hz), 7,51 (1H, DD, J=2.7 Hz, 8,8 Hz), 7,72 (1H, d, J=2.4 Hz), 1,70 (1H, users).
175Example of getting 3531H-NMR (CDCl3): of 1.28 (t, J=7.2 Hz, 3H), 1,49 (s, 9H), 2,84 (kV, J=7.2 Hz, 2H), to 3.09 (m, 4H), to 3.58 (m, 4H), 5,62 (users, 1H), 6,92 (d, J=9,2 Hz, 2H), 7,54 (d, J=9,2 Hz, 2H), 7,71 (users, 1H), or 10.60 (s, 1H).
176Example of getting 2921H-NMR (CDCl3): 1,60 (2H, users), 2,04-2,17 (4H, m), 2.91 in vs. 2.94 (4H, m), to 6.80 (1H, DD, J=2,8 Hz and 8.4 Hz), 6,91 (1H, d, J=2,8 Hz), 7,17 (1H, d, J=8,4 Hz).
177Example of getting 5161H-NMR (CDCl3): 2,13-2,22 (4H, m), 3,18-3,20 (4H, m), of 7.36 (1H, d, J=8,8 Hz), 8,35 (1H, DD, J=2,4 Hz and 9.2 Hz), 8,53 (1H, d, J=2,4 Hz).
178Example of getting 353ESI-: 462
179Example of getting 353ESI+: 400
180Example of getting 2921H-NMR (CDCl3): 0,16-0,20 (2H, m), 0.55, which is 0.59 (2H, m)to 0.97 (1H, m), 2.40 a (2H, d, J=6.4 Hz), a 2.75 (2H, m), 2,96 (4H, m), and 3.72 (2H, m), 6,79 (1H, DD, J=2,8 Hz and 8.4 Hz), 6.89 in (1H, d, J=2,8 Hz), 7,24 (1H, d, J=8,4 Hz).
181Example of getting 516EI: 329
182Example of getting 353ESI+: 483
183Example of getting 2921H-NMR (CDCl3): 1,80-of 1.88 (1H, m), 2.06 to and 2.14 (1H, m), 2,24 (6H, s), 2,85-3,20 (5H, m), the 3.65 (2H, users), is 6.78 (1H, DD, J=2,9 Hz, 8.5 Hz), 6.90 to (1H, d, J=2.7 Hz), 7,14 (1H, d, J=8,5 Hz).

Table 65
Example recip.SYN.Data
184Example of getting 5161H-NMR (CDCl3): 1,90-of 1.97 (1H, m), 2.21 are to 2.29 (1H, m), 2,32 (3H, s), 2.77-to 2,82 (1H, m), 3.43 points-of 3.53 (1H, m), 3,62-to 3.67 (3H, m), 6,79 (1H, d, J=9.5 Hz), 8,16 (1H, DD, J=2.7 Hz, 9.5 Hz), 8,53 (1H, d, J=2.7 Hz).
185Example of getting 3531H-NMR (CDCl3): of 1.29 (3H, t, J=7,3 Hz), 1,84-1,89 (1H, m), 2,12-of 2.16 (1H, m), and 2.26 (6H, s), 2,83-2,89 (3H, m), 3,20-to 3.41 (4H, m), to 5.57 (1H, users), to 7.09 (1H, d, J=8,8 Hz), 7,71-of 7.82 (3H, m), is 10.68 (1H, users).
186Example of getting 3531H-NMR (CDCl3): 1,10-1,15 (3H, m)of 1.30 (3H, t, J=7,3 Hz), 2,45-2,52 (2H, m), 2,85-2,97 (10H, m), to 5.57 (1H, users), 7,37-7,39 (1H, m), 7,73 (1H, users), 7,87-7,88 (2H, m), 10,86 (1H, users).
187Example of getting 2921H-NMR (CDCl3): the 1.04 (6H, d, J=6.3 Hz), 2,28 is 2.33 (2H, m), of 2.81 (2H, DD, J=2.0 Hz, 9.0 Hz), 3,02-of 3.07 (2H, m), of 3.69 (2H, users), is 6.78 (1H, DD, J=2.7 Hz, 8.5 Hz), 6.89 in (1H, d, J=2,9 Hz), to 7.15 (1H, d, J=8,5 Hz).
188Example of getting 5161H-NMR (CDCl3): 1,10 (3H, s), is 1.11 (3H, s), 2,48 of $ 2.53 (2H, m), is 3.08-3,13 (2H, m), up 3.22 (2H, d, J=10,7 Hz), 7,22 (1H, d, J=9.0 Hz), 8,29 (1H, DD, J=2.7 Hz, 9.0 Hz), and 8.50 (1H, d, J=2.7 Hz).
189Example of getting 3531H-NMR (CDCl3): 1,05-1,09 (6H, m), 1,22 of 1.46 (3H, m), 2,34-to 2.40 (2H, m), 2,71 is 3.76 (6H, m), to 5.57 (1H, users), 7,32 (1H, d, J=8.5 Hz), 7,74 (1H, users), a 7.85-7,88 (2H, m), 10,85 (1H, users).

Table 66
Example recip.SYN.Data
190Example of getting 2921H-NMR (CDCl3): of 1.41 (3H, s)of 1.42 (3H, s), 2,68 (3H, s), 2,87-2,90 (2H, m), of 2.81 (2H, DD, J=2.0 Hz, 9.0 Hz, 2H), 3,00 (m, 2H), 3,23 (m, 2H), 3,81 (users), to 6.80 (1H, DD, J=2,9 Hz, 8.5 Hz), to 6.88 (1H, d, J=2,9 Hz), 7,24 (1H, d, J=7,8 Hz).
191Example of getting 516 1H-NMR (CDCl3): to 1.15 (3H, s)of 1.16 (3H, s), a 2.36 (3H, s), 2,46-of 2.50 (2H, m), 2,79-to 2.85 (2H, m), 3,19 (2H, DD, J=2.7 Hz, 9.0 Hz), 7,22-7,24 (1H, m), 8,30 (1H, DD, J=2.7 Hz, 9.0 Hz), and 8.50 (1H, d, J=2.7 Hz).
192Example of getting 3531H-NMR (CDCl3): a 1.11 (6H, m)of 1.30 (3H, t, J=7,3 Hz), 2,33 is 2.44 (5H, m), 2,67-and 2.79 (2H, m), 2,85-only 2.91 (4H, m)5,54 (1H, users), 7,33 (1H, d, J=8,3 Hz), 7,73 (1H, users), a 7.85-7,87 (2H, m), 10,85 (1H, users).
193Example of getting 353ESI+: 362
194Example of getting 194ESI+: 377
195Example of getting 353ESI+: 389
196Example of getting 353ESI+: 403
197Example of getting 3531H-NMR (CDCl3): of 1.30 (3H, t, J=7,6 Hz)to 1.48 (9H, s), was 2.76-2.91 in (6H, m), 3,55 (4H, m), to 5.57 (1H, users), 7,31 (1H, d, J=8,8 Hz), 7,74 (1H, users), 7,86-of 7.90 (2H, m), 10,89 (1H, users).
198Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,6 Hz)to 1.48 (9H, s), 2,32 (3H, s), 2,82-is 2.88 (6H, m), of 3.56 (4H, t, J=4.9 Hz), 5,52 (1H, users), 6,98 (1H, d, J=8.5 Hz), and 7.3 (1H, d, J=2.7 Hz), 7,55 (1H, DD, J=2.7 Hz, 8.5 Hz), 7,72 (1H, users), to 10.62 (1H, users).

Table 67
Example recip.SYN.Data
199Example of getting 5161H-NMR (CDCl3): 0,99 (s, 6H), of 1.29 (t, J=5.6 Hz, 2H), 1,59-to 1.67 (m, 2H), 2,46 (s, 2H), to 2.67 (m, 2H), 3,67 (users, 2H), 6,77 (DD, J=2,9 Hz, 8.5 Hz, 1H), 6.89 in (d, J=2.7 Hz,1H), 7,16 (d, J=6,5 Hz, 1H).
200Example of getting 194ESI+: 417
201Example of getting 194ESI+: 476
202Example of getting 2921H-NMR (CDCl3): 1,81-of 1.85 (2H, m), 1,99-2,03 (2H, m), 2,18-of 2.21 (4H, m), 2,79-2,84 (2H, m), 3,01 totaling 3.04 (2H, m), 3,12-to 3.34 (4H, m), 3,66 at 3.69 (2H, m), 9,92 (1H, DD, J=2,4 Hz, 8.0 Hz), 6,98 (1H, d, J=2.4 Hz), 7,24 (1H, d, J=8,0 Hz).
203Example of getting 516EI: 343
204Example of getting 353ESI+: 497
205 Example of getting 353ESI-: 437
206Example of getting 353ESI-: 472
207Example of getting 2921H-NMR (CDCl3): 0,81 (3H, d, J=6,4 Hz)to 1.48 (3H, d, J=6.6 Hz), 2,68 (2H, q, J=11,0 Hz), of 2.81 (2H, d, J=4.9 Hz), with 2.93 (1H, DD, J=2,9 Hz, 12.9 Hz), 3,17 (1H, users), 3,29-3,44 (2H, m), a 3.87 (2H, users), 6,83 (1H, DD, J=2.7 Hz, 8,5 Hz), 6.89 in (1H, d, J=2.7 Hz), 7,29 (1H, d, J=8,3 Hz).
208Example of getting 5161H-NMR (CDCl3): of 0.79 (3H, d, J=6.3 Hz), was 1.04 (3H, d, J=6.4 Hz), 2,16-of 2.21 (2H, m), 2,28-of 2.34 (4H, m), of 2.44-2.50 (1H, m), 2,86-2,90 (2H, m), 7,56 (1H, d, J=8,8 Hz), 8,40 (1H, DD, J=2.7 Hz, 8,8 Hz), 8,55 (1H, d, J=2.7 Hz).
209Example of getting 353ESI+: 471
210Example of getting 292EI: 219
211Example of getting 516EI: 249
212Example of getting 353ESI+: 403

Table 68
Example recip.SYN.Data
213Example of getting 2921H-NMR (CDCl3): of 1.52-1.55V (2H, m), a 2.01 (2H, dt, J=4.4 Hz, and 8.4 Hz), 2,12-of 2.16 (2H, m), 2,84-to 2.94 (6H, m), 6.87 in (1H, DD, J=2,4 Hz and 8.4 Hz), 6,94 (1H, d, J=2.4 Hz), 7,10-7,21 (4H, m), 7,29 (1H, d, J=8,4 Hz).
214Example of getting 5161H-NMR (CDCl3): of 1.52-1.55V (2H, m), a 2.01 (2H, dt, J=4.4 Hz, to 12.8 Hz), 2,12-of 2.16 (2H, m), 2,84-of 3.31 (6H, m), 6,86-6,89 (1H, m), to 6.95 (1H, m), 7,10-7,19 (4H, m), 7,30 (1H, d, J=8,4 Hz).
215Example of getting 353ESI-: 528
216Example of getting 353ESI+: 403
217Example of getting 292EI: 344
218Example of getting 516EI: 374
219Example of getting 353ESI-: 526
220Example of getting 2921H-NMR (CDCl3): of 2.34 (3H, s), of 2.51 (4H, t, J=4,8 Hz), 3,17 (4H, t, J=4,8 is C), 3,63 (2H, users), to 6.58 (2H, s).
221Example of getting 5161H-NMR (CDCl3): of 2.38 (3H, s), 2,58 (4H, m)to 3.36 (4H, t, J=4,8 Hz), 8,15 (2H, s).
222Example of getting 353ESI-: 441
223Example of getting 2921H-NMR (CDCl3): 1,41-of 1.53 (10H, m), 1.69 in (2H, t, J=7,1 Hz), 2,86 (2H, s), 3,10 (2H, t, J=6,8 Hz)and 3.59 (2H, users), 6,77 (1H, d, J=2.7 Hz, 8.5 Hz), 6.90 to (1H, DD, J=2,5 Hz, 9.5 Hz), was 7.08 (1H, d, J=8,8 Hz).
224Example of getting 5161H-NMR (CDCl3): 1,42-1,57 (10H, m), of 1.85 (2H, t, J=7,1 Hz)to 3.33 (2H, s), 3,61 (2H, t, J=7.0 Hz), 6,77 (1H, d, J=9.5 Hz), 8,14 (1H, DD, J=2.7 Hz, 9.5 Hz), 8,53 (1H, d, J=2,9 Hz).

Table 69
Example recip.SYN.Data
225Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,6 Hz), 1,43-of 1.55 (10H, m), 2,32 (3H, s)of 1.75 (2H, t, J=7,1 Hz), 2,85 (2H, q, J=7,6 Hz), 3,06 (2H, s), of 3.32 (2H, t, J=6.8 Hz), of 5.50 (1H, users), 7,02 (1H, d, J=9.0 Hz), 7,69-7,71 (2H, m), 7,80 (1H, d, J=2.7 Hz), 10,61 (1H users).
226Example of getting 3531H-NMR (CDCl3): of 1.29 (3H, t, J=7,6 Hz), for 1.49 (9H, s), 2,85 (2H, q, J=7,6 Hz), 2,98 (4H, m), 3,61 (4H, t, J=5,1 Hz), 3,90 (3H, s)5,52 (1H, users), 6,87 (1H, d, J=8.5 Hz), 7,14 (1H, DD, J=2,4 Hz, 8.5 Hz), 7,38 (1H, d, J=2.2 Hz), 7,73 (1H, users), 10,70 (1H, users).
227Example of getting 353ESI+: 370
228Example of getting 413ESI-: 343
229Example of getting 4121H-NMR (CDCl3): of 1.50 (9H, s), is 2.37 (2H, m), 3,63-the 3.65 (2H, m)4,06 (2H, m), to 5.66 (1H, m), 7,44 (1H, d, J=8,3 Hz), 8,35 (1H, DD, J=2.2 Hz, 8,3 Hz), 8,54 (1H, d, J=2.2 Hz).
230Example of getting 3531H-NMR (CDCl3): of 1.30 (3H, t, J=7,3 Hz), for 1.49 (9H, s), 1.60-to of 1.78 (2H, m), of 2.81 (2H, m), is 2.88 (2H, q, J=7,3 Hz), 3.00 and-a 3.06 (1H, m), 4,24 (1H, m)to 5.56 (1H, m), 7,37 (1H, d, J=8.5 Hz), 7,74 (1H, m), a 7.85 (1H, DD, J=2,4 Hz, 8.5 Hz), 7,92 (1H, d, J=2.4 Hz), 10,90 (1H, users).
231Example of getting 353ESI+: 403
232Example of getting 353ESI+: 392
233 Example of getting 353ESI+: 390
234Example of getting 2921H-NMR (CDCl3): to 2.18 (3H, s), of 2.38 (3H, s), 2,58 (4H, users), and 2.83 (4H, users), 3,63 (2H, users), 6.35mm (1H, DD, J=2,8 Hz and 8.4 Hz), 6,98 (1H, d, J=8,4 Hz), 7,81 (1H, d, J=2,8 Hz), 8,66 (1H, users).

Table 70
Example recip.SYN.Data
235Example of getting 353ESI+: 432
236Example of getting 2921H-NMR (CDCl3+CD3OD): to 2.42 (3H, s), 2,69 (4H, users), of 2.86 (4H, users), was 3.05 (3H, s), 6,44 (1H, DD, J=2,8 Hz and 8.4 Hz), 6.87 in (1H, d, J=2,8 Hz), was 7.08 (1H, d, J=8,8 Hz).
237Example of getting 5161H-NMR (CDCl3): 2,39 (3H, s)of 2.64 (4H, users), of 2.97 (4H, t, J=4,8 Hz), 3,19 (3H, s), 7,28 (1H, d, J=8,8 Hz), 7,53 (1H, users), of 7.97 (1H, DD, J=2,4 Hz and 8.4 Hz), 8,31 (1H, d, J=2,4 Hz).
238Example of getting 353ESI+: 468
239 1H-NMR (CDCl3): 2,35 (3H, s), a 2.45 (4H, users), 2,85 (4H, t, J=4,8 Hz), of 3.54 (2H, users), 6,62-of 6.65 (2H, m), 6,92 (1H, d, J=9,2 Hz), 7,29 (1H, t, J=7,6 Hz), was 7.36 (2H, t, J=7,6 Hz), EUR 7.57 (2H, d, J=7,2 Hz).
240An example of retrieving 2401H-NMR (CDCl3): of 2.27 (3H, s), 2,34 (4H, users), 2,99 (4H, t, J=4,8 Hz), 7,01 (1H, d, J=9,2 Hz), 7,35 (1H, t, J=7.2 Hz), 7,44 (2H, t, J=7.2 Hz), 7,58 (2H, d, J=7,2 Hz), 8,08 (1H, d, J=2,8 Hz), 8,14 (1H, DD, J=2,8 Hz, 9,2 Hz).
241Example of getting 516ESI+: 348
242Example of getting 353ESI+: 451
243Example of getting 2921H-NMR (CDCl3): 1,91 (3H, s), of 2.34 (3H, s)to 2.55 (4H, users), 2,87 (4H, m), up 3.22 (3H, s)to 3.64 (2H, users), 6,47 (1H, s), of 6.66 (1H, d, J=8,8 Hz), to 6.95 (1H, d, J=8,4 Hz).
244Example of getting 2441H-NMR (CDCl3): to 1.98 (3H, s)to 2.35 (3H, s), of 2.56 (4H, t, J=4,8 Hz), 3,18 (4H, DD, J=3,6 Hz, 5.6 Hz), 3,26 (3H, s), 7,05 (1H, d, J=9,2 Hz), 7,98 (1H, d, J=2.4 Hz), 8,14 (1H, DD, J=2,4 Hz and 8.8 Hz).

Table 71
Example recip. SYN.Data
245Example of getting 353ESI+: 446
246Example of getting 2461H-NMR (CDCl3): of 0.90 (3H, t, J=7.8 Hz), 1,40-1.55V (15H, m), 1,61-of 1.64 (2H, m), 1,78-to 1.82 (2H, m), 3,39 (1H, m), 4,42 (1H, m).
247Example of getting 2471H-NMR CD3OD): of 0.90 (3H, t, J=7,6 Hz), 1.30 and of 1.54 (6H, m), 1,62-of 1.65 (3H, m), 2,52-of 2.58 (1H, m).
248Example of getting 2461H-NMR (CDCl3): of 0.91 (3H, t, J=7,6 Hz), 1.32 to-1,49 (13H, m), and 1.54 (2H, q, J=7,6 Hz), 1.60-to of 1.66 (2H, m), 1,88-of 1.93 (2H, m)and 3.59 (1H, m), 4,55 (1H, m).
249Example of getting 2491H-NMR (CD3OD): to 0.89 (3H, t, J=7,6 Hz), of 1.20 to 1.31 (2H, m), 1,38-to 1.45 (2H, m)of 1.55 (2H, q, J=7,6 Hz), 1,68-of 1.81 (4H, m), 2.70 height is 2.75 (1H, m).
250Example of getting a 2501H-NMR (CDCl3): of 0.91 (6H, d, J=6.8 Hz), 1,43-1,49 (11H, m)and 1.51-of 1.63 (5H, m), 1,81 of-1.83 (2H, m), 3,37 (1H, m)to 4.41 (1H, m).
251Example of getting 2511H-NMR (DMSO-d6): of 0.82 (6H, d, J=6.8 Hz), 124-1,31 (2H, m), USD 1.43-of 1.53 (3H, m), 1,65-to 1.67 (4H, m), 2,85-2,89 (1H, m), a 3.87 (1H, m), 7,88 (2H, m).
252Example of getting a 2501H-NMR (CDCl3): to 0.92 (6H, d, J=6.8 Hz), 1,43-1,45 (11H, m), of 1.52-1.55V (2H, m), 1,64 to 1.76 (3H, m), 1,88-of 1.92 (2H, m), 3,68 (1H, m), a 4.53 (1H, m).
253Example of getting 2531H-NMR (DMSO-d6): or 0.83 (6H, d, J=6.8 Hz), 1,25-1,32 (2H, m)to 1.48 (2H, m), 1,62 by 1.68 (3H, m), 1,82-of 1.88 (2H, m), 3,17 (1H, m)to 3.92 (1H, m), to 7.84 (2H, m).
254Example of getting 353ESI+: 453

Table 72
Example recip.SYN.Data
255Example of getting 2921H-NMR (CDCl3): to 1.48 (9H, s), 1.85 to of 1.93 (2H, m), of 2.23 (3H, s), 2,93-to 3.02 (4H, m), 3,45-3,59 (6H, m), 6,47 (1H, d, J=8,3 Hz), 6,53 (1H, s)6,86 (1H, d, J=8,3 Hz).
256Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,3 Hz), for 1.49 (9H, s), 1,91 is 1.96 (2H, m), 2,31 (3H, s)2,84 (2H, q, J=7,3 Hz), 3.00 and-is 3.08 (4H, m), 3,56-3,61 (4H, m), of 5.50 (1H, users), 7,01? 7.04 baby mortality (1H, m), 7,34 (1H, s), 7,52 (1H, m), 7,71 (1H, ush is RS), or 10.60 (1H, users).
257Example of getting 2921H-NMR (CD3OD): for 1.49 (9H, s), 2,02-of 2.20 (6H, m), is 2.37 (3H, s), 2.77-to of 2.86 (2H, m), 3.27 to to 3.34 (6H, m), 3,48-the 3.65 (6H, m), of 3.96 (1H, t, J=15,4 Hz), 7.18 in-of 7.23 (3H, m).
258Example of getting 5031H-NMR (CDCl3): of 1.47 (9H, s), 1,69-1,90 (6H, m)to 2.35 (3H, s), 2,61 is 2.80 (7H, m), 3,30-to 3.33 (2H, m), 3,42-to 3.50 (4H, m), of 6.96 (1H, d, J=8,3 Hz), 8,00-8,03 (2H, m).
259Example of getting 516ESI+: 235
260Example of getting 2921H-NMR (CDCl3): and 1.63 (2H, m), 2,03-2,94 (21H, m), 3,63 (2H, users), 6,34 (1H, d, J=8,4 Hz), 6,93 (1H, d, J=8,4 Hz), 7,81 (1H, s), 8,61 (1H, users).
261Example of getting 5031H-NMR (CDCl3): 1,64-of 1.73 (2H, m), 2,12 (2H, d, J=12,8 Hz), 2,24 (3H, s), 2,29-of 2.38 (1H, m), 2,31 (3H, s)of 2.50 (4H, users), to 2.66 (4H, users), a 2.75 (2H, t, J=12,4 Hz)and 3.15 (2H, d, J=12.0 Hz), 7,16 (1H, d, J=8,8 Hz), 7,92 (1H, DD, J=2,8 Hz and 8.8 Hz), 8,07 (1H, users), 9,16 (1H, d, J=2,4 Hz).
262Example of getting 5161H-NMR (CDCl3): to 2.29 (3H, s), 2,68 (4H, t, J=6.0 Hz), with 3.27 (4H, t, J=6.0 Hz), 7.23 percent (1H, d, J=8,8 Hz), of 7.97 (1H, DD, J=2,4 Hz and 8.8 Hz), 8,16 (1H, users), ,22 (1H, users).

Table 73
Example recip.SYN.Data
263Example of getting 353ESI+: 515
264Example of getting 2921H-NMR (CDCl3): and 1.63 (2H, m), 1,89 (3H, s)of 1.97 (2H, m), 2,56-3,21 (19H, m), 3,61 (2H, users), 6,47 (1H, d, J=2,8 Hz), is 6.61 (1H, DD, J=2,8 Hz and 8.4 Hz), 6,91 (1H, d, J=8,8 Hz).
265Example of getting 2441H-NMR (CDCl3): of 1.62 (2H, m), a 1.96 (3H, s), from 2.00 (2H, m)to 2.29 (3H, s), a 2.36 (1H, m), 2,48 (4H, users), 2,48 (4H, users), 2,61 (4H, users), of 2.86 (4H, m), of 3.48 (3H, s), 3,51 (2H, t, J=10,8 Hz), 7,03 (1H, d, J=9,2 Hz), of 7.96 (1H, d, J=2,8 Hz), 8,11 (1H, DD, J=2,8 Hz and 9.2 Hz).
266Example of getting 353ESI+: 529
267Example of getting 2921H-NMR (CDCl3): 0,62-0,66 (2H, m), 0,91-to 0.96 (2H, m), 2,35 (1H, m)to 2.35 (3H, s), 2.57 m (4H, users), 2,96 (4H, s), 3,42 (2H, users), between 6.08 (1H, d, J=2.4 Hz), 6,46 (1H, DD, J=2,4 Hz and 8.4 Hz), to 6.88 (1H, d, J=8,4 Hz).
268 An example of retrieving 2401H-NMR (CDCl3): 0,83 (2H, m)of 1.09 (2H, m)to 2.15 (1H, m), of 2.38 (3H, s), 2,62 (4H, users), 3,21 (4H, users), of 6.99 (1H, d, J=8,4 Hz), to 7.68 (1H, d, J=2,8 Hz), to 7.99 (1H, DD, J=2,4 Hz and 8.8 Hz).
269Example of getting 353ESI+: 415
270Example of getting 292EI: 251
271Example of getting 516EI: 281
272Example of getting 353ESI-: 433
273Example of getting 353ESI+: 482
274Example of getting 2921H-NMR (CD3OD): to 2.54 (3H, s), to 2.57 (3H, s), 2,90-to 2.94 (4H, m), 2,99-to 3.02 (4H, m), to 6.80 (1H, DD, J=2,4 Hz and 8.8 Hz), to 7.09 (1H, d, J=8,8 Hz), 7,22 (1H, d, J=2,4 Hz).

Table 74
Example recip.SYN.Data
275Example of getting 516276Example of getting 353ESI+: 432
277Example of getting 2921H-NMR (CD3OD): 1,69-1,71 (2H, m), 1,92-of 1.95 (2H, m)to 2.35 (3H, s)to 2.55 (3H, s), 2.57 m-2,82 (9H, m), 3,14 (2H, m), and 3.31 (2H, m)to 3.34 (6H, s), 6,86-to 6.88 (1H, m), 7,20-7,22 (2H, m).
278Example of getting 5031H-NMR (CDCl3): 1,71-of 1.80 (2H, m), 1,96 of 1.99 (2H, m), is 2.30 (3H, s), 2,49-2,64 (9H, m), 2,80 (6H, s)2,84 (2H, m), 3,57-of 3.60 (2H, m), 7,31 (1H, d, J=9,2 Hz), 8,30 (1H, DD, J=2,8 Hz and 9.2 Hz), 8,71 (1H, d, J=2,8 Hz).
279Example of getting 5161H-NMR (CDCl3): 2,69-of 2.72 (4H, m), of 2.86 (6H, s), 3,47-to 3.50 (4H, m), 7,39 (1H, d, J=8,8 Hz), at 8.36 (1H, DD, J=2,4 Hz and 8.8 Hz), 8,71 (1H, d, J=2,4 Hz).
280Example of getting 353ESI+: 565
281Example of getting 2921H-NMR (CDCl3): 2,48 (3H, s), 2,98 (4H, m), and 3.31 (7H, m), 6.90 to (1H, DD, J=2,8 Hz and 8.4 Hz), 7,21 (1H, d, J=2,8 Hz), 7,27 (1H, d, J=8,4 Hz).
282Sample receiving 516 EI: 328
283Example of getting 353ESI+: 468
284Example of getting 2921H-NMR (CDCl3): is 2.88 (3H, s), 2,96 (3H, s), 3,14 (3H, s), 3,19 of 3.56 (8H, m), to 7.09 (1H, s), 7,29 (2H, m).
285Example of getting 5161H-NMR (CDCl3): of 2.34 (3H, s), 2.49 USD is 2.51 (4H, m), is 2.88 (3H, s), 3,13-and 3.16 (2H, m)and 3.15 (3H, s)to 3.38 (2H, m), only 6.64 (1H, d, J=8,8 Hz), 8,14-8,18 (2H, m).

Table 75
Example recip.SYN.Data
286Example of getting 353ESI+: 446
287Example of getting 287EI: 211
288Example of getting 291ESI+: 244
289Example of getting 292FAB+: 214
290Example of getting 287 EI: 211
291Example of getting 291FAB+: 244
292Example of getting 292FAB+: 214
293Example of getting 298ESI+: 401
294Example of getting 299ESI+: 383
295Example of getting 298ESI+: 415
296Example of getting 298ESI+: 415
297Example of getting 299ESI+: 397
298Example of getting 298ESI-: 371
299Example of getting 299ESI-: 353
300Example of getting 298ESI-: 371
301Example of getting 299ESI-: 354
302 Example of getting 299ESI+: 397
303Example of getting 298ESI+: 310
304Example of getting 304ESI+: 306
305Example of getting 298ESI+: 352
306Example of getting 299FAB+: 334
307Example of getting 298ESI+: 338
308Example of getting 298ESI+: 330, 332
309Example of getting 298ESI+: 366
310Example of getting 299ESI+: 348
311Example of getting 311FAB+: 350
312Example of getting 299ESI-: 318
313Example of getting 298ESI+: 374
314Example of getting 299ESI+: 356
315Example of getting 298ESI+: 387
316Example of getting 298ESI+: 401

ESI+: 370
Table 76
Example recip.SYN.Data
317Example of getting 339ESI+: 292
318Example of getting 304ESI+: 326, 328
319Example of getting 339ESI-: 310
320Example of getting 299APCI-: 367
321Example of getting 299ESI-: 381
322Example of getting 298APCI-: 400
323An example of retrieving 98 ESI-: 336
324Example of getting 298ESI+: 364
325Example of getting 299ESI+: 384
326Example of getting 298ESI+: 388
327Example of getting 299APCI-: 368
328Example of getting 298ESI+: 392
329Example of getting 298ESI+: 404
330Example of getting 298ESI+: 326
331Example of getting 299ESI-: 318
332Example of getting 298ESI+: 388
333Example of getting 298ESI+: 427
334Example of getting 299ESI-: 344
335Example of getting 299ESI-: 386
336Example of getting 299ESI-: 373
337Example of getting 304ESI+: 322
338Example of getting 299ESI-: 407
339Example of getting 339ESI+: 308
340Example of getting 346ESI+: 412
341Example of getting 349ESI+: 370
342Example of getting 342ESI+: 387, 389
343Example of getting 342FAB+: 369
344Example of getting 298ESI+: 346
345Example of getting 298ESI+: 372
346Example of getting 346
347Example of getting 346ESI+: 396

Table 77
Example recip.SYN.Data
348Example of getting 349ESI+: 354
349Example of getting 349ESI+: 328
350Example of getting 298ESI+: 372
351Example of getting 298ESI+: 407, 409
352Example of getting 298ESI+: 330
353Example of getting 353ESI+: 355
354Example of getting 299ESI+: 389, 391
355Example of getting 346ESI+: 396
356/td> Example of getting 298ESI+: 330
357Example of getting 346ESI+: 354
358Example of getting 349ESI+: 354
359Example of getting 298ESI+: 310, 312
360Example of getting 353ESI+: 308, 310
361Example of getting 346ESI+: 354
362Example of getting 349ESI+: 312
363Example of getting 349ESI+: 312
364Example of getting 364ESI+: 292
365Example of getting 298ESI+: 364
366Example of getting 346ESI+: 388
367Example of getting 298 ESI+: 364
368Example of getting 346ESI+: 388
369Example of getting 349ESI+: 346
370Example of getting 349ESI+: 346
371Example of getting 298ESI+: 372
372Example of getting 346ESI+: 396
373Example of getting 349ESI+: 354
374Example of getting 298ESI+: 296
375Example of getting 298ESI+: 374
376Example of getting 298ESI+: 330
377Example of getting 298ESI+: 330
378Example of getting 298ESI+: 398

Table 78
Example recip.SYN.Data
379Example of getting 353FAB+: 327
380Example of getting 346ESI+: 422
381Example of getting 346ESI-: 396
382Example of getting 346ESI+: 320
383Example of getting 346ESI+: 354
384Example of getting 346ESI+: 354
385Example of getting 349ESI+: 380
386Example of getting 349ESI+: 356
387Example of getting 349ESI+: 278
388Example of getting 349 ESI+: 312
389Example of getting 349ESI+: 312
390Example of getting 353ESI+: 278
391Example of getting 353ESI+: 369, 371
392Example of getting 353ESI+: 361, 363
393Example of getting 353ESI+: 323
394Example of getting 353ESI+: 323
395Example of getting 353ESI+: 292
396Example of getting 397ESI+: 355
397Example of getting 397ESI+: 355
398Example of getting 398ESI+: 234, 236
399Example of getting 399ESI+: 229
400 Example of getting 400ESI+: 129
401Example of getting 353ESI+: 328
402Example of getting 353ESI-: 343
403Example of getting 353ESI+: 317
404Example of getting 353ESI+: 333
405Example of getting 353ESI+: 328
406Example of getting 516ESI+: 335
407Example of getting 292ESI+: 305
408Example of getting 353ESI+: 322
409Example of getting 353ESI+: 368

Table 79
Example recip.SYN.Yes is data
410Example of getting 353ESI+: 348
411Example of getting 353ESI+: 361
412Example of getting 412FAB+: 335
413Example of getting 413ESI+: 306
414Example of getting 353ESI+: 375
415Example of getting 353ESI+: 405
416Example of getting 353ESI+: 405
417Example of getting 417ESI+: 387
418Example of getting 353ESI+: 458
419Example of getting 353ESI+: 433
420Example of getting 353ESI+: 375
421 Example of getting 516ESI+: 349
422Example of getting 292ESI+: 319
423Example of getting 353ESI+: 488, 490
424Example of getting 353ESI+: 443
425Example of getting 353ESI+: 460
426Example of getting 516ESI+: 373
427Example of getting 353ESI+: 405
428Example of getting 353ESI+: 362
429Example of getting 353ESI+: 360
430Example of getting 430EI: 256, 258
431Example of getting 430EI: 270, 272
432Example of getting 432ESI+ 321
433Example of getting 432ESI+: 335
434Example of getting 292ESI+: 291
435Example of getting 292ESI+: 305
436Example of getting 292ESI+: 343
437Example of getting 353FAB+: 489, 491
438Example of getting 454ESI-: 409
439Example of getting 353ESI+: 405
440Example of getting 440ESI+: 538

Table 80
Example recip.SYN.Data
441Example of getting 455ESI+: 311
442 Example of getting 353ESI+: 443
443Example of getting 353ESI+: 374
444Example of getting 444ESI+: 252
445Example of getting 292ESI+: 222
446Example of getting 353ESI+: 355, 357
447Example of getting 353ESI+: 405
448Example of getting 464ESI+: 408
449Example of getting 468ESI+: 274
450Example of getting 353ESI+: 457
451Example of getting 516ESI+: 305
452Example of getting 292ESI+: 275
453Example of getting 353ESI+: 458
454Example of getting 454ESI+: 441
455Example of getting 455ESI+: 341
456Example of getting 516ESI+: 290
457Example of getting 292ES1+: 260
458Example of getting 353ESI+: 443
459Example of getting 516ESI+: 379
460Example of getting 292ESI+: 349
461Example of getting 353ESI+: 405
462Example of getting 454ESI+: 441
463Example of getting 455APCI/ESI+: 341
464Example of getting 464ESI+: 355
465 Example of getting 464ESI+: 438
466Example of getting 467ESI+: 277
467Example of getting 467ESI+: 291
468Example of getting 468ESI+: 221
469Example of getting 468ESI+: 304
470Example of getting 353ESI+: 404, 406
471Example of getting 353ESI+: 487, 489

Table 81
Example recip.SYN.Data
472Example of getting 472ESI+: 275
473Example of getting 473APCI/ESI+: 279
474Example of getting 292 APCI/ESI+: 249
475Example of getting 516APCI/ESI+: 237
476Example of getting 353APCI/ESI+: 432, 434
477Example of getting 292APCI/ESI+: 207
478Example of getting 454FAB+: 411
479Example of getting 455ESI+: 311
480Example of getting 464ESI+: 325
481Example of getting 468ESI+: 191
482Example of getting 464ESI+: 408
483Example of getting 464ESI+: 438
484Example of getting 468ESI+: 274
485Example of getting 353ESI+: 409
486 Example of getting 468ESI+: 304
487Example of getting 353ESI+: 404
488Example of getting 353ESI+: 374
489Example of getting 353ESI+: 487
490Example of getting 353ESI+: 457
491Example of getting 353APCI/ESI+: 390, 392
492Example of getting a 502EI: 220
493Example of getting 503ESI+: 419
494Example of getting 455ESI+: 319
495Example of getting 444ESI+: 295
496Example of getting 464ESI+: 333
497Example of getting 292 ESI+: 265
498Example of getting 292ESI+: 303
499Example of getting 444ESI+: 279
500Example of getting 353APCI/ESI+: 486, 488
501Example of getting 353ESI+: 420
502Example of getting a 502APCI/ESI+: 251

Table 82
Example recip.SYN.Data
503Example of getting 503APCI/ESI+: 335
504Example of getting 292APCI/ESI+: 305
505Example of getting 353APCI/ESI+: 406
506Example of getting 353APCI/ESI+: 433
507Example of getting 353APCI/ESI+: 420
508Example of getting 353APCI/ESI+: 419
509Example of getting 353APCI/ESI+: 488
510Example of getting a 502APCI/ESI+: 235
511Example of getting 503APCI/ESI+: 319
512Example of getting 292APCI/ESI+: 239
513Example of getting 353ESI+: 472
514Example of getting 432ESI+: 308
515Example of getting 432ESI+: 322
516Example of getting 516ESI+: 279
517Example of getting 292ESI+: 249
518The example on the teachings 516 ESI+: 295
519Example of getting 292APCI/ESI+: 265
520Example of getting 353ESI+: 404
521Example of getting 353ESI+: 420
522Example of getting 292ESI+: 292
523Example of getting 292ESI+: 278
524Example of getting 353ESI+: 475, 477
525Example of getting 353ESI+: 488, 490
526Example of getting 353ESI+: 502, 504
527Example of getting 353ESI+: 474, 476
528Example of getting 353ESI+: 474
529Example of getting 353ESI+: 461
530Example of getting 467ESI+: 278
531Example of getting 353ESI+: 461, 463
532Example of getting 353ESI+: 460, 462
533Example of getting 430EI: 270, 272

Table 83
Example recip.SYN.Data
534Example of getting 432ESI+: 335
535Example of getting 292ESI+: 305
536Example of getting 353ESI+: 488, 490
537Example of getting 432ESI+: 322
538Example of getting 292ESI+: 292
539Primecluster 353 ESI+: 475, 477
540Example of getting 353ESI+: 532, 534
541Example of getting 516ESI+:319
542Example of getting 292ESI+: 289
543Example of getting 545ESI+: 389
544Example of getting 353ESI+: 435
545Example of getting 545APCI/ESI+: 419
546Example of getting 417ESI+: 470
547Example of getting 353APCI/ESI+: 488
548Example of getting 3531H-NMR (CDCl3): of 1.28 (3H, t, J=7,3 Hz), a 2.36 (3H, s), 2,62 (4H, users), 2,85 (2H, q, J=7,6 Hz), 3,10 (4H, users), of 5.50 (1H, users), 6,91-6,99 (1H, m), 7,25 (1H, users), 7,53 (1H, d, J=14.4 Hz), 7,71 (1H, users), 10,71 (1H, users).
549Example of getting 53 ESI+: 506
550Example of getting 545ESI+: 490
551Example of getting 516ESI+:319
552Example of getting 292ESI+: 289
553Example of getting 353ESI+: 472
554Example of getting 5161H-NMR (CDCl3): 1,71-2,17 (6H, m), 2,35 (4H, m), 2,72 is 2.75 (4H, m), 2,99-to 3.02 (2H, m), 3,30-of 3.32 (4H, m), 6.87 in-6,92 (1H, m), 7,87-to 7.99 (2H, m).
555Example of getting 292ESI+: 293

Table 84
Example recip.SYN.Data
556Example of getting 3531H-NMR (CDCl3): 1,26-of 1.32 (3H, m), 1.56 to of 1.65 (2H, m), 1,84-of 1.97 (4H, m), is 2.30 (4H, m), 2,72-3,09 (12H, m)5,49 (1H, users), 6,90-to 6.95 (1H, m), 7,17-7,29 (1H, m), 7,52-7,56 (1H, m), 7,71 (1H, users), 10,71 (1H, users).
557Example of getting 5161H-NMR (CDCl3): to 1.59 (2H, m), 1,82-of 1.85 (2H, m), 1.93 and-to 1.98 (2H, m), and 2.27 (4H, users), a 2.75 (4H, t, J=4.6 Hz), 2.91 in vs. 2.94 (2H, m), 3,24-3,26 (4H, m), of 3.95 (3H, c), 6,87 (1H, d, J=9.0 Hz), of 7.70 (1H, d, J=2.4 Hz), the 7.85 (1H, DD, J=2.7, And 9.0 Hz).
558Example of getting 2921H-NMR (CDCl3): 1,65 is 2.00 (8H, m)to 2.29 (4H, users), 2,75 was 2.76 (4H, m), 2,93-3,03 (6H, m), 3,83 (3H, c), 6,23-of 6.26 (2H, m), 6,76 (1H, d, J=8,1 Hz).
559Example of getting 3531H-NMR (CDCl3): 1,57-1,98 (11H, m)to 2.29 (5H, m), 2,78 (4H, users), 2,94-2,96 (2H, m)to 3.09 (4H, users), 3,71 (1H, users), 3,90 (3H, c)to 5.56 (1H, users), 6,91 (1H, d, J=8.5 Hz), 7,13 (1H, DD, J=2,4, 8.5 Hz), was 7.36 (1H, d, J=2.4 Hz), 7,41 (1H, users), of 10.76 (1H, users).
560Example of getting 545ESI+: 502
561Example of getting 353ESI+: 423
562Example of getting 5451H-NMR (CDCl3): of 1.26 (6H, d, J=6.8 Hz), is 2.37 (3H, s), 2,62 (4H, users), 3,10 (4H, users), 3,40-3,47 (1H, m), 5,52 (1H, users), 6,91-of 6.96 (1H, m), 7.24 to 7,26 (1H, m), 7,53 (1H, DD, J=2.7, and 14.6 Hz), 7,69 (1H, users), 10,70 (1H, users).

1. The compound of formula (I) or its pharmaceutically acceptable salt:
[Formula I]
,
where the symbols have the meanings defined below:
-X-: group of the formula (II):

And: represents a chlorine, ethyl or isopropyl;
R1represents phenyl, in which the carbon at the 4-position is substituted by a group-W-Y-Z, and the carbon at the 3-position may be substituted by a group, select the Noah group, consisting of halogen, R00and-O-R00;
R00: lower alkyl which may be substituted by one or more halogen atoms;
W: communications, piperidine-1,4-diyl or piperazine-1,4-diyl;
-Y represents a bond;
Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which may be substituted by one or more substituents R00;
R2represents a
(i) is not necessarily associated bridge connection saturated With3-10cycloalkyl, which may be substituted by one or more groups selected from the group consisting of
-N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -HE,
-COOH, -CONH-RZBand morpholinyl, or
(ii) monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which may be substituted by one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo,
-CO-RZBand benzyl; and
RZB: phenyl which may be substituted by a group selected from the group consisting of halogen and-O-lower alkyl;
R3not only is em a-N.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where the specified connection is a 5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamide

3. The compound or its pharmaceutically acceptable salt according to claim 1, where the specified connection is a 6-ethyl-5-[(TRANS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamide.

4. The compound or its pharmaceutically acceptable salt according to claim 1, where the specified connection is a 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide.

5. The compound or its pharmaceutically acceptable salt according to claim 1, where the specified connection is a 6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide.

6. The compound or its pharmaceutically acceptable salt according to claim 1, where the specified connection is a 6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide.

7. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1represents phenyl, in which the carbon at the 4-position is amesen group, selected from the group consisting of 4-(4-methylpiperazin-1-yl)piperidine-1-yl, 4-(1-methylpiperidin-4-yl)piperazine-1-yl, 4-methylpiperazin-1-yl and 4-isopropylpiperazine-1-yl, and the carbon at the 3-position may be substituted by a group selected from the group consisting of fluorine, methyl, trifloromethyl and methoxy.

8. The connection according to claim 7 or its pharmaceutically acceptable salt, where R2is a 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl or tetrahydropyran-4-yl.

9. The compound according to claim 1 or its pharmaceutically acceptable salt, where the connection specified is a
6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamid,
6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,
5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-carboxamid,
6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamid,
6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,
5-[(TRANS-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazin-2-carboxamid, 6-ethyl-5-[(CIS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,
6-ethyl-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazine-1-yl)-3-were]amino}pyrazin-2-carboxamid,
6-ethyl-5-[(TRANS-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,
6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,
6-chloro-5-[(TRANS-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)pyrazin-2-carboxamid,
6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,
6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,
6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,
6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,
6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid,
6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamid the or
6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazine-1-yl]phenyl}amino)-5-(tetrahydro-2H-Piran-4-ylamino)pyrazin-2-carboxamide.

10. Pharmaceutical composition having the properties of a selective inhibitor of kinase activity of EML4-ALK hybrid protein, which comprises the compound according to claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

11. The inhibitor against the kinase activity of EML4-ALK hybrid protein, representing a compound according to claim 1 or its pharmaceutically acceptable salt.

12. Pharmaceutical composition having the properties of a selective inhibitor of kinase activity of EML4-ALK hybrid protein, for the prevention or treatment of cancer, lung cancer, non-small cell lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cell lung cancer, which comprises the compound according to claim 1 or its pharmaceutically acceptable salt.

13. The use of compounds according to claim 1 or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for the prevention or treatment of cancer, lung cancer, non-small cell lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EM4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cell lung cancer.

14. The compound according to claim 1 or its pharmaceutically acceptable salt having the properties of a selective inhibitor of kinase activity of EML4-ALK hybrid protein, for preparing a medicinal product which is used for prevention or treatment of cancer, lung cancer, non-small cell lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cell lung cancer.

15. The method of prevention or treatment mediated by the activity of the kinase activity of EML4-ALK hybrid protein cancer, lung cancer, non-small cell lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cell lung cancer, which includes the introduction of an effective amount of a compound according to claim 1 or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of general formula (I): wherein m and n independently represent 0 or 1; G and E represent oxygen, R1 and R2 together with a carbon atom whereto attached form a heterocycle including one or two heteroatoms specified in oxygen, sulphur, -S(O)-, -S(O)2-, -N=, -N(R5)-; one or more carbon atoms in the above heterocycle are optionally substituted by one or more identical or different substitutes specified among the substitutes R4; R3 represents alkoxy or halogenoxy; R4 represents hydrogen, alkyl or halogen; R5 represents hydrogen, alkyl carbonyl, alkoxy carbonyl or alkyl sulphonyl; X represents a bond, -CH2- or -NH-; A represents phenyl, pyridyl, pyrazynyl or quinolyl optionally substituted by one or more identical or different substitutes specified among the substitutes R4; or pharmaceutically acceptable salts, hydrates, N-oxides or salvates thereof.

EFFECT: invention also refers to the pharmaceutical composition of the above compounds as the phosphodiesterase PDE4 inhibitor for treating, eg skin diseases.

19 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to di(arylamino)aryl derivatives presented in the patent claim. The compounds show an inhibitory effect on protein EML4-ALK v1 and protein EGFR kinase activity. Also the invention refers to a pharmaceutical composition containing said compounds, the hybrid protein EML4-ALK and mutant protein EGFR kinase activity inhibitor, the use of said compounds for preparing the pharmaceutical composition, and to a method of preventing or treating non-small-cell lung cancer or EML4-ALK hybrid polynucleotide-positive and/or mutant EGFR polynucleotide-positive non-small-cell lung cancer.

EFFECT: use of di(arylamino)aryl as the protein EML4-ALK v1 and protein EGFR kinase activity inhibitors.

12 cl, 95 tbl, 55 ex

Ppar modulators // 2449999

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to new 1,3-dioxane derivatives of formula: wherein A, W, Ar, Ra and Rb have the values specified in the description, or to their pharmaceutical salts.

EFFECT: applying the modulators in treating a disease or a condition associated with PPAR modulation, such as diabetes, cancer, inflammation, neurodegenerative disorders and infections, and also development of based pharmaceutical compositions.

23 cl, 28 ex, 2 tbl, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with the general formula (I) in the racemic, enantiomeric form or in any combination of these forms and in which: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH-; Ra and Rb independently represent the hydrogen atom or a radical (C1-C6)alkyl; Rj represents the atom of hydrogen; a radical (C1-C8)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; R2 represents a radical (C1-C8)alkyl not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; (C2-C6)alkenyl; or a radical of the formula -(CH2)n-X1; each X1 independently represents (C1-C6)alkoxy, (C3-C7)cycloalkyl or heteroaryl, and radicals (C3-C7)cycloalkyl, aryl and heteroaryl are not necessarily replaced by one or more either identical or various assistants chosen from: -(CH2)n'-V1-Y1, halogen and; V1 represents -O-, -S- or a covalent bond; Y1 represents a radical (C1-C6)alkyl, not necessarily substituted hydroxyl or by one or more identical or different radicals of halogens; n represents an integer from 0 up to 6 and n ' - an integer from 0 up to 2 that if n is equal 0 then X1 does not represent a radical alkoxy); or R1 and R2 form together with the atom of nitrogen to which they are attached, heterobicycloalkyl or heterocycloalkyl, are not necessarily replaced by one or more either identical or various substitutes chosen from: hydroxy, (C1-C6)alkyl, not necessarily substituted by hydroxy, (C1-C6)alkoxycarbonyl, heterocycloalkyl and-C(O)NV1'Y1', in which V1' and Y1' independently represent the atom of hydrogen or (C1-C6)alkyl; or R1 and R2 together form a radical of the formula: R3 represents-Z3, -C(RZ3)(R'Z3)-Z3, -C(RZ3)(R'Z3)-(CH2)p-Z3 or -C(O)Z'3; RZ3 and R'Z3 independently represent atom of hydrogen or a radical (C1-C6)alkyl; Z3 represents Z3b, Z3c, Z3d or Z3e; Z3b represents (C1-C6)alkoxy, (C1-C6)alkythio, (C1-C6)alkylamino, or a radical di((C1-C6)alkyl) amino; Z3c represents aryl or a radical heteroaryl; Z3d represents C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, di((C1-C6)alkyl) aminocarbonyl, (C1-C6)alkyl-C(O)NH-, (C3-C7) cycloalkyl, heterocycloalkyl; and radicals (C3-C7) cycloalkyl and heterocycloalkyl are not necessarily replaced by one or more either identical or various substitutes chosen from: (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl and oxy, radicals aryl and heteroaryl are not necessarily replaced by one or more either identical or various substitutes chosen from: halogen, cyanogen, nitro, azide, oxy, (C1-C6)alkylcarbonyl-(C1-C6)alkenyl, (C1-C6)alkylaminocarbonyl-(C1-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31 and R32 form together with atom of nitrogen to which they are attached, heterocycloalkyl, V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR'3-SO2-, -NR'3-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or covalent bonds; Y3 represents the atom of hydrogen; radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; radical aryl or a radical aryl-(C1-C6)alkyl; Z3e represents a radical of the formula

, Z'3 represents a radical aryl, not necessarily replaced by one or more oreither identical or various substitutes chosen from: halogen, nitro and -(CH2)P"-V'3-Y'3; V'3 represents -O-, -C(O)-, -C(O)-O, -C(O)-NR'3-,-NH-C(O)-NR'3- or covalent bonds; Y'3 represents the atom of hydrogen or a radical (C1-C6)alkyl, not necessarily replaced by one or more either identical or different radicals of halogens; R'3 represents the atom of hydrogen (C1-C6)alkyl or a radical (C1-C6)alkoxy; p represents an integer from 1 up to 4; p' and p" independently represent an integer from 0 up to 4; R4 represents a radical of the formula -(CH2)S-R'4; R'4 represents a radical guanidine; heterocycloalkyl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or aralkyl; heteroaryl containing, at least, one atom of nitrogen and not necessarily substituted (C1-C6)alkyl or a radical of the formula -NW4W'4; W4 represents an atom of hydrogen or (C1-C8) alkyl; W'4 represents a radical of the formula -(CH2)S-Z4; Z4 represents an atom of hydrogen (C1-C8) alkyl, (C3-C7)cycloalkyl, heteroaryl and aryl; s and s' independently represent an integer from 0 up to 6; and i) if R3 represents -C(O)-Z'3 and R4 represents a radical of the formula -(CH2)S-NW4W'4, and W4 and W'4 independently represent an atom of hydrogen or a radical C1-C6)alkyl, then -(CH2)s represents neither radical ethylene nor radical -(CH2)-CH((C1-C4)alkyl) and ii), if R3 represents -Z3c and Z3c represents phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyanogen; also note that if R3 represents -Z3d, then Z3d, represents only one (C3-C7)cycloalkyl or heterocycloalkyl; or to their pharmaceutically acceptable salts. The invention also relates to the method of obtaining the compounds of the formula (I), to a pharmaceutical composition, and to the application of compounds of the formula (I) and (I ').

EFFECT: obtaining new biologically active compounds on their basis, possessing activity with respect to receptors MC4.

41 cl, 535 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of formula I: where n has values 0 or 1, and Cy represents a heteroaryl group, selected from such groups as 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl and 4-pyridinyl, where heteroaryl groups are optionally substituted by up to 3 substituents, different from hydrogen, independently selected fromC1-6alkyl, C2-6alkenyl, C2-6alkinyl, C3-8cycloalkyl, substituted phenyl, furyl, halogen, -OR', -CF3, -CN, -NO2, -SO2R', -SO2NR'R″, -R'SO2R″, where R' and R″ are independently selected from hydrogen, C1-6alkyl, where the term "substituted", applicable with respect to substituted phenyl, relates to substitution with one or several halogens, and their pharmaceutically acceptable salts, as well as to pharmaceutical compositions based on the said compounds.

EFFECT: application of the said compounds for treatment and/or prevention of wide spectrum of CNS diseases and disorders.

13 cl, 2 dwg, 1 tbl, 11 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to new positively charged NSAIA prodrugs of a common formula (1, 2a, 2b, 2c or 2d) of "1, 2a, 2b, 2c or 2d structure"

Structure 1, Structure 2a,

Structure 2b, Structure 2c, Structure 2d. Values of R, R1, R2, R3, R4, R5, Ary, X radicals are presented in Claims 1,2.

EFFECT: increasing agent penetration speed.

22 cl, 14 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 1,5-bis[(tert-butylamino)methyl]-N,N'-di-tert-butylbispidin-9-one and a method for production thereof. 1,5-bis[(tert-butylamino)methyl]-N,N'-di-tert-butylbispidin-9-one is obtained by condensation of acetone with 1,3,5-tri-(tert-butyl)-1,3,5-triazacyclohexane while heating in an alcohol in the presence of acetic acid. The reaction is carried out while heating in ethanol or another alcohol. The obtained product is extracted after condensation of the reaction mass in a vacuum with hot toluene and recrystallised from ethyl alcohol.

EFFECT: obtaining a novel compound which can be used as a starting substance when producing bispidine and 1,3-diazaadamantane derivatives.

2 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds in the form of a free base or a pharmaceutically acceptable acid addition salt specified in a group including: (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-azabicyclo[3.3.1]nonane, 5-{2-[(4S,5R)-(1-azabicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydroindol-2-one, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-azabicyclo[3.3.1]nonane, (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-azabicyclo[1.3.1]nonane and 5-{6-[(4S,5R)-(1-azabicyclo[3,3,1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydroindol-2-one, possess nAChR α7 agonist activity.

EFFECT: using them in pharmaceutical compositions and for preparing a drug applicable for preventing and treating a memory disorder.

21 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), having antibacterial properties, a method for synthesis thereof, use thereof and a pharmaceutical composition based on said compounds. In general formula (I) R1 is a (CH2)n-NH2 or (CH2)n-NHR radical, where R is (C1-C6)alkyl and n equals 1 or 2; R2 is a hydrogen atom; R3 and R4 together form a nitrogen-containing aromatic 5-member heterocycle with 1, 2 or 3 nitrogen atoms, possibly substituted with one or more R' groups, where R' is selected from a group consisting of a hydrogen atom and alkyl radicals with 1-6 carbon atoms.

EFFECT: improved method.

13 cl, 4 ex

Liquid hardening // 2447114

FIELD: chemistry.

SUBSTANCE: invention relates to curing agents for air-drying alkyd-based resins, coating compositions, such as paint, varnish, wood stain, inks and linoleum floor coverings. Described is a curable liquid medium containing a) from 1 to 90 wt % of an alkyd-based resin and b) from 0.0001 to 0.1 wt % of a siccative in form of an iron or manganese complex with a tetradentate, pentadentate or hexadentate nitrogen donor ligand.

EFFECT: said siccative has high activity and enables hardening of compositions at relatively low concentration in a curable liquid medium.

19 cl, 8 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (III) in form of a free base or an acid addition salt, use thereof as a pharmaceutical agent for preventing, treating and/or inhibiting progression of psychotic and neurodegenerative disorders, as well as pharmaceutical compositions based on said compound.

EFFECT: novel compound which can be used to prevent, treat or inhibit progression of diseases or a pathologic condition in which nAChR α7 activation participates or plays a role.

8 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to new 1,4-diaza-bicyclo[3.2.2]nonyl-oxadiazolyl derivatives of formula I or to their pharmaceutically acceptable salts; where Ar represents a phenyl group substituted by methylene dioxy or ethylene dioxy. Also, the invention refers to a pharmaceutical composition exhibiting cholinergic receptor activity on the basis of said compounds.

EFFECT: what is produced are new compounds and based pharmaceutical composition which can be effective for treating various diseases or disorders, such as those associated with the cholinergic system of the central nervous system, peripheral nervous system, diseases or disorders associated with smooth muscle contracture, endocrine diseases or disorders, neurodegenerative diseases or disorders, inflammatory diseases or disorders, pain and withdrawal syndromes caused by addictive chemical withdrawal.

10 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

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