New pyrazole-3-carboxamide derivative possessing antagonist activity on 5-НТ receptor

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

This invention relates to new pyrazole-3-carboxamide derivatives. The compounds of this invention are compounds useful as selective antagonists of the receptor 5-HT2Band useful for the prevention or treatment of various diseases associated with the specified receptor. This invention also relates to pharmaceutical compositions containing the above-mentioned derivatives.

PRIOR art

Serotonin (5-hydroxytryptamine), which was first opened in 1948, is one of the neurotransmitters and one of tryptamine derivatives distributed in a high concentration in the hypothalamic region, basal ganglia, serotonergic neurons of the nuclei of the seam in the brain and so on. Serotonin is a chemical substance found in animals, including humans, and biosynthesized from tryptophan. About 10 mg of serotonin found in the human body, most of which are distributed in the chromaffin cell of the mucosa of the small intestine. Serotonin is synthesized here working on muscles such as muscles of the intestine, and is largely associated with motor activity of the gastrointestinal tract. Serotonin is also found in the Central nervous system and contributes to the mental is aktivnosti person. Considerable attention is paid to the influence of serotonin in everyday life in mental disorders, as has been noted, such as depression and neurosis. In recent years we have developed medicines against these diseases with drugs that affect serotonin.

On the other hand, serotonin is one of associated with G-protein receptors, mainly in the Central nervous system. Serotonin is divided into 7 families of 5-HT1up to 5-HT7and recognized 14 subtypes. Although ongoing pharmacological studies for each subtype (non-patent literature 1), three subtypes, 5-HT2A, 5-HT2Band 5-HT2Cestablished in the family of 5-HT2. In addition, there are reports of various pharmacological effects on the receptor 5-HT2Buseful for the prevention and treatment of various diseases.

In General, it was found that antagonists of the receptor 5-HT2Buseful for the prevention or treatment of various diseases, such as migraine, pain, inflammation, nociceptive pain, fibromyalgia, chronic lumbar pain, visceral pain, gastroesophageal reflux disease (GERD), a higher, diarrhea, functional gastrointestinal disorder, irritable bowel syndrome (commonly referred to as the here IBS. The definition and criteria described in the ROME III, non-patent literature 2), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, cerebral stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible obstruction of the respiratory tract, the respiratory diseases of adults, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), idiopathic interstitial pneumonia, bronchitis, liver fibrosis, cryptogenic fibrosing alveolitis, multiple sclerosis, depression, anxiety and obesity (non-patent literature 3-7).

In addition, with regard receptors 5-HT2Bthe relationship of the specified receptor with digestive apparatus and pulmonary artery were studied on the basis of experiments using selective inhibitors of 5-HT2B.

As for the role of the digestive apparatus, the antagonists of the receptor 5-HT2Buseful for IBS based on the suppression of the reduction of the human intestine by electrostimulation (patent literature 1). Described that antagonists of 5-HT2Beffective in the treatment of functional bowel disorders, based on the reduction of the intestine in rats by stimulation of the serotonin (patent literature 2). In addition, it is reported to decrease the AI's pain threshold when the swelling of the large intestine in rats processed 2,4,6-trinitrobenzenesulfonic acid (hereafter denoted TNBS), which is regarded as a model of visceral hypersensitivity (non-patent literature 8).

In addition, antagonists of 5-HT2Breduce the increase defecation mass under stress in a model of stress-induced defecation in rats, which is often considered as a model of IBS, which confirms the usefulness of these antagonists in IBS with a dominant diarrhea. In addition, when rats are exposed to stress, increased pain response to distention of the colon, agonists of 5-HT2Binhibit the amplification of painful reaction.

As for the role of antagonists in pulmonary artery described that the relationship between the receptor 5-HT2Band recovery in models of pulmonary hypertension in mice with chronic hypoxia, connection-antagonists of 5-HT2Beffective in the treatment of pulmonary hypertension (non-patent literature 9). It is reported that selective antagonists of 5-HT2Breduce blood pressure in the study at an early phase II patients with pulmonary hypertension and chronic obstructive pulmonary disease (COPD), in a dual controlled trial using placebo as the reference (non-patent literature 10), which confirms the safety and usefulness for human selective antagonists of 5-T 2B.

The LIST of CITED MATERIALS

PATENT LITERATURE

Patent literature 1: international publication 02/056010, brochure

Patent literature 2: publication of unexamined patent application in Japan (translation of PCT application) No. 1997-510216

Non-PATENT LITERATURE

Non-patent literature 1: Pharmacol.Rev., 1994, 46, 157-203

Non-patent literature 2: Drossman et al., Journal of Gastrointestinal and Liver Diseases (2006) Vol.15 (3), 237-241

Non-patent literature 3: Johnson KwCephalalgia 23(2): 117-23(2003)

Non-patent literature 4: Allman JM et al, TRENDS In Cognitive Sciences 9(8): 367-373(2005)

Non-patent literature 5: Borman RA et al, Br J Pharmacol. 135 (5):114, 4-51(2002)

Non-patent literature 6: Beattie DT, et al, Br J Pharmacol. 143(5):549-60(2004)

Non-patent literature 7: Kubera M, et al., Psychiatry Res. 30; 134(3):251-8(2005)

Non-patent literature 8: The Journal of Pharmacology and Experimental Therapeutics, Vol.302, No.3, 1013-1022 (2002); Pharmacology (2008), 81(2), 144-150

Non-patent literature 9: Nature Medicine, 8(10): 1129-1135, 2002

Non-patent literature 10: PRX-08066: EPIX Pharmaceuticals

BRIEF description of the INVENTION

TECHNICAL PROBLEM

The purpose of this invention is to develop a drug or pharmaceutical composition containing as active ingredients compounds with selective antagonistic activity against receptor 5-HT2B. In addition, the purpose of this invention is the reduction of a variety of adverse impact is, which tends receptor antagonist 5-HT2Bdue to the high selective affinity for the receptor and reduce interactions with other receptors.

SOLUTION

The authors of this invention solve the above-mentioned problems found that new pyrazole-3-carboxamidine derivative with a unique chemical structure are selective and strong antagonistic activity against receptor 5-HT2Brelated to the number of subtypes of serotonin receptors. In addition, the authors confirmed that the new pyrazole-3-carboxamide derivatives effectively improve the sensitivity threshold of visceral pain in TNBS-induced model of IBS rats. Thus, the new 5-substituted-1H-pyrazole-3-carboxamide derivatives useful for the prevention or treatment of disease conditions mediated by stimulation of the above receptor, such as migraine, pain, inflammation, nociceptive pain, fibromyalgia, chronic lumbar pain, visceral pain, gastroesophageal reflux disease (GERD), a higher, diarrhea, functional gastrointestinal disorder, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, brain in the ult, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible obstruction of the respiratory tract, the respiratory diseases of adults, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), idiopathic interstitial pneumonia, bronchitis, liver fibrosis, cryptogenic fibrosing alveolitis, multiple sclerosis, depression, anxiety and obesity.

In connection with the foregoing, the invention is complete and provides the following compounds or the corresponding pharmaceutically acceptable salts of these compounds or the corresponding pharmaceutically acceptable salts as active ingredients for the prevention or treatment of disease associated with the receptor 5-HT2Bpharmaceutical compositions containing these compounds or the corresponding pharmaceutically acceptable salt, or a method of treatment using these compounds or their respective pharmaceutically acceptable salts.

Namely, this invention is as follows:

[1] the Compound of the following General formula (I0or its pharmaceutically acceptable salt,

,

where

R1means linear, branched or cyclic lower alkyl group with 1-6 carbon atoms or a linear, branched or cyclic will stifle halogenating group with 1-6 carbon atoms;

R2means (hetero)cyclic aryl group of the following General formula (Ar);

,

R3means a hydrogen or halogen atom;

R4means linear, branched or cyclic lower alkyl group with 1-6 carbon atoms, linear, branched or cyclic halogenating group with 1-6 carbon atoms; OH, OR1A, halogen, -(CH2)aOH, CO2H, CONH2, CONHR1A, CONR1AR1A, CN, COR1A, NH2, Other1A, NR1AR1A, NHCOR1A, SR1A, SOR1A, SO2R1A, SO2NH2, SO2Other1A, SO2NR1AR1Aor NHSO2R1Awhen q is plural, R4may be the same or different; when R4has two R1A, these substituents may be the same or different, or R1Acan be combined with other R1A;

R5means linear, branched or cyclic lower alkyl group with 1-6 carbon atoms, -(CH2)aOH, -(CH2)aOR1B, halogen, CONH2, CONR1BR1B, COR1B, SO2R1B, -OCH2CH2NR1BR1Bor a linear, branched or cyclic halogenating group with 1-6 carbon atoms; when p is plural, R5may be the same or different is a diversified, or R5can be combined with other R5;

each of R1Aand R1Bindependently means a linear, branched or cyclic lower alkyl group with 1-6 carbon atoms, or a linear, branched or cyclic halogenating group with 1-6 carbon atoms;

a is 0, 1 or 2;

m is 0, 1 or 2;

n is 1 or 2;

p is 0, 1, 2, 3, 4 or 5 and

q is 0, 1, 2 or 3;

X is CH2, NH, O, S, SO, SO2, CHR5, CR5R5(R5is the same as described above, and may be the same or different) or NR5(R5is the same as defined above);

W denotes an oxygen atom, (H, H), (H, R5) or (R5, R5), when X is CH2, NH, O, CHR5, CR5R5or NR5or W signifies (H, H), (H, R5) or (R5, R5)when X represents S, SO or SO2; where (H, H), (H, R5) or (R5, R5means that W is a two monovalent group, and these two monovalent groups are H and H, H and R5, R5and R5;

Y represents NH, NR1, O or S;

each of the Z1, Z2, Z3, Z4, Z5and Z6independent means N, C, CH or CR4(R4is the same as above, and 1, 2 or 3 of the Z1-Z6can mean a nitrogen atom).

[2] the Compound of the following General formula is (I) or its pharmaceutically acceptable salt,

,

where

A means 3-8-membered cycle and may contain 0-4 heteroatoms selected from O, S and N;

R1means C1-C6is an alkyl group or a C1-C6-halogenation group;

R2means a saturated or partially or fully unsaturated monocyclic or bicyclic aryl group which may be substituted, R4;

R3means a hydrogen or halogen atom;

R4means C1-C6is an alkyl group, a C1-C6-halogenation group, OH, OR1A, halogen, -(CH2)aOH, CO2H, CONH2, CONHR1A, CONR1AR1A, CN, COR1A, NH2, Other1A, NR1AR1A, NHCOR1A, SR1A, SOR1A, SO2R1A, SO2NH2, SO2Other1A, SO2NR1AR1Aor NHSO2R1Awhen q is plural, R4may be the same or different; when R4has two R1A, these substituents may be the same or different, or R1Acan be combined with other R1A;

R5means C1-C6is an alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen, CONH2, CONR1BR1B, COR1B, SO2R1B, -OCH2CH2NR1BR1Bor C1-C6-halogenation group; it is when p is plural, R5may be the same or different, or R5can be combined with other R5;

each of R1Aand R1Bindependently mean C1-C6is an alkyl group or a C1-C6-halogenation group;

a is 0, 1 or 2;

m is 0, 1 or 2;

n is 1 or 2;

p is 0, 1, 2, 3, 4 or 5 and

q is 0, 1, 2, or 3.

[3] the Compound or its pharmaceutically acceptable salt, as described in the above item [2], where R2means the following Ar1, Ar2, Ar3or Ar4,

,

where,

R4and q are the same as described in the above item [2];

Y represents NH, NR6, O or S;

each of the Z1, Z2, Z3, Z4, Z5and Z6independent means N, C, CH or CR4(1, 2 or 3 of the Z1-Z6can represent a nitrogen atom); and

R6means hydrogen, C1-C6is an alkyl group, a C1-C6-halogenation group, C1-C6-alkoxy-C1-C6is an alkyl group, hydroxyl-C1-C6is an alkyl group, halogen-C1-C6-alkoxy-C1-C6is an alkyl group, di-C1-C6-alkylamino-C1-C6is an alkyl group, mono-C1-C6-alkylamino-C1-C6is an alkyl group, amino-C1-C6is an alkyl group, a C3- 8-cyclo-C1-C6is an alkyl group (specified C3-C8-cyclo-C1-C6is an alkyl group may be substituted by 1 or 2 groups, each of which is independently selected from hydroxy, C1-C6-alkoxy and C1-C6-acyloxy, and may contain S (sulfur), O (oxygen) or NR1), aminocarbonyl-C1-C6is an alkyl group, mono-C1-C6-alkylaminocarbonyl-C1-C6is an alkyl group, di-C1-C6-alkylaminocarbonyl-C1-C6is an alkyl group, hydroxycarbonyl-C1-C6is an alkyl group or a C1-C6-alkylsulfonyl group,

,

where

R4and q are the same as described in the above item [2]; and

each of the Z1, Z2, Z3, Z4, Z5, Z6, Z7and Z8independent means N, C, CH or CR4(1, 2 or 3 of the Z1-Z8can represent a nitrogen atom).

[4] the Compound or its pharmaceutically acceptable salt, as described in the above item [3], where Ar1, Ar2, Ar3or Ar4represented by the following General formula:

,

where

R4and q are the same as described in the above item [2];

R6means hydrogen or C1-C6is an alkyl group, and

(R4)q can the t to replace one of the two cycles or both of the loop.

[5] the Compound or its pharmaceutically acceptable salt, as described in the above item [2], where A cycle is a morpholine, piperidine, pyrrolidine or azetidine, which is connected to N;

n = 1;

p is 0, 1 or 2 and

q is 0, 1 or 2.

[6] the Compound or its pharmaceutically acceptable salt, as described in the above item [2], where the connection represented by the General formula (I)are selected from the group including

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide;

1-methyl-5-{5-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide;

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{7H-pyrrolo[2,3-d]pyrimidine-6-yl}-1H-pyrazole-3-carboxamide;

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-[5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-yl]-1H-pyrazole-3-carboxamide;

1-methyl-5-{5-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{5-cyano-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{6-fluoro-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{5H-pyrrolo[2,3-b]pyrazin-6-yl}-1H-pyrazole-3-carboxym is d;

5-{5-cyano-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

N-[2-(3,3-diversecity-1-yl)ethyl]-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide;

N-[2-(azetidin-1-yl)ethyl]-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide;

1-methyl-5-(2-methyl-1H-indol-5-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-(1,2-dimethyl-1H-indol-5-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-[1-(2-methoxyethyl)-1H-indol-3-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-(4-acetamido-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{imidazo[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{6-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{7-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

5-{6-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;

N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide;

N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide and

5-{7-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide.

[7] Ex is offered by the connection for the connection described in the above item [2]represented by the General formula (1A):

,

where each definition is the same as described in the above item [2].

[8] the Intermediate connection for compounds described in the above item [2]represented by the General formula (IB):

,

where R1, R2, R3the same as defined for formula (I), OH and carboxylic acid can be replaced deleted Deputy.

[9] the Preventive or therapeutic agent against diseases that involve the receptors 5-HT2Bwhere the effective ingredient is a compound or its pharmaceutically acceptable salt according to any one of p.p.[2]-[6].

[10] the Pharmaceutical composition containing the compound or its pharmaceutically acceptable salt according to any one of points [2]-[6], and a pharmaceutically acceptable carrier.

[11] the Pharmaceutical composition for prevention or treatment of a pathological state mediated by receptors 5-HT2Bat the mammal containing an effective amount of the compound or its pharmaceutically acceptable salt according to any one of points [2]-[5], and a pharmaceutically acceptable carrier.

[12] a Pharmaceutical composition comprising a compound according to any one of points [2]-[6] and optionally containing another pharmacologic the ski active agent.

[13] the Compound or its pharmaceutically acceptable salt according to any one of points [2]-[6] used in the prevention or treatment of a pathological state mediated by receptors 5-HT2B.

[14] Use of the compound or its pharmaceutically acceptable salt according to any one of points [2]-[6], in the manufacture of a medicine for the prevention or treatment of a condition mediated by receptors 5-HT2B.

[15] a Method of prevention or treatment of diseases such as migraine, pain, inflammation, nociceptive pain, neuropathic pain, fibromyalgia, chronic lumbar pain, visceral pain, gastroesophageal reflux disease (GERD), a higher, diarrhea, functional gastrointestinal disorder, irritable bowel syndrome, asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, vasculitis, renal ischemia, cerebral stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible obstruction of the respiratory tract, the respiratory syndrome diseases of adults, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), idiopathic interstitial pneumonia, bronchitis, liver fibrosis, cryptogenic fibrosing alveolitis, multiple sclerosis, depression, anxiety, or obesity, is kiuchumi introduction human or mammal an effective amount of the pharmaceutical composition, containing the compound or its pharmaceutically acceptable salt according to any one of points[2]-[6] and a pharmaceutically acceptable carrier.

USEFUL EFFECTS of the INVENTION

Effective ingredient a pyrazole-3-carboxamide derivatives according to this invention, has a new kernel and inhibits strongly and selectively function of the receptor 5-HT2B. Strong antagonistic activity against receptor 5-HT2Bmedicines in this invention manifests itself in therapeutic action is based on an excellent pharmaceutical effects. In addition, the high selectivity of the drug for this invention is useful for weakening a wide range of side effects, based on the activities of a receptor other than the receptor 5-HT2B.

BRIEF DESCRIPTION of DRAWINGS

Fig. 1 is a graph showing the results of a study of the swelling of the colon using a model of TNBS-induced IBS rats using connection example 24.

DESCRIPTION of embodiments

The connection according to this invention has a specific activity of binding of the receptor 5-HT2B. The connection according to this invention selectively inhibits the activity of the receptor 5-HT2Bby linking antagonistically with the receptor 5-HT2Bthat is useful for the treatment or pre the satisfactory treatment of a mammal, from a disease associated with the specified receptor.

The term “active agent" also means the antagonist and implies that the drug acts antagonistically against the agonist and reduces the effects. The ability to partial linking these antagonists and agonists is called the binding affinity of, and evaluation of the affinity of binding, as in the following examples, carried out by comparing the Ki values calculated in the study of receptor binding in vitro, or values IC50calculated in the studies of receptor binding in the same conditions, in some cases.

In the study of receptor binding, when the IC50cannot be calculated because of napravleniya sufficient antagonistic activities, IC50connections can be regarded as exceeding the specified concentration.

The connection according to this invention has a binding affinity of the receptor 5-HT2Band the value of the IC50that demonstrates the activity of inhibition of serotonin (inhibitory activity), is preferably less than 1000 nm, more preferably below 100 nm, even more preferably below 10 nm and, most preferably, below 1 nm.

According inhibitory activity against 5-HT2Bcompared with other receptors connection Yes is a specific invention or its pharmaceutically acceptable salt is suitable as a “selective”. “Selective” means that the inhibitory activity against the specified receptor is higher than inhibiting activity against “other receptors”. “Selective” in this invention means that the value of the IC50activity inhibition of the specified receptor is one tenth or less, preferably, one hundredth or less and, more preferably, one-thousandth or less, compared with the value of the IC50for “other receptors”.

“Other receptors“ means here other receptors that are specified for an existing non-selective serotonin antagonist. In particular, after determining selectively against 5-HT2A, 5-HT2Cthe estimation of the characteristic compounds on the impact on existing receptors and enzymes is positive.

Inhibiting activity or receptor selective antagonistic activity against 5-HT2Bantagonists of this invention can be easily estimated by known methods mentioned below.

In this context, the term "C1-C6"as indicated in the above General formula, if not stated otherwise, denotes a linear or branched carbon chain with 1-6 carbon atoms. Thus, " C1-C6is an alkyl group" means an alkyl group with 1-6 carbon atoms, inclusive, preferably methyl hereafter sometimes referred to as Me), ethyl (hereafter sometimes referred to as Et), propyl, isopropyl, butyl, isobutyl, tert-butyl.

"Halogen" means the 17th group of the periodic table, including, preferably, F, Cl, Br or I.

"Halogenation group" means C1-C6is an alkyl group substituted by 1-5 atoms (atoms) halogen.

"Aryl cycle" means mono - or bicyclic ring which may be saturated or partially or fully unsaturated. Aryl means a Deputy, which is connected in place of one removed from aryl cycle of the hydrogen atom, including, preferably, Ar1, Ar2, Ar3and Ar4.

Unsaturated monocyclic ring group includes, for example, as mentioned, phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolin, triazolyl, furutani.

Unsaturated bicyclic ring group includes, for example, as mentioned, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophene, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazoles, benzimidazoles, hinely, ethanolic, cinnoline, phthalazine, hintline, honokalani.

An example of a saturated cyclic group includes the cycle, which is partially saturated or fully saturated to unsaturated hour and above mono - or bicyclic ring groups.

“R1Acan be combined with other R1A” means that NR1AR1Asuch as NR1AR1A, CONR1AR1Aand SO2NR1AR1Amay designate a specified combination of 3-13-membered carbon-containing cyclic group (e.g., r is equal to 1-12 in the following scheme (IIa)).

From among these groups is convenient 3-8-membered carbon-containing cyclic group (e.g., r is 1-6 in the following scheme (IIa)). In fact, CONR1AR1Aand NR1AR1Ain R4can be provided by the following scheme (IIa). However, binding is not limited to the following schema.

“R1Bcan be combined with other R1B” has the same meaning as described above when replacing R1Afor R1B.

Remove the substituents are illustrated by such groups as ethoxy, phenoxy, halogen, alkoxycarbonyl, aryloxypropanolamine, imidazol-1-yl, 4-nitrophenoxy, but are not limited to only the listed groups.

Salts of compounds of formula (I) are pharmaceutically acceptable salts include the acid-additive and primary additive salts (including dicyclomine salt and disnology salt).

Typically, a suitable acid additive salts derived from acids which form non-toxic salts. Examples included the t of such salts, as acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, Etisalat, Eilat, formate, fumarate, gluceptate, gluconate, hexaflurophosphate, hibenzate, hydrochloride, hydrobromide, hydroiodide, isetionate, lactate, malate, maleate, malonate, mesilate, methyl sulfate, naftilan, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/phosphate/dihydrophosphate, saharat, stearate, succinate, tartrate, tosylate and triptorelin.

Suitable basic salts derived from bases which form non-toxic salts. Examples of basic salts include aluminium salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. Look, if necessary, Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) can easily be obtained by mixing a solution of the desired acid or required basis. The resulting salt can be precipitated and collected by filtration, or can be isolated by evaporating the solvent. The degree of ionization in the resulting salts can vary from fully ionized to almost deionizovannoy.

Compounds according to the invention can exist in resolutional and solvated forms. the Ermin “MES” is used here to denote a molecular complex, including a connection according to the invention and a stoichiometric amount of one or more molecules, pharmaceutically acceptable solvent, such as ethanol. The term “hydrate” is used when the specified solvent is water.

Pharmaceutically acceptable solvate according to the invention include those solvate in which the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6-sulfoxide.

In the scope of the invention included complexes, such as clathrates, the inclusion complexes of drug substance is the master, where, in contrast to the above solvate, drug and host are present in stoichiometric or non-stoichiometric amounts. In addition, the scope of the invention include complexes of medicinal substance containing two or more organic and/or inorganic component, which may be stoichiometric or non-stoichiometric amounts. The formed complexes can be ionized, partially ionized or neionizirovanne. Look, if necessary, J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

Hereafter, all references to the compounds of formula (I) include references to the corresponding salt, solvate, and complexes of these compounds and the solvate and complexes of these salts.

Connection image is the shadow include the compounds of formula (I), as defined above, including polymorphs and habitus crystals, prodrugs and isomers (including optical, geometric and tautomeric isomers)as defined below, and isotope-labeled compounds of formula (I).

As indicated, the so-called “prodrugs” of the compounds of formula (I) or the corresponding salts are also included in the scope of the invention. However, some derivatives of compounds of formula I which may have a low pharmacological activity or not possess pharmacological activity themselves can, when introduced into the body, developing into compounds of formula (I)having the desired activity, for example, by hydrolytic cleavage. Such derivatives are called “prodrugs”. For more information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs of this invention may be, for example, obtained by replacing appropriate functionalities present in the compounds of formula (I), by some groups, well-known specialists in the field called “programmy”, as indicated, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs according to the invention include:

when the compound of formula (I) or salt indicated the data connection contains a carboxylic acid functionality (-COOH), the corresponding ester and, for example, ethyl ether, phenyl ether, carboxymethoxy ether, dimethylaminomethylene ether, pivaloyloxymethyl ether, ethoxycarbonylmethylene ether, Caligraphy ester, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, 1-(cyclohexyloxycarbonyloxy)ethyl ester, methylamide) and the like;

when the compound of formula (I) or salt of the compounds contains an alcohol functionality (-OH), a compound in which the hydroxy functionality is subjected to acylation, alkylation, phosphorylation and boronovanii, for example, acetyl connection, which connection, propanol connection, pivaloyl connection, succinyl connection, alanyl-connection, dimethylaminomethylene connection, and the like. In addition, depending on the substituents, the prodrug can form N-oxides. Such N-oxides are also included in the scope of the inventions;

when the compound of formula (I) or salt of the compounds contains amino functionality, the corresponding amide, for example, a connection in which, depending on the specific case, one or both of the hydrogen of the amino functionality subjected to acylation, alkylation and phosphorylation, for example, eicosanoic connection, alanyl-connection, intramyocardial connection, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy shall arbonyl connection, tetrahydrofuranyl connection, pyrrolidinyloxyl connection, tert-butyl connection, and the like.

Additional examples of substituting groups, in accordance with the above examples, and the examples of other types of prodrugs may be found in the above links. In addition, some compounds of formula I may themselves act as prodrugs of other compounds of formula (I).

The compounds of formula (I)containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. When the compound of General formula (I) contains alkenylphenol or alkenylamine group, possible geometric CIS/TRANS (or Z/E) isomers. When the compound contains, for example, keto - or axisgroup or aromatic group, may occur tautomeric isomerism (“tautomerism”). Hence, a separate connection may have several types of isomerism.

In the scope of this invention include all stereoisomers, geometric isomers and tautomeric forms of the compounds of General formula (I), including compounds exhibiting more than two types of isomerism, and mixtures of one or more isomeric forms. Also included are acid-additive or basic additive salts, in which protivin is optically active, for example, D-lactate or L-lysine, or the rat is practical, for example, DL-tartrate or DL-arginine.

CIS/TRANS-isomers can be separated by conventional methods, well known to experts in this field, for example, by chromatography or fractional crystallization. Conventional methods of acquisition/allocation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or separation of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be subjected to interaction with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of General formula (I) contains an acidic or basic group, with an acid or a base, such as tartaric acid or 1-phenylethylamine. Formed diastereomers the mixture can be separated by chromatography and/or fractional crystallization, and one or both of diastereoisomer converted into the corresponding pure enantiomer(s) well known to the specialist methods.

Chiral compounds according to the invention (and the corresponding chiral precursors) can be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase is, consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50 (wt./mass.)% isopropanol, typically from 2 to 20 (wt./wt.)%, and from 0 to 5 (wt./mass.)% the alkylamine, typically of 0.1 (wt./mass.)% diethylamine. Concentration of the eluate gives a rich mixture.

Stereoisomeric conglomerates can be separated by conventional methods known to the person skilled in the art - see, for example, Stereochemistry of Organic Compounds by E L Eliel (Wiley, New York, 1994).

This invention includes all pharmaceutically acceptable isotopically-labeled compounds of General formula (I)in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, of nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

The substitution of heavier isotopes such as deuterium, i.e,2H, can provide certain therapeutic advantages arising after the tvii greater metabolic stability, for example, increased half-life in vivo or lowering the required dosage, and therefore, in some cases, it may be more preferable than1H - normal connection.

The substitution of a positron-emitting isotopes, such as11C,18F,15O and13N, can be used in positron emission tomography (PET) studies to assess the extent of employment of the receptor substrate.

Individual isotope-labeled compounds of formula (I), for example, compounds containing a radioactive isotope, are useful in studies of the distribution of a drug and/or substrate tissue. Radioactive isotopes tritium, i.e,3H, and carbon-14, i.e,14C, particularly useful for this purpose in connection with the easy on and easy ways of detection.

All compounds of General formula (I) can be obtained by methods described in the following General methods, or specific methods described in the Examples section, or certain modifications appropriate ways. The invention also encompasses any one or a number of such methods of obtaining compounds of General formula (I) and, in addition, any used new intermediate compounds.

The compound of General formula (I) according to this invention can be floor is constrained by the known method of obtaining or can be obtained according to the General method or method of obtaining, represented by the following reaction scheme. Unless otherwise stated, R1-R5and X, Y and Z in the following ways have the above values. The term “protective group”as used below means a hydroxyl - or amino-protective group selected from typical hydroxy-, ethane - or amino-protective groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). In addition, each connection is indicated in the reaction scheme, except when the compound inhibits the interaction may form a salt, which includes the same salt as the compound (I). The prodrug according to this invention can be obtained by introducing a specific group at the stage of intermediate connection or engagement with the use of the compounds similar to the above-mentioned protective group. Interaction, such as esterification, amidation and dehydration may be carried out using standard techniques, well known specialist in this field.

Obtaining pharmaceutical compositions for parenteral administration in sterile conditions, for example, by lyophilization, can be easily performed using standard pharmaceutical techniques well known to the specialist in this field.

Obtaining the compounds of formula IAfrom connected to the I formula II according to the process A-2 (method 1) and obtaining the compounds of formula I Aof the compounds of formula II according to the process A-3 (Method 2) below.

In the callout R sB, R' is OH, O-lower alkyl, lower alkyl or fluorine, and s is 2 or 3, B denotes boron atom. As a concrete image of a Deputy, stated (OH)2B, (O-lower alkyl)2B, (lower alkyl)2B, thriftimart potassium (BF3-)(BF3K), but when in the case (O-lower alkyl)2B between the lower alkyl groups may form a cyclic ring.

Process A-1

At this stage, containing iodine compounds of the formula III can be obtained dorectory synthesis in the presence of suitable agents for iodination via diazonium salts, or after the formation of salts of the page, these compounds can be obtained by attaching suitable agents for iodination. Obtaining salts of the page can be made by well-known methods. According to a typical method, a receipt page is performed with the use of sodium nitrite in acid solution. As the acid solution may be used, for example, a solution of acetic acid, hydrochloric acid, formic acid or sulfuric acid, which is preferred is acetic acid. The interaction proceeds from 10 minutes to 12 hours, but usually from 30 minutes to 6 hours. The reaction temperature is RA meets the range of about -20°C to 30°C, but, as a rule, from -10°C to 5°C. a Suitable iodination agent is potassium iodide, sodium iodide or iodide, where the potassium iodide is preferred. In the reaction scheme, Me means methyl group (the same below).

Process A-2

At this stage, the compound (VI) can be obtained using the reaction cross-combination of aryl with compound (III)obtained in process A-1. The specified compound (VI) can be obtained by combining in the presence of a suitable catalyst based on transition metal and reason (or no reason) in a mixture of water-organic solvent. As a suitable R sB Deputy in the reagent-based armetale mentioned, for example, (OH)2B, (O-lower alkyl)2B, (lower alkyl)2B, potassium salt (BF3K) thriftimart(BF3-), but in the case of (O-lower alkyl)2B, between the lower alkyl groups can be formed circular ring.

As the catalyst based on transition metal is suitable, for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II)chloride, copper(0), acetate of copper(I)bromide copper(I)chloride copper(I)iodide copper(I)oxide copper(I), triftorbyenzola copper(I)acetate, copper(II)bromide copper(II)chloride copper(II)iodide copper(II)oxide copper(II), copper(II)triftorbyenzola(II), palladium(II)acetate, is lurid palladium(II), bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride and the like. Particularly suitable are tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II)chloride, palladium(II)acetate, bis(acetonitrile)dichloropalladium(II), Tris(dibenzylideneacetone)dipalladium(0), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride. As a reagent based armetale mentioned, for example, but not in the manner restrictions, reagents based on Bronevoy acid, such as a derivative of 2-undeliverable acid, and reagents based on esters Bronevoy acid, such as a derivative of the ester 2-undeliverable acid. As a suitable organic solvent in the mixed aqueous-organic solution, for example, in the presence or absence of a water-soluble base, such as potassium hydroxide solution, sodium hydroxide, lithium hydroxide and potassium carbonate, mentioned tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide (DMF), acetonitrile, alcohols, such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride; or diethyl ether. This interaction can be performed in the presence of appropriate additional factors. In which the quality of such additional factors mentioned, for example, triphenylphosphine, titrat-butylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, tri-2-furifosmin, 2-(dichlorophenylphosphine)biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium methylate or sodium), sodium hydroxide, sodium carbonate, potassium phosphate, cesium carbonate, sodium bicarbonate or sodium iodide. This interaction is carried out at approximately 0°C-200°C and, as a rule, approximately at 20°C-120°C. the interaction Period is approximately from 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. In addition, during interaction can be used in a microwave reactor. In addition, when Y represents NH, the nitrogen atom may be protected by lower alkoxycarbonyl group (e.g., the Boc group) and (n-alkyl)benzolsulfonate group (e.g., benzolsulfonate and p-toluensulfonyl group).

Can be used other than the above-mentioned reaction cross combination Suzuki-Miyaura, the reaction cross-combination style using triamcinolone instead of R sB Deputy, and the reaction cross combination Negishi, using zinc-halogen, where the halogen mentioned chlorine, bromine, iodine, instead of R sB Deputy.

Process A-3

At this stage, the heterocyclic compound (VI), meet the future of General formula R 2can be obtained by transformation with the formation of complex arylboronic ether by the reaction of C-H boilerhouse between pinacolborane (HBpin) or bis(pinacolato)DIBORANE (B2pin2, pin=Me4C2O2) and the heterocyclic compound (V) in the presence of a suitable catalyst based on transition metal (e.g., iridium) and the appropriate organic solvent. (C-H borylation; T. Ishiyama et al., Organic Synthesis (2005), 82, 126-133.) The product of the combination of the compound (VI) can be obtained by Suzuki-Miyaura the interaction of the formed complex arylboronic ether compound (III). These interactions can be performed by single-stage or two-stage reaction method.

As the catalyst based on a transition metal can be mentioned, for example, [Ir(OMe)(COD)]2(COD means 1, 5cyclooctadiene), Cp*Rh(η4-C6Me6) (Cp* means C5Me5), Ir(η5-C9H7)(COD), [IrCl(COD)]2, [IrCl(COE)2]2or RhCl{P(i-Pr)3}(N2). As an auxiliary component, for example, 1,2-bis(dimethylphosphino)ethane(dmpe), 2,2'-bipyridine-(dpy), 4,4'-di-tert-butyl-2,2'-bipyridine-(dtbpy) or dppe. As a suitable organic solvent mentioned, for example, hydrocarbons such as n-hexane, or cyclohexane. A convenient option is to use as a cat who lyst combination 1/2[IrCl(COD)] 2and 4,4'-di-tert-butyl-2,2'-bipyridine-(dtbpy) in hexane in the interaction of pinacolborane or bis(pinacolato)of DIBORANE with aryl compound. Then the reaction complex arylboronic esters, obtained as described above with compound (III)is transferred to the compound (VI) by the reaction of Suzuki-Miyaura. This interaction is essentially the same as described in process A-2. Can be used the same reagents and reaction conditions in the process A-3,which is similar to the above process A-2. Provided that such interaction is carried out as a one-step process for the Suzuki reaction of Miyaura, suitable is a combination of N,N-dimethylformamide (DMF) or 1,4-dioxane as solvent, solid potassium phosphate (K3PO4as the base, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (PdCl2(dppf)) as a palladium catalyst.

The above-described C-H bilirubine, followed by reaction of the direct introduction of the bicyclic heteroaryl group (V), which is similar to the Suzuki reaction of Miyaura, may be replaced by direct reaction of arilirovaniya, mediated by palladium (non-patent literature 10), rhodium (non-patent literature 11) and copper (non-patent literature 12).

Non-patent literature 11: Aldrichimica Acta Vol.40, No.2-(2007) 35-41.

Non-patent literature 12: Tetrahedron Letter 49 (2008) 1598-600.

Process A-4

At this stage, carboxylate compound (VII) can be obtained by hydrolysis of the ester compound (VI) in the reaction solvent.

The hydrolysis may be carried out under known from the publication method. According to a typical method, the hydrolysis can be carried out under alkaline conditions, such as sodium hydroxide, potassium hydroxide or lithium hydroxide. As a suitable solvent mentioned, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol or ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) or 1,4-dioxane; amides such as N,N-dimethylformamide (DMF) or hexamethylphosphorotriamide; sulfoxidov, such as dimethylsulfoxide (DMSO)or water. The reaction period is from about 30 minutes to 48 hours, and typically from about 60 minutes to 30 hours. The reaction temperature corresponds to the range from approximately -20°C to 100°C, and typically ranged from approximately 20°C to 75°C.

The hydrolysis can be carried out in an acid medium, for example, mentioned hydrogenogenic, such as hydrochloride or hydrogen bromide; sulfonic acids such as p-toluensulfonate acid or benzolsulfonat acid; pyridi-p-toluensulfonate; and carboxylic acids such as acetic acid or triperoxonane acid. In the operation of a suitable solvent mentioned, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol or ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) or 1,4-dioxane; or a halogenated hydrocarbon such as 1,2-dichloroethane; or amides such as N,N-dimethylformamide (DMF) or hexamethylphosphorotriamide; sulfoxidov, such as dimethylsulfoxide (DMSO)or water. The reaction period is from about 30 minutes to 24 hours, and typically from about 60 minutes to 10 hours. The reaction temperature corresponds to the range from approximately -20°C to 100°C, and typically is from about 0°C to 65°C.

Process A-5

At this stage, the amide compound (IA) can be obtained in the presence or absence of binding reagent in an inert solvent in the reaction of a combination of amine compound (VIII) with carboxylates compound (VII) in the reaction solvent. In addition, this interaction can be carried out in the presence or absence of auxiliary components, such as 1-hydroxybenzotriazole (HOBt) or 1-gidroksibenzotriazola. As a suitable solvent mentioned, for example, acetone, nitromethane, N,N-dimethylformamide (DMF), sulfolane, dimethylsulfoxide (DMSO), 1-methyl-2-pyrrolidinone (NMP), 2-butanone, acetonitrile; halogenated hydrocarbons, such as dichloro the Academy of Sciences, 1,2-dichloroethane, chloroform; ethers such as tetrahydrofuran and 1,4-dioxane. The reaction period is from about 5 minutes to 1 week, and typically from about 30 minutes to 24 hours. The reaction temperature corresponds to the range from approximately -20°C to 100°C, and typically is from about 0°C to 60°C. as a suitable bonding agent may be used by the agent, commonly used in peptide synthesis, for example, dicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC), hexaphosphate-O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU), 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, 2-bromo-1 ethylpyridine terraforming acid (BEP), 2-chloro-1,3-dimethylimidazolidine, benzotriazol-1-yloxytris(dimethylamino)phosphodiesterase (BOP), diethylazodicarboxylate-triphenylphosphine, diethylthiophosphate, diethylphosphonate, 2-chloro-1-methylpyridinium, N,N'-carbonyldiimidazole, benzotriazol-1-ilgetinteger, ethylchloride or isobutylparaben. In addition, it is desirable to carry out the interaction in the presence of bases, such as N,N-diisopropylethylamine, N-methylmorpholine, 4-(dimethylamino)pyridine or triethylamine. Amide compound (IA) can be obtained through the appropriate allalone obtained by the interaction with a halogenation agent such as oxali the chloride, the phosphorus oxychloride or thionyl chloride. The resulting allalone can be converted into the corresponding amide compound (IA) processing aminoven compound (VIII) without the use of reagents condensation specified for this stage.

Synthesis azaindole cycle (method 3) using the reaction of formation of the loop in the process B-6 shown below.

Process B-1

At this stage, compound IX can be obtained by hydrolysis of ester compounds (III). This interaction is essentially the same as in process A-4, and the same reagents and reaction conditions as in process A-4, can be used similar to the process A-4.

Process B-2

At this stage, compound X can be obtained by the amidation reaction carboxilate compounds (IX) aminoven compound (VIII). This interaction is essentially the same as in process A-5, and the same reagents and reaction conditions as in process A-5, can be used similar to the process A-5.

Process B-3

At this stage, the compound (XI) can be obtained by the reaction of the cross-combination of compound (X) with an acetylene compound, protected trialkylsilyl group, such as trimethylsilyl group, in the presence of a catalytic amount the VA palladium reagent and salts of copper(I) or palladium reagent and a phosphine ligand, in a suitable solvent, comprising a base, or using only the base itself as a solvent. As a preferred example of the palladium reagent mentioned tetrakis(triphenylphosphine)palladium and bis(triphenylphosphine)palladium(II)chloride. As preferable examples of the salt of copper(I) mentioned iodide copper(I) bromide copper(I). As the phosphine ligand is mentioned, for example, bis(diphenylphosphino)butane (DPPB). As an example, the Foundation mentioned, for example, diethylamine, triethylamine, diisopropylethylamine, dicyclohexylamine, potassium carbonate and sodium carbonate. In addition, as the reaction solvent, referred to, for example, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide (DMF), acetonitrile, ethyl acetate, hydrocarbons, such as n-hexane, cyclohexane, benzene, toluene, and diethyl ether. The reaction period is from about 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. The reaction temperature is range from about -78°C to 200°C, and typically ranged from approximately -20°C to 80°C. in Addition, during interaction can be used in a microwave reactor.

Process B-4

At this stage, the compound (XII) can be obtained by removing trialkylsilyl protective group using the common, a is m known way, such as the method described in John wiley & Sons, Protecting Groups in Organic Synthesis (1999). As a conventional method of removing the protection can be done in the presence of a base such as potassium carbonate and sodium carbonate, in an alcoholic solvent such as methyl alcohol and ethyl alcohol.

Process B-5

This interaction is, essentially, the same as in process B-3, the compound (XIV) can be obtained by the reaction Sonogashira combination of acetylene compounds (XII) and arylalkenes compounds (XIII), where the diagram P1means hydrogen, tert-butoxycarbonyl group or amino-protective group, using the same reagents and reaction conditions as in process B-3, which can be used similar to the process B-3.

Process B-6

At this stage, the compound (IB) can be obtained by the reaction of intramolecular cycloaddition of acetylene compounds (XIV) using a suitable base. As a suitable base using tert-butyl potassium, tert-butyl sodium, tert-butyl cesium, cesium hydroxide, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,1,3,3-tetramethylguanidine, triethylamine and the like, and the interaction is carried out in a suitable solvent. As a suitable solvent mentioned N,N-dimethylformamide (DMF), N-methylpyrrole is Denon (NMP), toluene, 1,4-dioxane, alcohols, such as methanol and ethanol. The reaction period is from about 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. The reaction temperature is range from about -78°C to 150°C, and typically ranged from approximately -20°C to 150°C. Preferably, the interaction is carried out with the use of potassium tert-butylate in DMF in the temperature range from room temperature to 80°C. In another way, intramolecular cycloaddition can be carried out using a palladium catalyst, where dichlorobis(triphenylphosphine)palladium(II)iodide copper(I), triethylamine, DMF mentioned as a characteristic combination. In addition, it can be a catalyst based on metal or complexes of metals, including copper, gold, iridium, mercury, molybdenum, platinum and rhodium. In addition, when NHP1Deputy means phenolic or Tilney group, intramolecular cycloaddition can be carried out in the above conditions that lead to obtaining appropriate benzothiophenes and benzofurans derivatives. In addition, after the cyclization reaction, when the remains of the protective group (P1), removing the protective group may be carried out when the corresponding condition.

Presented below is a synthesis of imidazo[1,2-a]pyridine cycle is (method 4) using the reaction of formation of the loop, according to process C-3.

The process C-1

At this stage, compound XVI can be obtained by the reaction of N-alkylation of compound XV, which can be easily obtained, according to the literature, using a suitable base and alkylhalogenide. As a suitable reason mentioned, but not in the manner restrictions, for example, sodium ethylate, tert-butyl potassium, potassium hydride, sodium hydride, bis(trimethylsilyl)amide, sodium, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide. In addition, as a suitable organic solvent mentioned, for example, tetrahydrofuran, N,N-dimethylformamide (DMF), diethyl ether, acetonitrile. The reaction period is from about 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. The reaction temperature is range from about -78°C to 250°C and typically ranged from approximately -20°C to 150°C.

The process C-2

At this stage, compound XVII can be obtained by the reaction of alpha-halogenation (X=Cl, Br, I) compounds (XVI) using a suitable halogenation reagent. As a suitable halogenation reagent mentioned, for example, bromine, chlorine, sulfurylchloride, Pomodoro, N-bromosuccinimide (NBS), 5,5-dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, penultimate monotropoid. As a suitable organic solvent can be used, for example, acetic acid, carbon disulfide, simple ether, tetrahydrofuran, N,N-dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride. The reaction period is from about 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. The reaction temperature is range from about -78°C to 250°C, and typically ranged from approximately -20°C to 150°C.

Process C-3

At this stage, compound XIX can be obtained by the reaction of the cyclic condensation of alpha-halogenating compound (XVII) with an appropriate aminoven compound in the presence of a suitable solvent, by heating. As a suitable solvent mentioned, for example, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide (DMF), acetonitrile, alcohols, such as methanol and ethanol. The reaction period is from about 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. The reaction temperature meets the range of about from 0°C to 250°C and typically ranged from approximately 30°C to 150°C.

Process C-4

At this stage, compound XX can be obtained by hydrolysis of the ester compound (XIX). Specified in aimogasta is basically, the same as in process A-4, and the same reagents and reaction conditions as in process A-4, can be used similar to the process A-4.

Process C-5

At this stage, the connection of the ICcan be obtained by the amidation reaction carboxilate compounds (XX) aminoven compound (VIII). This interaction is essentially the same as in process A-5, and the same reagents and reaction conditions as in process A-5, can be used similar to the process A-5.

Changing the amine side chain (method 5) using the process D-3 below.

Process D-1

At this stage, compound XXII can be obtained by the amidation reaction carboxilate compounds (VII) aminoven compound (XXI). This interaction is essentially the same as in process A-5, and the same reagents and reaction conditions as in process A-5, can be used similar to the process A-5.

Process D-2

At this stage, the compound (XXIII) can be obtained by removing acetaldol protective group using conventional, generally known method such as the method described in John wiley & Sons, Protecting Groups in Organic Synthesis (1999). As a conventional method of removing the protection can be done in risotti acid, such as dilute hydrochloric acid, p-toluensulfonate acid, or in an acid medium in a conventional organic solvent.

Process D-3

At this stage, the compound (ID) can be obtained by the reaction of reductive amination of the aldehyde compound (XXIII) aminoven compound XXIV using a suitable reducing agent. As a suitable reducing agent mentioned, for example, sodium borohydride (NaBH4), cyanoborohydride sodium (NaBH3CN), triacetoxyborohydride sodium [NaBH(OAc)3]. As a suitable solvent can be used, for example, acetic acid, tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and, if necessary, a catalytic amount of acetic acid or Lewis acids such as titanium tetrachloride, tetraisopropoxide [Ti(O-iPr)4]. When using cyanoborohydride (NaBH3CN), the interaction can also be carried out in an acid environment. The reaction period is from about 5 minutes to 96 hours, and typically from about 30 minutes to 24 hours. The reaction temperature meets the range of about from 0°C to 250°C, and typically is from about 30°C to 100°C.

Changing the amine side chain (ways is 6) using the process E below.

The process E-1

At this stage, the connection of the IEcan be obtained by the reaction of binding of halogenated compounds (X) derived from arylboronic acid (or a complex ester). This interaction is essentially the same as in process A-2, and the same reagents and reaction conditions as in process A-2, can be used similar to the process A-2.

Changing the side chain R2(method 7) using the process F is presented below. The following compound XXVI, P2means a protective group selected from lower alkoxycarbonyl group, benzyloxycarbonyl group, benzolsulfonate and 4-alkylbenzenesulfonates group.

Process F-1

At this stage, the connection XXVI can be obtained by the reaction of binding of halogenated compounds (X) derived from heteroarylboronic acid (or a complex ester) XXV, which may be protected by tert-butoxycarbonyl group or benzolsulfonate or 4-alkylbenzenesulfonates group. This interaction is essentially the same as in process A-2, and the same reagents and reaction conditions as in process A-2, can be used similar to the process A-2.

Process F-2

On dannysstudio, the compound (IF) can be obtained by removing the protective trialkylsilyl group and arylsulfonyl group, using conventional, generally known method such as the method described in John Wiley & Sons, Protecting Groups in Organic Synthesis (1999). As a conventional method of removing butoxycarbonyl protective group can be performed in the presence of an acid catalyst, such as dilute hydrochloric acid, p-toluensulfonate acid, or in an acid medium in a conventional organic solvent. Removing the protective benzolsulfonate or 4-alkylbenzenesulfonates group can be performed in the presence of an alkaline reagent, such as potassium carbonate, sodium carbonate, cesium carbonate and sodium hydroxide, in combination with a conventional organic solvent.

Process F-3

At this stage, the compound (I'F) can be obtained by transformation of the N-H bond on the heteroaryl loop IFN-R6-communication. When R6-X reagent is alkylhalogenide, this interaction is essentially the same as in process C-1, and the interaction can be carried out under the same conditions as in process C-1. In addition, O-tosylate, O-mesilate and O-triflate containing a leaving group on the hydroxyl group (-OH), can be used interchangeably. Further, when R6means alcalali niloy group, the interaction is essentially the same as in process C-1, where alkylsulfonate used in the same conditions as in process C-1.

The intermediate compound (IA) is useful for obtaining compounds of this invention. For example, the intermediate compound X, specified in the process B, in total synthesis, effectively for use in obtaining the compounds according to this invention.

The intermediate compound (IB) is useful for obtaining compounds of this invention. For example, intermediate compounds VI and VII in the process A, XIX and XX in C-synthesis process, XXI in D process of synthesis, total synthesis, effective for use in obtaining the compounds according to this invention.

Pharmacological action of the compounds according to this invention as antagonists of 5-HT2Bcan be estimated by measuring the positive dynamics of increase in pulmonary blood pressure in animal models (rats, mice), subjected to chronic hypoxia. Existing drugs for pulmonary arterial hypertension (e.g., drugs sildenafil and prostaglandin) and RS-127445, known as a selective antagonist of 5-HT2Bcan be used as compounds of the comparison.

Other pharmacological actions of the compounds according to this invention as antagonists of 5-HT2Bcan be estimated by measuring protestera what's effects in animal models (rats, mouse), subjected to the action of drugs or stress. Existing Antidiarrhoeal tools (e.g., loperamide and berberine) and RS-127445, known as a selective antagonist of 5-HT2Bcan be used as compounds of the comparison.

Thus, the compounds obtained can be isolated and purified in free form or in salt form in the conventional processing, leading to the formation of salt. Isolation and purification can be achieved by conventional chemical methods such as extraction, concentration, dilution, crystallization, filtration, recrystallization, various chromatography and so on.

Various isomers can be isolated by a common way, using the difference in physicochemical properties between the isomers. For example, optical isomers can be separated and purified by formation of diastereoisomeric salts of the racemate with an optically active organic acid (e.g., tartaric acid) and further fractionated crystallization, or column chromatography using a chiral stationary phase. In addition, optically active compounds can be obtained using a suitable optically active compounds as source materials. In this case, a mixture of diastereomers can also b shall be separated by fractionated crystallization or chromatography to the corresponding pure enantiomers (enantiomer).

ORAL INTRODUCTION

Compounds according to the invention can be administered orally. Oral administration can include ingestion, so that the connection came in the gastrointestinal tract, or may be used buccal or sublingual introduction when the connection enters the bloodstream directly from the mouth.

Compositions suitable for oral administration include solid compositions, such as, for example, tablets containing particles, liquids or powders, capsules, lozenges (including fluid-filled), chews, multicystic, nanoparticles, gels, solid solutions, liposomes, film (including mucoadhesive), suppositories, sprays and liquid composition.

Liquid compositions include, for example, suspensions, solutions, syrups and elixirs. Such compositions can be used as fillers in soft or hard capsules and usually contain a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and emulsifying agents and/or suspendida substances. Liquid compositions can also be obtained by resuspending solids, for example, from the sachet in the water, and the like.

Compounds according to the invention can also be used in the instant, rapidly decaying dosage forms, such cacophany in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may be from about 1 wt.% up to 80 wt.% from dosage forms, mainly, from about 5 wt.% up to 60 wt.% from dosage forms.

In addition to the drug as the active ingredient, the tablets usually contain disintegrant. Examples of disintegrants include such substances as sodium salt starch glycolate, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, crosspovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, substituted lower alkilani hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Usually disintegrant is from about 1 wt.% up to 25 wt.%, preferably, from about 5 wt.% up to 20 wt.% from dosage forms.

Binders are usually used to impart adhesive properties of the pelletized compositions.

Tableted composition may contain a binder for imparting cohesive properties, other than the drug as the active ingredient. Suitable binders include such as microcrystalline cellulose, gelatin, lactose (monohydrate, spray dried m is Novigrad, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, and hydroxypropylcellulose, dehydrat of dicalciumphosphate and hypromellose, and the like.

The pill can also optionally include surfactants such as sodium lauryl sulfate and Polysorbate 80, and substances that contribute to the slide, such as silicon dioxide and talc. If present, the surfactant can be from about 0.2 wt.% up to 5 wt.% tablets and substances promoting sliding, can be from about 0.2 wt.% up to 1 wt.% tablets.

Tablets also usually contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium fumarate and mixtures of magnesium stearate with sodium lauryl. Lubricants typically comprise from about 0.25 wt.% up to 10 wt.%, preferably, from about 0.5 wt.% up to 3 wt.% tablets.

Other possible ingredients include antioxidants, colorants, flavorings, preservatives, substances, amending the taste and smell of medicines, and the like.

Typical tablets contain up to about 80 wt.% medicinal substance, from about 10 wt.% up to 90 wt.% the connection is the pollutant specific from about 0 wt.% to 85 wt.% diluent, from about 2 wt.% up to 10 wt.% disintegrant and from about 0.25 wt.% up to 10 wt.% the lubricant.

Methods of making tablets is not limited, although there may be used conventional methods of making tablets. For example, a tablet of the mixture can be extruded directly or through a rotating machine to obtain tablets. The tabletting mixture or portions mixtures, alternative, can be granular, wet, dry or melt, cooled to a solidified melt or extruded prior to pelletizing. The final tablet may contain one or more layers and may be with shell or without shell; this composition can be encapsulated.

With regard to the preparation of tablets, you can reference the material contained in "Pharmaceutical Dosage Forms: Tablets Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980 (ISBN 0-8247-6918-X).

Solid compositions for oral administration can be formulated for immediate and/or modified release. Composition of modified release include, for example, deferred, delayed, intermittent, controlled, targeted and programmed release.

Suitable compositions of modified release for the purposes of the invention described in the patent is SHA No. 6106864. Detailed descriptions of other appropriate technologies release, such as high energy dispersions and osmotic particles and particles with the shell, can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve a controlled release described in WO 00/35298.

PARENTERAL

Compounds according to the invention can also be entered directly into the blood stream, into muscle, or into an internal organ. Suitable methods of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, be, vnutrigrudne, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microhylinae) the injectors, the injectors without needle and infusion equipment.

Compositions for parenteral injection may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of about 3 to 9). These compositions can generally be aqueous solutions, but, for some applications, such compositions can be prepared in a more convenient form, such as a sterile non-aqueous solution or as a dried form to be used in combination with a suitable diluent, such as sterile, pyrogen-free in the A.

Obtaining compositions for parenteral administration in sterile conditions, for example, by lyophilization, can be easily made using standard pharmaceutical techniques well known to the specialist in this field.

The solubility of the compounds of formula (I)used in receiving parenteral solutions may be increased by applying appropriate technologies of preparation, such as the inclusion of amplifiers solubility.

Compositions for parenteral administration may be formulated for immediate and/or modified release. Composition of modified release include, for example, deferred, delayed, intermittent, controlled, targeted and programmed release. Such compounds according to the invention can be formulated as a solid, semi-solid substance or thixotropic liquid for administration as an implanted depot providing modified release of the active compounds. Examples of such compositions include drug-eluting stents and PGLA microspheres.

LOCAL INTRODUCTION

Compounds according to the invention can also be entered locally through the skin or mucous membrane, i.e., dermal or transdermal. Typical compositions for this purpose include, for example, gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, transdermal patches, pads, implants, napkins, yarn, dressings and microemulsions. Can also be used liposomes. Typical carriers include, for example, alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol and propylene glycol or water, and the like. Can be included substances that promote penetration - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other ways local injection include, for example, delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and using microholes or without needle (e.g. Powderject (registered trademark), Bioject (registered trademark) etc.) the injection.

Compositions for local injection can be made for immediate and/or modified release. Composition of modified release include, for example, delayed, prolonged, intermittent, controlled, targeted and programmed release.

OTHER TECHNOLOGIES

Compounds according to this invention can be combined with soluble macromolecular compounds such as cyclodextrin and suitable derivatives of cyclodextrin or containing polyethylene glycol polymers, to improve the value of solubility, the dissolution rate, taste masking, improved bioavailability and/or stability for use in any of the above routes of administration.

For example, it was found that the complexes of drug-cyclodextrin generally useful for most dosage forms and routes of administration. Can be used as inclusion complexes, and without inclusions. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary substance, i.e. as a carrier, diluent or a solubilizer. Often for these purposes, use of alpha-, beta - and gamma-cyclodextrins, examples of which can be found in WO 91/11172, WO 94/02518 and WO 98/55148.

Sets consisting of several components

The scope of the present invention provides that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, it is expedient to unite in the form of a kit, convenient for the introduction of combination, for example, co-administration of compositions.

Thus, the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the formula (I) according to the invention, and means separate storage of such compositions, such the AK container, a divided bottle or a divided foil bag. An example of such a set is the usual blister pack, used for packing tablets, capsules and the like.

Set according to the invention is particularly convenient for the introduction of different dosage forms, for example, for oral and parenteral administration of separate compositions at different intervals between initiation or titration of the individual compositions of different composition. According to the legislation, the kit generally includes instructions for use and may be provided with a so-called mnemonic representation of the information.

DOSAGE

For administration to patients-people, on the basis that the average person has a weight of about 65 kg to 70 kg, the total daily dose of the compounds according to the invention corresponds generally to range approximately from 0.05 mg to 1000 mg, preferably in a range approximately from 0.1 mg to 100 mg, more preferably in a range approximately from 0.5 mg to 20 mg of Course, depending on the method of administration, for example, oral administration may require a total daily dose of approximately 1 mg to 500 mg, whereas intravenous dose may be required only in the range from approximately 0.5 mg to 250 mg Total daily dose may be entered as a single dose or divided by total dosyalari dosage can vary depending on gender, age or medical conditions of the subjects-people.

As described above, the connection according to the invention has an antagonistic activity against 5-HT2B. Antagonist of 5-HT2Bin this invention it is useful to combine with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer, inflammatory diseases, immunomodulirutaya diseases and gastrointestinal disorders, for example, motility disorders of the gastrointestinal tract and sensory irritation, or to regulate blood pressure in the lungs and restore the arteries.

For example, an antagonist of 5-HT2Bin particular, the compound of formula (I) or pharmaceutically acceptable salt of the compounds as defined above can be administered simultaneously, sequentially or separately in combination with one or more means selected from the group including:

[List 1]

Light laxatives: e.g., mentioned regulon (registered trademark) and celiac (registered trademark);

Anticonvulsant drug mentioned, e.g., mebeverine, inverin, uilani bromide, trimebutine with the effect of the relaxation of smooth muscles; e.g., dicycloverine, giostsiamin and cimetropium with the Academy of Sciences of muskarinovymi actions.

Opioid/Central action of the drug is mentioned, e.g., loperamide, naltrexone, methylnaltrexone, module (registered trademark), alvimopan, which is MOR agonists; e.g., fedotozine and asimadoline, which is the KOR agonists; e.g., imipramine, amitriptyline, clomipramine, desipramine and lofepramine, which is the tricyclic antidepressants, e.g., sertraline, paroxetine, fluoxetine and ESCITALOPRAM, which are selective inhibitors of serotonin reuptake; e.g., venlafaxine and DULOXETINE, which are selective inhibitors of reuptake of serotonin, norepinephrine; e.g., moclobemide, which is acting reversible inhibitor of monoamine oxidase; e.g., diazepam, diazepam, clonazepam and dextofisopam, which are agonists of the benzodiazepine; e.g., Oxymorphone ER and tramadol, which is a centrally acting analgesics; e.g., isocarboxazid, phenelzine, tranylcypromine and selegiline, which is the monoamine oxidase inhibitors.

Serotonergic receptor modulators: referred to, e.g., alosetron, ondansetron, tropisetron, palonosetron, ramosetron, mitrazapine, indication, cilansetron, granisetron and dolasetron, which are antagonists of 5-HT3; e.g., Tegaserod, mosapride, which are agonists of 5-HT4; e.g., MKC-733, which is an agonist of 5-HT3 ; e.g., renzapride, which is an agonist of 5-HT4/5-HT3; e.g., indication, which is an antagonist of 5-HT3/5-HT4; e.g., DR-4004, SB-269970, SB-258719 and SB-258741, which is an antagonist of 5-HT7; e.g., buspirone and eperon, which are agonists or antagonists of 5-HT1A; e.g., buspirone, which is an agonist of 5-HT1A/1B/D; e.g., ergotamine, sumatriptan and rizatriptan, which protivomigrenoznami means.

The means of improving the motility of the gastrointestinal tract: referred to, e.g., maropitant, either aprepitant and ezlopitant, which are antagonists of NK1; e.g., nepadutant and saredutant, which are antagonists of NK2; e.g., talnetant, which is the NK3 antagonist; e.g., CP-154526, NBI-35965 and CRA-1000, which are antagonists of CRF1 receptor; e.g., dexloxiglumide, which is an antagonist of CCK receptor-A; e.g., mitemcinal and PF-4548043, which methylinosine agonists; e.g., lubiprostone:, which is the agonist sodium channels (type 2); e.g., linaclotide, which is the agonist guanilatziklazu; e.g., GTP-010, which is the agonist of like peptide-1; e.g., ibutamoren and capromorelin, which are agonists greenboro receptor.

Antibiotics: referred to, e.g., sulfacetamide, erythromycin, rifaximin, tobramycin and ciprofloxacin.

Probiotic bacteria: referred to, e.g., non-pathogenic Bifidobacterium bifidobacterium infantis 3564 and E. coli E.coli.

Antianalgesic means: referred to, e.g., clonidine, medetomidin, lofexidine, dexmedetomidine and AGN-2-3818, which is the alpha-2-adrenalectomy; e.g., solabegron, which is beta-3-adrenergenic; e.g., GRC-10622, GW842166 and S-777469, which cannabinoid -1 or -2 agonists; e.g., celecoxib, rofecoksib, valdecoxib, etoricoxib and lumiracoxib, which is a selective COX-2 inhibitors; e.g., piroxicam, naproxen, ibuprofen, diclofenac and indomethacin, which is a nonsteroidal anti-inflammatory drugs (NSAIDs); e.g., dizocilpine, which NMDA-antagonist; e.g., resiniferatoxin and capsazepine, which are modulators TRPs (subtypes V1, V3, V4, M8, A1); e.g., gabapentin, pregabalin and 3-matlhabaphiri, which is the alpha-2-Delta ligands; e.g., topiramate, cinolazepam and clonazepam, which is a GABA-agonists.

Anti-inflammatory drugs: referred to, e.g., dexamethasone, prednisolone, ciclesonide and budesonide, a synthetic hormone of the adrenal cortex; e.g., anakinra, talisuna and mepolizumab, which is therapeutic means, on the basis of interleukin.

Antiallergic drug mentioned, e.g., montelukast, zafirlukast and pranlukast, which are leukotriene antagonists; e.g., albuterol, levalbuterol, salmeterol, formoterol and arformoterol, which is a beta-2 - agonists; the APR., roflumilast, Tiotropium and separant used in asthma and/or chronic obstructive pulmonary disease.

Other therapeutic agent mentioned, e.g., palyful (registered trademark), Metamucil (registered trademark), crofelemer and plantain seed husk.

Associated pulmonary hypertension: referred to, e.g., beraprost derived prostaglandin; e.g., sildenafil, which is a PDE5 inhibitor; e.g., bosentan, which is an antagonist of endothelin-1.

EXAMPLES

Further, the present invention is explained in detail using examples, but the following examples in no way limit the invention, and can be used in a variety of changes that are not beyond the scope of the invention. These various changes, not beyond the scope of the invention, also included in the scope of the invention.

The invention is illustrated by the following non-limiting examples in which, unless stated otherwise: all operations carried out at room temperature or ambient temperature, that is, in the range of about 18-25°C; evaporation of the solvent produced using rotary evaporator under reduced pressure and a bath temperature of about 60°C; monitoring of interactions is performed using thin-layer chromatography (TLC)and the time of interaction is given only for illustration purposes; the melting temperature (TPL) is given without amendments (polymorphism may result in different melting points); structure and purity of all isolated compounds confirm at least one of the following methods: TLC (plate for TLC F254pre-coated silica gel 60, Merck, or plates for WATCH F254swith pre-printed NH2, Merck), mass spectrometry, nuclear magnetic resonance (NMR), infrared absorption spectra (IR) or microanalysis. Outputs are provided solely for the purpose of illustration. Flash column chromatography is carried out using silica gel 300HG, WAKO (40-60 μm) or Fuji Silysia Chromatorex (registered trademark) DU3050 (amino-type, 30-50 μm), or silica Biotage (32-63 mm, KP-Sil), or amino-bonded silica Biotage (35-75 mm, KP-NH).

Used to communicate microwave equipment is Emrys optimizer (Personal chemistry) or Initiator (registered trademark) Sixty (Biotage). Used to communicate ultrasonic equipment is Ultra Sonic Cleaner SINGLE Frequency (AS ONE). Abbreviations for designation of the reaction solvent include tetrahydrofuran (THF), dimethylsulfoxide (DMSO) and dimethylformamide (DMF). In addition, hexaflurophosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetraethylurea (HBTU).

Purification of final compounds with the use of the HPLC perform the following apparatus under the following conditions.

Hardware: MS-trigger system AutoClean MS-trigger AutoPurification (registered trademark) system, waters (referred to hereafter cleaning device (A)

Column: XTerra C18, 19×50 mm, particles of 5 microns;

Method A: methanol or acetonitrile/0,05% (vol./vol.), an aqueous solution of formic acid or

method B: methanol or acetonitrile/0.01% of (about./vol.), an aqueous solution of ammonia.

Confirmation of chemical purity in the cleaning method using the device for A cleaning is carried out using the following apparatus under the following conditions.

Equipment: detector Acquity Ultra Parformance LC on TUV Detector and mass spectrometer ZQ mass spectrometer, waters

Column: waters ACQUITY C18, of 2.1×50 mm, 7 µm particles

The column temperature: 60°C, flow rate: 10 ml/min, UV detector: 210 nm,

MS-detection: ESI - mode definition of positive ions, method: QC_neutral_full_1pt5min.

Eluent: acetonitrile/10 mm solution of ammonium acetate,

Gradient: 5% (0-0,1 min), 5 to 95% (0,10-8 min), 95% (0.8 to 1 min), analysis time: 1,5 min

Purification using HPLC perform the following apparatus under the following conditions.

Equipment: UV - triggered preparative HPLC system UV-trigger system, waters (referred to hereafter cleaning device B).

Column: XTerra C18, 5 μm, 19×50 mm or 30×50 mm,

Detector: UV 254 nm,

Flow rate: 20 ml/min (19×50 mm) or 40 ml/min (30×50 mm) at room temperature is.

The data of mass spectra of low-resolution (EI) get on the mass spectrometer Integrity (waters) or mass spectrometer Automass 120 (JEOL) or 6890GC/5793MSD (GC-MS technology from Agilent).

The data of mass spectra of low-resolution (ESI) receive the following apparatus under the following conditions.

Hardware: system for HPLC waters Alliance on mass spectrometer ZQ or ZMD and UV detector.

When the molecule contains a few atoms of bromine, taking into account the relative isotopic composition can be specified two or more numerical values depending on the number of bromine atoms.

Column: waters Xterra (registered trademark) C18, of 2.1×30 mm, particles of 3.5 micrometers,

Gradient: 4-96% (0-2 min), 96% (2-4 min), flow rate: 0.5 ml/min,

UV detection: 254 nm,

MS-detection: ESI-method posi/nega,

Eluent: acetonitrile/0.025% of (about./about.) an aqueous solution of ammonium formate (full neutral range), acetonitrile/0.05% of an aqueous solution of formic acid (full acid range), acetonitrile/0.01% of aqueous ammonia (complete main range).

These receive NMR at 270 MHz spectrometer JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300), using as solvent deuterated chloroform (99.8% of D) or dimethylsulfoxide (99.9% of D), unless otherwise stated, regarding tetramethylsilane (TMS) as internal standard, in the millions of dollars the x (ppm).

Used abbreviations: s=singlet, d=doublet (d), t=triplet (t), q=Quartet (kV), m=multiplet (m), ush.=broadened etc. IR spectrum of the receive infrared spectrometer Shimadzu infrared spectrometer (IR-470). Optical rotation was measured using a polarimeter JASCO DIP-370 Digital Polarimeter (Japan Spectroscopic Co., Ltd.). Chemical symbols have common values; BP. (boiling point), TPL (melting point), l (liter(s)), ml (milliliter(s)), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (mmol). In addition, the protective group Ts means p-toluensulfonate acid.

Connection example 1: synthesis of 5-(1H-indol-2-yl)-1-methyl-N-[2-(piperidine-1-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 2: synthesis of methyl 3-cyano-2-nutriose-2-propenoate

A small piece of metallic sodium (75,87 g, and 2.79 mol) is added in small portions to a cooled ice-methanol (1.2 l). After the disappearance of the metallic sodium, a mixture of dimethylmaleic acid (300 g, 2,541 mol) and acetonitrile (114,72 g, and 2.79 mol) in methanol is added dropwise to the methanolic solution obtained previously of sodium methylate. After concentrating the mixture in vacuo giving a yellow intermediate compound 2 (377,4 g, 99.5% yield). Intermediate compound 2 is used in the next stage without additional purification.

Intermediate compound 3: saintesmariesdelamer

Sulfonic acid (23,4 g, 0,238 mol) is added dropwise to a 40% solution of methylhydrazine (25 g, 0,217 mol). After complete addition, the reaction mixture is kept for 4 hours. The resulting mixture is dried by sublimation and receive the intermediate compound 3.

Intermediate compound 4: synthesis of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate

Intermediate compound 3 (280 g, 1.94 mol) are added to a methanol suspension (1.5 l) of intermediate compound 2 (263,39 g, 1.77 mol). The mixture was incubated for 48 hours at room temperature. Then to the reaction mixture are added 2 M sodium hydroxide (200 ml) and dichloromethane (1 l)and the organic layer separated. Then the obtained organic layer was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. After filtration of the drying substance, concentrating the obtained filtrate in vacuo gives yellow crystals of crude intermediate compound 4 (82,20 g, 30% yield). The obtained intermediate compound 4 is used in the next stage without additional purification.

The intermediate compound 5: synthesis of methyl 5-iodine-1-methyl-1H-pyrazole-3-carboxylate

A solution of sodium sulfite (17,06 g, 0,247 mol) is added carefully dropwise to a solution of intermediate compound 4 (32,0 g, 0,206 mol) and potassium iodide (342,4 g of 2.06 mol) in acetic acid-water (3/1 (vol./vol.), 300 ml). After the dropwise adding the, the reaction mixture was kept for 3 hours at 0°C. After confirming slashdowns intermediate compound 4 by TLC (mixture of ethyl acetate: hexane=1:4 (vol./vol.), the resulting mixture was adjusted to pH 10 to pH 11 by addition of solid sodium bicarbonate. The aqueous layer was extracted three times 1100 ml of ethyl acetate. Then, the collected organic layer is dried over anhydrous sodium sulfate. After filtration, concentrated under reduced pressure the filtrate gives a brown, syrupy, crude intermediate compound 5. The resulting crude intermediate compound 5 purified column chromatography using silica gel (mixture of ethyl acetate/petroleum ether, (0/1-1/3 (about./about.)) and receive the intermediate compound 5 (16.4 g, 30% yield) as white crystals.

1H-NMR (270 MHz, CDCl3) δ 6,98 (s, 1H), 4,01 (s, 3H), 3,92 (s, 3H).

MS(EEC)m/z: [M+H]+267.

Intermediate compound 7: synthesis of 5-(1H-indol-2-yl)-1-methyl-1-1H-pyrazole-3-carboxylic acid

Synthesis of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole method C-H - boilerhouse

Solution (25 ml) of a mixture of 1H-indole (2.50 g, is 21.3 mmol), [Ir(OMe)(COD)]2(28.4 mg, 0,042 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (22.9 mg, of 0.085 mmol) and bis(pinacolato)DIBORANE (3.25 g, 12.8 mmol) in absolute dioxane is kept at 80°C for 1 hour. The specified reaction solution used in the next stage without PTS is tough.

The intermediate compound 6 obtained by a combination of Suzuki: synthesis of methyl 5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxylate

The intermediate compound 5 (of 3.73 g, 14.0 mmol), Tris(dibenzylideneacetone)dipalladium(0) (128 mg, 0.14 mmol), a solution of potassium phosphate (4,88 g, 23 mmol), tricyclohexylphosphine (78.5 per mg, 0.28 mmol) and water (3 ml) is added to the above solution of the reaction mixture.

1H-NMR (270 MHz, CDCl3) δ 8,40 (USS, 1H), 7,68 (d, J=7,3 Hz, 1H), 7,44 (d, J=6,6 Hz, 1H), 7,31-7,25 (m, 1H), 7,21-to 7.15 (m, 1H),? 7.04 baby mortality (s, 1H), 6.75 in (s, 1H), 4,15 (s, 3H), of 3.97 (s, 3H).

Intermediate compound 7: synthesis of 5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

The reaction solution of intermediate compound 6 (742 mg, only 2.91 mmol) and 2M sodium hydroxide solution (5 ml, 10 mmol) in methanol (15 ml) - THF (5 ml) maintained at 70°C for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3 with 2M HCl solution and diluted with saturated sodium chloride. The mixture is extracted with dichloromethane, the combined organic layer is dried over anhydrous magnesium sulfate. After filtration, the organic layer is concentrated under reduced pressure, and the crude product is an intermediate compound 7 (673 mg, 96%), isolated as a white solid.

1H-NMR (300 MHz, DMSO-d6) δ 11,58 (s, 1H), to 7.61 (d, J=8.0 Hz, 1H), 7,42 (d, J=8.0 Hz, 1H), 7,22-7,10 (m, 2H), 7,09-7,02 (m, 1H), to 6.88 (s, 1H), 4,12 (who, 3H).

No peak due to NH.

MS(EEC)m/z: [M+H]+242, [M-H]-240.

Intermediate compound 7: alternative synthesis of 5-(1H-indol-2-yl)-1-methyl-1-1H-pyrazole-3-carboxylic acid

Intermediate compound 8: synthesis of tert-butyl 2-[3-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-yl]-1H-indole-1-carboxylate

The intermediate compound 5 (3,14 g of 11.8 mmol), palladium acetate (265 mg, 1.18 mmol) and triphenylphosphine (1.24 g, 4,71 mmol) is dissolved in a solution of dioxane/toluene (3,5/1 (./vol.), 27 ml). The resulting solution was incubated at room temperature for 10 minutes. Then, to the reaction solution was added tert-butyl ester 2-(dihydroxyaryl)-1H-indole-1-carboxylic acid (4,00 g of 15.3 mmol), water (3 ml) and sodium carbonate (3.12 g, 29.5 mmol). The solution is heated to boiling point under reflux for 1.5 hours. After cooling, the reaction solution was added to water (150 ml). Then the aqueous layer was extracted with ethyl acetate (150 ml ×2). Then the obtained organic layer is dried over magnesium sulfate, the desiccant was filtered. The filtrate is concentrated under reduced pressure. The residue is pre-treated by the method of column chromatography (ethyl acetate), using silica gel impregnated with the amine. Then the intermediate compound 8 (1,72 g, 41% yield) are obtained in the form of a white solid purification using column chromate is graphy on silica gel (hexane-diethyl ether (1,5/1-1/1) (about./vol.)).

1H-NMR (300MHz, CDCl3) δ 8,29 (d, J=8,1 Hz, 1H), to 7.61 (d, J=8.0 Hz, 1H), 7,42 (t, J=7,3 Hz, 1H), 7,31 (t, J=7,3 Hz, 1H), to 6.88 (s, 1H), of 6.71 (s, 1H), 3.96 points (s, 3H), 3,79 (s, 3H), of 1.39 (s, 9H).

MS(EEC)m/z: [M+H]+356.

Intermediate compound 7: Synthesis of 5-(1H-indol-2-yl)-1-methyl-1-1H-pyrazole-3-carboxylic acid

2M sodium hydroxide solution (12.1 ml, and 24.2 mmol) are added to a methanol solution of intermediate compound 8 (1,72 g, 4,84 mmol) at 50°C for 7 hours. After cooling, the mixture is added to the reaction solution to pH 3. then add water to the mixture. The resulting precipitate is filtered and washed with a small amount of water. Receive intermediate compound 7 (106 g, 90% yield) as a white solid.

1H-NMR (300MHz, DMSO-d6) δ 11,59 (s, 1H), to 7.61 (d, J=7,3 Hz, 1H), 7,42 (d, J=8,1 Hz, 1H), 7,18 (t, J=8.0 Hz, 1H), 7,14 (s, 1H), 7,06 (t, J=8,1 Hz, 1H), to 6.88 (s, 1H), 4,12 (s, 3H).

NO PEAK DUE TO NH.

MS(EEC)m/z: [M+H]+242, [M-H]-240.

The intermediate connection 10: Synthesis of 5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

Intermediate compound 9: Synthesis of tert-butyl 5-fluoro-2-[3-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-yl]-1H-indole-1-carboxylate

Sodium carbonate (2,53 g, 23,89 mmol) and water (3 ml) is added to the intermediate compound 5 (2.50 g, of 9.56 mmol), palladium(II) acetate (215 mg, 0.96 mmol), triphenylphosphine (100 g, is 3.82 mmol) and tert-butyl ether, 2-(dihydroxybis the Nile)-5-fluoro-1H-indole-1-carboxylic acid (3,20 g, 11,47 mmol) in a mixture of dioxane (20 ml) and toluene (10 ml). The resulting mixture is heated to boiling point under reflux for 1.5 hours. After cooling to room temperature, the reaction solution was added to water (80 ml) and extracted with ethyl acetate (100 ml ×2). The combined extract is dried over anhydrous magnesium sulfate. The desiccant is filtered. The filtrate is concentrated under reduced pressure. The resulting residue is purified column chromatography (hexane/ethyl acetate=2:1 (vol./vol.), using aminoalkyl. This intermediate compound 10 (990 mg, 37% yield) are obtained in the form of a white solid.

MS(EEC)m/z: [M+H]+374.

The intermediate connection 10: synthesis of 5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxylic acid

2M sodium hydroxide solution (6.6 ml, 13,26 mmol) are added to a solution (10 ml) of intermediate compound 9 (990 mg, to 2.65 mmol) in THF. The resulting solution was stirred at 45°C for 2 hours and stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure. Then, 2M aqueous HCl (8 ml) is added to the obtained residue. The resulting solution is extracted with ethyl acetate (120 ml×2), and the combined extract is dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate is concentrated under reduced pressure. You get a prom which mediate the connection 10 (680 mg, 100% yield) as a pale brown-yellow solid.

1H-NMR (300 MHz, CDCl3/DMSO-d6(1 drop)) δ 10,49 (USS, 1H), 7,40-7,25 (m, 2H)7,13 (s, 1H), 6,66 (s, 1H), 7,00-6,94 (m, 1H), 4,15 (s, 3H).

MS(EEC)m/z: [M+H]+260, [M-H]-258.

Connection example 1: synthesis of 5-(1H-indol-2-yl)-1-methyl-N-[2-(piperidine-1-yl)ethyl]-1H-pyrazole-3-carboxamide

The solution (0.5 ml) hexaphosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea (36 mg, 1.5 equivalents) in DMF are added to a solution (0.5 ml) of the intermediate compound 7 (15 mg), amine (1.1 equivalent, 14 mg of 2-(piperidine-1-yl)Ethan-1-amine), triethylamine (0,026 ml, 3 equivalents) in DMF at room temperature. The resulting solution was stirred at 50°C for 2 hours. Then the resulting solution was concentrated under reduced pressure, to the residue add 1 m sodium hydroxide solution (0.5 ml)and the mixture is extracted twice with ethyl acetate (1 ml). The remainder of the combined organic layer was dissolved in a small amount of methanol. The solution is loaded into a SCX cartridge (strong cation exchange cartridge), followed by rinsing with methanol (10 ml), and finally elute 1M solution of ammonia-methanol (8 ml). The crude product obtained by concentration, purified preparative HPLC (cleaning device A described in the beginning of this section {examples}).

MS(EEC)m/z: [M+H]+352.

Below are examples of compounds of sintezirovany is using interaction similar to those described above:

Connection example 2:

5-(1H-indol-2-yl)-N-[2-(4-methoxypiperidine-1-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide

Connection example 3:

N-[2-(4-hydroxypiperidine-1-yl)ethyl]-5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Connection example 4:

N-[2-(4-ethylpiperazin-1-yl)ethyl]-5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Connection example 5:

N-[2-(3-hydroxypiperidine-1-yl)ethyl]-5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Connection example 6:

1-(2-{[5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-yl]formamide}ethyl)piperidine-3-carboxamide

Connection example 7:

5-(1H-indol-2-yl)-1-methyl-N-{2-[4-(propane-2-yl)piperidine-1-yl]ethyl}-1H-pyrazole-3-carboxamide

Connection example 8:

5-(1H-indol-2-yl)-1-methyl-N-[2-(4-methylpiperidin-1-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 9:

5-(1H-indol-2-yl)-1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 10:

5-(1H-indol-2-yl)-1-methyl-N-[2-(2-methylpiperidin-1-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 11:

N-[2-(4,4-deformability-1-yl)ethyl]-5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Connection example 12:

N-[2-(2,6-dimethylmorpholine-4-yl)ethyl]-5-(1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Connection example 13:

5-(1H-indol-2-yl)-1-methyl-N-[3-(morpholine-4-yl)propyl]-1H-pyrazole-3-ka is boxlid

Connection example 14:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 15:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 16:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(3S)-3-hydroxypyrrolidine-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Table 2
Connection exampleMS(EEC)m/zConnection exampleMS(EEC)m/z
2[M+H]+3823[M+H]+368
4[M+H]+3805[M+H]+368
6[M+H]+3957[M+H]+394
8[M+H]+3669[M+H]+338
[M+H]+36611[M+H]+388
12[M+H]+38213[M+H]+368
14[M+H]+40015[M+H]+400
16[M+H]+372

The method of synthesis of the compound from example 17: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide

The intermediate connection 11: synthesis of methyl 1-methyl-5-(quinoline-3-yl)-1H-pyrazole-3-carboxylate

Tris(dibenzylideneacetone)dipalladium(0) (540 mg, 0.59 mmol) is added to a mixed solution of intermediate compound 5 (1,57 g 5,90 mmol), 3-henrikromby acid (102 g, 5,90 mmol), potassium phosphate (1.88 g, cent to 8.85 mmol) and 1,4-dioxane (65 ml) with three(cyclohexyl)phosphine (165 mg, 0.59 mmol) and water (15 ml). The reaction mixture was stirred at 100°C overnight (15 hours). After cooling to room temperature, the mixed solution was diluted with an ethyl acetate solvent, and filtered through celite to remove the catalyst. Then the organic layer of the filtrate was separated, the water layer in the charity and love, is extracted with an ethyl acetate solvent. Then the combined organic layer was washed with a saturated solution of sodium chloride, dried over sodium sulfate. After filtration receive the remainder. Purification of the residue column chromatography (hexane-ethyl acetate=(1/1) (about./about.) - (2/3) (about./vol.), using silica gel that gives an intermediate compound 11 (873 mg, 55% yield) as slightly yellow crystals.

1H-NMR (300 MHz, CDCl3) δ 8,99 (d, J=2.2 Hz, 1H), 8,23 (d, J=2.2 Hz, 1H), 8,18 (d, J=8,8 Hz, 1H), 7,79 to 7.75 (m, 2H), 7,54-7,52 (m, 1H),? 7.04 baby mortality (s, 1H), of 4.05 (s, 3H), 3,98 (s, 3H).

MS(EEC)m/z; [M+H]+268.

The intermediate connection 12: synthesis of 1-methyl-5-(quinoline-3-yl)-1H-pyrazole-3-carboxylic acid

A methanol solution (30 ml) of the intermediate compound (11) (870 mg, 3.25 mmol) and 2M sodium hydroxide solution (4,20 ml, 8.20 mmol) was stirred at 75°C for 2 hours. After removal of solvent, the remaining solution was adjusted to PH 6-7 with hydrochloric acid. The precipitated solid is filtered off with suction, dried in the presence of phosphorous pentoxide in a vacuum and receive intermediate compound 12 (790 mg, 96% yield) as light brown crystals.

1H-NMR (300 MHz, DMSO-d6) δ 12,8 (USS, 1H), 9,11 (d, J=2.2 Hz, 1H), 8,69 (d, J=2.2 Hz, 1H), 8,1,3-of 8.04 (m, 2H), of 7.90-7,81 (m, 1H), 7,75-7,66 (m, 1H), 7,13 (s, 1H), of 4.05 (s, 3H).

MS(EEC)m/z; [M+H]+254, [M-H]-252.

The method of synthesis of the compound from example 17: synthesis of 1-methyl-N-[2-(morpholine-1-yl)ethyl]-5(quinoline-3-yl)-1H-pyrazole-3-carboxamide

According to such method for compounds of example 1, the compound from example 17 (628 mg, 86% yield) are obtained in the form of white crystals of intermediate compound 12 (506 mg, 2.00 mmol) and 4-(2-amino-ethyl)research (286 mg, of 2.20 mmol).

1H-NMR (300 MHz, CDCl3) δ 8,99 (d, J=2.2 Hz, 1H), 8,21 (d, J=2.2 Hz, 1H), 8,17 (d, J=8,1 Hz, 1H), of 7.90 (d, J=8,1 Hz, 1H), 7,94-7,76 (m, 1H), 7,70-of 7.60 (m, 1H), 7,34-7,22 (m, 1H), 7,01 (s, 1H), 4.00 points (s, 3H), 3,79-and 3.72 (m, 4H), 3,63-of 3.54 (m, 2H), 2,66-2,48 (m, 6H).

MS(EEC)m/z; [M+H]+366.

Below are examples of compounds synthesized using interaction, similar to those described above:

Connection example 18:

1-methyl-N-[2-(piperidine-1-yl)ethyl]-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide

Connection example 19:

1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide

Table 3
Connection exampleAminConnection exampleAmin
MS (EEC) m/z MS (EEC) m/z
[M+H]+364[M+H]+350

Connection example 20: synthesis of 1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-5-{1H-pyrrolo[3,2-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide

The intermediate connection 13: Synthesis of tert-butyl 2-(dihydroxyaryl)-1H-pyrrolo[3,2-b]-pyridine-1-carboxylate

n-Utility (8,3 ml, 1.65 M solution in hexane) is added dropwise to a THF-solution (10 ml) Diisopropylamine (1.39 g, of 13.8 mmol) in cooling with ice under nitrogen atmosphere for 5 minutes. Mixture under conditions cooling with ice for 20 minutes gives a THF-solution of diisopropylamide lithium.

THF-solution of diisopropylamide lithium obtained above is added dropwise to the mixture (20 ml) of tert-butyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate 12 (2.00 g, 9,16 mmol) and triisopropyl ester of boric acid (2.76 g, 14,66 mmol) in THF at -20°C in nitrogen atmosphere for 1 hour. After stirring the obtained mixture at -10°C for 3 hours, the reaction solution was added 10% solution of potassium hydrosulfate, and the resulting mixture extracted with ethyl acetate. The resulting layer of the extract is washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After the filter is for, the filtrate is concentrated under reduced pressure, separating the crude intermediate compound 13. Intermediate compound 13 is suspended in diisopropyl ether. The formed precipitate is filtered, and get crystal intermediate compound 13 (1.90 g, 79% yield).

1H-NMR (300 MHz, DMSO-d6) δ to 8.45 (1H, d, J=4.4 Hz), at 8.36 (2H, s), with 8.33 (1H, d, J=8,8 Hz), 7,28 (1H, DD, J=8,1, 5,1 Hz), 6,72 (1H, s)to 1.61 (9H, s).

MS(EEC)m/z: [M+H]+263.

The intermediate connection 14: synthesis of methyl 5-{1-[(tert-butoxy)carbonyl]-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylate

According to the method of obtaining the intermediate 8, the intermediate compound 14 (0,37 g, 27% yield) synthesized from intermediate 13 (1.3 g, 5.0 mmol) and intermediate 5 (10 g, 3.8 mmol).

1H-NMR (300 MHz, DMSO-d6) δ 8,61 (1H, d, J=5,1 Hz), 8,53 (1H, d, J=8,8 Hz), 7,34 (1H, DD, J=8,8, 5,1 Hz), 6,93 (2H, s), of 3.96 (3H, s), 3,82 (3H, s)of 1.41 (9H, s).

MS(EEC)m/z: [M+H]+357.

The intermediate connection 15: synthesis of 1-methyl-5-{1H-pyrrolo[3,2-b]pyridine-2-yl}-1H-pyrazole-3-carboxylic acid

According to such method (hydrolysis) alternative synthesis described for intermediate 7, the intermediate compound 15 (87 mg) synthesized from intermediate 14 (210 mg, 0.59 mmol) with 61% yield.

1H-NMR (300 MHz, DMSO-d6) δ 11,83 (1H, USS), scored 8.38 (1H, d, J=2,9 Hz), 7,80 (1H, d, J=8.1 Hz), 7,21 (1H, s), 7,18 (1H,DD, J=4,4, 8.1 Hz),? 7.04 baby mortality (1H, s)to 4.15 (3H, s).

No peak due to NH.

MS(EEC)m/z: [M+H]+243.

Connection example 20: synthesis of 1-methyl-N-[2-(pyrrolidin-1-yl)ethyl]-5-{1H-pyrrolo[3,2-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide

Intermediate compound 15 (120 mg, 0.5 mmol) and N-(2-amino-ethyl)pyrrolidine (59 mg, 0.5 mmol) dissolved in DMF (4 ml). The triethylamine (260 mg, 2.6 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (98 mg, 0.5 mmol)and 1-hydroxybenzotriazole (39 mg, 0.3 mmol) are successively added to the resulting mixture at room temperature. The resulting mixture was stirred at room temperature for 2 days. The solvent is removed under reduced pressure and the resulting crude product was then purified on a preparative HPLC system (cleaning device B), obtaining the crystalline product (15 mg, 9% yield).

MS(EEC)m/z: [M+H]+339.

For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Connection example 21: synthesis of N-[2-(3-hydroxypiperidine-1-yl)ethyl]-1-methyl-5-{1H-pyrrolo[3,2-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide

According to the method for compound from example 20, compound from example 21 (16 mg, 34% yield) is obtained from intermediate 15 (30 mg, 0.12 mmol) and 1-(2-amino-ethyl)piperidine-3-ol (27 mg, 0,19 mmol).

For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Connection example 22: Synthesis of 1-methyl-5-{5-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The intermediate connection 16: synthesis of 5-iodine-1-methyl-1H-pyrazole-3-carboxylic acid

2M sodium hydroxide solution (of 56.4 mmol, 28,2 ml) are added to a methanol solution (100 ml) of intermediate compound 5 (6.0 g, and 22.6 mmol)and the mixture heated to 50°C. After two hours, the methanol solvent is removed under reduced pressure and the remaining solution was adjusted to pH 2-3 using 2M HCl solution in terms of cooling with ice. Then the obtained precipitated crystals are dissolved in ethyl acetate, the organic layer is separated and then the aqueous layer was extracted twice with ethyl acetate. Then the combined organic layer of the extract is washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give crude intermediate compound 16 (of 5.68 g, quantitative yield) as a pale yellow solid.

1H-NMR (270 MHz, DMSO-d6) δ 12,81 (USS, 1H), 6.89 in (s, 1H), 3,92 (s, 3H).

MS(EEC)m/z; [M+H]+253, [M-H]-251.

The intermediate connection 17: SinTe the 5-iodine-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

4-(2-amino-ethyl)morpholine (4.15 g, 31.9 per mmol), triethylamine (12.1 ml of 86.9 mmol), 1-hydroxybenzotriazole (8,9 g, to 57.9 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (11.1 g, to 57.9 mmol) are successively added to a solution (150 ml), intermediate 16 (7,3 g, 29,0 mmol) in dichloromethane at room temperature. Then the resulting mixture was stirred at room temperature for 20 hours, the reaction solution was added a saturated solution of sodium bicarbonate, and the aqueous layer was extracted with dichloromethane. The resulting organic layer is dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and produce crude intermediate compound 17. Purification of column chromatography (mixture of ethyl acetate/methanol =9/1 (about./about.)) using silica gel gives the intermediate compound 15 (9,8 g, 93% yield) as white crystals.

1H-NMR (mg, CDCl3) δ to 6.95 (s, 1H), 3,95 (s, 3H), 3,80-to 3.64 (m, 4H), 3,62 is 3.40 (m, 2H), 2.57 m (t, J=6.3 Hz, 2H), 2,54-is 2.37 (m, 4H).

No peak due to NH.

MS(EEC)m/z; [M+H]+365.

The intermediate connection 18: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-[2-(trimethylsilyl)ethinyl]-1H-pyrazole-3-carboxamide

The triethylamine (6,12 ml and 43.9 mmol) are added to THF-solution (45 ml) of the intermediate compound 17 (4,00 g, 10,98 mmol), copper iodide(I) (209 mg, 1.10 mmol), trimet is silylation (2,33 ml, 16.5 mmol) and dichlorobis(acetonitrile)palladium(II)chloride (770 mg, 1.10 mmol) under nitrogen atmosphere and the reaction mixture stirred at room temperature for 2 hours. Then, the mixture was filtered through celite and the resulting filtrate concentrated under reduced pressure. The residue is purified column chromatography (mixture of dichloromethane/methanol=30/1 (about./vol.), using silica gel that gives an intermediate compound 18 (3,67 g, 100% yield) as a yellow-brown solid.

1H-NMR (300 MHz, CDCl3) δ 7,22-7,14 (USS, 1H), 6.90 to (s, 1H), 3,93 (s, 3H), 3,78-3,70 (m, 4H), to 3.58-of 3.48 (m, 2H), 2,62 at 2.45 (m, 6H), and 0.28 (s, 9H).

MS(EEC)m/z; [M+H]+335.

The intermediate connection 19: synthesis of 5-ethinyl-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

A methanol solution (60 ml) of the intermediate compound 18 (3,43 g of 10.3 mmol) and potassium carbonate (2,13 g of 15.4 mmol) was stirred at room temperature for 1.5 hours. Then, the mixture was filtered through celite and the resulting filtrate concentrated under reduced pressure. The residue was diluted with a saturated solution of sodium chloride/water (1/1 (vol./about.))(40 ml) and dichloromethane (200 ml). After extraction, the organic layer separated. Then the obtained organic layer is dried over anhydrous sodium sulfate, the desiccant was filtered and the filtrate concentrated under reduced pressure. The residue is purified column of chromatography is th (a mixture of dichloromethane/methanol=30/1-20/1 (about./vol.), using silica gel that gives an intermediate compound 19 (2,23 g, 83% yield) as a light brown solid.

1H-NMR (mg, CDCl3) δ 7,20 (USS, 1H), of 6.96 (s, 1H), 3.96 points (s, 3H), of 3.77-3,70 (m, 4H), to 3.58-of 3.48 (m, 3H), 2,62 is 2.46 (m, 6H).

MS(EEC)m/z; [M+H]+263.

The intermediate connection 20: Synthesis of 5-[2-(3-amino-6-methylpyridin-2-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The palladium acetate (19 mg, or 0.027 mmol) are added to the combined acetonitrile solution (5.0 ml) of the intermediate compound 19 (308 mg, 1.18 mmol), 3-amino-2-bromo-6-methylpyridine (200 mg, 107 mmol), 1,4-bis(diphenylphosphino)butane (dppb) (18.3 mg, 0,043 mmol) and potassium carbonate (444 mg, is 3.21 mmol), under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 15 hours. Then, the mixture was filtered through celite and the resulting filtrate concentrated under reduced pressure. The residue is purified column chromatography (mixture of dichloromethane/methanol=25/1-10/1 (about./vol.), using silica gel that gives an intermediate compound 20 (36,9 mg, 9,4% yield) as dark yellow crystals.

1H-NMR (300 MHz, CDCl3) δ 7,28-7,18 (USS, 1H), 7.03 is-6,98 (m, 3H), 4,14 (USS, 2H), Android 4.04 (s, 3H), 3,78-3,71 (m, 4H), 3,59-to 3.50 (m, 2H), 2.63 in at 2.45 (m, 6H), 2,47 (s, 3H).

MS(EEC)m/z; [M+H]+369.

Connection example 22: synthesis of 1-methyl-5-{5-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Tert-butyl potassium (56 mg, 0.5 mmol who) are added to DMF- (1 ml) solution of intermediate 20 (36,9 mg, 0.1 mmol) at room temperature, for once. The resulting mixture is heated under stirring at 35°C for 2 hours. After the interaction, the resulting mixture is treated with water (0.5 ml) and the solvent is removed by concentration under reduced pressure. The resulting residue is purified column chromatography (mixture of dichloromethane/methanol=25/1-10/1 (about./vol.), using silica gel that gives compound from example 22 (31,3 mg, 84% yield) as yellow crystals.

1H-NMR (300 MHz, CDCl3) δ 10,4 (USS, 1H), of 7.70 (d, J=8,8 Hz, 1H), 7,50-7,40 (m, 1H), 7,42 (s, 1H), 7,06 (d, J=8,8 Hz, 1H), 6.87 in (s, 1H), 4,15 (s, 3H), 3,80 at 3.69 (m, 4H), 3,67-3,55 (m, 2H), 2,68 (s, 3H), 2,66-to 2.57 (m, 2H), 2,55-2,44 (m, 4H).

MS(EEC)m/z: [M+H]+369, [M-H]-367.

Connection example 23: Synthesis of 5-{5,7-dimethyl-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The intermediate connection 21: synthesis of 5-[2-(3-amino-4,6-dimethylpyridin-2-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to the method for compound from example 20, the intermediate compound 21 (46.8 mg, 13.3% of output) is obtained from intermediate 19 (240 mg, 0,915 mmol) and 3-amino-2-bromo-4,6-dimethylpyridine (184 mg, 0,915 mmol).

1H-NMR (300 MHz, CDCl3) δ 7,30-7,20 (m, 1H), 7,02 (s, 1H), 6,91 (s, 1H), 4,11 (USS, 2H), Android 4.04 (s, 3H), 3,80-3,71 (m, 4H), 3,60-to 3.50 (m, 2H), 2,65-2,48 (m, 6H), 2,43 (s, 3H), 2,19 (s, 3H).

MS(EEC)m/z: [M+H]+383, [M+HCO2]-427.

Connection example 23: synthesis of 5-{5,7-dimethyl-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the compound from example 23 (31,3 mg, 84% yield) obtained as pale-yellow crystals from intermediate 21 (46.8 mg, 0,122 mmol).

1H-NMR (300 MHz, CDCl3) δ 9,75 (USS, 1H), 7,40-7,35 (m, 1H), 7,18 (s, 1H), to 6.88 (s, 1H), PC 6.82 (s, 1H), 4.09 to (s, 3H), 3,80-to 3.67 (m, 4H), 3,57-3,44 (m, 2H), 2,62 (s, 3H), 2,60-to 2.40 (m, 6H), of 2.54 (s, 3H).

MS(EEC)m/z: [M+H]+383, [M-H]-381.

Connection example 24: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide

The intermediate connection 22: synthesis of 5-[2-(2-aminopyridine-3-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The triethylamine (404 mg, 4.0 mmol) are added to THF-solution (6 ml) of the intermediate compound 19 (262 mg, 1.00 mmol), 2-amino-3-iodopyridine (264 mg, 1.20 mmol), dichlorobis(acetonitrile)palladium(II)chloride (70.1 mg, 0.1 mmol) and copper(I) - (19 mg, 0.1 mmol) under nitrogen atmosphere. The reaction solution is stirred at room temperature for 7.5 hours. Then, the mixture was filtered through celite and the resulting filtrate concentrated under reduced pressure. The residue is purified column chromatography (mixture of dichloromethane/methanol=20/1 (about./vol.), using silica gel that provides intermediate compounds is of 22 (207 mg, 58,4% yield) as yellow crystals.

1H-NMR (300 MHz, CDCl3) δ 8,14-8,08 (m, 1H), 7,65-of 7.60 (m, 1H), 7,27-7,20 (m, 1H), 6,99 (s, 1H), 6.73 x-6,65 (m, 1H), 5,06 (USS, 2H), 4,01 (s, 3H), 3,78-3,71 (m, 4H), 3,59-to 3.50 (m, 2H), 2,63-2,47 (m, 6H).

MS(EEC)m/z: [M+H]+355, [M-H]-353.

Connection example 24: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the compound from example 24 (51,5 mg, 26% yield) are obtained as yellow crystals from intermediate 22 (200 mg, 0,56 mmol).

1H-NMR (300 MHz, CDCl3) δ 12,2 (USS, 1H), 8,45 is 8.38 (m, 1H), 8,04-of 7.97 (m, 1H), was 7.36 (s, 1H), 7,40-7,30 (m, 1H), 7.23 percent-7,14 (m, 1H), 6,69 (s, 1H), 4.16 the (s, 3H), 3,82-to 3.73 (m, 4H), 3,71-3,62 (m, 2H), 2,70-2,61 (m, 2H), 2,60-of 2.50 (m, 4H).

MS(EEC)m/z: [M+H]+355, [M-H]-353.

Connection example 25: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{5H-pyrrolo[3,2-d]pyrimidine-6-yl}-1H-pyrazole-3-carboxamide

The intermediate connection 23: synthesis of 5-[2-(5-aminopyridine-4-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to the method of synthesis of intermediate compound 22, the intermediate compound 23 (112 mg, 41% yield) obtained as a dark brown solid substance by heating under stirring at 100°C for 16 hours, from compound 19 (200 mg, 0,762 mmol) and 4-bromopyrimidine-5-amine (159 mg, 0,914 mmol).

1H-NMR (300 MHz, CDCl3) δ 8,64 (s, 1H), 8.34 per (s, H), to 7.09 (s, 1H), to 4.41 (USS, 2H), 4,06 (s, 3H), 3,82 at 3.69 (m, 4H), 3,64-3,51 (m, 2H), 2,62 is 2.46 (m, 6H).

No peak due to NH.

MS(EEC)m/z: [M+H]+356, [M-H]-354.

Connection example 25: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{5H-pyrrolo[3,2-d]pyrimidine-6-yl}-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude compound from example 25 (41 mg, yield 37%) was obtained as a light brown solid from intermediate 23 (112 mg, 0,315 mmol).

1H-NMR (300 MHz, CDCl3) δ 11,51 (USS, 1H), 9,03 (s, 1H), 9,00 (s, 1H), 7,65 (s, 1H), 6,94 (s, 1H), 4,22 (s, 3H), 3,80-3,62 (m, 6H), 2,67-to 2.42 (m, 6H).

No peak due to NH.

MS(EEC)m/z: [M+H]+356, [M-H]-354.

For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Connection example 26: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{7H-pyrrolo[2,3-d]pyrimidine-6-yl}-1H-pyrazole-3-carboxamide

Intermediate compound 24: synthesis of 5-[2-(4-aminopyridine-5-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 22, compound 19 (200 mg, 0,762 mmol) and 5-iodopyrimidine-4-amine (253 mg, to 1.14 mmol) is heated with stirring at 90°C for 16 hours to give crude intermediate compound 24 (mg) as a pale yellow syrup.

1H-NMR (300 MHz, CDCl3) δ 8,56 (s, 1H), 8,44 (s, 1H), 7,32-7,28 (m, 1H), 7,00 (s, 1H), between 6.08 (USS, 2H), 4.00 points (s, 3H), 3,76-to 3.73 (m, 4H), 3,57-3,51 (m, 2H), 2,63-2,49 (m, 6H).

MS(EEC)m/z: [M+H]+356, [M-H]-354.

Connection example 26: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{7H-pyrrolo[2,3-d]pyrimidine-6-yl}-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 22, the intermediate compound 24 (115 mg, 0,324 mmol) is heated with stirring, at 70°C for 1 hour. Then, the crude compound from example 26 (41 mg, 37% yield) obtained as a light brown solid.

1H-NMR (300 MHz, CDCl3) δ 12,01 (USS, 1H), 9,03 (s, 1H), of 8.90 (s, 1H), 7,89 (s, 1H), 7,55-7,51 (m, 1H), 6,77 (s, 1H), 4,22 (s, 3H), 3.96 points-3,90 (m, 2H), 3,78 of 3.75 (m, 4H), 2,72 is 2.51 (m, 6H).

MS(EEC)m/z: [M+H]+356, [M-H]-354.

For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Connection example 27: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-[5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-yl]-1H-pyrazole-3-carboxamide

Intermediate compound 25: synthesis of 5-{2-[3-amino-6-(trifluoromethyl)pyridin-2-yl]ethinyl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 20, the intermediate compound 19 (262 mg, 1.00 mmol) and 3-amino-2-iodine-6-trif ornatipinnis (288 mg, 1.00 mmol) is heated with stirring, at 80°C for 14 hours and get the crude product. The product was then purified column chromatography (mixture of dichloromethane/methanol=30/1-20/1 (about./vol.), using silica gel that gives an intermediate compound 25 (245 mg, 58% yield) as white crystals.

1H-NMR (300 MHz, CDCl3) δ of 7.48 (d, J=8,8 Hz, 1H), 7,28-7,20 (m, 1H), 7,15 (d, J=8,8 Hz, 1H), 7,05 (s, 1H), 4,67 (USS, 2H), of 4.05 (s, 3H), 3,80 at 3.69 (m, 4H), 3,59-to 3.49 (m, 2H), 2.63 in at 2.45 (m, 6H).

MS(EEC)m/z: [M+H]+423, [M-H]-421.

Connection example 27: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-[5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-yl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude product is obtained as white crystals from intermediate 25 (240 mg, 0,578 mmol) and of potassium tert-butylate (324 mg, 2.89 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=15/1 (about./vol.), using silica gel that gives an intermediate compound 27 (187 mg, 78% yield) as white crystals.

1H-NMR (300 MHz, DMSO-d6) δ 12,3 (USS, 1H), 8.17-a 8,08 (m, 1H), 8,03 (d, J=8,8 Hz, 1H), to 7.64 (d, J=8,8 Hz, 1H), 7.23 percent (s, 1H), 7,21 (s, 1H), 4,17 (s, 3H), 3,62-to 3.52 (m, 4H), 3,4, 4-3,30 (m, 2H), 2,54-of 2.36 (m, 6H).

MS(EEC)m/z: [M+H]+383, [M-H]-381.

Connection example 28: synthesis of 1-methyl-5-{5-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The intermediate connection is out 26: synthesis of 5-[2-(2-amino-5-methylpyridin-3-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 20, the intermediate compound 19 (393 mg, 1.50 mmol) and 2-amino-3-iodine-5-methylpyridin (421 mg, of 1.80 mmol) is heated with stirring, at 80°C for 14 hours and get the crude product. The product was then purified column chromatography (mixture of dichloromethane/methanol=30/1-20/1 (about./vol.), using silica gel that gives an intermediate compound 26 (245 mg, 58% yield) as white crystals.

1H-NMR (300 MHz, CDCl3) δ 7,94 (d, J=2.2 Hz, 1H), 7,46 (d, J=2.2 Hz, 1H), 7,30-to 7.18 (m, 1H), 6,98 (s, 1H), 4,88 (USS, 2H), 4.00 points (s, 3H), 3,78-3,70 (m, 4H), 3,60-to 3.50 (m, 2H), 2,64 is 2.46 (m, 6H), of 2.21 (s, 3H).

MS(EEC)m/z: [M+H]+369.

Connection example 28: synthesis of 1-methyl-5-{5-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude product obtained from intermediate 26 (460 mg, 1.25 mmol) and of potassium tert-butylate (1200 mg, about 10.7 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=50/1 (about./vol.), using aminoalkyl, and recrystallized from a mixture of methanol and diisopropyl ether, giving the compound from example 28 (229 mg, 50% yield) as white crystals.

1H-NMR (300 MHz, CDCl3) δ 11.8 in (USS, 1H), 8,25 (d, J=1.5 Hz, 1H), 7,78 (USS, 1H), 7,38-7,27 (m, 1H), 7,34 (s, 1H), 6,59 (s, 1H), 4,14 (s, 3H), 3,80-3,62 (m, 6H), 2,68-of 2.50 (m, 6H), 2,47 (s, 3H).

MS(EEC)m/z: [M+H]+39.

Connection example 29: synthesis of 5-{5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 27: 5-[2-(2-amino-5-herperidin-3-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The triethylamine (309 mg, of 3.05 mmol) are added to THF- (10 ml) solution of intermediate compound 19 (200 mg, from 0.76 mmol), 5-fluoro-3-iodopyridine-2-amine (218 mg, 0,915 mmol), dichlorobis(triphenylphosphine)palladium(II)dichloride (54 mg, 0,076 mmol), copper iodide(I) (14,5 mg, 0,076 mmol) and the mixture is stirred at room temperature for two days. The reaction solution is concentrated under reduced pressure, and the obtained oily brown residue is purified column chromatography (ethyl acetate as solvent), using aminoalkyl that gives intermediate compound 27 (187 mg, 66% yield) as a white solid.

1H-NMR (300 MHz, CDCl3) δ of 8.00 (d, J=2,9 Hz, 1H), 7,39 (DD, J=2,9, 8.0 Hz, 1H), 7,01 (s, 1H), 4,91 (USS, 2H), 4,01 (s, 3H), 3,74 (t, J=4.4 Hz, 4H), of 3.54 (DD, J=5,9, 11.7 Hz, 2H), 2,59 (t, J=6.6 Hz, 2H), 2,50-of 2.20 (m, 4H).

No peak due to NH amide.

MS(EEC)m/z: [M+H]+373.

Connection example 29: synthesis of 5-{5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude product obtained from promezhutochnogo the connection 27 (180 mg, 0.48 mmol) and of potassium tert-butylate (271 mg, is 2.41 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=10/1 (about./vol.), using silica gel and recrystallized from a mixture of methanol and diisopropyl ether, giving intermediate compound 29 (110 mg, 61% yield) as white crystals.

1H-NMR (300 MHz, CDCl3) δ 11.30 on (USS, 1H), 8,23 (d, J=2.2 Hz, 1H), to 7.64 (DD, J=2,9, 8,8 Hz, 1H), 7,58 (s, 1H), 7,41 (USS, 1H), 6,66 (d, J=2.2 Hz, 1H), 4,17 (s, 3H), 3,83-3,70 (m, 6H), to 2.66 (t, J=5,9 Hz, 2H), 2,56-of 2.50 (m, 4H).

MS(EEC)m/z: [M+H]+373, [M-H]-371.

Connection example 30: synthesis of 5-{5-cyano-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 28: 5-[2-(3-amino-6-cyano-2-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound from example 20, the intermediate compound 19 (262 mg, 1.00 mmol) and 3-amino-2-iodine-6-cyanopyridine (245 mg, 1.00 mmol) is heated with stirring, at 80°C for 14 hours and get the crude product. The product was then purified column chromatography (mixture of dichloromethane/methanol=20/1 (about./vol.), using silica gel that gives an intermediate compound 28 (231 mg, 61% yield) as a light brown solid.

1H-NMR (300 MHz, DMSO-d6) δ 8,20-to 8.12 (m, 1H), 7,68 (d, J=8,8 Hz, 1H), 7,18 (d, J=8,8 Hz, 1H), 7,11 (s, 1H), 6,83 (USS, 2H), was 4.02 (s, 3H), 3,60-of 3.53 (m, 4H), 3,40-3,30 (who, 2H), 2,48 to 2.35 (m, 6H).

MS(EEC)m/z: [M+H]+380.

Connection example 30: 5-{5-cyano-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude product obtained from intermediate 28 (227 mg, of 0.60 mmol) and of potassium tert-butylate (674 mg, 6,00 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=15/1 (about./vol.), using silica gel and recrystallized from a mixture of methanol and diisopropyl ether, giving the compound from example 30 (229 mg, 50% yield) as white crystals.

1H-NMR (300 MHz, DMSO-d6) δ 12,5 (USS, 1H), 8,20-to 8.12 (m, 1H), 8,00 (d, J=8,8 Hz, 1H), 7,76 (d, J=8,8 Hz, 1H), 7,22 (total 2H in the result of the superposition of different (s, 1H) peaks), 4,17 (s, 3H), 3,62-to 3.52 (m, 4H), 3,43-3,30 (m, 2H), 2,55 to 2.35 (m, 6H).

MS(EEC)m/z: [M+H]+380, [M-H]-378.

Connection example 31: synthesis of 5-{6-fluoro-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 29: 5-[2-(5-herperidin-3-nitropyridine-2-yl)ethinyl]-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound from example 29, intermediate compound 29 (307 mg, 50% yield) are obtained in the form of a brownish-yellow solid from intermediate 19 (400 mg, 1.53 mmol), 2-chloro-5-fluoro-3-nitropyridine (323 mg, 1.83 m is ol), bis(triphenylphosphine)palladium(II)dichloride (176 mg, 0.15 mmol), copper iodide(I) (29 mg, 0.15 mmol) and triethylamine (617 mg, 6,10 mmol).

1H-NMR (300 MHz, CDCl3) δ 8,81 (d, J=2.2 Hz, 1H), 8,24 (DD, J=2,2, 7,3 Hz, 1H), 7,18 (s, 1H), 4,13 (s, 3H), of 3.75 (t, J=5.1 Hz, 4H), to 3.58-to 3.52 (m, 2H), 2,59 (t, J=5,9 Hz, 2H), 2,58-2,49 (m, 4H).

No peak due to NH amide.

Intermediate compound 30: 5-[2-(3-amino-5-herperidin-2-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

A methanol solution of intermediate 29 (690 mg, 1,72 mmol), tin chloride(II) (4877 mg of 25.7 mmol), ammonium chloride (1376 mg of 25.7 mmol) and water (927 mg, 51,4 mmol) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture is brought to pH 12 with 2M sodium hydroxide solution. The resulting mixture was filtered through celite and washed with methanol. The filtrate is concentrated under reduced pressure, and the residue was diluted with dichloromethane and washed with a saturated solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration of the drying agent, the obtained residue concentrated under reduced pressure to give crude intermediate compound 30 (405 mg, 63%) as a yellow solid.

MS(EEC)m/z: [M+H]+373, [M-H]-371.

Connection example 31: 5-{6-fluoro-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to under the service method of synthesis of compounds according to example 22, the crude product obtained from intermediate 30 (400 mg, 107 mmol) and of potassium tert-butylate (603 mg, 5.37 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=20/1 (about./vol.), using silica gel and recrystallized from methanol, giving the compound from example 31 (71 mg, 18% yield) as a white solid.

1H-NMR (300 MHz, CDCl3) δ 11,23 (USS, 1H), at 8.36 (s, 1H), 7,46 (d, J=8,8 Hz, 1H), 7,22 (s, 1H), 6.87 in (s, 1H), 4,14 (s, 3H), of 3.77-to 3.73 (m, 4H), 3,60-to 3.50 (m, 2H), 2,63-of 2.50 (m, 6H).

No peak due to NH pyrrolo[3,2-b]pyridine.

MS(EEC)m/z: [M+H]+373, [M-H]-371.

Connection example 32: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]5-{5H-pyrrolo[2,3-b]pyrazin-6-yl}-1H-pyrazole-3-carboxamide

Intermediate compound 31: 5-[2-(3-amino-pyrazin-2-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound from example 20, the intermediate compound 19 (393 mg, 1.50 mmol) and 2-amino-3-chloropyrazine (233 mg, of 1.80 mmol) is heated with stirring, at 80°C for 14 hours and get the crude product. The product was then purified column chromatography (mixture of dichloromethane/methanol=20/1-15/1 (about./vol.), using silica gel that gives an intermediate compound 31 (272 mg, 51% yield) as a pale yellow solid.

1H-NMR (300 MHz, CDCl3) δ of 8.04 (d, J=2,2 Hz, 1H), to 7.99 (d, J=2.2 Hz, 1H), 7,30-7,20 (m, 1H), 7,07 (s, 1H), 13th (USS, 2H), of 4.05 (s, 3H), 3,80-3,70 (m, 4H), 3,60-to 3.50 (m, 2H), 2,65 at 2.45 (m, 6H).

MS(EEC)m/z: [M+H]+380, [M-H]-378.

Connection example 32: 1-methyl-N-[2-(morpholine-4-yl)ethyl]5-{5H-pyrrolo[2,3-b]pyrazin-6-yl}-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude product obtained from intermediate 31 (267 mg, 0.75 mmol) and of potassium tert-butylate (420 mg, 3,76 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=20/1-15/1 (about./vol.), using silica gel and recrystallized from methanol and diisopropyl ether, giving the compound from example 32 (183 mg, yield 69%) as white crystals.

1H-NMR (300 MHz, DMSO-d6) δ 12,6 (USS, 1H), 8,46 (d, J=2,9 Hz, 1H), 8,31 (d, J=2,9 Hz, 1H), 8,18-of 8.09 (m, 1H), 7,25 (s, 1H), 7,13 (s, 1H), 4,17 (s, 3H), 3,62-of 3.53 (m, 4H), 3,43-3,30 (m, 2H), 2,55 to 2.35 (m, 6H).

MS(EEC)m/z: [M+H]+356, [M-H]-354.

Connection example 33: synthesis of 5-{5-cyano-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 32: 5-[2-(2-amino-5-cyano-3-yl)ethinyl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound from example 20, the intermediate compound 19 (393 mg, 1.50 mmol) and 2-amino-3-iodine-5-cyanopyridine (441 mg, of 1.80 mmol) is heated with stirring, at 80°C for 14 hours and get the crude product. The product cleans the colon is the offered by chromatography (mixture of dichloromethane/methanol=15/1 (about./vol.), using silica gel that gives an intermediate compound 32 (122 mg, 21% yield) as a pale yellow solid.

1H-NMR (300 MHz, DMSO-d6) δ 8,43 (d, J=2.2 Hz, 1H), 8,16 (d, J=2.2 Hz, 1H), 8,18-8,08 (m, 1H), 7,50 (USS, 2H), 7,02 (s, 1H), 4.00 points (s, 3H), 3,60-of 3.53 (m, 4H), 3,40-3,30 (m, 2H), 2,48 to 2.35 (m, 6H).

MS(EEC)m/z: [M+H]+380, [M-H]-378.

Connection example 33: 5-{5-cyano-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the crude product obtained from intermediate 32 (122 mg, 0.32 mmol) and of potassium tert-butylate (360 mg, 3,20 mmol). The product was then purified column chromatography (mixture of dichloromethane/methanol=15/1 (about./vol.), using silica gel and recrystallized from methanol and diisopropyl ether, giving the compound from example 33 (57 mg, 47% yield) as white crystals.

1H-NMR (300 MHz, DMSO-d6) δ 12,9 (USS, 1H), 8,68 (d, J=2.2 Hz, 1H), at 8.60 (d, J=2.2 Hz, 1H), 8,16-8,08 (m, 1H)7,22 (s, 1H),? 7.04 baby mortality (s, 1H)4,14 (s, 3H), 3,62-of 3.53 (m, 4H), 3,42-3,30 (m, 2H), 2,55 to 2.35 (m, 6H).

MS(EEC)m/z: [M+H]+380, [M-H]-378.

Connection example 34: synthesis of 5-{imidazo[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 33: synthesis of ethyl-5-acetyl-1-methyl-1H-pyrazole-3-carboxylate

DMF solution (10 ml) of ethyl-5-acetyl-1H-pyrazole-3-carboxylate (1.50 g, 8,23 mmol, reference: US547062) is added dropwise to DMF-suspension (10 ml), 60% (wt./mass.; in oil) of sodium hydride (442 mg, 11.5 mmol) in cooling with ice. The resulting mixture was stirred at room temperature for 10 minutes, and the reaction solution add itmean (103 ml, 16.5 mmol) and stirred at room temperature for 30 minutes. Then, the reaction solution was added to water (20 ml) and the aqueous layer was extracted with diethyl ether (80 ml × 2). Then the obtained organic layer is dried over magnesium sulfate, the desiccant was filtered and the filtrate concentrated under reduced pressure. The residue is purified column chromatography (hexane/ethyl acetate=10/1-6/1 (about./vol.), using silica gel that gives an intermediate compound 33 (180 mg, 11% yield) as white solid crystals.

1H-NMR (300 MHz, CDCl3) δ of 7.36 (s, 1H), 4,43 (kV, J=7,3 Hz, 2H), 4,24 (s, 3H), of 2.56 (s, 3H), of 1.42 (t, J=7,3 Hz, 3H).

MS(EEC)m/z: [M+H]+197.

Intermediate compound 34: synthesis of ethyl-5-(2-bromoacetyl)-1-methyl-1H-pyrazole-3-carboxylate

Phenyltrimethylammonium (148 mg, 0.40 mmol) are added to THF-solution (1 ml) of the intermediate 33 (79 mg, 0.40 mmol)and the mixture stirred at room temperature for 1.5 hours. The resulting reaction solution was added to water (20 ml). The aqueous layer was extracted with diethyl ether (20 ml ×2). Then the obtained organic layer is dried over magnesium sulfate, the desiccant was filtered and the filtrate concentrated under PON the leaders introduce pressure. The residual solid is washed with a small amount of isopropyl ether/hexane=1/2 (about./vol.), and the intermediate connection 34 (114 mg, quantitative yield) are obtained in the form of white crystals.

1H-NMR (300 MHz, CDCl3) δ was 7.45 (s, 1H), of 4.44 (q, J=7,3 Hz, 2H), or 4.31 (s, 2H), 4.26 deaths (s, 3H), of 1.42 (t, J=7,3 Hz, 3H).

MS(EEC)m/z: [M+H]+275 and 277.

The intermediate connection 35: synthesis of ethyl-5-{imidazo[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylate

A methanol solution (2 ml) of the intermediate 34 (114 mg, 0.41 mmol) and 2-aminopyridine (39 mg, 0.41 mmol) is heated to the boiling temperature under reflux for 20 hours. After cooling, the reaction solution was added to saturated sodium bicarbonate solution (20 ml) and the aqueous layer was extracted with dichloromethane (20 ml ×2). The obtained organic layer is dried over magnesium sulfate. Then the desiccant was filtered and the filtrate concentrated under reduced pressure. The residue is purified column chromatography (hexane/ethyl acetate=1/3 (about./vol.), using silica gel that gives an intermediate compound 35 (64 mg, 57% yield) as a pale yellow solid.

1H-NMR (300 MHz, CDCl3) δ is 8.16 (d, J=6,6 Hz, 1H), 7,81 (s, 1H), 7,65 (d, J=8,8 Hz, 1H), 7,28-7,20 (m, 1H), to 7.09 (s, 1H), 6.87 in (t, J=7,3 Hz, 1H), 4,43 (kV, J=6,6 Hz, 2H), 4,34 (s, 3H), USD 1.43 (t, J=6.6 Hz, 3H).

MS(EEC)m/z: [M+H]+271.

The intermediate connection 36: synthesis of 5-{imides is[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylic acid

2M sodium hydroxide solution (0.25 ml, 0.50 mmol) are added to a methanol solution (1 ml), intermediate 35 (60 mg, 0.22 mmol)and the mixture stirred at 70°C for 1 hour. After cooling, to the reaction solution was added 2M HCl (0.25 ml, 0.50 mmol)and the resulting mixture was concentrated under reduced pressure, giving an intermediate compound 36 (54 mg) as white crystals composed of a mixture of sodium chloride. Intermediate compound used for subsequent interactions without additional purification.

1H-NMR (300 MHz, CDCl3) δ to 8.57 (d, J=7,3 Hz, 1H), 8,42 (s, 1H), to 7.64 (d, J=10,2 Hz, 1H), 7,33 (t, 10,3 Hz, 1H), 7,00 (s, 1H), 6,98 (t, J=7,3 Hz, 1H), 4,25 (s, 3H).

No peak due COOH.

MS(EEC)m/z: [M+H]+243, [M-H]-241.

Connection example 34: synthesis of 5-{imidazo[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Hexaphosphate-O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (126 mg, 0.33 mmol) are added to the combined acetonitrile solution (1 ml), intermediate 36 (54 mg), 4-(2-amino-ethyl)research (32 mg, 0.24 mmol) and triethylamine (and 0.09 ml, 0.67 mmol), and the mixture is stirred at room temperature. Then the resulting solution was concentrated under reduced pressure. The residue is purified column chromatography (mixture of dichloromethane/methanol=30/1 (about./vol.), using silica gel treated is first an amine, that gives colorless oily crude product (79 mg).

1H-NMR (300 MHz, CDCl3) δ 8.17 and (d, J=7,3 Hz, 1H), 7,83 (s, 1H), 7,63 (d, J=9.5 Hz, 1H), 7,30-7,20 (m, 1H),? 7.04 baby mortality (s, 1H), 6,86 (t, J=6,6 Hz, 1H), 6,15 (USS, 1H), 4,30 (s, 3H), 3,78-3,68 (m, 4H), 3,61-of 3.53 (m, 2H), 2,65 at 2.45 (m, 6H).

MS(EEC)m/z: [M+H]+355.

For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Connection example 35: synthesis of 5-(1,3-benzothiazol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

DMSO solution (0.7 ml) of the intermediate compound 17 (100 mg, 0,275 mmol), benzothiazole (31 mg, 0,229 mmol), copper iodide(I) (44 mg, 0,229 mmol), triphenylphosphine (12 mg, 0.046 mmol) and tribalista (97 mg, 0,458 mmol) was stirred at 160°C for 1 hour in nitrogen atmosphere. The resulting residue is purified column chromatography (mixture of dichloromethane/methanol=10/1 (about./about.)) and process SCX (strong cation exchange cartridge) in a manner analogous to that described for compound of example 1, which gives the crude product 35 (100 mg).

For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+372.

Connection example 36: Synthesis of 5-{5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-piraso the-3-carboxamide

Methyliodide (14,2 mg, 0.10 mmol) are added to the combined acetonitrile solution (5 ml) of the compound from example 29 (30 mg, 0.08 mmol) and cesium carbonate (52 mg, 0.16 mmol). The reaction solution was stirred at 60°C for 3 hours. After cooling to room temperature, the reaction solution was diluted with dichloromethane. Then the resulting solution was washed with water and saturated sodium chloride solution, and dried over sodium sulfate. Then the desiccant was filtered and the filtrate concentrated under reduced pressure, and the crude product (32 mg) was obtained as a yellow amorphous substance. For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+387.

Connection example 37: 5-(5-fluoro-1H-indol-2-yl)-N-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

The intermediate connection 37: synthesis of N-(2,2-dimethoxymethyl)-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Hexaphosphate-O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (505 mg, of 1.33 mmol) are added to the combined acetonitrile solution (10 ml) of intermediate compound 10 (230 mg, 0.89 mmol), diethylacetal of aminoacetaldehyde (93 mg, 0.89 mmol), triethylamine (0,50 ml, 3,55 mmol) at room temperature. The reaction solution was stirred at room temperature is E. 16 hours. The reaction solution was diluted with ethyl acetate. Then the resulting solution was washed with water, the organic layer is dried over magnesium sulfate. Then the desiccant was filtered and the filtrate concentrated under reduced pressure. the residue is purified column chromatography (hexane/ethyl acetate=1/2 (about./vol.), using silica gel that gives an intermediate compound 37 (307 mg, quantitative yield) as a white solid.

1H-NMR (300 MHz, CDCl3) δ 9.28 are (s, 1H), 7,42-7,39 (m, 1H), 7,32-7,26 (m, 1H), 7,20 for 7.12 (m, 2H), 7,05-6,98 (m, 1H), of 6.68 (d, J=1.5 Hz, 1H), 4,50 (t, J=5,9 Hz, 1H), 4,11 (s, 3H), of 3.64 (t, J=5,9 Hz, 2H), 3,42 (s, 6H).

MS(EEC)m/z: [M-H]-345.

The intermediate connection 38: synthesis of 5-(5-fluoro-1H-indol-2-yl)-1-methyl-N-(2-oxoethyl)-1H-pyrazole-3-carboxamide

2M HCl (5 ml) are added to THF-solution (5 ml) of intermediate 37 (294 mg, 0.85 mmol) and the resulting solution was stirred at 50°C for 2 hours. After cooling, the reaction solution is neutralized by adding 2M sodium hydroxide solution (5 ml), and extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and dried over magnesium sulfate. Then the desiccant was filtered and the filtrate concentrated under reduced pressure, obtaining an intermediate compound 38 (300 mg, quantitative yield) as a white solid. Intermediate compound used to further the interactions without additional purification.

MS(EEC)m/z: [M+H]+301.

Connection example 37: 5-(5-fluoro-1H-indol-2-yl)-N-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

THF-solution of 4.2 ml) of intermediate 38 (30 mg, 0.10 mmol), (R)-(-)-2-pyrrolidineethanol (15 mg, 0.15 mmol) and acetic acid (0.15 ml) was stirred at room temperature for 10 minutes. Then to the solution was added THF solution (0.2 ml) triacetoxyborohydride sodium (63 mg, 0.30 mmol) and the resulting solution is stirred over night at room temperature. Then the reaction solution is concentrated and the residue is completely dissolved by adding ethyl acetate (0.7 ml) and 2M sodium hydroxide solution (0.5 ml). Then the obtained organic layer loaded on SCX cartridge (strong cation exchange cartridge), washed with methanol (5 ml) and, finally, elute with a mixture of ammonia-methanol (1M, 4 ml). The crude product obtained by concentration, purified preparative HPLC (cleaning device A described in the beginning of this section for EXAMPLES).

MS(EEC)m/z: [M+H]+386.

Below are examples of compounds synthesized using interaction, similar to those described above:

Connection example 38:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(3R)-3-(hydroxypyrrolidine-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 39:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(3S)-3-(hydroxide Eridan-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 40:

5-(5-fluoro-1H-indol-2-yl)-1-methyl-N-{2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl]ethyl}-1H-pyrazole-3-carboxamide

Connection example 41:

N-[2-(3,3-diversecity-1-yl)ethyl]-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Connection example 42:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 43:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(3R)-3-ftorpirimidinu-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 44:

5-(5-fluoro-1H-indol-2-yl)-N-{2-[(3S)-3-ftorpirimidinu-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 45:

5-(5-fluoro-1H-indol-2-yl)-N-[2-(4-foreperiod-1-yl]ethyl}-1-methyl-1H-pyrazole-3-carboxamide

Connection example 46:

5-(5-fluoro-1H-indol-2-yl)-1-methyl-N-[2-(1,4-oxazepam-4-yl]ethyl}-1H-pyrazole-3-carboxamide

Connection example 47:

N-[2-(azetidin-1-yl)ethyl]-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide

Table 5
Connection exampleMS(EEC)m/zConnection exampleMS(EEC)m/z
38 [M+H]+37239[M+H]+386
40[M+H]+38441[M+H]+378
42[M+H]+38643[M+H]+374
44[M+H]+37445[M+H]+388
46[M+H]+38647[M+H]+342

An alternative method of synthesis of the compound from example 17: synthesis of 1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide

According to the above similar method for the intermediate compound (11), Tris(dibenzylideneacetone)dipalladium(0) (66 mg, 0,0723 mmol) are added to a mixed solution of 1,4-dioxane (20 ml)-water(3 ml), intermediate compound 17 (526 mg, 1.44 mmol), 3-henrikromby acid (250 mg, 1.44 mmol), potassium phosphate (458 mg, of 2.16 mmol) and tricyclohexylphosphine (40,4 mg, 0.14 mmol). The reaction solution was stirred at 100°C overnight (15 hours). The resulting residue is purified column chromatography (mixture of dichloromethane/methanol=20/1 (about./about)), using silica gel, giving white crystals. Then the compound from example 17 (204 mg, 39% yield) are obtained as white crystals by recrystallization from a mixture of hexane-ethyl acetate.

Below are examples of compounds synthesized using interaction, similar to that described above, or using the reaction conditions for the intermediate 8:

Connection example 48:

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(quinoline-6-yl)-1H-pyrazole-3-carboxamide

Connection example 49:

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(quinoline-7-yl)-1H-pyrazole-3-carboxamide

Connection example 50:

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(naphthalene-2-yl)-1H-pyrazole-3-carboxamide

Connection example 51:

5-(6-methoxynaphthalene-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 52:

5-(7-methoxynaphthalene-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 53:

5-(1-benzothiophen-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 54:

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(cinoxacin-6-yl)-1H-pyrazole-3-carboxamide

Table 7
Connection example MS(EEC)m/zConnection exampleMS(EEC)m/z
48[M+H]+36649[M+H]+366
50[M+H]+36551[M+H]+395
52[M+H]+39553[M+H]+371
54[M+H]+367

The synthesis of the compounds according to example 55: synthesis of 5-(1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl)-1H-pyrazole-3-carboxamide

The intermediate connection 39: synthesis of 5-[1-(benzazolyl)-1H-indol-3-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 17 (200 mg, 0.55 mmol), palladium acetate (25 mg, 0.11 mmol) and triphenylphosphine (58 mg, 0.22 mmol) is dissolved in a solution of dioxane/toluene (3,3/1 (./vol.), 5,2 ml) and the resulting mixture was stirred at room temperature for 10 minutes. Then, to the reaction solution was added 1-(phenylsulfonyl)-3-indovino acid (215 mg, 0.71 mmol), water (1.2 ml) and sodium carbonate (233 mg, of 2.20 mmol)and the resulting mixture n is grebaut to the boiling temperature under reflux for 16 hours. After cooling, the reaction solution was diluted with ethyl acetate. To the resulting solution add sodium sulfate to remove water and the resulting mixture filtered. Then the filtrate is concentrated under reduced pressure, the residue is pre-treated with column chromatography (ethyl acetate), using silica gel. Then, the obtained organic layer loaded on SCX cartridge (strong cation exchange cartridge), washed with methanol and finally, elute with a mixture of ammonia-methanol (1M). The eluate concentrated under reduced pressure, obtaining an intermediate compound 39 (271 mg, quantitative yield) as a crude product. Intermediate compound used for subsequent interactions without additional purification.

MS(EEC)m/z: [M+H]+494.

Connection example 55: synthesis of 5-(1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 39 (271 mg) was dissolved in methanol (5 ml), and to the solution was added 2M sodium hydroxide solution (5 ml), the resulting solution was stirred at 70°C for 30 minutes. After cooling, to the reaction solution was added water (10 ml)and the resulting mixture is extracted three times with dichloromethane (50 ml). Then the combined organic layer is dried over magnesium sulfate, the desiccant was filtered and the filtrate concentrated under reduced pressure. Statomat column chromatography (mixture of dichloromethane/methanol=10/1 (about./vol.), using silica gel, giving the crude product (169 mg) as a light brown solid. For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+354.

The synthesis of the compound from example 56: 1-methyl-5-(1-methyl-1H-indol-3-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 55 (50 mg) dissolved in acetonitrile (1 ml) and the resulting solution was added cesium carbonate (138 mg, 0.42 mmol) and methyliodide (of 0.013 ml, 0.21 mmol)and the mixture heated to the boiling temperature under reflux for 1 hour. After cooling, insoluble materials are removed by filtration, and the filtrate concentrated under reduced pressure. The residue is purified column chromatography (mixture of dichloromethane/methanol=10/1 (about./vol.), using silica gel, giving the crude product (45 mg) as a colourless syrup. For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+368.

Below are the intermediate and connection examples synthesized using interaction, similar to those described above:

Connection example 57:

1-IU the Il-5-(3-methyl-1H-indol-5-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 58:

1-methyl-5-(2-methyl-1H-indol-5-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 59:

1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{1H-pyrrolo[2,3-b]pyridine-3-yl}-1H-pyrazole-3-carboxamide

Connection example 60:

5-(5-methoxy-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 61:

5-(5-fluoro-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 62:

5-(1,2-dimethyl-1H-indol-5-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 63:

5-(1,3-dimethyl-1H-indol-5-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 64:

1-methyl-5-{1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 65:

5-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 66:

5-(5-fluoro-1-methyl-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 67:

1-methyl-5-(1-methyl-1H-indol-4-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 68:

5-[1-(2-methoxyethyl)-1H-indol-3-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 69:

5-(1-ethyl-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-Piras the l-3-carboxamide

Connection example 70:

5-(4-fluoro-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 71:

5-(6-fluoro-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 72:

5-(6-methoxy-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 73:

5-(7-methoxy-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 74:

5-[1-(2-methoxyethyl)-2-methyl-1H-indol-5-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 75:

5-[1-(2-hydroxyethyl)-2-methyl-1H-indol-5-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Below are examples of compounds synthesized using interaction, similar to those described above: where, how easy it is to understand the person skilled in the art, instead of under the conditions can be used corresponding to the examples alkylhalogenide.

Connection example 76: synthesis of 5-(4-methanesulfonyl-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The intermediate connection 49: synthesis of 1-(benzazolyl)-4-(methylsulfanyl)-1H-indole

Meantioned sodium (1300 mg, 18,16 mmol) and 1N aqueous HCl-diethyl ether (20 ml) is added, in an ice bath, to THF- (50 ml) solution of 1-(be solarpanel)-4,5,6,7-tetrahydro-1H-indol-4-it (1250 mg, of 4.54 mmol), obtained from 4,5,6,7-tetrahydro-1H-4-it reference to patent literature (JP-7-247263A), and the mixture is stirred at room temperature overnight. Then to the mixture is added diethyl ether (30 ml). The resulting mixture was washed with saturated sodium bicarbonate solution (50 ml) and dried over anhydrous magnesium sulfate. Then the desiccant was filtered and the resulting filtrate concentrated under reduced pressure, giving an oily residue. The oily residue is dissolved in toluene (15 ml) and to the mixture is added DDQ (1500 mg, for 6.81 mmol). The mixture is heated to boiling point under reflux for 2 hours. After cooling, the resulting mixture was concentrated under reduced pressure to give crude oily intermediate connection 49. The resulting crude intermediate compound 49 cleanse column chromatography (hexane-ethyl acetate=10:1 (vol./vol.), using silica gel that gives an intermediate compound 49 (690 mg, 50% yield) as a white semi-solid substance.

1H-NMR (300 MHz, CDCl3) δ 7,88-7,79 (m, 3H), 7,58 (d, J=4.0 Hz, 1H), EUR 7.57-to 7.50 (m, 1H), 7,46-7,41 (m, 2H), 7,43-7,24 (m, 1H), was 7.08 (d, J=7,3 Hz, 1H), 6,78 (d, J=3,7 Hz, 1H), to 3.58 (s, 3H).

MS(EEC)m/z: [M+H]+304.

The intermediate connection 50: synthesis of [1-(benzazolyl)-4-(methylsulfanyl)-1H-indol-2-yl]barandilla

n-Utility (2.5 ml, 4,12 mmol, 1,65M cyclohexane solution) was added drop is to THF-solution (5 ml) Diisopropylamine (417 mg, of 0.58 mmol)on an ice bath, and the mixture is stirred for 20 minutes, which gives sitedisability.

The above sitedisability add in an ice bath, is added dropwise to a THF-solution (25 ml) of the intermediate compound 49 (833 mg, of 2.75 mmol) and ether triisopropylsilane acid (620 mg, 3,29 mmol)obtained separately. Two hours later, additionally added dropwise same number of sitedisability, in an ice bath. Then the mixture is stirred on an ice bath for 1 hour, to the mixture of 1M aqueous HCl, and bring the solution to pH 3. The resulting solution was extracted with ethyl acetate (25 ml ×2), and the combined mixture is dried over anhydrous magnesium sulfate. Then the desiccant was filtered and the resulting filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (hexane/ethyl acetate), using silica gel, giving the crude intermediate compound 50 (953 mg, 100% yield) as a yellow semi-solid substance.

The intermediate connection 51: synthesis of 5-[1-(benzazolyl)-4-(methylsulfanyl)-1H-indol-2-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 8 in example 1, the intermediate compound 51 (390 mg, 29% yield) are obtained in the form of a white semi-solid substance from the intermediate compound 17 (909 mg, of 2.50 mmol), between the exact connection 50 (953 mg, to 2.74 mmol), palladium(II) acetate (56 mg, 0.25 mmol), triphenylphosphine (262 mg, 1.00 mmol) and sodium carbonate (661 mg, 6,24 mmol).

MS(EEC)m/z: [M+H]+539.

The intermediate connection 52: synthesis of 5-[1-(benzazolyl)-4-(methanesulfonyl)-1H-indol-2-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Oxon-persulfate compound (683 mg, 1.11 mmol) are added to a solution of intermediate 51 (200 mg, and 0.37 mmol) in a mixture of dioxane/water (8 ml/3 ml)at room temperature. The reaction solution was stirred at room temperature for 2.5 hours. The reaction solution is dried over anhydrous magnesium sulfate. Then the desiccant was filtered and the resulting filtrate concentrated under reduced pressure, giving a yellow, oily, intermediate compound 52 (61 mg, 29% yield).

MS(EEC)m/z: [M+H]+572.

Connection example 76: synthesis of 5-(4-methanesulfonyl-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The monohydrate tetrabutylammonium (140 mg, of 0.53 mmol) are added to THF-solution (5 ml) and intermediate 52 (61 mg, 0.11 mmol)and the mixture heated to the boiling temperature under reflux for 3 hours. After cooling to room temperature, the residue obtained under reduced pressure, purified by SCX cartridge (strong cation exchange cartridge) is absolutely the same link is in example 1, that gives the crude product 76 as a yellow solid. Additional purification column chromatography (mixture of dichloromethane/methanol=10/1 (about./about.)) using silica gel gives compound from example 76 (17 mg, 37% yield) as a yellow solid.

MS(EEC)m/z: [M+H]+432.

Connection example 77: synthesis of 5-(4-acetamido-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 78: synthesis of 5-(4-methanesulfonamido-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The intermediate connection 55: Synthesis of 5-(1H-4-amino-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxymethylated

The intermediate connection 53: synthesis of 1-(tert-butyl)-4-(di-tert-butyl)amino-2-indovinelli acid

n-Utility (0.63 ml, 1,65M, solution in hexane) is added dropwise to a cooled THF-solution (5 ml) Diisopropylamine (105 mg, 104 mmol), in terms of cooling with ice for 5 minutes under nitrogen atmosphere. The resulting mixture was stirred for 20 minutes and gives a THF-solution of sitedisability.

THF-solution of sitedisability obtained above, add in an ice bath, is added dropwise to a THF-solution (5 ml) of 1-(tert-butyl)-4-(di-tert-butyl)aminoindole (300 mg, 0,694 mmol) and triisopropylsilane (157 mg, 0,832 mmol)obtained separately. Then the reaction mixture is displaced is more, in an ice bath for 1 hour, the solution is brought to pH 3 by addition of 1M HCl solution. The resulting solution was extracted with ethyl acetate (15 ml ×2), and the combined solution was dried over anhydrous magnesium sulfate, receiving the crude product 53, 1-(tert-butyl)-4-(di-tert-butyl)amino-2-indovino acid. The crude product was used for subsequent interactions without additional purification.

The intermediate connection 54: synthesis of 5-[1-(tert-butyl)-4-(di-tert-butyl)aminoindole-2-yl]-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 17 (178 mg, 0.49 mmol), palladium acetate (14 mg, 0,063 mmol) and triphenylphosphine (52 mg, 0.20 mmol) is dissolved in a solution of dioxane/toluene (3,3/1 (./vol.), 5,2 ml) and the mixture is stirred at room temperature for 10 minutes. Then to the reaction solution was added 1-(tert-butyl)-4-(di-tert-butyl)amino-2-indovino acid 53 (256 mg, 0.54 mmol), water (5 ml) and sodium carbonate (129 mg, 1,22 mmol)and the mixture heated to the boiling temperature under reflux for 1.5 hours. After cooling, the reaction solution was diluted with ethyl acetate and added to a solution of the sodium sulfate to remove water. Then the obtained solution is filtered. Then the filtrate is concentrated under reduced pressure, the product is purified column chromatography (ethyl acetate), using silica gel with amino-layer, which gives 5-{-(tert-butyl)-4-(di-tert-butyl)aminoindole-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide 54 and 5-{-4-(di-tert-butyl)aminoindole-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide, obtained in the form of a mixture (127 mg, colorless solid). This mixture is not subjected to any additional separation and used for further interaction.

The intermediate connection 55: synthesis of 5-(1H-4-amino-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide dihydrochloride

Compound (127 mg)containing the above-mentioned intermediate connection 54 and 10% HCl-methanol (15 ml) in a flask of 100 ml is kept in a nitrogen atmosphere at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure, and get salt 55 - 5-(1H-4-aminoindole-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide the dihydrochloride, (99 mg, quantitative yield).

1H-NMR (300 MHz, CD3OD) δ 7,50-7,47 (m, 1H), 7.23 percent-was 7.08 (m, 4H), 4,10 (s, 3H), 4,03-to 3.99 (m, 2H), a 3.87 is 3.76 (m, 4H), 3,67-3,63 (m, 2H), 3.43 points is 3.40 (m, 2H), 3,29-3,19 (m, 2H).

Other protons are not observed due to overlap with the peaks of the solvent, based on CD3OD.

MS(EEC)m/z: [M+H]+369.

The following connection examples obtained essentially the same way as described above for process (F-3, and conditions selected from the above process F-3.

Connection example 77: synthesis of 5-(4-acetamido-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 78: 5-(4-methanesulfonamido-1H-indol-2-yl)-1-methyl-N-[2-(orphelin-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 77 and connection example 78 in the below table are in the presence of base (triethylamine) in 1,2-dichlorethane solution using each reagent (acetylchloride or acetic anhydride, methansulfonate) and the intermediate connection 55. For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Connection example 79: synthesis of 5-(1-methanesulfonyl-1H-indol-3-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 80: synthesis of 5-(1-methanesulfonyl-3-methyl-1H-indol-5-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Connection example 79 and connection example 80 in the below table are in the presence of a base (sodium hydride) in DMF-solution using each reagent (methanesulfonate) and the intermediate connection 55. For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

Reagents and examples below.

Connection example 81: synthesis of 1-methyl-5-(3-methyl-1H-indol-1-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

3-Methylindole (27 mg, 0.21 mmol), arbonet cesium (179 mg, 0.55 mmol) and copper iodide(I) (52 mg, 0.28 mmol) are added to a solution of intermediate compound 17 (50 mg, 0.14 mmol)dissolved in DMF (1 ml)and the mixture stirred at 110°C for 20 hours. After cooling, insoluble materials are removed by filtration, the filtrate is concentrated under reduced pressure. The residue is pre-treated with column chromatography (mixture of dichloromethane/ethanol (10/1) (about./vol.), using the processed amine silica gel, and then loaded on a SCX cartridge (strong cation exchange cartridge), washed with methanol (10 ml) and, finally, elute with a mixture of ammonia-methanol (1M, 8 ml). The crude product obtained by concentration, purified preparative HPLC (cleaning device A described in the beginning of this section for EXAMPLES).

MS(EEC)m/z: [M+H]+368.

Connection example 82: synthesis of 5-{5-cyano-1H-pyrrolo[2,3-b]pyridine-2-yl}-N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide

The intermediate connection 56: synthesis of N-(2,2-diatexite)-5-iodine-1-methyl-1H-pyrazole-3-carboxamide

According to such a method of synthesis of compounds of example 1, triethylamine (3,32 ml, 23,80 mmol) are added to a solution of the mixture in anhydrous DMF (50 ml), intermediate 16 (2.00 g, 7,94 mmol), diethylacetal of aminoacetaldehyde (1.27 g, 9,52 mmol) and HBTU (4.52 g, to 11.9 mmol), and the mixture is stirred at room temperature. The resulting residue is purified of colonos the Oh chromatography (hexane/ethyl acetate 2:1 (vol./vol.), using silica gel that gives an intermediate compound 56 (3,84 g) as a pale yellow oil.

1H-NMR (300 MHz, CDCl3) δ 6,99 (USS, 1H), 6,94 (s, 1H), br4.61-4,55 (m, 1H), 3,94 (s, 3H), 3,80-3,68 (m, 2H), 3,64-to 3.50 (m, 4H), of 1.23 (t, J=7.0 Hz, 6H).

The intermediate connection 57: synthesis of N-[2-(3,3-diversecity-1-yl)ethyl]-5-iodine-1-methyl-1H-pyrazole-3-carboxamide

The reaction mixture of THF solution (50 ml) of the intermediate 56 (3,84 g, 10,45 mmol) and 2M HCl solution (25 ml) was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture is brought to a pH above 10 saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride and dried over hydrochloride sodium. Then the desiccant was filtered and the filtrate concentrated under reduced pressure, obtaining a light yellow solid. Triacetoxyborohydride sodium (6,64 g, 31,35 mmol) is added, in several portions, to a mixture of 1,2-dichloroethane (50 ml) of the crude aldehyde intermediate compound and 3,3-deforestationrelated (1.35 g, 10,45 mmol) and ethyl acetate (10 ml). Then the resulting mixture was stirred at room temperature for 15 hours, the reaction mixture is brought to a pH above 10 saturated sodium bicarbonate solution and the solution extracted three times with dichloromethane. The obtained organic layer industry is with a saturated solution of sodium chloride and dried over sodium sulfate. Then the desiccant was filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (mixture of dichloromethane/methanol=40/1-30/1 (about./vol.), using silica gel that gives an intermediate compound 57 (2,93 g, 76% yield) as a colorless oil.

1H-NMR (300 MHz, CDCl3) δ 7,05 (USS, 1H), 6,94 (s, 1H), 3,95 (s, 3H), 3,70-to 3.58 (m, 4H), 3,47-3,39 (m, 2H), 2,80-to 2.74 (m, 2H).

MS(EEC)m/z: [M+H]+371.

The intermediate connection 58: synthesis of N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-[2-(trimethylsilyl)ethinyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 18 as described for the compound in example 22, triethylamine (3.46 in ml, 24,86 mmol) are added to a solution (30 ml) in anhydrous THF intermediate 57 (2.30 g, 6.21 mmol), trimethylsilylacetamide (1,32 ml, to 9.32 mmol), copper iodide(I) (118 mg, 0,621 mmol) and dichlorobis(acetonitrile)palladium(II)chloride (436 mg, 0,621 mmol)and the resulting mixture was stirred at room temperature for 1.5 hours. After conventional treatment, the residue is purified column chromatography (hexane/ethyl acetate 3:2-1:1 (vol./vol.), using silica gel that gives an intermediate compound 58 (1,76 g, 83% yield) as a yellowish brown oil. And the resulting intermediate compound 58 is used in the next stage, without defining any physical characteristics.

<> The intermediate connection 59: synthesis of N-[2-(3,3-diversecity-1-yl)ethyl]-5-ethinyl-1-methyl-1H-pyrazole-3-carboxamide

Methanol mixture (30 ml) of the intermediate compound 58 (1,76 g, 5.17 mmol) and potassium carbonate (107 g of 7.75 mmol) was stirred at room temperature for 2 hours. After the interaction, the potassium carbonate is filtered. The filtrate is concentrated under reduced pressure. The resulting residue is again diluted with dichloromethane and washed with water and then a saturated solution of sodium chloride. Then the solution is dried over sodium sulfate. After the desiccant was filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (hexane/ethyl acetate 1:2 (vol./vol.), using silica gel that gives an intermediate compound 59 (1,32 g, 95% yield) as a yellow solid.

1H-NMR (300 MHz, CDCl3) δ 7,12 (USS, 1H), 6,95 (s, 1H), 3.96 points (s, 3H), 3,70-of 3.54 (m, 5H), 3,48 is 3.40 (m, 2H), 2,82-to 2.74 (m, 2H).

MS(EEC)m/z: [M+H]+269.

Intermediate compound 60: synthesis of 5-[2-(2-amino-5-cyano-3-yl)ethinyl]-N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide

According to the method of synthesis of intermediate compound 20, the intermediate compound 59 (300 mg, 1.12 mmol) and 2-amino-3-iodine-5-cyanopyridine (329 mg, of 1.34 mmol) is heated with stirring at 85°C for 14 hours, and receive the intermediate compounds is their 60 (29.0 mg, 6,7% yield) as a pale yellow solid.

MS(EEC)m/z: [M+H]+386, [M-H]-384.

Connection example 82: synthesis of 5-{5-cyano-1H-pyrrolo[2,3-b]pyridine-2-yl}-N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide

According to such a method of synthesis of the compound in example 22, the compound from example 82 (21 mg, 72% yield) are obtained as a pale yellow solid from intermediate 60 (29 mg, of 0.075 mmol).

1H-NMR (300 MHz, DMSO-d6) δ 12,85 (USS, 1H), 8,68 (d, J=2.2 Hz, 1H), 8,59 (d, J=2.2 Hz, 1H), 8,20-to 8.12 (m, 1H), 7.23 percent (s, 1H),? 7.04 baby mortality (s, 1H), 4,14 (s, 3H), 3,68-of 3.53 (m, 4H), 3,31-3,20 (m, 2H), 2,73-2,63 (m, 2H).

MS(EEC)m/z: [M+H]+355, [M-H]-353.

Connection example 83: synthesis of N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide

The intermediate connection 61: synthesis of 5-[2-(2-aminopyridine-3-yl)ethinyl]-N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide

According to the method of synthesis of intermediate compound 18, the intermediate compound 59 (250 mg, 1.12 mmol) and 3-iodine-2-aminopyridine (226 mg, of 1.03 mmol) was stirred at room temperature for 3 hours, which gives an intermediate compound 61 (50,3 mg, 15% yield) as a pale yellow solid.

MS(EEC)m/z: [M+H]+361.

Connection example 83: synthesis of N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-feast of the ol-3-carboxamide

According to such a method of synthesis of the compound in example 22, the compound from example 83 (to 37.9 mg, 75% yield) are obtained as a pale yellow solid from intermediate 61 (50 mg, of 0.075 mmol).

1H-NMR (300 MHz, DMSO-d6) δ 12,19 (USS, 1H), 8,31 compared to 8.26 (m, 1H), 8,15-8,08 (m, 1H), 8,05-7,98 (m, 1H), 7.18 in-was 7.08 (m, 2H), 6.89 in (s, 1H), 4,12 (s, 3H), 3,66-of 3.54 (m, 4H), 3,30-3,20 (m, 2H), 2,72 2.63 in (m, 2H).

MS(EEC)m/z: [M+H]+361, [M-H]-359.

Connection example 84: synthesis of 5-{6-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

The intermediate connection 62: synthesis of ethyl-5-{6-torymidae[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylate

According to such a method of synthesis of intermediate compound 35 for connection to example 34, a methanol solution (2 ml) of the intermediate 34 (114 mg, 0.41 mmol) and 2-amino-5-herperidin (39 mg, 0.41 mmol) is heated with stirring for 20 hours. The residue is purified column chromatography (hexane/ethyl acetate 1/3 (about./vol.), using silica gel that gives an intermediate compound 62 (101 mg, 48% yield) as a pale yellow solid.

1H-NMR (300 MHz, CDCl3) δ 8,11-of 8.09 (m, 1H), 7,81 (s, 1H), 7,65-of 7.60 (m, 1H), 7,21-7,14 (m, 1H), 7,07 (s, 1H), 4,43 (t, J=7,3 Hz, 2H), 4,33 (s, 3H), of 1.42 (t, J=7,3 Hz, 3H).

MS(EEC)m/z: [M+H]+289.

Intermediate compound 63: synthesis of 5-{6-torymidae[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carbon is Oh acid

According to such a method of synthesis of intermediate compound 36 for connection to example 34, 2M sodium hydroxide solution (0,175 ml, 0,350 mmol) are added to a methanol solution (5 ml) of the intermediate compound 62 (101 mg, 0,350 mmol)and the resulting mixture was stirred at 70°C for 1 hour. After neutralization with 2 m HCl solution of intermediate compound 63 (67 mg, 73% yield) are obtained in the form of white crystals. Intermediate compound used for subsequent interactions without additional purification.

1H-NMR (300 MHz, DMSO-d6) δ 8,75 (USS, 1H), scored 8.38 (s, 1H), 8,23 (s, 1H), 7,70-the 7.65 (m, 1H), 7,39-7,33 (m, 1H), 7,06 (s, 1H), 4,24 (s, 3H).

MS(EEC)m/z: [M+H]+261.

Connection example 84: synthesis of 5-{6-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of compounds of example 1, the crude compound from example 84 (52,3 mg, 54% yield) is obtained in the form of white crystals of intermediate 63 (67 mg, 0,257 mmol) and 4-(2-amino-ethyl)research (36,9 mg, 0,283 mmol). For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+373.

Connection example 85: synthesis of 5-{7-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Sub the internal connection 64: synthesis of ethyl-5-{7-torymidae[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylate

According to such a method of synthesis of intermediate compound 35 for connection to example 34, a methanol solution (2 ml) of the intermediate 34 (114 mg, 0.41 mmol) and 2-amino-4-herperidin (39 mg, 0.41 mmol) is heated with stirring for 20 hours. Then the resulting residue is purified column chromatography (hexane/ethyl acetate=1/3 (about./vol.), using silica gel that gives an intermediate compound 64 (120 mg, 57% yield) as a pale yellow solid.

1H-NMR (300 MHz, CDCl3) δ 8,10 (USS, 1H), 7,81 (s, 1H), 7,65-of 7.60 (m, 1H), 7,22-to 7.15 (m, 1H), 7,07 (s, 1H), 4,46-and 4.40 (t, J=7,3 Hz, 2H), 4,33 (s, 3H), of 1.42 (t, J=7,3 Hz, 3H).

MS(EEC)m/z: [M+H]+289.

Intermediate compound 65: synthesis of 5-{7-torymidae[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylic acid

According to such a method of synthesis of intermediate compound 36 for connection to example 34, 2M sodium hydroxide solution (of 0.21 ml, 0,416 mmol) are added to a methanol solution (5 ml) of the intermediate compound 64 (120 mg, 0,416 mmol)and the resulting mixture was stirred at 70°C for 1 hour. After neutralization with 2 m HCl solution of intermediate compound 65 (67 mg) was obtained as white crystals. Intermediate compound used for subsequent interactions without additional purification.

1H-NMR (300 MHz, DMSO-d6) δ 8,81-8,79 (m, 1H), to 8.41 (s, 1H), 7,75-of 7.70 (m, 1H), 7,46-7,39 (m, 1H), 7,07 (s, 1H), 4,23 (s, 3H).

MS(EEC)m/z: [M+H] +261.

Connection example 85: synthesis of 5-{7-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of compounds of example 1, the crude compound from example 85 (102 mg) is obtained in the form of white crystals of intermediate 65 (67 mg, 0,257 mmol) and 4-(2-amino-ethyl)research (36,9 mg, 0,283 mmol). For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+373.

Connection example 86: synthesis of 5-{6-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 66: synthesis of ethyl-5-{6-bromoimidazo[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylate

According to such a method of synthesis of intermediate compound 35 for connection to example 34, ethanol solution (10 ml) of the intermediate 34 (235 mg, 0,854 mmol) and 2-amino-5-bromopyridine (148 mg, 0,854 mmol) is heated to the boiling temperature under reflux for 20 hours, and then the resulting residue is purified column chromatography (hexane/ethyl acetate 1/4 (about./vol.), dichloromethane/methanol=30/1 (about./vol.), using silica gel that gives an intermediate compound 66 (106 mg, 36% yield) as a pale yellow solid.

1H is the Mr (300 MHz, CDCl3) δ 8,32 (s, 1H), to 7.77 (s, 1H), 7,56-7,53 (m, 1H), 7,32-7,27 (m, 1H), 7,09-was 7.08 (m, 1H), 4,4, 4-4,39 (m, 2H), 4,34-to 4.33 (m, 3H), of 1.42 (t, J=7,3 Hz, 3H).

MS(EEC)m/z: [M+H]+349 and 351.

Intermediate compound 67: synthesis of 5-{6-bromoimidazo[1,2-a]pyridine-2-yl}-1-methyl-1H-pyrazole-3-carboxylic acid

According to such a method of synthesis of intermediate compound 36 for connection to example 34, 2M sodium hydroxide solution (0,304 ml, 0,608 mmol) are added to a methanol solution (15 ml) of the intermediate compound 66 (106 mg, 0,304 mmol)and the resulting mixture was stirred at 70°C for 1 hour. After neutralization with 2 m HCl solution of intermediate compound 67 (66,7 mg) are obtained in the form of a white solid. Intermediate compound used for subsequent interactions without additional purification.

1H-NMR (300 MHz, DMSO-d6) δ 8,93 (s, 1H), scored 8.38 (s, 1H), 7,65 (d, J=10.4 Hz, 1H), 7,50 (d, J=10.4 Hz, 1H), 7,10 (s, 1H), 4,23 (s, 3H).

MS(EEC)m/z: [M+H]+321 and 323.

The intermediate connection 68: synthesis of 5-{6-bromoimidazo[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of compounds of example 1, crude intermediate compound 68 (77 mg, 0,078 mmol) obtained from intermediate 67 (67 mg, 0,209 mmol) and 4-(2-amino-ethyl)research (29,9 mg, 0.23 mmol). Then the residue purified SCX, and the intermediate connection 68 (74,9 mg, 83% yield) are obtained in the form of a white TV is Gogo substances.

MS(EEC)m/z: [M+H]+433 and 435.

Connection example 86: synthesis of 5-{6-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

In anhydrous DMF mixture (4 ml) of the intermediate 68 (74,9 mg, 0,173 mmol) and cyanide zinc (12.5 mg, 0,107 mmol), and tetrakis(triphenylphosphine)palladium (20.0 mg, of 0.017 mmol) was stirred at 100°C for 20 hours. After cooling to room temperature, to the reaction solution was added water, and the mixture was extracted with a mixture of ethyl acetate/toluene (9/1). Since most of the compounds are transferred to the aqueous layer, the aqueous layer was again concentrated under reduced pressure. The obtained solid residue fractionary a small amount of methanol. The obtained solid is dried under reduced pressure, giving crude compound from example 86 (58,0 mg, 88% yield) as a white solid. For further purification using preparative HPLC system (cleaning device (A), which was used for the purification of the compound of example 1.

MS(EEC)m/z: [M+H]+380, [M-H]-378.

Connection example 87: synthesis of N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 11 to compound in example 17, 1,4-dioxane solution (10 ml) of the intermediate compound 57 (224 m is, 0,605 mmol) and 3-henrikromby acid (122 mg, 0,666 mmol) is heated under stirring at 100°C for 15 hours, the resulting residue is purified column chromatography (mixture of dichloromethane/methanol=30/1-20/1 (about./vol.), using silica gel that gives compound from example 81 (181 mg, 80% yield) as a light brown solid. Connection example (181 mg) purified by recrystallization from a solution of ethyl acetate and hexane, giving the compound from example 87 (121 mg).

1H-NMR (300 MHz, CDCl3) δ 9,00-8,97 (m, 1H), 8,23-to 8.14 (m, 2H), 7,93-to 7.77 (m, 2H), 7,69-of 7.60 (m, 1H), 7,19 (USS, 1H), 7,01 (s, 1H), 4.00 points (s, 3H), of 3.73-3,61 (m, 4H), 3,54 is-3.45 (m, 2H), 2,86-2,78 (m, 2H).

MS(EEC)m/z: [M+H]+372.

Connection example 88: synthesis of 5-{7-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

Intermediate compound 69: synthesis of 5-acetyl-1-methyl-1H-pyrazole-3-carboxylic acid

According to such a method of synthesis of intermediate compound 16 to compound in example 22, 2M sodium hydroxide solution (2.55 ml, 5,10 mmol) are added to a methanol solution (12 ml) of the intermediate 33 (500 mg, 2.55 mmol)and the resulting mixture is stirred at room temperature for 16 hours. After neutralization with 2M HCl solution, the residue is washed with cold water, which gives an intermediate compound 69 (220 mg, 51% yield) as a white solid.

MS(EEC)m/z: [M+H]+169,[M-H] -167.

Intermediate compound 70: synthesis of 5-acetyl-N-(2,2-diatexite)-1-methyl-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 56 for connection to example 82, triethylamine (397 mg, 3.93 mmol) are added to a mixed solution (5 ml), anhydrous DMF, the intermediate 69 (220 mg, 1,31 mmol) and diethylacetal of aminoacetaldehyde (192 mg, 1.44 mmol), HBTU (595 mg, 1.57 mmol). The resulting mixture was stirred at room temperature for 3 hours. After the usual processing, the obtained residue is purified column chromatography (hexane/ethyl acetate 2/1 (vol./vol.), using silica gel that gives an intermediate compound 70 (351 mg, 95% yield) as a white solid.

MS(EEC)m/z: [M-H]-282,27.

Intermediate compound 71: synthesis of 5-(2-bromoacetyl)-N-(2,2-diatexite)-1-methyl-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 34 for connection to example 34, phenyltrimethylammonium (466 mg, 1,24 mmol) are added to THF-solution (5 ml) of the intermediate compound 70 (351 mg, 1,24 mmol), the mixture was stirred at room temperature. After the usual processing, the obtained residue is purified column chromatography (hexane/ethyl acetate 3/1 (vol./vol.), using silica gel that gives an intermediate compound 71 (223 mg, 50% yield) as a white t is ejogo substances.

MS(EEC)m/z: [M+H]+362 and 364, [M-H]-360 and 362.

The intermediate connection 72: synthesis of 5-{7-cyanoimino[1,2-a]pyridine-2-yl}-N-(2,2-diatexite)-1-methyl-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 35 for connection to example 34, ethanol solution (10 ml) of the intermediate 71 (222,9 mg of 0.615 mmol) and 2-amino-4-cyanopyridine (73,3 mg of 0.615 mmol) is heated with stirring for 15 hours. The residue is purified column chromatography (mixture of dichloromethane/methanol 30/1 (about./vol.), using silica gel that provides an intermediate compound of 72 (174,1 mg, 74% yield) as a pale yellow solid.

MS(EEC)m/z: [M+H]+337.

Connection example 88: synthesis of 5-{7-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide

According to such a method of synthesis of intermediate compound 57 for connection to example 82, the reaction mixture THF solution (5 ml) of the intermediate 72 (174,1 mg, 0,455 mmol) and 2M HCl solution (2.5 ml) was stirred at 50°C for 1 hour. After cooling to room temperature, the reaction solution was adjusted to pH over 10 with 2M sodium hydroxide solution (2.5 ml)and the resulting solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated solution of sodium chloride, and the solution is dried over sodium sulfate. Then assimilability, the filtrate is concentrated under reduced pressure and get a light yellow solid. Triacetoxyborohydride sodium (289,3 mg, 1.365 mmol) are added to a mixture of crude intermediate aldehyde compound and 1,2-dichlorethane solution(5 ml) of the research (39,2 mg, 0,455 mmol) and acetic acid (1 ml) at room temperature. Then the resulting mixture was stirred at room temperature for 15 hours, the reaction mixture is brought to a pH above 10 sodium bicarbonate solution and the solution extracted three times with dichloromethane, the organic layer was washed with a saturated solution of sodium chloride and dried over sodium sulfate. Then the desiccant was filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified column chromatography (mixture of dichloromethane/methanol=30/1-10/1 (about./vol.), using silica gel. After which the compound from example 88 (7 mg, 4% yield) are obtained as a pale orange solid.

MS(EEC)m/z: [M+H]+380.

The list of intermediates for the synthesis of compounds according to the examples below in tables 11-1 - 11-4.

Test the binding of 5-HT2Bperson

The binding affinity of the receptor 5-HT2B

Cells CHO-K1, transfetsirovannyh 5-HT2Bman, buying from Euroscreen (no cat.: ES-314-F) and grown on site. The collected cells are suspended in 50 mm HEPES (pH 7,4), with the addition of a mixture of protease inhibitors (SIGMA, dilution 1:100) and 1 mm EDTA, and homogenized using a disintegrator transmitter station PT1200, put on full power for 30 seconds on ice. The homogenates centrifuged at 1000 rpm and 4°C for 5 min, and supernatant frozen at -80°C for 10 min and Then frozen supernatant resuspended in 50 mm HEPES (pH of 7.4), homogenized and centrifuged again in the same way. Supernatant centrifuged at 25000 rpm and 4°C for 60 minutes and then the precipitate in the test tube after centrifugation resuspended in 50 mm HEPES (pH of 7.4), homogenized, divided into portions and stored at -80°C until use. Aliquot share of the membrane fractions are used to determine protein concentration using the test kit for protein content using BCA (PIERCE) and the plate reader ARVOsx (Wallac).

For the experiments on receptor binding, 20 μl of test compounds are incubated with 100 μl of [3H]-mesulergine (GE healthcare, 10 nm) and 80 μl of membrane homogenate (20 μg protein) for 120 min at room temperature. Nonspecific binding is determined using 10 μm mianserin (SIGMA) at final concentration. All incubation would complete what trim vacuum filtration through paper on a glass filter with impregnation of 0.2 (about./vol.)% PEI, using a Filtermate harvester (PerkinElmer), with the subsequent five-fold washing with 50 mm HEPES (pH 7,4). Receptore-associated radioactivity determined by counting pulses in the liquid phase using a TopCount (PerkinElmer).

According to the results of the experiment, all connections examples show affinity to the receptor 5-HT2Bperson.

Test calcium influx using cells CHO-K1 transfected with the 5-HT2Bperson

The binding affinity of the receptor 5-HT2Bcompounds according to this invention is demonstrated by the following methods.

Cells CHO-K1, transfetsirovannyh 5-HT2Bman, get at Euroscreen and grow. Cells are grown at 37°C and 5% CO2in UltraCHO medium (Cambrex) supplemented with 400 μg/ml G418 and 250 μg/ml of zeocin, 100 U/ml penicillin, 100 μg/ml streptomycin and 1(V/V)% cialisbuynow FBS (fetal calf serum). After growing up to 60-80% confluence, the culture medium of cells replace KRH-buffer (1.8 mm CaCl2, 1 mm MgSO4115 mm NaCl, 5.4 mm KCl, 11 mm D-glucose, 0.96 mm NaH2PO4, 25 mm HEPES, brought to a pH of 7.4 with NaOH), including 5 μm Fura-2 AM. Cells incubated for 120 min at room temperature. After incubation, the cells divide mixture of 0.05 (weight/weight)% trypsin/1 mm EDTA and washed with PBS. Then these cells are suspended in KRH buffer, receiving a concentration of 1.0×106cells/ml

384-well plate is pre-treated with compounds according to this invention (50 μl/well). 34 μl of cell suspension (3,4×104cells) are distributed in each cell 384-well black analytical tablet with a transparent bottom. Analytical tablets placed on the FDSS6000 (Hamamatsu Photonics) and begin monitoring signals. Thirty seconds into each well automatically add 6 ál of serial dilutions of the compounds, and continue to monitor on FDSS6000 4,5 min to study the antagonistic activity. The cells are then incubated for 10 min at room temperature in the dark. Analytical tablets again placed on the FDSS6000 and begin monitoring signals. Thirty seconds into each well automatically add 20 µl of 9 nm 5-HT, and continue to monitor on FDSS6000 another 4.5 min for the study of values IC50the tested compounds. Reference to this experiment is Br. J. Pharmacol., 1999 September; 128(1): 13-20.

The antagonistic activity of the receptor 5-HT2B(IC50nm) all 88 of the compounds according to the examples in the following tables 12-15 range from 0.1 nm to 100 nm.

Test calcium influx using 3T3 cells transfected with the 5-HT2Bperson

The binding affinity of the receptor 5-HT2Bcompounds p the present invention is determined by the following methods.

3T3 cells, transfetsirovannyh 5-HT2Bman, get on the spot. Cells are grown at 37°C and 5% CO2in DMEM (Invitrogen) supplemented with 400 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and 10 (V/V)% FBS. After growing up to 60-80% confluence, the culture medium of cells replace KRH-buffer (1.8 mm CaCl2, 1 mm MgSO4115 mm NaCl, 5.4 mm KCl, 11 mm D-glucose, 0.96 mm NaH2PO4, 25 mm HEPES, brought to a pH of 7.4 with NaOH), including 5 μm Fura-2 AM. Cells incubated for 120 min at room temperature. After incubation, the cells divide mixture of 0.05% trypsin/1 mm EDTA and washed with PBS. Then these cells are suspended in KRH buffer, receiving a concentration of 0.3×106cells/ml

384-well tablets are pre-treated with compounds according to this invention (50 μl/well). 34 μl of cell suspension (1,0×104cells) are distributed in each cell 384-well black analytical tablet with a transparent bottom. Analytical tablets placed on the FDSS6000 (Hamamatsu Photonics) and begin monitoring signals. Thirty seconds into each well automatically add 6 ál of serial dilutions of the compounds, and continue to monitor on FDSS6000 4,5 min to study the antagonistic activity. The cells are then incubated for 10 min at room temperature in the dark. Analytical tablets again placed the on FDSS6000 and begin monitoring signals. Thirty seconds into each well automatically add 20 µl of 90 nm 5-HT, and continue to monitor on FDSS6000 another 4.5 min for the study of values IC50the tested compounds. Reference to this experiment is Br. J. Pharmacol., 1999 September; 128(1): 13-20.

Test calcium influx using 3T3 cells transfected with the 5-HT2Cperson

The binding affinity of the receptor 5-HT2Ccompounds according to this invention is determined by the following methods.

3T3 cells, transfetsirovannyh 5-HT2Cman, get on the spot. Cells are grown at 37°C and 5% CO2in DMEM (Invitrogen) supplemented with 20 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and 10 (V/V)% FBS. After growing up to 60-80% confluence, the culture medium of cells replace KRH-buffer (1.8 mm CaCl2, 1 mm MgSO4115 mm NaCl, 5.4 mm KCl, 11 mm D-glucose, 0.96 mm NaH2PO4, 25 mm HEPES, brought to a pH of 7.4 with NaOH), including 5 μm Fura-2 AM. Cells incubated for 120 min at room temperature. After incubation, the cells divide mixture of 0.05% trypsin/1 mm EDTA and washed with PBS. These cells are suspended in KRH buffer, receiving a concentration of 0.45×106cells/ml

384-well tablets are pre-treated with compounds according to this invention (50 μl/well). 34 μl of cell suspension (1.5 x 104cells) are distributed into each well of 384-lonodn the th black analytical tablet with a transparent bottom. Analytical tablets placed on the FDSS6000 (Hamamatsu Photonics) and begin monitoring signals. Thirty seconds into each well automatically add 6 ál of serial dilutions of the compounds, and continue to monitor on FDSS6000 4,5 min to study the antagonistic activity. The cells are then incubated for 10 min at room temperature in the dark. Analytical tablets again placed on the FDSS6000 and begin monitoring signals. Thirty seconds into each well automatically add 20 µl of 3 nm 5-HT, and continue to monitor on FDSS6000 another 4.5 min for the study of values IC50the tested compounds. Reference to this experiment is Br.J. Pharmacol., 1999 September; 128(1): 13-20.

Evaluation of therapeutic action in IBS rats

Pharmacological action of the tested compounds according to this invention is evaluated by defining positive effects against lowering the threshold of pain sensitivity by stimulating the stretching of the colon in the model of TNBS-induced IBS.

For further details, please refer to the literary source, Katsuyo Ohashi et al., Pharmacology, 81(2): 144-150(2008).

Experimental methods

Produce a median incision under anesthesia animals male SD rats, 240-270, a Solution of TNBS (50 mg/kg, 30% methanol) handle start of the rectum of rats. After processing, blind intestine return is in the abdominal cavity. Then the muscular wall of the stitch. After surgery, animals kept in normal conditions and used for pharmacological evaluation after 7 days after surgery. Stimulation stretching of the rectum is used to assess compounds, L. Diop et al., J Pharmacol Exp Ther.302(3): 1013-22(2002). The cylinder (5 cm) is inserted through the anus and held in place (the top of the cylinder 5 cm from the anus). Then the balloon is gradually step by step stuff, from 0 to 70 mm Hg, using barostat (Barostat DISTENDER II R, G & J, CANADA). The pain threshold is determined by the pressure, calling the first abdominal reduction (abdominal cramp: Wesselmann U, et al., (1998) Neurosci Lett 246: 73-76).

The results for the compound from example 24 is presented on figure 1. The number of animals in each group is 8. The graph shows the average data. The column chart shows values of 25% and 75%. Statistical analysis is performed on the closed criterion, using the criterion of Mann-Whitney.

The vertical axis indicates the pressure pain threshold. In this case, p.o. 10 mg/kg gives positive effects against lowering the threshold of pain sensitivity with TNBS. Thus, new pyrazole-3-carboxamide derivatives can be useful for the treatment of IBS.

INDUSTRIAL APPLICABILITY

The connection according to this invention is useful as a selective antagonist of the receptor 5-HT 2Band it is useful for pre-treatment or prevention of various diseases associated with the receptor 5-HT2B.

1. The compound of the following General formula (I) or its pharmaceutically acceptable salt

where
A means morpholinyl, 1,4-oxazepine, piperidinyl, pyrrolidinyl or azetidinol, which is connected to N;
R1means C1-C6is an alkyl group;
R2means bicyclic aryl group selected from 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, chinoline, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolo[2,3-b]pyrazinyl and khinoksalinona, which can be substituted for R4,
R3means a hydrogen or halogen atom;
R4means C1-C6is an alkyl group, a C1-C6-halogenation group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1Aor NHSO2R1A;
R5means C1-C6is an alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; when p is plural, R5may be the same or different, or R5can be combined with other R5;
each of R1Aand R1Bindependently mean C1-C6is an alkyl group; a is 0, 1 or 2;
n is 1 or 2 and
p is 0, 1, 2, 3, 4 or 5.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where the cycle is A means morpholinyl, piperidinyl, pyrrolidinyl or azetidinol, which is connected to N;
n = 1;
p is 0, 1 or 2.

3. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound represented by the General formula (I)selected from the group including
1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide;
1-methyl-5-{5-methyl-1H-pyrrolo[3,2-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide;
1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{7H-pyrrolo[2,3-d]pyrimidine-6-yl}-1H-pyrazole-3-carboxamide;
1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-[5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-2-yl]-1H-pyrazole-3-carboxamide;
1-methyl-5-{5-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{5-cyano-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{6-fluoro-1H-pyrrolo[3,2-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
1-methyl-N-[2-(morpholine-4-yl)ethyl]-5-{5H-pyrrolo[2,3-b]pyrazin-6-yl}-1H-pyrazole-3-carboxamide;
5-{5-cyano-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(Moholy the-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
N-[2-(3,3-diversecity-1-yl)ethyl]-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide;
N-[2-(azetidin-1-yl)ethyl]-5-(5-fluoro-1H-indol-2-yl)-1-methyl-1H-pyrazole-3-carboxamide;
1-methyl-5-(2-methyl-1H-indol-5-yl)-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-(1,2-dimethyl-1H-indol-5-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-(4-acetamido-1H-indol-2-yl)-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{imidazo[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{6-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{7-torymidae[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
5-{6-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide;
N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-(quinoline-3-yl)-1H-pyrazole-3-carboxamide;
N-[2-(3,3-diversecity-1-yl)ethyl]-1-methyl-5-{1H-pyrrolo[2,3-b]pyridine-2-yl}-1H-pyrazole-3-carboxamide and
5-{7-cyanoimino[1,2-a]pyridine-2-yl}-1-methyl-N-[2-(morpholine-4-yl)ethyl]-1H-pyrazole-3-carboxamide.

4. The intermediate connection for connection according to claim 1 represented by General formula (IA):

where A denotes morpholinyl or azetidine;
R1means C1-C6-alkyl GRU is PU;
R3means hydrogen;
R5means halogen;
n is 1 or 2;
p is 0, 1, 2, 3, 4 or 5.

5. The intermediate connection for connection according to claim 1 represented by General formula (IB):

where R1means C1-C6is an alkyl group;
R2means bicyclic aryl group selected from 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, chinoline, imidazo[1,2-a]pyridyl, which can be substituted for R4,
R3means hydrogen,
R4means C1-C6is an alkyl group or halogen.

6. Prophylactic or therapeutic agent against diseases that involve the receptors 5-HT2Bwhere the effective ingredient is a compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3.

7. Pharmaceutical composition having antagonistic activity against receptors 5-HT2Bcontaining an effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

8. Pharmaceutical composition for prevention or treatment of a pathological state mediated by receptors 5-HT2Bat the mammal containing an effective amount of the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, and pharmaceutically acceptable Eitel.

9. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3, applicable in the prevention or treatment of a pathological state mediated by receptors 5-HT2B.

10. The use of compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3 in the manufacture of a medicine for the prevention or treatment of a condition mediated by receptors 5-HT2B.

11. The method of prevention or treatment of diseases such as visceral pain, gastroesophageal reflux disease (GERD), a higher, diarrhea, functional gastrointestinal disorder, irritable bowel syndrome, Crohn's disease or ulcerative colitis, comprising the administration to a human or mammal an effective amount of a pharmaceutical composition containing the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: there are described new derivatives of imidazo[1,2-b][1,2,4,5]tetrazines of general formula (I) wherein: Het=4-methylimidazol-1-yl, R=H or Het=3,5-dimethylpyrazol-1-yl, R=propylthio, and based anticancer agents for treating oncological patients.

EFFECT: higher clinical effectiveness.

2 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid salts, wherein an acid addition salt is specified in a group consisting of phosphate, malate and tartrate; a base addition salt is specified in a group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, tetramethylammonium salt, tetraethylammonium salt, ethanolamine salt, choline salt and arginine salt. The invention also refers to methods for preparing the above salts, to a therapeutic agent as a dipeptidyl peptidase (DPP-IV) inhibitor based thereon.

EFFECT: there are prepared new (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid salts which can find application in medicine as the therapeutic agent for treating type 2 diabetes, hyperglycemia, obesity or insulin resistance.

16 cl, 4 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a compound having a structure according to formula I:

,

compositions containing the compounds of the above formula applicable to stimulate neurogenesis and/or inhibition of neuron degeneration.

EFFECT: invention may be used in treating diseases and conditions characterised by neuron loss and lower neurogenesis, including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury and depression.

8 cl, 2 tbl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a novel crystalline salt of sitagliptin - sitagliptin malate and containing it pharmaceutical composition; the described salt is dipeptidylpeptidase-IV inhibitor and can be applied in medicine in treatment of type 2 diabetes mellitus.

EFFECT: invention can be applied in medicine in treatment of type 2 diabetes mellitus.

2 cl, 17 ex, 29 tbl, 18 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of heterocyclic compounds - derivatives of 2-dialkylaminopyrrolo[1,2-alpha][1,4]benzodiazepine of general formula I where 1a R1=OMe, R2=morpholin-4-yl; 1b R1=H, R2=morpholin-4-yl; 1c R1=H, R2=piperidin -1-yl; 1d R1=OMe, R2=pyperidin -1-yl; 1e R1=H, R2=diethylamino; 1f R1=OMe, R2=diethylamino. Method of obtaining derivatives of 2-dialkylaminomethylpyrrolo[1,2-alpha][1,4]benzodiazepine of general formula I consists in introduction of dialkylaminomethyl group in β-position of pyrrole ring of pyrrolo[1,2-alpha][1,4]benzodiazepine derivatives as a result of aminomethylation by Mannich of derivatives of pyrrolo[1,2-a][1,4]diazepine, reaction is carried out with boining said compounds in acetohitryl for 4-10 hours with addition of mixture of formalin, acetic acid and secondary amine (4,2 mmol : 17.4 mmole : 1,2 mmole) per 1 mmole of pyrrolo[1,2-alpha][1,4]diazepine.

EFFECT: elaborated is method of obtaining novel compounds, which can be applied as biologically active substances and semiproducts for synthesis of novel heterocyclic systems.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts specified in a group consisting of phosphate salt, hydrochloride salt, sulphate salt, mesylate salt, maleate salt or malate salt. Also, the invention refers to a method for preparing the above salts, using them and a pharmaceutical composition on the basis of the above salts.

EFFECT: there are prepared new pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts effective in treating diabetes.

5 cl, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted pyrazino-quinolines of formula: , wherein the values R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, X and Y are presented in clause one of the patent claim, and to their pharmaceutically acceptable salts.

EFFECT: compounds can be used for treating cancer.

14 cl, 24 dwg, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 7-R-pyrido[1,2-a]benzimidazoles of the general formula where R=a) CF3, b) CN, c) COOH, d) C(O)NH2, e) COOCH3, f) COOC2H5, consisting in the following: reduction of chlorides of N-(2-nitro-4-R-phenyl)pyridinium is carried out in a mixture of alcohol and 4% hydrochloric acid, taken at a ratio 1:1, by means of electric current in a diaphragm cell in a galvanostatic mode at a temperature of 40-45°C on a lead cathode, with passing through an electrolytic cell 4 F charge for 0.5 h, with current intensity 0.6 A, as an anolyte used is 15% of sulphuric acid, and as an anode - platinum; target products are separated by filtration of a precipitated sediment after processing of a reaction mixture with ammonium hydroxide.

EFFECT: novel reagent-free method, making it possible to reduce synthesis cost and simplify the process of the target product separation, is elaborated.

7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing quinazoline derivatives of structural formula I:

,

where values of radicals R1-R6, R8, W, P are given in the claim. The method involves reacting an aldehyde of formula II:

with ethylene carbonate to form a compound of formula III:

and reacting a compound of formula III with a compound of formula IV:

to form a compound of formula I. The invention also relates to methods of producing derivatives of the compound of formula I of structural formulae VI and VIII.

EFFECT: said methods enable to obtain products with low content of impurities and high output.

23 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bicyclic heterocyclic compounds of formula (I), which can be applied in prevention or treatment of abnormal or pathological condition, mediated by FGFR kinase, such as cancer. In formula compound, (i) in case when R1 and R2 independently represent hydrogen or C3-8cycloalkyl; A is group Aa, which represents aromatic group, representing phenyl; R3 represents hydrogen or C1-6alkyl; R4 represents group R4a, which represents amino, halogen, C1-6alkyl, -X-R5, phenyl or aromatic heterocyclic group, where said heterocyclic group represents 5- or 6-membered heterocyclyl group and contains 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen or sulphur, where said phenyl or said heterocyclyl group can be optionally substituted with one or two Rb groups; or (ii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ab, which represents aromatic 5-membered heterocyclic group; R3 represents hydrogen or C1-6alkyl; R4 is group R4a, which represents halogen; or (iii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ac, which represents aromatic 6-membered heterocyclic group, containing one nitrogen atom as heteroatom; R3 represents hydrogen or C1-6alkyl; R4 is group R4b, which represents halogen, C1-6alkyl, -X-R5 or aromatic heterocyclic group, containing 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Other values of radicals are given in the invention formula.

EFFECT: obtaining novel derivatives of bicyclic heterocyclic compounds.

21 cl, 7 tbl, 250 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

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