N-containing heteroaryl derivatives as jak3 kinase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

 

The technical field to which the invention relates

The present invention relates to a novel series of N-containing heteroaryl derivatives and methods for their preparation, containing their pharmaceutical compositions and to their use in therapy.

Background of the invention

Janus kinases (JAKs) are cytoplasmic tyrosine protein kinases, which play a key role in the pathways that modulate cellular functions in lymphatic hematopoietic system, which is crucial for cell proliferation and survival of cells. JAKs are involved in the initiation triggered by cytokines signaling events through activation through tyrosine phosphorylation of signal transducers and activators of transcription (STAT) proteins. Signal transmission JAK/STAT is involved in mediation of many abnormal immune responses such as graft rejection and autoimmune diseases, as well as in solid and hematologic malignancies such as leukemias and lymphomas, and myeloproliferative disorders and, thus, was of interest as a target for drug intervention.

To date identified four members of the JAK family: JAK1, JAK2, JAK3 and Tyk2. Unlike JAK1, JAK2 and Tyk2 whose expression is ubiquitous, JAK3 discovered, mainly to the�Ohm, in hematopoietic cells. JAK3 binds a non-covalent manner with the γc subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15. These cytokines play an important role in the differentiation and proliferation of T lymphocytes. JAK3-deficient T-cell mice do not respond to IL-2. This is the main cytokine in the regulation of T lymphocytes. In this regard, it is known that antibodies directed against the receptor of IL-2, is able to prevent graft rejection. In patients with X - severe combined immune deficiency (X-SCID), were found very low levels of JAK3 expression and genetic defects in the γc subunit of the receptor, indicating that immunosuppression is a consequence of changes in JAK3 signaling pathway.

Animal studies have shown that JAK3 not only plays an important role in the maturation of T - and b-lymphocytes, but also that JAK3 is required to maintain the function of lymphocytes. Modulation of immune activity through this new mechanism may be useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.

It was also shown that JAK3 plays an important role in the fat cells, because it was found that antigen-induced degranulation and mediator release are significantly reduced in mast cells in mice with deficiency of JAK3. Untill�tecnost JAK3 has no effect on the proliferation of mast cells, neither the levels of expression of the IgE receptor. On the other hand, JAK3-/- and JAK3+/+ mast cells contain the same intracellular mediators. Thus, JAK3, apparently, is necessary in IgE-induced release of mediators in mast cells, and thus, its inhibition could be an effective treatment of allergic reactions.

In conclusion, it is recognised that inhibitors of JAK3 kinase represent a new class of effective immunosuppressive agents, useful for the prevention of transplant rejection and for the treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, type I diabetes and diabetic complications, allergic reactions and leukemia (see, for example, O She J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).

Accordingly, it would be desirable to provide new compounds which are capable of inhibiting signaling pathways JAK/STAT, and which, in particular, is able to inhibit JAK3 activity, and which are good candidates for medicines. Compounds should possess good activity in pharmacological testsin vitroandin vivogood�her oral absorption when administered orally, and to be metabolically stable and possess favourable pharmacokinetic profile. In addition, the compound should not be toxic and should have little side effects.

Description of the invention

One aspect of the invention relates to a compound of formula I or II

where

And is the carbon and B represents nitrogen, or represents a nitrogen and B is carbon;

W represents CH or N;

R1and R2, independently, represent hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8;

R3represents C1-4alkyl, R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, R12R7N-C0-4alkyl, R13CONR7-C0-4alkyl, R13R7NCO-C0-4alkyl, R12R7NCONR7-C0-4alkyl, R13CO2NR7-C0-4alkyl, R13SO2NR7-C0-4alkyl, -OR12or Cysub> 2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -OR12, -NR7R12or Cy2-C0-4alkyl, where Cy2optionally substituted by one or more substituents R11;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16CO2-C0-4alkyl, R16CO-O-(C1-4alkyl, tsianos1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11;

R7represents hydrogen or C1-4alkyl;

R8represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl or C1-4alkoxyl1-4alkyl;

R9represents halogen, -CN, -CONR7R12, -COR13, -CO2R12, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13;

R10represents C1-4alkyl or R9-C0-4alkyl;

R11represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -CONR7R14, -COR14, -CO2R15, -OR14, -OCONR7R14, -SO2R15, -SO2NR7R14, -NR7R14, -NR7COR14, -NR7CONR7R14, -NR7CO2R15or-NR7SO2R15;

R12represents hydrogen or R13;

R13represents C1-5alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, Cy2-C0-4alkyl or R14R7N-C1-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R14represents hydrogen or R15;

R15represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl;

R16represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl or cyanos1-4alkyl;

Cy1represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring which is saturated,partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and

Cy2represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

Compounds of the formula I or II are inhibitors of the kinase JAK, particularly JAK3, and, thus, may be useful for the treatment or prevention of any disease mediated by Jaks, particularly JAK3.

Thus, another aspect of the present invention relates to a compound of formula I or II or

where

And is the carbon and B represents nitrogen, or represents a nitrogen and B is carbon;

W represents CH or N;

<> R1and R2, independently, represent hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8;

R3represents C1-4alkyl, R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, R12R7N-C0-4alkyl, R13CONR7-C0-4alkyl, R13R7NCO-C0-4alkyl, R12R7NCONR7-C0-4alkyl, R13CO2NR7-C0-4alkyl, R13SO2NR7-C0-4alkyl, -OR12or Cy2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -OR12, -NR7R12or Cy2-C0-4alkyl, where Cy2optionally substituted by one or more substituents R11;

R6represents hydrogen, C1-4alkyl, C1-4 alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16CO2-C0-4alkyl, R16CO-O-(C1-4alkyl, tsianos1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11;

R7represents hydrogen or C1-4alkyl;

R8represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl or C1-4alkoxyl1-4alkyl;

R9represents halogen, -CN, -CONR7R12, -COR13, -CO2R12, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13;

R10represents C1-4alkyl or R9-C0-4alkyl;

R11represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -CONR7R14, -COR14, -CO2R15, -OR14, -OCONR7R14, -SO2R15, -SO2NR7R14, -NR7R14, -NR7COR14, -NR7CONR7R14, -NR7CO2R15or-NR7SO2 R15;

R12represents hydrogen or R13;

R13represents C1-5alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, Cy2-C0-4alkyl or R14R7N-C1-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R14represents hydrogen or R15;

R15represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl;

R16represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl or cyanos1-4alkyl;

Cy1represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and

Cy2represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring, which is the saturation�tion, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2;

for use in therapy.

Another aspect of the present invention relates to pharmaceutical compositions containing the compound of formula I or II or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salt to obtain drugs for treatment or prevention of diseases mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, represents at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, are selected from transplant rejection or immune�x, autoimmune or inflammatory diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disease.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salt to obtain drugs for treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In a preferred embodiment the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment the disease is a proliferative disease.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salt to obtain drugs for treatment or prophylaxis of a disease selected from the following: transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetic complications, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, oposredovany�e fat cells of the allergic reaction, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a compound of formula I or II or its pharmaceutically acceptable salt for use in the treatment or prevention of a disease caused by JAKs, particularly JAK3. More preferably, the disease caused by JAKs, particularly JAK3, represents at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, are selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disease.

Another aspect of the present invention relates to a compound of formula I or II or its pharmaceutically acceptable salt for use in treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative or proliferative diseases. In a preferred embodiment the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment the disease is a proliferative disease.

Another aspect of the present invention relates to a compound of formula I or II or its pharmaceutically acceptable salt for use in the treatment or prevention of a disease selected from the following: transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetic complications, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mediated by mast cells allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salts for the treatment or prevention of diseases mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, represents at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, not�rodegenerative diseases or proliferative diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, are selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disease.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salt for treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment, the disease is a proliferative disease.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salts for the treatment or prophylaxis of a disease selected from the following: transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetic complications, with multiple�Leros, systemic lupus erythematosus, atopic dermatitis; mediated mast cells allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a method of treatment or prophylaxis of a disease mediated by JAKs, particularly JAK3, the needy in this subject, in particular in humans, which includes the introduction of a specified subject amount of a compound of formula I or II or its pharmaceutically acceptable salt, is effective for treatment of the specified disease. More preferably, the disease mediated by JAKs, particularly JAK3, represents at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, are selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disease.

Another aspect of the present invention �tositsa to method of treatment or prevention, at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative diseases of the needy in this subject, in particular in humans, which includes the introduction of a specified subject amount of a compound of formula I or II or its pharmaceutically acceptable salt, is effective for treatment of the specified disease. In a preferred embodiment the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In another preferred embodiment, the disease is a proliferative disease.

Another aspect of the present invention relates to a method of treatment or prophylaxis of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetic complications, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mediated by mast cells of allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas, in need of a subject, in particular, in humans, which includes the introduction of�to the amount specified principal amount of a compound of formula I or II or its pharmaceutically acceptable salt, effective for treatment of the indicated diseases.

Another aspect of the present invention relates to a method of obtaining a compound of formula I or II defined above, which includes:

(a) for a compound of formula I, the interaction of a compound of formula VI with a compound of the formula III

where A, B, W, R1, R2, R3, R4and R5have the meaning given above for compounds of formula I or II; or

(b) for compounds of formula I, the interaction of a compound of formula VI with a compound of formula IV

where A, B, W, R1, R2, R3, R4and R5have the meaning given above for compounds of formula I or II; or

(c) when in the compound of formula II, R5represents hydrogen (compound of formula IIa), the interaction of a compound of formula VI as defined above with a synthetic equivalent for CO synton.

where A, B, W, R1, R2, R3and R5have the meaning given above for compounds of formula I or II; or

(d) when in the compound of formula II, R6is different from hydrogen, the interaction of a compound of formula II with a compound of the formula V (R6-X in the presence of base, where X represents contain no cleavable group; or

(e) converting, in one� or more steps compounds of the formula I or II into another compound of formula I or II.

In the above definitions, the term C1-5alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 5 carbon atoms and includes, inter alia, the group of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and ISO-pentyl. Similarly, the term C1-4alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

With1-4alkoxy group, as a group or part of a group, means a group of the formula-OC1-4alkyl, where C1-4alkyl fragment has the previously described meaning. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Deut-butoxy and tert-butoxy.

With1-4alkoxyl1-4the alkyl group means a group resulting from substitution of one or more hydrogen atoms from C1-4the alkyl groups one or more C1-4the alkoxy groups as defined above, which may be the same or different. Examples include, among others, the group methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl, isobutoxide, �Thor-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,2-diatexites, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropan, 3-tert-butoxypropyl and 4-methoxybutyl.

Halogen or abbreviated “halo” means fluorine, chlorine, bromine or iodine.

Halogens1-4the alkyl group means a group resulting from substitution of one or more hydrogen atoms from C1-4alkyl group by one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which may be the same or different from each other. Examples include, among other things, a trifluoromethyl group, vermeil, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromacil, 2-Iodate, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-forproper, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-terbutyl, nonattributed, 1-chloro-2-fluoroethyl and 2-bromo-1-chloro-1-forproper.

Hydraxis1-4the alkyl group means a group resulting from substitution of one or more hydrogen atoms from C1-4the alkyl group one or more hydroxy groups. Examples include, among others, the group gidroximetil, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxyl�Teal, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl.

Tsianos1-4the alkyl group means a group resulting from substitution of one or more hydrogen atoms from C1-4alkyl group by one or more cyano groups. Examples include, among others, the group cyanomethyl, dicyanamide, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2,3-decanediol and 4-cyanomethyl.

Halogens1-4alkoxygroup means a group resulting from substitution of one or more hydrogen atoms from C1-4alkoxy group by one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which may be the same or different from each other. Examples include, among others, groups of triptoreline, formatosi, 1-chloroethoxy, 2-chloroethoxy, 1-forecox, 2-floratone, 2-bromoethoxy, 2-iodoxy, 2,2,2-triptoreline, pentaborate, 3-forproperty, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropane, heptafluoropropoxy, 4-forbooks, nonattributable, 1-chloro-2-floratone and 2-bromo-1-chloro-1-forproperty.

The term C0alkyl indicates an alkyl group is absent.

Thus, the term R9-C0-4alkyl includes R9and R9-C1-4alkyl. The term R9-C1-4alkyl refers to a group resulting from substitution of one atom of nitric acid�and C 1-4the alkyl groups one group R9.

The terms R12R7N-C0-4alkyl, R13CONR7-C0-4alkyl, R13R7NCO-C0-4alkyl, R12R7NCONR7-C0-4alkyl, R13CO2NR7-C0-4alkyl, R13SO2NR7-C0-4alkyl, R16CO-C0-4alkyl and R16CO2-C0-4the include alkyl-NR7R12and R12R7N-C1-4alkyl, -NR7COR13and R13CONR7-C1-4alkyl, -CONR7R13and R13R7NCO-C1-4alkyl, -NR7CONR7R12and R12R7NCONR7-C1-4alkyl, -NR7CO2R13and R13CO2NR7-C1-4alkyl, -NR7SO2R13and R13SO2NR7-C1-4alkyl, -COR16and R16CO-C1-4alkyl, and-CO2R16and R16CO2-C1-4alkyl, respectively.

The group R12R7N-C1-4alkyl, R14R7N-C1-4alkyl, R13CONR7-C1-4alkyl, R13R7NCO-C1-4alkyl, R12R7NCONR7-C1-4alkyl, R13CO2NR7-C1-4alkyl, R13SO2NR7-C1-4alkyl, R16CO-C1-4alkyl, R16CO2-C1-4alkyl or R16CO-O-(C1-4alkyl means a group resulting from substitution of one hydrogen atom from C 1-4the alkyl groups one group-NR7R12, -NR7R14, -NR7COR13, -CONR7R13, -NR7CONR7R12, -NR7CO2R13-NR7SO2R13, -COR16, -CO2R16or-OCOR16respectively.

The group Cy1refers to 3-to 7-membered monocyclic or 6-11-membered bicyclic carbocyclic or heterocyclic ring which is saturated, partially unsaturated or aromatic. If the ring is heterocyclic, it comprises from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic ring formed either by condensation of two rings via two adjacent C atom or N, or two non-adjacent C atom or N to form a ring with an internal bridge, or else they are formed by linking two rings through a common C atom with the formation of spirocerca. Cy1connected with the rest of the molecule through any available atom C. When Cy1is saturated or partially unsaturated, one or more C or S atoms of the indicated ring optionally oxidized with the formation of the groups CO, SO or SO2. Cy1not necessarily substituted as disclosed above in the definition of a compound of formula I or II, these substituents may be the same or different from each other and can be� located in any available position of the ring system.

The group Cy2refers to 3-to 7-membered monocyclic or 6-11-membered bicyclic carbocyclic or heterocyclic ring which is saturated, partially unsaturated or aromatic. If the ring is heterocyclic, it comprises from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic ring formed either by condensation of two rings via two adjacent C atom or N, or two non-adjacent C atom or N to form a ring with an internal bridge, or otherwise, they are formed by linking two rings through a common C atom with the formation of spirocerca. Cy2connected with the rest of the molecule through any available C or n atom When Cy2is saturated or partially unsaturated, one or more C or S atoms of the indicated ring optionally oxidized to form groups CO, SO or SO2. Cy2not necessarily substituted as disclosed above in the definition of a compound of formula I or II, these substituents may be the same or different from each other and may be located at any available position of the ring system.

Examples Cy1or Cy2include, among other things, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidine, aziridine, oxirane, oxetane, imidazolidinyl ureido, isothiazol�idini, isoxazolidine, oxazolidine, pyrazolidine, pyrrolidine, thiazolidine, dioxane, morpholinyl, thiomorpholine, 1,1-dioxothiazolidine, piperazinyl, homopiperazine, piperidine, pyranyl, tetrahydropyranyl, homopiperazine, oxazinyl, oxazolyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazoline, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazinyl, 2-oxo-1,2-dihydropyridine, 2-oxo-1,2-dihydropyrazine, 2-oxo-1,2-dihydropyrimidine, 3-oxo-2,3-dihydropyridin, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazole, benzofuranyl, isobenzofuranyl, indole, isoindole, benzothiophene, benzothiazole, chinoline, ethenolysis, phthalazine, hintline, honokalani, zanolini, naphthyridines, indazoles, imidazopyridines, pyrrolopyridine, thienopyridines, imidazopyrimidines, imidazopyridines, imidazopyridines, pyrazolopyrimidines, pyrazolopyrimidines, pyrazolopyrimidines, benzo[1,3]dioxole, phthalimide, 1-oxo-1,3-dihydroisobenzofuran, 1,3-diokso-1,3-dihydroisobenzofuran, 2-oxo-2,3-dihydro-1H-indole, 1-oxo-2,3-�ihydro-1H-isoindolyl, chromanol, perhydrosqualene, 1-oxo-perhydrosqualene, 1-oxo-1,2-dihydroisoquinoline, 4-oxo-3,4-dihydroquinazolines, 2-Aza-bicyclo[2.2.1]heptenyl, 5-Aza-bicyclo[2.1.1]hexenyl, 2H-Spiro[benzofuran-3,4'-piperidine], 3H-Spiro[isobenzofuran-1,4'-piperidine], 1-oxo-2,8-diazaspiro[4.5]decanol and 1-oxo-2,7-diazaspiro[4.5]decenyl.

When the definitions used in the present description for the cyclic groups, examples belong to the radical of the ring in General terms, for example, piperidinyl, tetrahydropyranyl or indolyl included all the available binding provisions, unless specified limit in the corresponding definition of the specified cyclic group, for example, that the ring is linked via an atom in Cy1in this case, this restriction is applicable. Thus, for example, in the definitions Cy2that do not include any restrictions relating to the situation of communication, the term piperidinyl includes 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl; tetrahydropyranyl includes 2-tetrahydropyranyl, 3-tetrahydropyranyl and 4-tetrahydropyranyl; and includes indole 1-indole, 2-indole, 3-indole, 4-indole, 5-indole, 6-indole and 7-indole.

In the above definitions Cy1and Cy2when the above examples are Bicycle in General terms, includes all the possible arrangements of atoms. Thus�time for example, the term pyrazolopyrimidines includes groups such as 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl, the term imidazopyridines includes groups such as 1H-imidazo[4,5-b]pyrazinyl, imidazo[1,2-a]pyrazinyl and imidazo[1,5-a]pyrazinyl, and the term pyrazolopyrimidines includes groups such as 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl and pyrazolo[1,5-c]pyrimidinyl.

The term Cy2-C0-4alkyl includes Cy2and Cy2-C1-4alkyl.

Cy2-C1-4the alkyl group means a group resulting from substitution of one hydrogen atom from C1-4the alkyl groups one group Cy2. Examples include, among other things, the group (piperidinyl-4-yl)methyl, 2-(piperidinyl-4-yl)ethyl, 3-(piperidinyl-4-yl)propyl, 4-(piperidinyl-4-yl)butyl, (tetrahydropyran-4-yl)methyl, 2-(tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl, 4-(tetrahydropyran-4-yl)butyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, (indolinyl-1-yl)methyl, 2-(indolinyl-1-yl)ethyl, 3-(indolinyl-1-yl)propyl and 4-(indolinyl-1-yl)butyl.

In the definition of a compound of formula I or II, or a represents carbon, and B represents nitrogen, or represents a nitrogen and B is carbon. Thus, the connection forms�ly I or II include the following types of connections:

The expression "optionally substituted with one or more" means that the group may be substituted by one or more, preferably 1, 2, 3 or 4 substituents, more preferably 1, 2 or 3 substituents, and more preferably 1 or 2 substituents, provided that the group has sufficient provisions suitable for the substitution. The substituents may be the same or different from each other, and are located in any available position.

In some embodiments of the incarnation Cy1as described below , a nitrogen atom which may be substituted, means a nitrogen atom which has a hydrogen substituent.

In the present description, the term "treatment" refers to the elimination, reduction, or intensity reduction of the causes or consequences of the disease. For the purposes of the present invention, the treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; reducing the extent of the disease; stabilization (i.e., not worsening) state of disease; delay or slowing of disease progression; amelioration or temporary relief or weakening of the disease state; and remission (whether partial or total).

Used in this application, Ter�in "prevention" refers to preventing the occurrence of a disease in a subject who is predisposed to the disease or have risk factors, but not yet showing symptoms. Prevention also includes the prevention of relapse in a subject who has previously suffered from a specified disease.

Any formula presented in the present application, is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotope-labeled compounds have structures shown by the formulas presented in the present application, except that one or more atoms replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as2H,3H11C,13C,14C,15N,18O,17O,31P,32P,35S,18F,36Cl and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C) studies of the reaction kinetics (for example,2H or3H) methods for the detection or visualization [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)] including analyses of the distribution of medicinal�of funds or tissue substrate, or in radioactive treatment of patients. In particular,18F or11C-labeled compound may be particularly preferred for PET or SPECT studies. In addition, the substitution of heavier isotopes such as deuterium (i.e.,2(H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase the half-life ofin vivoor lowering the required dosages. Isotope-labeled compounds of the present invention in the General case can be obtained by carrying out procedures disclosed in the schemes or in the examples described below and the receipt, not by replacing isotope labelled reagent readily available isotope-labeled reagent. In addition to the unmarked form, all isotopically labeled forms of compounds of formula I and II are included in the scope of the present invention.

Any formula presented in the present application represents the corresponding tautomeric form. "Tautomer" refers to alternate forms of a molecule that differ in the position of the protons. Examples include, among others, the tautomers, the enol-keto and Yiming-enamin and tautomeric forms of heteroaryl groups containing a-N=CH-NH - arrangement of the atoms of the ring, such as pyrazoles, imidazolov, benzimidazoles, triazoles and tetrazole.

The invention, thus, from�OSISA to compounds of the formula I or II, specified above.

In another embodiment, the invention relates to a compound of formula I or II

where

And is the carbon and B represents nitrogen, or represents a nitrogen and b is a carbon;

W represents CH or N;

R1and R2, independently, represent hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8;

R3represents C1-4alkyl, R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, R12R7N-C0-4alkyl, R13CONR7-C0-4alkyl, R13R7NCO-C0-4alkyl, R12R7NCONR7-C0-4alkyl, R13CO2NR7-C0-4alkyl, R13SO2NR7-C0-4alkyl, -OR12or Cy2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen, C1-4alkyl, Halogens1-4 alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -OR12, -NR7R12or Cy2-C0-4alkyl, where Cy2optionally substituted by one or more substituents R11;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11;

R7represents hydrogen or C1-4alkyl;

R8represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl or C1-4alkoxyl1-4alkyl;

R9represents halogen, -CN, -CONR7R12, -COR13, -CO2R12, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13;

R10represents C1-4alkyl or R9-C0-4alkyl;

R11represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -CONR7R14, -COR14, -CO2R15 , -OR14, -OCONR7R14, -SO2R15, -SO2NR7R14, -NR7R14, -NR7COR14, -NR7CONR7R14, -NR7CO2R15or-NR7SO2R15;

R12represents hydrogen or R13;

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl or Cy2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R14represents hydrogen or R15;

R15represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl;

Cy1represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and

Cy2represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic� ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to a compound of formula I or II

where

And is the carbon and B represents nitrogen, or represents a nitrogen and B is carbon;

W represents CH or N;

R1and R2, independently, represent hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8;

R3represents C1-4alkyl, R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, R12R7N-C0-4alkyl, R13CONR7- 0-4alkyl, R13R7NCO-C0-4alkyl, R12R7NCONR7-C0-4alkyl, R13CO2NR7-C0-4alkyl, R13SO2NR7-C0-4alkyl, -OR12or Cy2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen, C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -OR12, -NR7R12or Cy2-C0-4alkyl, where Cy2optionally substituted by one or more substituents R11;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16CO2-C0-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11;

R7represents hydrogen or C1-4alkyl;

R8represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl or C1-4alkoxyl1-4alkyl;

R9represents halogen, -CN, -CONR7R12, -COR13, -CO2R12, -OR12, -OCONR7R12, -SO2R13, -SO2NRsub> 7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13;

R10represents C1-4alkyl or R9-C0-4alkyl;

R11represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, halogen, -CN, -CONR7R14, -COR14, -CO2R15, -OR14, -OCONR7R14, -SO2R15, -SO2NR7R14, -NR7R14, -NR7COR14, -NR7CONR7R14, -NR7CO2R15or-NR7SO2R15;

R12represents hydrogen or R13;

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl or Cy2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11;

R14represents hydrogen or R15;

R15represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl;

R16represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl or cyanos1-4alkyl;

Cy1p�establet a 3-7-membered monocyclic or 6-11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and

Cy2represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of formula I.

In another embodiment, the invention relates to compounds of the formula II.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a carbon and B is nitrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B PR�dstanley a carbon.

In another embodiment, the invention relates to compounds of the formula I or II, where W represents CH.

In another embodiment, the invention relates to compounds of the formula I or II, where W represents N.

In another embodiment, the invention relates to compounds of the formula I or II, where R1and R2, independently, represent hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN.

In another embodiment, the invention relates to compounds of the formula I or II, where R2represents hydrogen. In another embodiment, the invention relates to compounds of the formula I or II, where R2represents-CN.

In another embodiment, the invention relates to compounds of the formula I or II, where R1represents hydrogen, halogen, -CN, -OR8or-SR8, more preferably hydrogen or-CN; and R2represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where R1represents hydrogen or-CN.

In another embodiment, the invention relates to compounds of the formula I or II, where R1represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where R1is a nitric acid�; and R2represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where R1represents-CN; and R2represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is an R9-C1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1which is optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1and Cy1represents a 3-to 7-membered monocyclic or 6-11-membered bicyclic ring which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and O, where the specified ring is connected to the rest of the molecule via Liu�Oh available C atom, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; where the specified Cy1optionally substituted by one or more substituents R10provided that if the ring contains a nitrogen atom which may be substituted, then the said nitrogen atom is substituted by one substituent R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1; and Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1; and Cy1in R3is a 3-7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic, containing�m from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1; and Cy1in R3is a 5-6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1; and Cy1in R3is a 5-6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, at least one of the Kotor�x represents N; where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1; and Cy1in R3is a 3-7-membered, preferably 5-6-membered saturated monocyclic ring that is heterocyclic containing 1 to 3 heteroatoms, independently selected from N, S and O, at least one of which represents N; where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is piperidinyl or pyrrolidinyl, preferably a piperidine-3-yl or pyrrolidin-3-yl, which are optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to with�the unifications of the formula I or II, where R3is piperidinyl or pyrrolidinyl, preferably a piperidine-3-yl or pyrrolidin-3-yl, which is substituted by one substituent R10on the N atom piperidinyl or pyrrolidinyl ring and which optionally additionally is substituted by one or more groups R10.

In another embodiment, the invention relates to compounds of formula II, where R3is piperidinyl or pyrrolidinyl, preferably a piperidine-3-yl or pyrrolidin-3-yl, which are optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of formula II, where R3is piperidinyl or pyrrolidinyl, preferably a piperidine-3-yl or pyrrolidin-3-yl, which is substituted by one substituent R10on the N atom piperidinyl or pyrrolidinyl ring and which optionally additionally is substituted by one or more groups R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is piperidinyl, preferably a piperidine-3-yl, which are optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3 is piperidinyl, preferably a piperidine-3-yl, substituted with one substituent R10on the N atom piperidinyl ring and optionally additionally substituted by one or more groups R10.

In another embodiment, the invention relates to compounds of formula II, where R3is piperidinyl, preferably a piperidine-3-yl, which are optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of formula II, where R3is piperidinyl, preferably a piperidine-3-yl, substituted with one substituent R10on the N atom piperidinyl ring and optionally additionally substituted by one or more groups R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula

where Cy1and Cy1optionally substituted with one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula

In another embodiment, the invention relates to compounds of formula II, where R3 is a cycle of formula

where Cy1and Cy1boptionally substituted with one or more substituents R10.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula Cy1a.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula Cy1a.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula Cy1aand Cy1ahas (S) stereochemistry.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula Cy1aand Cy1ahas (S) stereochemistry.

In another embodiment, in�of translate it the invention relates to compounds of the formula I or II, where R3is a cycle of formula Cy1b.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy2-C1-4alkyl, where Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy2-C1-4alkyl; and Cy2represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or several�Kimi substituents R 11.

In another embodiment, the invention relates to compounds of the formula I or II, where R5represents hydrogen or Cy2; where Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R5represents hydrogen or Cy2; and Cy2represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16O 2-C0-4alkyl, R16CO-O-(C1-4alkyl, tsianos1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16CO2-C0-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16CO2-C0-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl, R16COsub> 2-C0-4alkyl or R16CO-O-(C1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents hydrogen or C1-4alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R6represents C1-4alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, �de R 6represents C1-4alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where R6is methyl.

In another embodiment, the invention relates to compounds of formula II, where R6represents ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R9represents-CONR7R12, -COR13, -CO2R12, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13preferably R9represents-COR13.

In another embodiment, the invention relates to compounds of the formula I or II, where R10is an R9-C0-4alkyl, preferably R9.

In another embodiment, the invention relates to compounds of the formula I or II, where R10is an R9; and R9in R10represents-COR13or-SO2R13. In another embodiment, the invention relates to compounds of the formula I or II, where R10is an R9; and R9in R10represents-COR13.

In another vari�NTE embodiment of the invention relates to compounds of the formula I or II, where R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl or Cy2-C0-4alkyl; where Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R13represents C1-5alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, more preferably methyl, isopropyl or cyanomethyl, and even more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, more preferably methyl, isopropyl or cyanomethyl, and even more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R13is methyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R13is�Oh isopropyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R13is cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R13represents Cy2-C0-4alkyl where Cy2optionally substituted by one or more substituents R11.

In another embodiment, the invention relates to compounds of the formula I or II, where R9represents-CONR7R12, -COR13, -CO2R13, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13preferably-CO2R13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl and, more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R10is an R9; R9in R10represents-COR13; and R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, g�DRAXIS 1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl and, more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is an R9-C1-4alkyl; and

R9represents-CONR7R12, -COR13, -CO2R12, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is an R9-C1-4alkyl; R9represents-CONR7R12, -COR13, -CO2R13, -OR12, -OCONR7R12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12, -NR7CONR7R12, -NR7CO2R13or-NR7SO2R13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R3represents Cy1preferably Piperi�inil or pyrrolidinyl, more preferably, piperidinyl-3-yl or pyrrolidin-3-yl; where Cy1in R3optionally substituted by one or more substituents R10; and

R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula

and R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula

and R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula

R10is an R9-C0-4alkyl, preferably R9;

R9represents-COR13or-SO2R13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxy 1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula

R10is an R9-C0-4alkyl, preferably R9;

R9represents-COR13or-SO2R13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula Cy1a; and

R10is an R9-C0-4alkyl, preferably R9more preferably,-COR13or-SO2R13even more preferably,- COR13.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula Cy1a; and

R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13 or-SO2R13even more preferably,- COR13.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula Cy1a;

R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13even more preferably,- COR13; and R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula Cy1a;

R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13even more preferably,- COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R3 is a cycle of formula Cy1Awith (S)-stereochemistry;

R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13even more preferably,- COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula Cy1Awith (S)-stereochemistry;

R10is an R9-C0-4alkyl, preferably R9more preferably,- COR13or-SO2R13even more preferably,- COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R3is a cycle of formula Cy1b; and

R10is an R9-C0-4alkyl, preferably� R 9more preferably,- SO2R13.

In another embodiment, the invention relates to compounds of formula II, where R3is a cycle of formula Cy1b; and

R10is an R9-C0-4alkyl, preferably R9more preferably,- SO2R13.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy1represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy1is a 3-7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with images�of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy1is a 5-6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy1is a 5-6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, at least one of which represents N; where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy1is a 5-6-membered saturated monocyclic ring that is heterocyclic containing 1 to 3 heteroatoms, independently selected from N, S and O, at least one of which represents N; where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy1is piperidinyl or pyrrolidinyl, preferably piperidinyl-3-yl or pyrrolidin-3-yl.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy2represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom or N, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy2is a 3-7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available� C atom, and one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy2is a 5-6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy2is a 5-6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, at least one of which represents N; where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2.

In another embodiment, the invention relates to compounds of the formula I or II, where Cy2is piperidinyl or pyrrolidinyl.

In another embodiment, the invention �tositsa to compounds of the formula I or II, where:

A represents nitrogen and B is carbon; and

R1and R2, independently, represent hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN; and

R2represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon; R1and R2represent hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1and R2, independently, represent hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN; and

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10.

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R1and R2represent hydrogen; and R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3presented�a splash zones R 9-C1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3represents Cy1which is optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where R1and R2represent hydrogen; and R3represents Cy1which is optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen;

R3represents Cy1where Cy1br 3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR3or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest moleculaires any available C atom, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon; R1and R2represent hydrogen; and R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4 alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3is an R9-C1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon; R1and R2represent hydrogen; and R3is an R9-C1-4alkyl.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8and more pre�occhialino hydrogen or-CN;

R2represents hydrogen; and

R3represents Cy1which is optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon; R1and R2represent hydrogen; and R3represents Cy1which is optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected Castelnau part of the molecule through any available C atom, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrole�in-3-yl; where specified Cy1optionally substituted by one or more substituents R10.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR9preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry.

In another embodiment, the invention relates to compounds of formula II where a is a nitrogen and B is carbon;

R1represents hydrogen, C1-4alkyl, Halogens1-4alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, C1-4alkoxyl1-4alkyl, halogen, -CN, -OR8or-SR8preferably hydrogen, halogen, -CN, -OR8or-SR8, and more preferably hydrogen or-CN;

R2represents hydrogen; and

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry.

In another embodiment, the invention relates to connected�Yam formulas I or II, where A represents a nitrogen and B is carbon; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen; and R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon; R1and R2represent hydrogen; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -C, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R5represents hydrogen; and

R6represents hydrogen or C1-4alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R1and R2represent hydrogen; R5represents hydrogen; and R6represents hydrogen or C1-4alkyl, preferably�orod, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R5represents hydrogen; and

R6represents C1-4alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where R1and R2represent hydrogen; R5represents hydrogen; and R6represents C1-4alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy 2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN: and R2represents hydrogen;

R3is an R9-C1-4alkyl; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1and R2represent hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1p�ecstasy a hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected with tha�Noah part of the molecule through any available C atom, and where one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula II, where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is a cycle of formula Cy1a; preferably with (S)-stereochemistry; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1the performance�t a hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R5represents hydrogen; and

R6represents hydrogen or C1-4alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1and R2represent hydrogen;

R5represents hydrogen; and

R6represents hydrogen or C1-4alkyl, preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R5represents hydrogen; and

R6represents C1-4alkyl, preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II, where A represents a nitrogen and B is carbon;

R1and R2represent hydrogen;

R5represents hydrogen; and

R6represents C1-4alkyl, preferred�Stateline methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W represents CH;

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl; and

R6represents hydrogen.

In another embodiment, invented�e refers to compounds of the formula I or II, where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10; and

R5is�dared.

In another embodiment, the invention relates to compounds of the formula I or II where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidine and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably� hydrogen; and R2represents hydrogen:

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula II, where:

W represents CH;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W is a N;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W is a N;

R1and R2represent hydrogen;

R3is an R9-C 1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W is a N;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W is a N;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W is a N;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

W is a N;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom,and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment waples�of the invention relates to compounds of the formula I or II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R1-C1-4alkyl; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated�th or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3before�provide piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and

R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, predpochtitel�but hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy 2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds �of ormula I or II, where;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or g�teracycline, containing 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered saturated monocyclic number�CH which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1is �Wallpaper of hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4al�Il, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR9or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C14 alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where;

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted� one or more substituents R 11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of the formula I or II where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably a piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents 10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or R12R7N-C1-4alkyl, preferably hydrogen or C1-4alkyl, and more preferably hydrogen, methyl or ethyl.

In another embodiment, the invention relates to compounds of formula I, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; R1represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more co�the teli R 11; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula I, where:

A represents nitrogen and B is carbon;

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula I, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably�Gorod, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula I, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7N-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted with one linescale substituents R 11; and

R5represents hydrogen.

In another embodiment, the invention relates to compounds of formula I, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl; where specified Cy1optionally substituted by one or more substituents R10;

R4represents hydrogen, C1-4alkyl, R12R7-C0-4alkyl or Cy2-C0-4alkyl, preferably hydrogen, C1-4alkyl, -NR7R12or Cy2; where Cy2optionally substituted by one or more substituents R11; and

R5ameri� a hydrogen.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or NR7R12-C1-4alkyl, preferably hydrogen or C1-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1and R2represent hydrogen;

R3is an R9-C1-4alkyl, Cy1or Cy2-C1-4alkyl, where Cy1and Cy2optionally substituted by one or more substituents R10; R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4 alkyl, hydroxys1-4alkyl or NR7R12-C1-4alkyl, preferably hydrogen or C1-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3represents Cy1which is optionally substituted by one or more substituents R10;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or NR7R12-C1-4alkyl, preferably hydrogen or C1-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN, more preferably hydrogen; and R2represents hydrogen;

R3performance�ulation of a Cy 1where Cy1in R3represents a 3-to 7-membered monocyclic ring that is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and where specified Cy1optionally substituted by one or more substituents R10;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or NR7R12-C1-4alkyl, preferably hydrogen or C1-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen, halogen, -CN, -OR8or-SR8, preferably hydrogen or-CN; and R2represents hydrogen;

R3represents Cy1where Cy1in R3is a 3-7-membered, preferably 5-6-membered,�ysanne monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms, independently selected from N, S and O, where the specified ring is connected to the rest of the molecule through any available C atom, and wherein one or more ring C atoms or S optionally oxidized with the formation of CO, SO or SO2; and, more preferably, Cy1in R3is piperidinyl or pyrrolidinyl, and even more preferably, the piperidine-3-yl or pyrrolidin-3-yl; where the specified Cy1optionally substituted by one or more substituents R10;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or NR7R12-C1-4alkyl, preferably hydrogen or C1-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1or Cy1b;

R5represents hydrogen; and

R6represents hydrogen, C1-4�lkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R15CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen; and

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl.

In each�m embodiments, the invention relates to compounds of the formula II, where:

R3is a cycle of formula Cy1Aor Cy1b;

R5represents hydrogen;

R10represents-COR13or-SO2R13and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

W represents CH;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R10represents-COR13; and

R13represents C1-4alkyl, halo�Jens 1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

W is a N;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen; and

R10represents-COR13.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B repre�ulation of a carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

R3is a cycle of formula Cy1aor Cy1b;

R5represents hydrogen;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl;

R10represents-COR13or-SO2R13; and

R13represents C 1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1aor Cy1b;

R5represents hydrogen;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl; and

R10represents-COR13or-SO2R13.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4and�Kil, hydraxis1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

W represents CH;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C 0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

W is a N;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, preferably C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R R7N-C1-4alkyl, R16CO-C0-4alkyl or R16CO2-C0-4alkyl, more preferably C1-4alkyl, and even more preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl, preferably C1-4alkyl or cyanos1-4alkyl, and more preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents C1-4alkyl, preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl or cyanos1-4alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

W represents CH;

R1is with�fight is hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents C1-4alkyl, preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl or cyanos1-4alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

W is a N;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1apreferably with (S)-stereochemistry;

R5represents hydrogen;

R6represents C1-4alkyl, preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl or cyanos1-4alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen and R2is�Oh hydrogen;

R3is a cycle of formula Cy1Awith (S)-stereochemistry;

R5represents hydrogen;

R6represents C1-4alkyl, preferably methyl or ethyl;

R10represents-COR13; and

R13represents C1-4alkyl or cyanos1-4alkyl, preferably methyl or cyanomethyl.

In another embodiment, the invention relates to compounds of formula II, where:

A represents nitrogen and B is carbon;

R1represents hydrogen or-CN, preferably hydrogen; and R2represents hydrogen;

R3is a cycle of formula Cy1b;

R5represents hydrogen;

R6represents C1-4alkyl, preferably methyl or ethyl; and

R10is a-SO2R13.

In addition, the present invention covers all possible combinations of individual and preferred embodiments described above.

In another embodiment, the invention relates to a compound of formula I or II selected from the list of compounds described in examples 1-37.

In another embodiment, the invention relates to a compound of formula I or II, which provides more than 50% inhibition of JAK3 activity at 10 μm, more preferably�individual with 1 μm, and even more preferably at 0.1 μm, in the analysis of JAK3, such as the analysis described in example 38.

In additional embodiments, the invention relates to a compound of formula I or II, which provides more than 50% inhibition of JAK2 activity at 10 μm, more preferably at 1 μm and still more preferably at 0.1 μm, in the analysis of JAK2, such as analysis, described in example 39.

Compounds of the present invention contain one or more basic nitrogen atoms and can, therefore, form salts with organic or inorganic acids. Examples of such salts are, among others, include: salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, itestosterone acid, nitric acid, Perlina acid, sulfuric acid or phosphoric acid; and salts of organic acids such as methanesulfonic acid, triftormetilfullerenov acid, econsultancy acid, mixture of Benzenesulfonic acid, para-toluensulfonate acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid. Some of the compounds of the present invention can contain one or more�of acidic protons and, thus, they can form salts with bases. Examples of such salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc and the like; and salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyethylamine, lysine, arginine, N-methylglucamine, procaine, and the like.

There are no restrictions regarding the type of salt that can be used, provided that such salts are pharmaceutically acceptable when they are used in therapeutic purposes. The term pharmaceutically acceptable salt refers to those salts which are, according to medical assessment, suitable for use in contact with tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in this field.

Salt of a compound of formula I or Il can be obtained during the final isolation and purification of the compounds of the present invention, or can be obtained by treatment of a compound of formula I or II sufficient amount of the desired acid or base to give a salt in the usual way. Salts of compounds of the formula I or II can be converted into other salts of compounds of the formula I or II by ion exchange with ISPO�Itanium ion-exchange resins.

Compounds of the formula I or II and their salts may differ in certain physical properties, but they are equivalent for the purposes of the present invention. All salts of the compounds of formula I or II is included in the scope of the present invention.

Compounds of the present invention can form complexes with solvents with which they interact or from which they are precipitated or crystallized. These complexes are known as solvates. Used in the present application the term solvate refers to a complex of variable stoichiometry formed by the dissolved substance (compound of formula I or II or its salt) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. Complex with water is known as a hydrate. Solvates of the compounds of the present invention (or their salts), including hydrates, are included in the scope of the present invention.

Compounds of the formula I or II may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the present invention may have the ability to crystallize in more than one form - a characteristic known as polymorphism. Polymorphs may differ in various physical properties, well known in this field, such as DEFRA�tional radiograph, the melting point or solubility. All physical forms of compounds of formula I or II, including all polymorphic forms ("polymorphs") are included in the scope of the present invention.

Some compounds of the present invention can exist in the form of several diastereomers and/or more optical isomers. The diastereomers can be separated by conventional methods such as chromatography or fractional crystallization. The optical isomers can be separated by conventional methods of optical resolution with obtaining optically pure isomers. This separation can be carried out on any chiral synthetic intermediate connection or on the products of the formula I or II. Optically pure isomers can also be obtained separately, using enantiospecific synthesis. The present invention encompasses all individual isomers and mixtures thereof (e.g. racemic mixtures or mixtures of diastereoisomers), as obtained by synthesis or by physical mixing.

The present invention also covers all unlabeled and isotope-labeled forms of compounds of formula I or II.

The present invention also encompasses all tautomeric compounds of the formula I or II.

Compounds of the formula I or II can be obtained in the following ways, described below. How to�can safely be obvious to a person skilled in the art, the exact method used to obtain this compound, can vary depending on the chemical structure of the compounds. Moreover, some of the methods described below, it may be necessary or desirable to protect the reactive or labile groups of conventional protective groups. And the nature of these protective groups and their introduction and removal are well known in the art (see for example Greene T. W. and Wuts P. G. M, "Protecting Groups in Organic Synthesis", John Wiley & Sons, 3rdedition, 1999). As an example, as a protective group for the functional amino group can be used tert-butoxycarbonyl (BOC). In each case, the presence of protective groups will be necessary further stage of removal of the protective group can be carried out in standard conditions in the course of organic synthesis, such as the conditions described in the above referenced document.

Typically, the compound of formula I or II can be obtained from compounds of formula VI, as shown in the following diagram:

where A, B, W, R1, R2, R3, R4and R5have the meaning given above for compounds of formula I or II; R6in the compound of the formula V or IIb has the meaning described above for compounds of formula I or II, except hydrogen; and X performance�et a contain no cleavable group.

Compounds of formula I can be obtained by reacting the compound of formula VI or the corresponding isothiocyanate aldehyde III or IV.

Reaction with isothiocyanate III can be carried out in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, in a suitable solvent, such as dichloro methane, and heated at a suitable temperature, typically in the range of from 100 to 200°C. the Heating may be thermal or irradiation with microwaves at a power which achieves the above-indicated temperature.

The reaction between compounds of formula VI and IV can be carried out in a suitable solvent, such as ethanol, butanol, N,N-dimethylformamide or dimethylacetamide, in the presence of acid, such as acetic acid, para-toluensulfonate acid or sodium bisulfite, and heated, preferably at a temperature between 100 and 200°C. the Heating may be thermal or irradiation with microwaves at a power which achieves the above-indicated temperature. If necessary, the reaction can be completed by subsequent addition of water.

The compound of formula II (i.e., compounds of formula IIA and IIb) can be obtained from compounds of formula VI.

Compounds of the formula IIA (i.e., the compound of formula II, where R6represents hydrogen) can be obtained by reacting the compound of formula VI with synthetic�m equivalent to CO synton. In principle, you can use any synthetic equivalent, described in the literature, for example, 1,1'-carbonyldiimidazole (CDI), phosgene, diphosgene or triphosgene. The reaction is carried out in the presence of base, such as N,N-diisopropylethylamine; and in a suitable solvent, such as tetrahydrofuran (THF), and preferably at room temperature. The reaction can be completed by subsequent addition of water.

Compounds of formula IIb (i.e., the compound of formula II, where R6is different from hydrogen) can be obtained by alkylation of a compound of formula II alkylating agent R6-X (V), where X represents contain no cleavable group, and R6different from H; suitable examples of X include, among others, halogen, such as Cl, Br or I, mesilate, tosylate or triflic. This reaction can be carried out in the presence of base, such as Cs2CO3, K2CO3, NaOH, t-BuOK or NaH, in a suitable solvent, such as acetone, toluene, 1,2-dimethoxyethane, and preferably dimethylformamide, at a suitable temperature between 0°°C and the boiling temperature to reflux.

Compounds of formula VI can be obtained by recovering the compounds of formula VII, as shown in the following diagram:

where A, B, W, R1, R2, R3and R5have the meaning specified �ove in respect of a compound of formula I or II.

The reaction can be carried out with gaseous hydrogen using a platinum catalyst, such as Pt/C, in the presence of thiophene in diisopropylethylamine; in a suitable solvent, such as EtOH, and preferably at room temperature.

Compounds of formula VII can be obtained by reacting the compound of formula VIII or a compound of the formula IX or X, as shown in the following diagram:

where A, B, W, R1, R2, R3and R5has the meaning previously described in relation to compounds of formula I or II; and BY2is Bronevoy acid or ester.

The reaction between the compounds of formulae VIII and IX can be carried out using the conditions described in the literature for the reaction combinations Suzuki. For example, the reaction can be carried out in the presence of Pd catalyst such as Pd(PPh3)4; in the presence of base, such as Na2CO3; in a mixture of solvents, such as dimethoxyethane and water, and when heated.

Direct coupling between compounds of formula VIII and X can be carried out with a palladium catalyst such as, for example, tetrakis (triphenylphosphine)palladium(0) (Pd(PPh3)4), and preferably palladium acetate (II), Pd(OAc)2in the presence of triphenylphosphine and bases, such as, for example, triethylamine, and �predpochtitelno potassium acetate. The reaction is usually carried out in an anhydrous and anaerobic conditions. The reaction can be carried out in a solvent such as dioxane, N,N-dimethylformamide, toluene, and preferably in dimethylacetamide, and when heated at a temperature usually in the range 60°C to 100°C.

Compounds of formula IX and formula X can be easily obtained from commercial compounds by known methods.

Furthermore, compounds of formula VII where a is a nitrogen and B is the carbon (VIIa), can be obtained by reacting the compound of formula XI with a compound of formula XII, as shown in the following diagram:

where W, R1, R2, R3and R5have the meaning given above for compounds of formula I or II; and represents An iodine, 2,4-dinitrophenolate, para-toluensulfonate or 2,4,6-trimethylbenzenesulfonyl.

The reaction can be carried out in the presence of Tetra-n-butylammonium (TBAF) in THF and a base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,4-diazabicyclo[2.2.2]octane (DABCO), preferably 1,8 - diazabicyclo[5.4.0]undec-7-ene (DBU), in a solvent such as Ν,Ν-dimethylformamide, dimethylsulfoxide, dichloro methane, toluene or acetonitrile, preferably acetonitrile, at temperatures between -78°C and room temperature.

Alternatively, the compound of formula VIIa can�to teach by reacting the compound of formula XII with a derivative of a compound of formula XI (XIb) with removed protective group, which was obtained using standard conditions.

Compounds of formula XII can be obtained by reacting the compound of formula XIII with aminosulfonic acid in the presence of HI aqueous solution; and bases, such as K2CO3, NaOH or KOH; in a solvent such as dichloro methane, tetrahydrofuran, water, ethanol, methanol, isopropanol, or acetonitrile; and when heated, preferably at reflux, as shown in the following diagram

where R1and R2have the meaning given above for compounds of formula I or II; and An is the value described above.

Compounds of formula XI can be obtained by reacting the compound of formula VIII with trimethylsilylacetamide, as shown in the following diagram:

where W, R3and R5have the meaning given above for compounds of formula I or II.

The reaction with trimethylsilylacetamide can be carried out under reaction conditions Sonogashira, with a palladium catalyst such as e.g. tetrakis (triphenylphosphine)palladium(0) (Pd(PPh3)4), preferably bis(triphenylphosphine)dichloropalladium(II) (Pd(Ph3P)2Cl2), in the presence of triphenylphosphine, catalyst cu(I) as co-catalyst, �such as CuI, and bases, such as diethylamine, N,N-diisopropylethylamine, triethylamine or isopropylethylene. The reaction is usually carried out in an anhydrous and anaerobic conditions. The reaction can be carried out in a solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran or toluene, at room temperature or when heated.

Compounds of formula VIII can be obtained by reacting the compound of formula XIV with a compound of formula XV as shown in the following diagram:

where W, R3and R5have the meaning given above for compounds of formula I or II.

The reaction between the compounds of formulae XIV and XV can be carried out in the presence of base, such as diisopropylethylamine, diethylamine or triethylamine, in a suitable solvent, such as THF or acetonitrile, and at a temperature between -78°C and room temperature.

Compounds of formula XIV and XV are commercial or can be easily obtained from commercial compounds using standard procedures.

Furthermore, some compounds of the present invention can also be obtained from other compounds of formula I or II by appropriate conversion reactions of functional groups in one or more steps, using well-known organic chemistry reactions in accordance with� standard experimental conditions. These transformations can be realized, for example, R3and they include, for example, substitution of primary or secondary amine by treatment with alkylating agent interaction acid or ester with an amine to provide the corresponding amide, the conversion of an amine into a sulfonamide and ester hydrolysis with obtaining carboxylic acids, in some of these transformations may be necessary or desirable to protect the reactive or unstable groups using conventional protective groups.

As will be obvious to a person skilled in the art, these interconversion reactions can be carried out on compounds of formula I or II, any suitable synthesized intermediate compound.

As stated above, the compounds of the present invention act by inhibiting the signaling pathways JAK/STAT, in particular by inhibiting JAK3 activity. Consequently, the compounds of the present invention is expected to be useful for the treatment or prevention of diseases in which JAKs, particularly JAK3 plays a role in mammals, including humans. These diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative�s disease (see, for example, O'shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).

Acute or chronic graft rejection, which can be treated or prevented with the compounds of the present invention include any type of xenografts or allografts cell, tissue or organ such as the heart, lungs, liver, kidneys, pancreas, uterus, joints, pancreatic islets, bone marrow, limb, cornea, skin, hepatocytes, beta cells of the pancreas, pluripotent cells, nerve cells and cells of the myocardium, as well as graft-versus-host (see, for example, Rousvoal G. et al, Transpl. Int. 2006, 19(12): 1014-21; Borie DC. et al, Transplantation 2005, 79(7):791-801; Paniagu R. et al, Transplantation 2005, 80(9):1283-92; Higuchi T. et al, J. Heart Lung Transplant. 2005, 24(10):1557-64; Saemann D. et al, Transpl Int. 2004, 17(9) 481-89; Silva Jr HT. et al, Drugs 2006, 66(13):1665-1684).

Immune, autoimmune or inflammatory diseases that can be treated or prevented with the compounds of the present invention, include, among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia and neutropenia), autoimmune gastritis and inflammatory� bowel disease (for example, ulcerative colitis and Crohn's disease), scleroderma, type I diabetes and diabetic complications, hepatitis type b, hepatitis type C, primary biliary cirrhosis, severe myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin burns, suppression of HIV replication, infertility of autoimmune type, autoimmune thyroid disease (graves ' disease), interstitial cystitis; mediated mast cells allergic reactions such as asthma, angioedema, anaphylaxis, bronchitis, rhinitis and sinusitis; and inflammatory or autoimmune ocular diseases such as dry eye syndrome, glaucoma, Sjogren syndrome, uveitis and retinopathy of prematurity (see, for example, Sorber LA. et al, Drugs of the Future 2007, 32(8):674-680; O'shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15); 1767-84; Muller-Ladner U. et al, J. Immunol. 2000, 164(7): 3894-3901; Walker JG. et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Milici AJ. et al, Arthritis Rheum. 2006, 54 (9, Suppl): abstr 789; J. M. Kremer et al, Arthritis Rheum. 2006, 54, 4116, presentation no. L40; Cetkovic-Cvrlje M. et al, Arch Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82; Malaviya, R. et al, J. Pharmacol. Exp. Ther. 2000, 295(3):912-26; Malaviya, R. et al, J. Biol. Chem. 1999, 274(38):27028-38; Wilkinson B et al, Ann. Rheum. Dis. 2007, 66(Suppl 2): Abst. THU0099; atsumoto M. et al, J. Immunol. 1999, 162(2):1056-63, West K., Curr Opin Inventig Drugs 2009:10(5);491-504, Y. Huang et al., Exp Eye res 2007:85(5):684-95, Killedar SY et al. Laboratory investigation 2006:86:1243-1260, Egwuagu C. E., Cytokine 2009:47(3):149-156, Bfield G., Investigative Ophtalmology &Viral Science 2009:50:3360).

Neurodegenerative diseases that can be treated or prevented with the compounds of the present invention, include, among other things, amyotrophic lateral sclerosis and Alzheimer's disease (see, for example, Trieu VN. et al, Biochem. Biophys. Res. Commun. 2000, 267(1):22-5).

Proliferative diseases that can be treated or prevented with the compounds of the present invention, include, among other things, leukemia, lymphoma, multiform glioblastoma, carcinoma of the colon and embolism and allergic complications associated with this disease (see, for example, Sudbeck EA. et al, Ciin. Cancer Res. 1999, 5(6):1569-82; Naria RK. et al, Clin. Cancer Res. 1998, 4(10):2463-71; Lin Q. et al, Am J. Pathol. 2005, 167(4):969-80; Tibbies HE. et al, J. Biol. Chem. 2001, 276(21):17815-22).

It was found that certain compounds of formula I or II, in addition to inhibiting JAK3 activity, also inhibit JAK2 kinase to varying degrees, and consequently can also be useful for the treatment or prevention of any disease mediated by JAK2 kinase. Groups such JAK2-mediated diseases represent myeloproliferative diseases, including true polycythemia Vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myeloid leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic melomano�itary leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodysplastic syndrome (see, for example, Geron I. et al, Cancer cell 2008, 13.321-330; Pardanani A. et al, Leukemia 2007, 21 (8):1658-68; Mathur A. et al, Biochem Pharmacol 2009, 78(4):382-9; Manshouri T. et al, Cancer Sci. 2008, 99(6): 1265-73; Wernig G. et al. Cancer cell 2008, 13(4):311-20. Elizabeth O. et al, Blood, 111(12: 5663-5671).

It was found that the compounds of the formula I or II, where R1and R2represent hydrogen, in particular useful as inhibitors of JAK2, and thus, can be particularly useful, in addition to the treatment or the prevention of all mentioned in the previous paragraphs diseases, for the treatment or prevention of myeloproliferative disorders (MPD).

Thus, another aspect of the present invention relates to a compound of formula I or II or its pharmaceutically acceptable salt for use in the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2, is a myeloproliferative disease. In a preferred embodiment, the compound of formula I or II are those compounds in which R1and R2represent hydrogen.

Another aspect of the present invention relates to the use of a compound of formula I or II or its farmatsevticheskii salt to obtain drugs for treatment or prevention of diseases, mediated JAK2. More preferably, the disease mediated by JAK2, is a myeloproliferative disease. In a preferred embodiment, the compound of formula I or II are those compounds in which R1and R2represent hydrogen.

Another aspect of the present invention relates to a method of treatment or prophylaxis of a disease mediated by JAK2, the needy in this subject, in particular in humans, which includes the introduction of a specified subject a compound of formula I or II or its pharmaceutically acceptable salt. More preferably, the disease mediated by JAK2, is a myeloproliferative disease in a preferred embodiment of a compound of formula I or II are those compounds in which R1and R2represent hydrogen.

Another aspect of the present invention relates to a compound of formula I or II or its pharmaceutically acceptable salt for use in treating or preventing a myeloproliferative disease. In a preferred embodiment, the myeloproliferative disorder is selected from the following: polycythemia Vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myeloid leukemia, hypereosinophilic syndrome, chronic Natrii�iny leukemia, chronic mielomonocitarnyi leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodysplastic syndrome. In a preferred embodiment of a compound of formula I or II are those compounds in which R1and R2represent hydrogen.

Another aspect of the present invention relates to the use of a compound of formula I or II or its pharmaceutically acceptable salt to obtain drugs for treatment or prevention of myeloproliferative diseases. In a preferred embodiment, the myeloproliferative disorder is selected from the following: polycythemia Vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myeloid leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic mielomonocitarnyi leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodysplastic syndrome. In a preferred embodiment, the compound of formula I or II are those compounds in which R1and R2represent hydrogen.

Another aspect of the present invention relates to a method of treating or preventing�Chiki myeloproliferative disease in needy in this subject in particular, in humans, which includes the introduction of a specified subject a compound of formula I or II or its pharmaceutically acceptable salt. In a preferred embodiment, the myeloproliferative disorder is selected from the following: polycythemia Vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myeloid leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic mielomonocitarnyi leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodysplastic syndrome. In a preferred embodiment, the compound of formula I or II are those compounds in which R1and R2represent hydrogen.

Biological assays that can be used to determine the ability of compounds to inhibit JAKs, particularly JAK3 and JAK2, are well known in this field. For example, the connection test can be incubated in the presence of the desired JAK, such as JAK3 or JAK2 to determine whether inhibition of JAK enzymatic activity, as described in the analysis of JAK3 and JAK2 in examples 38 and 39, respectively. Other usefulin vitrothe tests that can be used for measurement of JAK3-inhibiting activity, include cellular assays, �of primer, IL-2-induced proliferation of T-lymphocytes. Immunosuppressive activity of compounds of the present invention can be tested using the standardin vivoof animal models for immune and autoimmune diseases, which are well known in this field. For example, you can use the following tests: delayed-type hypersensitivity (DTH) (see, for example, a method disclosed in the reference document Kudlacz E. et al, Am J. Transplant. 2004, 4(1):51-7, the content of which is incorporated in this application by reference), models of rheumatoid arthritis, such as collagen-induced arthritis (see, for example, a method disclosed in the reference document Holmdahl R et al, APMIS, 1989, 97(7):575-84, the content of which is incorporated in this application by reference), models of multiple sclerosis, such as experimental autoimmune encephalomyelitis (EAE) (see, for example, a method disclosed in the reference document Gonzalez-Rey et al, Am. J. Pathol. 2006, 168(4): 1179-88, the content of which is incorporated in this application by reference) and models of transplant rejection (see, for example, various animal models disclosed in the references listed above for the treatment of transplant rejection, incorporated in this application by reference). Antiproliferative activity of the compounds of the present invention can be tested�ü using the standard in vivoanimal model well-known in this field, such as research xenotransplantation (see, for example, Mohammad RH. et al, Pancreas. 1998; 16(1):19).

For selecting active compounds for JAK3, tested at 10 μm should result in showing more than 50% inhibition of JAK3 activity in the test described in example 38. More preferably, when tested in this analysis, the connection should show more than 50% inhibition at 1 μm, and more preferably, should show more than 50% inhibition at 0.1 µm.

For selecting active compounds for JAK2, tested at 10 μm should result in showing more than 50% inhibition of JAK2 activity in the test described in example 39. More preferably, when tested in this analysis, the connection should show more than 50% inhibition at 1 μm, and more preferably, should show more than 50% inhibition at 0.1 µm.

The tests that can be used to predict the PK profile of compounds, well known in this field. For example, analysis of CACO-2 can be used to determine thein vitropotential for oral absorption of compounds. To demonstrate a good PK profile, the connection should also have a suitable purity as determined in a standard test using, for example, the human liver in the analysis�, such as described in example 40.

Standard tests can be used to assess potential toxic effects of drug candidates, all of whom are well known in this field. Such tests include, for example, tests of viability in different cell lines, such as cells of the carcinoma of human hepatocytes (Hep G2), and can be performed by following the standard procedures such as the procedure described in example 41.

The present invention also relates to a pharmaceutical composition that includes a compound of the present invention (or pharmaceutically acceptable salt or solvate) and one or more pharmaceutically acceptable excipients. Excipient must be "acceptable" in the sense of compatibility with other ingredients of the composition and is not harmful to their recipients.

Compounds of the present invention can be administered in the form of pharmaceutical compositions, the nature of which, as is well known, will depend on the nature of the active substance and the route of administration. Can be used by any method of administration, e.g., oral, parenteral, nasal, ocular, rectal and topical administration.

Solid compositions for oral administration include tablets, granules and capsules. In any case, the method is based on about�the mixture, dry granulation or wet granulation of the active compound with excipients. These excipient can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogen phosphate; binders, such as starch, gelatin or povidone; leavening agents, such as natrocarbonatite or nutritionnelles; and lubricating agents such as, for example, magnesium stearate, stearic acid or talc. The tablets can additionally be covered with a suitable excipient using known techniques to delay their decomposition and absorption in the gastrointestinal tract, providing, thus, a sustained action over a long period, or simply to improve their organoleptic properties or their stability. Active compound can also be incorporated by coating the inert granules with natural or synthetic film-forming substances. You can also use soft gelatin capsules in which the active substance is mixed with water or an oil medium, for example, coconut oil, mineral oil or olive oil.

Powders and granules for the preparation of oral suspensions by the addition of water can be obtained by mixing the active compounds with dispersing agent�mi or humidifiers; suspendresume agents and preservatives. You can also add other fillers, for example, sweeteners, flavors and dyes.

Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogol) and propylene glycol. These compositions can also contain additives such as moisturizers, suspendresume substances, sweeteners, flavorings, preservatives and buffers.

Preparations for injection, in accordance with the present invention, for parenteral administration include sterile solutions, suspensions or emulsion, in an aqueous or nonaqueous solvent, such as propylene glycol, polyethylene glycol or vegetable oil. These compositions can also contain additives such as humectants, emulsifying substances, dispersing substances and preservatives. They can be sterilized by any known method, or they can be obtained in the form of solid sterile compositions which are dissolved in water or any other sterile environment for injection immediately before use. You can also obtain them on the basis of sterile substances, and keep them in these conditions throughout the entire process manufacturer�deposits.

For rectal administration, the active compound can be preferably formulated into a suppository oil-based, such as, for example, vegetable oil or solid semisynthetic glycerides, or on a hydrophilic base such as polyethylene glycols (macrogol).

Compounds of the present invention can also be formulated for topical application for the treatment or prevention of pathologies in the areas of or bodies that are achievable in this way, such as the eyes, skin and gastrointestinal tract. The compositions include creams, lotions, gels, powders, solutions, and patches, in which the compound is dispersed or dissolved in suitable excipient.

For nasal administration or for inhalation, the compound can be formulated in aerosol form, and his release is convenient to carry out with the use of suitable propellants.

The dose and frequency of administration depend on the nature and severity of the disease being treated, the age, General condition and body weight of the patient, and also features input connections and routes of administration, among other factors. A representative example of a suitable range of doses comprises from 0.01 mg/g to about 100 mg/kg per day, this amount can be administered in a single dose or several separate doses.

The following examples illustrate the present volume�present invention.

EXAMPLES

In the examples the following abbreviations are used:

AcOH: acetic acid

AcN: acetonitrile;

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DIPEA: N,N-diisopropylethylamine

DMAC: N,N-dimethylacetamide

DMF: N,N-dimethylformamide

EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide

EtOAc: ethyl acetate;

EtOH: ethanol

HATU: 2-(1H-7-Asobancaria-1-yl)-1,1,3,3-tetramethyl uroni hexaflurophosphate of methenamine

HOBt: 1-hydroxy-benzotriazole

HPLC: high performance liquid chromatography

LC-MS: liquid chromatography/mass spectrometry

MeI: itmean

MeOH: methanol;

PTSA: the pair-toluensulfonate acid

TBAF: tetrabutylammonium

TBME: tert-butylmethylamine ether

TEA: triethylamine;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

TLC: thin layer chromatography

tR: retention time

To determine the spectra of the LC-MS used one of the following ways:

Method 1: Column SunFire C183,5 µm, 100 mm ×2.1 a), flow rate: 0.3 ml/min, eluent A = CH3CN:MeOH 1:1 B = NH4Ac 5 mm pH 7, gradient: 0 min 10% A; 17 min 95% A; 10 min 95% A.

Method 2: Column XBridge, 3.5 µm (50 mm ×4,6), temperature: 30 ░ C flow rate: 2 ml/min, eluent A = NH4HCO310 mm (pH=9), B = AcN; gradient: 0 min 5% B; 4,8 min 100% B;

Method 3: Column XBridge, 3.5 µm (50 mm ×4,6), temperature: 50°C, flow rate: 1.6 ml/min, eluent A = NH4 HCO310 mm (pH=9), B = AcN; gradient: 0 min 5% B; 3.5 minutes 1005% B;

Method 4 (Palau): Column Waters Acquity UPLC BEH C18 (1.7 μm, 2.1 mm ×50 mm), temperature: 40°C, flow: 0.5 ml/min, eluent: ACN (A)/ammonium bicarbonate 10 mm (B), gradient: 0 min 10% - 3,75 min 90% A

Method 5: Column YMC, 3.5 µm (50 mm ×4,6), temperature: 50°C, flow rate: 1.3 ml/min, eluent A = H2O (with 0.1% HCOOH), B = AcN (with 0.1% HCOOH), gradient: 0 min 5% B; a 3.5 min 100% B.

REFERENTIAL EXAMPLE 1

2,4,6-Trimethylbenzenesulfonyl 1-amino-4-triftormetilfullerenov

To a solution of 4-triftormetilfullerenov (2,23 g, of 15.2 mmol) in CH2Cl2(66 ml) at 0°C was added O-(mesitylenesulfonyl)hydroxylamine (3,27 g, of 15.2 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered to obtain the desired product with a quantitative yield.

LC-MS (method 4): tR= 1.07 min; m/z = 199 (MH-).

REFERENTIAL EXAMPLE 2

(S)-3-(4-(1-Acetylpiperidine-3-ylamino)-5-aminopyrimidine-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

Following the procedure similar to that described in example 1 (section a-d), but using (S)-1-acetyl-3-aminopiperidine instead of tetrahydro-2H-Piran-4-amine, was obtained the desired connection.

LC-MS (method 3): tR= 1.59 min; m/z = 377 (MH+).

Following the procedure similar to that described in reference example 2, but using in each case corresponding to the source of matter, received the following �connection:

Reference exampleNameThe initial substanceThe HPLC methodtR(min)m/z
2A(S)-tert-butyl 3-(5-amino-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4-ylamino)piperidine-1-carboxylate1-amino-4-methylpyridine 2,4,6-trimethylbenzoyl-sulfonate(1), (S)-3-amino-(1-tert-butoxycarbonyl)-piperidine and 2,4-dichloro-5-nitropyrimidin32,32424
2btert-butyl 4-(5-amino-2-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-4-ylamino)piperidine-1-carboxylate1-aminopyridine-iodide, 4-amino-(1-tert-butoxycarbonyl)-piperidine and 2,4-dichloro-5-nitropyrimidin42,00410
2c2-(pyrazolo[1,5-a]pyridin-3-yl)-N4-tetrahydro-2H-Piran-4-yl)pyrimidine-4,5-diamine1-aminopyridine-iodide, tetrahydro-2H-Piran-4-amine and 2,4-dichloro-5-nitropyrimidin3 1,55311

2d(S)-tert-butyl 3-(3-amino-6-(pyrazolo[1,5-a]pyridin-3-yl)pyridin-2-ylamino)piperidine-1-carboxylate1-aminopyridine-iodide, (S)-3-amino-(1-tert-butoxycarbonyl)-piperidine and 2,6-dichloro-3-nitropyridine32,43409
2e3-(5-amino-4-(8-ferroman-4-ylamino)pyrimidine-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril1-amino-4-cyanopyridine 2,4,6-trimethylbenzoyl-sulfonate, 8-ferroman-4-amine and 2,4-dichloro-5-nitropyrimidin19,28402
2f(S)-3-(6-(1-acetylpiperidine-3-ylamino)-5-aminopyridin-2-yl)pyrazolo[1,5-a] pyridin-5-carbonitril1-amino-4-cyanopyridine 2,4,6-trimethylbenzoyl-sulfonate, (S)-1-acetyl-3-aminopiperidin and 2,6-dichloro-3-nitropyridine31,58377
2g6-(pyrazolo[1,5-a]pyridin-3-yl)-N2-tetrahydro-2H-Piran-4-yl)pyridine-2,3-diamine 1-aminopyridinium, tetrahydro-2H-Piran-4-amine and 2,6-dichloro-3-nitropyridine51,68310

2h(S)-tert-butyl 3-(3-amino-6-(5-cyanopyridyl[1,5-a]pyridin-3-yl)pyridin-2-ylamino)piperidine-1-carboxylate1-amino-4-cyanopyridine 2,4,6-trimethylbenzoyl-sulfonate, (S)-3-amino-(1-tert-butoxycarbonyl)-piperidine and 2,6-dichloro-3-nitropyridine32,50434
2i3-(5-amino-4-(TRANS-4-hidroxizina-hexylamino)-pyrimidine-2-yl)-pyrazolo[1,5-a]pyridin-5-carbonitril1-amino-4-cyanopyridine 2,4,6-trimethylbenzoyl-sulfonate, TRANS-4-aminocyclo-hexanol and 2,6-dichloro-3-nitropyridine31,45350
(1) described in Zhang et al Journal of Heterocyclic Chemistry; 44; 4; 2007; 919-922

EXAMPLE 1

3-(8-Oxo-9-tetrahydro-2H-Piran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

a) 2-Chloro-5-nitro-N-tetrahydro-2H-Piran-4-Yeremey-4-amine

To a solution of 2,4-dichloro-5-nitropyrimidine (1.03 g, 5,15 mm�l) in THF (40 ml) at -78°C was added DIPEA (2.0 ml, Of 11.86 mmol) and tetrahydro-2H-Piran-4-amine (0.54 ml, 5,15 mmol). The reaction mixture was stirred at a temperature of from -78 to -50°C for 5 hours. The crude mixture was quenched using H2O (50 ml), extracted using EtOAc (3×40 ml) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of EtOAc/hexane with increasing polarity, to obtain 1.04 g of the desired compound (78% yield).

b) 5-Nitro-N-(tetrahydro-2H-Piran-4-yl)-2-[(trimethylsilyl)ethinyl]pyrimidine-4-amine

To a suspension of the compound obtained in the previous section (1.01 g, 3.90 mmol), Pd(PPh3)2Cl2(137 mg, 0,19 mmol) and CuI (37 mg, 0,19 mmol) in toluene (40 ml), was added tea (1.6 ml, 11.7 mmol) and trimethylsilylacetamide (0.7 ml, 5.07 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated aqueous solution of NH4Cl (70 ml) and extracted using EtOAc (3×40 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was chromatographically to flash the system with silica gel (SP1 biotage AB), using as eluent a mixture of EtOAc/hexane with increasing polarity, to obtain 0.96 g of the desired product (77% yield.

c) 3-[5-Nitro-4-(tetrahydro-2H-Piran-4-ylamino)pyrimidine-2-yl]pyrazolo[1,5-a]pyridin-5-carbonitril

To a suspension of the compound obtained in the previous section (500 mg, 156 mmol), and 2,4,6-trimethylbenzenesulfonyl 1-amino-4-cyanopyridine (498 mg, 1.56 mmol) in AcN (30 ml) at 0°C was added 1M solution of TBAF in THF (1,56 ml, 1.56 mmol) and a solution of DBU (of 0.47 ml, of 3.12 mmol) in AcN (10 ml). The reaction mixture was stirred at 0°C for 5 minutes and for 3 hours at room temperature. The reaction mixture was evaporated to dryness. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of EtOAc/hexane with increasing polarity, to obtain 227 mg of the desired compound (48% yield).

d) 3-[5-Amino-4-(tetrahydro-2H-Piran-4-ylamino)pyrimidine-2-yl]pyrazolo[1,5-a]pyridin-5-carbonitril

The mixture of compounds obtained in the previous section (119 mg, 0,32 mmol) in EtOH (12 ml) were gidrirovanie using Pt/C 5% (149 mg, 0.02 mmol) as catalyst in the presence of thiophene in DIPEA (4% V/V, 9 drops). The reaction mixture was stirred in an atmosphere of N2(gas) at room temperature for 1.5 hours. The reaction mixture was filtered through a layer of celite® and the solvent was evaporated to obtain 78 mg of the desired product (71% yield).

e) 3-(8-Oxo-9-tetrahydro-2H-Piran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To Rast�Ouro connection obtained in the previous section (78 mg, 0,23 mmol) in THF (7 ml) was added 1,1'-carbonyldiimidazole (188 mg, of 1.16 mmol). The reaction mixture was stirred at room temperature for 4 hours, quenched with a saturated aqueous NaCl solution (15 ml) and extracted using EtOAc (3×15 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of MeOH/CH2Cl2with increasing polarity, to obtain 5.1 mg of the desired compound (61% yield).

LC-MS (method 1): tR=14,25 minutes; m/z=362 (MH+).

Following the procedure similar to that described in example 1, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
1Amethyl (2R)-2-[2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propanoateD-laminotomy ester, hydrochloride1 14,48364
1b(S)-tert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(S)-tert-butyl 3-aminopiperidine-1-carboxylate22,23461
1c(R)-tert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(R)-tert-butyl 3-aminopiperidine-1-carboxylate22,23461

1d(S)-3-(9-(1-methoxypropan-2-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril(S)-1-methoxypropan-2-amine2Of 1.82350
1e3(9-(4,4-diverticulosis)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril4,4-diverticle-hexanamine22,03396
3-(9-(1,1-dioxotetrahydrofuran-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril3-amino-1,1-dioxalate-hydrotype21,43396
1g3-(9-(2-terbisil)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril2-forbindelsen116,58386
1h3-(9-(4-methoxybutyl-1-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril4-methoxybutan-1-amine115,15396

1iMethyl (2S)-2[2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propanoateL-laminotomy ester, hydrochloride31,83436
1j9-(1-acetylpiperidine-4-yl)-2-(5-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he (1) 1-acetyl-4-aminopiperidine, hydrochloride41,68446
1k(S)-tert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate(S)-tert-butyl 3-aminopyrrolidine-1-carboxylate52,72447
1l(R)-tert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate32,25447
1m(S)-tert-butyl 3-(2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate (2)(S)-tert-butyl 3-aminopiperidine-1-carboxylate32,47450

1nEthyl 2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)acetateEthyl 2-aminoacetate 3Of 1.82364
1o3-(9-(TRANS-4-hydroxycyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilTRANS-4-aminocyclo-hexanol31,55376
1p3-(9-(8-ferroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril8-ferroman-4-amine1One in 15.43428
1qtert-butyl 4-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylatetert-butyl 4-aminopiperidine-1-carboxylate32,33461
1rtert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)azetidin-1-carboxylatetert-butyl 3-aminoamides-1-carboxylate32,20433

1s9-(1-acetylpiperidine-4-yl)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he (2)1-acetyl-4-aminopiperidine, hydrochloride41,38392
(1) stage (c) was performed, using reference example 1 instead of 2,4,6-trimethylbenzenesulfonyl 1-amino-4-cyanopyridine
(2) stage c) is carried out using 2,4,6-trimethylbenzenesulfonyl 1-amino-4-methylpyridine (described in Zhang et al Journal of Heterocyclic Chemistry; 44; 4; 2007; 919-922) instead of 2,4,6-trimethylbenzenesulfonyl 1-amino-4-cyanopyridine

EXAMPLE 2

3-(2-Oxo-3-(tetrahydro-2H-Piran-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

a) 6-Chloro-3-nitro-N-(tetrahydro-2H-Piran-4-yl)pyridin-2-amine

To a suspension of 2,6-dichloro-3-nitropyridine (6 g, 31,1 mmol) in AcN (200 ml) at 0°C was added tea (9 ml, representing 62.2 mmol) and tetrahydro-2H-Piran-4-amine (3,15 g, 31,1 mmol). The reaction mixture was stirred at 0°C for 1.5 hours. The crude reaction mixture was heated and stirred at room temperature for 18 hours.

The reaction mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed three times with a saturated aqueous solution of NaHCO3. The combined organic phases were dried over MgSO4and concentri�up dry.

The crude residue was chromatographically to flash the system with silica gel (ISCO Combiflash) using as eluent a mixture of hexane/TBME with increasing polarity, receiving 5,23 g of the desired product (65% yield).

b) 3-Nitro-N-(tetrahydro-2H-Piran-4-yl)-6-((trimethylsilyl)ethinyl)pyridin-2-amine

Following the procedure similar to that described in example 1 section b, but using as starting substances of the compound obtained in the previous section, was obtained the desired compound (87% yield).

c) 3-(5-Nitro-6-(tetrahydro-2H-Piran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

Following the procedure similar to that described in example 1, section c, but using as starting substances of the compound obtained in the previous section, was obtained the desired compound (16% yield).

d) 3-(5-Amino-6-(tetrahydro-2H-Piran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

Following the procedure similar to that described in example 1, section d, but using as starting substances of the compound obtained in the previous section, was obtained the desired compound (19% yield).

(e) Specified in the header connection

Following the procedure similar to that described in example 1, part e, but using as starting substances of the compound obtained in the previous section, was obtained the desired compound (23% yield).

LC-MS (method 3): tR=,83 min; m/z=361 (MH+)

Following the procedure similar to that described in example 2, but using in each case corresponding to the source of matter, received the following connections:

Reference exampleNameThe initial substanceThe HPLC methodtR(min)m/z
(MH+)
2A(S)-tert-butyl 3-(2-oxo-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate(S)-3-amino-(1-tert-butoxycarbonyl)-piperidine and iodide 1-aminopyridine32,47435
2b(R)-tert-butyl 3-(2-oxo-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate and iodide 1-aminopyridine32,27421
2c(S)-tert-butyl 3-(2-oxo-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate and iodide 1-aminopyridine32,27421

2d(S)-tert-butyl 3-(5-(5-cyanopyridine-[1,5-a]pyridin-3-yl)-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate(S)-3-amino-(1-tert-butoxycarbonyl)-piperidine and 1-amino-4-cyanopyridine 2,4,6-trimethylbenzoyl-sulfonate32,50434
2e5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-hetetrahydro-2H-Piran-4-amine and iodide 1-aminopyridine31,80336
2f(R)-tert-butyl 3-(2-oxo-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate(R)-3-amino-(1-tert-butoxycarbonyl)-piperidine and iodide 1-aminopyridine42,15435

EXAMPLE 3

2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Pyra�-4-yl)-7H-purin-8(9H)-he

Following the procedure similar to that described in example 1, but using 1-aminopyridinium instead of 1-amino-4-cyanopyridine 2,4,6-trimethylbenzenesulfonyl, was obtained the desired compound (84% yield).

LC-MS (method 3): tR=1.62 min; m/z=337 (MH+).

Following the procedure similar to that described in example 3, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
3A2-(pyrazolo[1,5-a]pyridin-3-yl)-9-((tetrahydro-2H-Piran-4-yl)methyl)-7H-purin-8(9H)-he(tetrahydro-2H-Piran-4-yl)methanamine21,63351
3b(S)-tert-butyl 3-(8-oxo-2-pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate(S)-tert-butyl 3-aminopiperidine-1-carboxylate22,33436
3c 9-(2-methoxyethyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- 7H-purin-8(9H)-he2-methoxyethylamine21,55311
3d9-(8-ferroman-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he8-ferroman-4-amine116,07403
3eMethyl (2S)-2-(8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7,8-dihydro-9H-purin-9-yl)propanoateMethyl ester of L-alanine, hydrochloride31,73339

3f(S)-tert-butyl 3-(8-oxo-2-pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate(S)-tert-butyl 3-aminopiperidine-1-carboxylate32,13422
3gtert-butyl 3-(8-oxo-2-pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylatetert-butyl 4-aminopiperidine-1-carboxylate 3Of 2.35461
3h9-(1-demerol-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he1-demerol-4-amine41,38350
3i5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(2,2,6,6-tetramethylpiperidine-4-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he2,2,6,6-tetramethyl-piperidine-4-amine41,48391

EXAMPLE 4

3-(7-Methyl-8-oxo-9-tetrahydro-2H-Piran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To the solution of compound of example 1 (48 mg, 0.13 mmol) in DMF (6 ml) was added 55-65% NaH dispersion in mineral oil (7.3 mg, 0,18 mmol) and the resulting solution was stirred at room temperature for 10 minutes. Was then added MeI (of 0.015 ml, 0.25 mmol) and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was quenched with a saturated aqueous solution of NaCl (10 ml) and extracted using EtOAc (3×10 ml) and CH2Cl2(2×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. Obtained in this �the Braz crude product was chromatographically on silica gel, using as eluent a mixture of MeOH/CH2Cl2with increasing polarity, to give 50 mg of the desired compound (quantitative yield).

LC-MS (method 1): tR=Equal to 15.48 minutes; m/z=376 (MH+).

Following the procedure similar to that described in example 4, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
4A(S)-tert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylateExample 1b23,22475
4b(R)-tert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylateExample 1C23,22475
4c9-(8-ferroman-4-yl)-7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-Puri�-8(9H)-he Example 3d1Equal to 16.83417

EXAMPLE 5

(S)-tert-Butyl 3-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate

To the solution of compound of example 3b (70 mg, 0,160 mmol) in DMF (3.5 ml) at 0°C was addedt-BuOK (27 mg, 0,24 mmol) and MeI is 0.019 ml, 0,32 mmol). The reaction mixture was stirred at room temperature for 20 minutes and evaporated to dryness. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain 64 mg of the desired product (89% yield).

LC-MS (method 3): tR=2,58 minutes; m/z=450 (MH+).

Following the procedure similar to that described in example 5, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
5A7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-7H-purin-8(9H)-he Example 321,83351
5b3-(1-methyl-2-oxo-3-(tetrahydro-2H-Piran-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 222,62375
5c9-(2-methoxyethyl)-7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 3C21,77325

5d7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-[(tetrahydro-2H-Piran-4-yl)methyl]-
7H-purin-8(9H)-he
Example 3A21,87365
5e3-(9-(4,4-diverticulosis)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 1E22,32410
5f3-(9-(1,1-diokso-tete�agitation-3-yl)-8,9-dihydro-7-methyl-8-oxoborn-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril Example 1f21,75410
5g(S)-tert-butyl 3-(5-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-piperidine-1-carboxylateExample 2d22,54474
5h3-(9-(2-terbisil)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 1g117,66400
5i9-(1-acetylpiperidine-4-yl)-7-methyl-2-(5-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 1j41,85460
5j(S)-tert-butyl 3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-yl)piperidine-1-carboxylateExample 2a32,73449

5k(S)-tert-butyl 3-(2-(5-cyano-pyrazolo[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylateExample 1k32,52461
5l(R)-tert-butyl 3-(2-(5-cyano-pyrazolo[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylateExample 1l32,50461
5m(S)-tert-butyl 3-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylateExample 3f32,40436
5n(R)-tert-butyl 3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-yl)pyrrolidine-1-carboxylateExample 2b32,50435
5o(S)-tert-butyl 3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-yl)pyrrolidine-1-carboxylateExample 2c 52,98436
5p(S)-tert-butyl 3-(1-ethyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-yl)piperidine-1-carboxylate (1)Example 2a42,57463
5qtert-butyl 4-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)-piperidine-1-carboxylateExample 3g32,68475

5r(S)-tert-butyl 3-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylateExample 3b32,62450
5s1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(tetrahydro-2H-Piran-4-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 2e32,02350
5t(R)tert-butyl 3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carboxylate Example 2f32,73449
5utert-butyl 4-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylateExample 1q32,68475
5vtert-butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)azetidin-1-carboxylateExample 1r32,47447
(1) as the starting substances used ethyliodide instead of methyliodide

EXAMPLE 6

(S)-3-(8-Oxo-9-(piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochloride

To the solution of compound of example 1b (45 mg, 0.10 mmol) in dioxane (3 ml) was added 4M HCl solution in dioxane (2 ml, 8.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to obtain 48 mg of the desired compound (100% yield).

LC-MS (method 2): tR=1,73 min; m/z=361 (MH+).

Following the procedure similar to that described in example 6, but the IP�alzua in each case corresponding to the source of the substance, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
6A(R)-3-(8-oxo-9-(piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-3-yl-5-carbonitrile hydrochlorideExample 1c21,73361
6b(R)-3-(7-methyl-8-oxo-9-(piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 4b22,05375
6c(S)-3-(7-methyl-8-oxo-9-(piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 4a22,05375
6d9-(piperidine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heWhen�er 3g 21,28336

6e(S)-3-(2-oxo-3-(piperidine-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 2d2A 1.54360
6f(S)-3-(1-methyl-2-oxo-3-(piperidine-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 5g21,68374
6g(S)-1-methyl-3-(piperidine-3-yl)-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he hydrochlorideExample 5j112,46349
6h(S)-3-(7-methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 5k31,62361
6i(R)-3-(7-methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 5l31,62361
6j(S)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-he hydrochlorideExample 3f31,23322

6k(S)-7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-he hydrochlorideExample 5m31,48336
6l(S)-3-(8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochloride (1)Example 1k3Of 1.35347
6m(R)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he hydrochlorideExample 5n1,57335
6n(R)-5-pyrazolo[1,5-a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he hydrochloride (1)Example 2b31,40321
6o(R)-3-(8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochloride (1)Example 1l31,33347
6p(S)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(pyrrolidin-3-yl)- 7H-purin-8(9H)-he hydrochlorideExample 2c31,40321

6q(S)-1-methyl-5-pyrazolo[1,5-a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he hydrochlorideExample 5o31,57335
6r(S)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-9-(piperidine-3-yl-7H-purin-8(9H)-he hydrochloride Example 1m31,57350
6s(S)-1-ethyl-3-(piperidine-3-yl)-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he hydrochlorideExample 5p41,56363
6t7-methyl-9-(piperidine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he hydrochlorideExample 5q41,23350
6u(S)-7-methyl-9-(piperidine-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he hydrochlorideExample 5r31,67350
6v(S)-9-(piperidine-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-he hydrochlorideExample 3b31,43336
6w(R)-1-methyl-3-(piperidine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3�) Example 5t31,77349

6x(S)-3-(piperidine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he hydrochlorideExample 2a31,60335
6y3-(7-methyl-8-oxo-9-(piperidine-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 5u31,67375
6z(S)-3-(3-(piperidine-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 18e31,68344
6aa(S)-3-(2-methyl-3-(piperidine-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 18f31,72358
6ab3-(8-oxo-9-(piperidine-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril (1)Example 1q111,13361
6ac3-(9-(azetidin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile hydrochlorideExample 5v31,50347
6ad(S)-3-(piperidine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine hydrochlorideExample 18i3The 1.65319
6ae(S)-2-methyl-3-(piperidine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine hydrochlorideExample 21m31,48333
(1) the reaction was carried out using TFA/CH2Cl2instead of 4M HCl solution in dioxane, and washed with a saturated aqueous solution of NaHCO3.

EXAMPLE 7

(S)-3-(9-(1-(2-Cyanoacetyl)piperidine-3-yl)--oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a solution of the compound obtained in example 6 (45 mg, 0,095 mmol) in anhydrous DMF (3 ml) was added 2,5-dioxopiperidin-1-yl 2-cyanoacetate (69 mg, 0,38 mmol) and anhydrous TEM (0,09 ml, 0,665 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent evaporated. The mixture was quenched with a saturated aqueous solution of NaHCO3(15 ml) and extracted using EtOAc (3×15 ml). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of hexane/acetone with increasing polarity, with the receipt of 11.7 mg of the desired compound (29% yield).

LC-MS (method 2): tR=1,93 min; m/z=428 (MH+).

Following the procedure similar to that described in example 7, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
7a(R)-3-(9-(1-(2-cyanoacetyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-yl)pyrazolo[1,5-a]Piri�in-5-carbonitril Example 6a21,93428
7b(R)-3-(9-(1-(2-cyanoacetyl)piperidine-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6b22,30442
7c(S)-3-9-(1-(2-cyanoacetyl)piperidine-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6c22,30442

7d3-(9-(1-(2-cyanoacetyl)-pyrrolidin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril3-(7-methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo-[1,5-a]-pyridine-5-carbonitrile hydrochloride (1)21,68428
7e3-(9-((1-(2-cyanoacetyl)piperidine-4-yl)methyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril 3-(7-methyl-8-oxo-9-(piperidine-4-ylmethyl)-8,9-dihydro-7H-purin-2-yl)pyrazolo-[1,5-a]-pyridine-5-carbonitrile hydrochloride (2)21,80456
7f(S)-3-oxo-3-(3-(8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-yl)propanenitrileExample 6v22,05403

7g(S)-3-(3-(7-methyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-yl)3-oxopropanenitrileExample 6u2Of 2.58417
7h(S)-3-3-(1-(2-cyanoacetyl)piperidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo-[4,5-b]pyridin-1-yl)pyrazolo-
[1,5-a]pyridin-5-carbonitril
Example 6e2Of 1.64427
7i(S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo-
[1,5-a]pyridin-3-yl)-1H-imidazo-[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrile
Example 6g 51,95416
7j3-(9-(1-(2-cyanoacetyl)azetidin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6ac22,10414
7k(S)-3-(3-(2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-yl)-3-oxopropanenitrileExample 6r31,73417

7l(S)-3-(3-(1-ethyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrileExample 6s41,87430
7m3-oxo-3-(4-(8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-yl)propanenitrileExample 6d41,32403
7n(S)-3-(3-(1-(2-cyanoacetyl�)piperidine-3-yl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitril Example 6f32,02441
7o(R)-3-(3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrileExample 6w41,71416

7p(S)-3-oxo-3-(3-(2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-yl)piperidine-1-yl)propanenitrileExample 6x31,75402
7q3-(9-(1-(2-cyanoacetyl)piperidine-4-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6y3Of 1.82442
7r(S)-3-(3-(1-(2-cyanoacetyl)piperidine-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6z52,20411
7s(S)-3-(3-(1-(2-cyanoacetyl)piperidine-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6aa52,09425

7t(S)-3-(3-(2-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-yl)-3-oxopropanenitrileExample 6ae31,85400
7u(S)-3-oxo-3-(3-(5-(pyrazolo[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-yl)propanenitrileExample 6ad31,77386
(1) obtained as in example 6, but as the starting substances used tert-butyl 3-aminopyrrolidine-1-carboxylate.
(2) obtained as in example 6, but as the starting substances used tert-butyl 4-(aminomethyl)piperidine-1-carboxylate.

EXAMPLE 8

(S)-3-(9-(1-Acetylpiperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

� the solution of compound, obtained in example 6 (31 mg, 0,063 mmol) in anhydrous DMF (3 ml) was added acetic anhydride (0,007 ml, 0.08 mmol) and anhydrous TEM (0.02 ml, are 0.127 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent evaporated. The mixture was quenched with a saturated aqueous solution of NaHCO3(15 ml) and extracted using EtOAc (3×15 ml). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of hexane/acetone with increasing polarity, to obtain 14.5 mg of the desired compound (57% yield).

LC-MS (method 2): tR=To 1.87 min; m/z=403 (ΜH+).

Following the procedure similar to that described in example 8, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
8A(S)-9-(1-acetylpiperidine-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6v 21,55378
8b3-9-(1-acetylpiperidine-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6ab113,31403
8c9-(1-acetylpiperidine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6d41,30378
8d(S)-3-(1-isobutylpyrazine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he (1)Example 6x32,00405

8e(S)-3-(9-(1-acetylpiperidine-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl) pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6c31,88417
8f(S)-3-(1-acetylpiperidine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b-2(3H)-he Example 6x31,72377
8g3-(9-(1-acetylpiperidine-4-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6y31,78417
8h3-(9-(1-acetylisatin-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6ac31,62389
(1) used isobutyramide instead of acetic anhydride as the starting material.

EXAMPLE 9

(S)-3-(9-(1-(methyl-sulfonyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a solution of the compound obtained in example 6 (31 mg, 0,063 mmol) in anhydrous DMF (3 ml) was added methanesulfonic anhydride (13 mg, 0,08 mmol) and anhydrous TEM (0.02 ml, are 0.127 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent evaporated. The mixture was quenched with a saturated aqueous solution of NaHCO3(15 ml) and extracted with the help�and EtOAc (3×15 ml). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of hexane/acetone with increasing polarity, receiving 14,3 mg specified in the title compound (52% yield).

LC-MS (method 1 PCB): tR=2,08 min; m/z=439 (MH+).

Following the procedure similar to that described in example 9, but using the appropriate initial matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
9a(S)-9-(1-(methyl-sulfonyl)piperidine-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6v and methane-sulfonyl chloride21,70414
9b(S)-3-(8-oxo-9-(1-(propylsulfonyl)-piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and propane-1-sulfonyl chloride 52,48467
9c(S)-3-(8-oxo-9-(1-(2,2,2-triftormetilfullerenov)-piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 2,2,2-Cryptor-ethane-sulfonyl-chloride52,55507

9d(S)-3-(9-(1-(isobutylphenyl)-piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 2-methylpropan-1-sulfonyl chloride32,70481
9e(S)-3-(8-oxo-(1-(3,3,3-triftormetilfullerenov)-piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 3,3,3-Cryptor-propane-1-sulfonyl chloride32,70521
9f(S)-1-methyl-3-(1-(methyl-sulfonyl)piperidine-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and methane-sulfonyl-chloro�d 41,81427
9g(S)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-9-(1-(methyl-sulfonyl)piperidine-3-yl)-7H-purin-8(9H)-heExample 6r and methane-sulfonyl chloride31,87428
9h7-(2-oxopropyl)-9-(1-(2-oxopropyl)piperidine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6d and 1-chloropropane-2-he41,66448
9i9-(1-acetylpiperidine-4-yl)-7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6t and acetyl chloride41,42392

9j(S)-3-(3-(1-isobutylpyrazine-3-yl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6E and isobutyryl chloride52,52430
9k(S)-3-(3-(1-(methyl-sulfonyl)piperidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6E and methane-sulfonyl chloride31,92438
9l(S)-3-(7-methyl-9-(1-(methyl-sulfonyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6C and methane-sulfonyl chloride32,05453
9m(S)-3-(9-(1-(ethylsulfonyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and ethyl-sulfonyl-chloride31,90453
9n(S)-3-(9-(1-isobutylpyrazine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and isobutyryl chloride31,95431
9o3-(7-methyl-9-(1-(methyl-sulfonyl)piperidine-4-�l)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril Example 6y and methane-sulfonyl chloride31,95453

9p3-(9-(1-(methyl-sulfonyl)piperidine-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6ab and methanol-vanilloid114,06439
9q(S)-3-(1-(methyl-sulfonyl)piperidine-3-yl)-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6x and methane-sulfonyl chloride31,85413
9r3-(7-methyl-9-(1-(methyl-sulfonyl)azetidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6ac and methane-sulfonyl chloride32,30425
9s(S)-3-(3-(1-acetylpiperidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl) pyrazolo[1,5-a]pyridin-5-carbonitrilWhen�6e er and acetyl chloride 52,25402
9t(S)-3-(1-(2-methoxyacetyl)piperidine-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and methoxy-acetyl chloride41,68421

9u(S)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(1-(2,2,2-triftormetilfullerenov)-piperidine-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and 2,2,2-Cryptor-ethanal-vanilloid42,17495

EXAMPLE 10

(S)-3-(9-(1-(2-(Dimethylamino)acetyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a solution of N,N-dimethylglycine (10 mg, 0,095 mmol) in anhydrous DMF (2 ml) was added ΗΟΒt·Η2Ο. After 15 minutes, was added EDC·HCl (24 mg, 0,126 mmol) and the compound obtained in example 6 (31 mg, 0,063 mmol). The reaction mixture was stirred at room temperature for 2.5 hours and the solvent evaporated. The mixture was quenched with a saturated aqueous solution of NaHCO3(15 ml) and extracted using EtOAc (3×15 ml). Join�record the organic phase was dried over anhydrous Mg 2SO4, filtered and concentrated. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of hexane/acetone with increasing polarity, to obtain 8.2 mg specified in the title compound (29% yield).

LC-MS (method 3): tR=To 1.67 min; m/z=446 (MH+).

Following the procedure similar to that described in example 10, but using the appropriate initial matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
10A(S)-3-(9-(1-(2-hydroxyacyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and glycolic acid3Of 1.52419
10b(S)-3-(9-(1-(2-hydroxy-2-methylpropanoyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 2-hydroxy-2-methyl-propane acid3 1,75447
10c3-(8-oxo-9-((S)-1-((S)-tetrahydrofuran-2-carbonyl)piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and (S)-tetrahydro-furan-2-carboxylic acid31,75549
10d(S)-3-(9-(1-(2-methoxyacetyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 2-methoxy-acetic acid3The 1.65433
10e(S)-3-(9-(1-(2-ethylbutanol)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 2-ethyl-butane acid32,20459

10f(S)-3-(9-(1-(2-(3-methylisoxazol-5-yl)acetyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 2-(3-methyl-izocsazol-5-yl)acetic acid 3Of 1.82484
10g3-(9-((S)-1-((S)-2-methoxypropanol)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and (S)-2-methoxy-propane acid52,23447
10h(S)-3-(8-oxo-9-(1-(3,3,3-triptocaine)piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and 3,3,3-Cryptor-propane acid31,97471
10i(S)-2-(5-methylpyrazolo[1,5-a]-pyridin-3-yl)-9-(1-Propionaldehyde-3-yl)-7H-purin-8(9H)-heExample 6r and propane acid31,85406
10j(S)-9-(1-(2-methoxyacetyl)piperidine-3-yl)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6r and 2-methoxy-acetic acid31,72422
10k(S)-7-(2-methoxyacetyl)-9-(1-(2-methoxyacetyl)piperidine-3-yl)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6r and 2-methoxy-acetic acid32,13494

10l(S)-9-(1-acetylpiperidine-3-yl)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6r and acetic acid31,70392
10m(S)-9-(1-(2-hydroxyacyl)piperidine-3-yl)-2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6r and 2-hydroxy-acetic acid31,60408
10n(S)-3-(9-(1-(cyclopropanecarbonyl)-piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6 and cyclopropane-carboxylic acid31,88429
10o(S)-3-(1-(2-hydroxy-2-m�dipropenyl)piperidine-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he Example 6g and 2-hydroxy-2-methyl-propane acid4Of 1.76435
10p(S)-3-(1-(2-hydroxyacyl)piperidine-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and 2-hydroxy-acetic acid41,59407
10q(S)-3-(1-(2-(dimethylamino)acetyl)-piperidine-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and N,N-dimethyl-glycine4The 1.65434

10r1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3-((S)-tetrahydrofuran-2-carbonyl)piperidine-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and (S)-tetrahydro-furan-2-carboxylic acid4Of 1.76447
10s(S)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(1-(3,3,3-triptocaine)piperidine-3-yl)-1H-imidazo1,5-b]pyridin-2(3H)-he Example 6g and 3,3,3-Cryptor-propane acid41,99459

EXAMPLE 11

(S)-3-(2-(5-Cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N,N-dimethylpiperidin-1-sulfonamide

To a solution of the compound obtained in example 6 (110 mg, 0,22 mmol) in anhydrous DMF (3 ml) was added N,N-dimethylsulphamoyl (0.03 ml, 0.27 mmol) and anhydrous TEM (0,13 ml of 0.90 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent evaporated. The mixture was quenched with a saturated aqueous solution of NaHCO3(15 ml) and extracted using EtOAc (3×15 ml). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of hexane/acetone with increasing polarity, with the receipt of 39.2 mg specified in the title compound (38% yield).

LC-MS (method 1): tR=1,95 min; m/z=468 (MH+).

Following the procedure similar to that described in example 11, but using the appropriate initial matter, received the following connection:

ExampleNameSource �emesto The HPLC methodtR(min)m/z
(ΜH+)
11a(S)-N,N-dimethyl-3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-sulfonamideExample 6g42,05456

EXAMPLE 12

3-(9-(1-Acetylpyrrolidine-3-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

a) tert-Butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate

Following the procedure similar to that described in example 1, but using tert-butyl 3-aminopyrrolidine-1-carboxylate instead of tetrahydro-2H-Piran-4-amine, was obtained the desired connection.

b) tert-Butyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate

Following the procedure similar to that described in example 5, but using as starting substances of the compound obtained in the previous section, was obtained the desired compound (25% yield).

c) 3-(7-Methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrided

Following the procedure similar to that described in example 6, but using as starting substances compounds�s, obtained in the previous section, was obtained the desired compound (100% yield).

(d) Specified in the header connection

Following the procedure similar to that described in example 8, but using as starting substances of the compound obtained in the previous section, was obtained the desired compound (22% yield).

LC-MS (method 2): tR=To 1.67 min; m/z=403 (MH+).

EXAMPLE 13

3-(7-Methyl-9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

Following the procedure similar to that described in example 9, but using as starting substances of the compound obtained in example 12, section c, was obtained the desired compound (15% yield).

LC-MS (method 2): tR=1.83 min; m/z=439 (MH+).

Following the procedure similar to that described in example 13, but using the appropriate initial matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
13A(S)-3-(7-methyl-9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilP�emer 6h 3Of 2.35439
13b(R)-3-(7-methyl-9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6i3Of 2.35439

13c(S)-9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6j31,53400
13d(S)-7-methyl-9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6k31,77414
13e(S)-3-9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6l31,63425
13f(R)-1-IU�Il-3-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he Example 6m31,90413
13g(R)-3-(1-methyl-sulfonyl)pyrrolidin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6n31,72399
13h(R)-3-(9-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 6o31,62425

13i(S)-3-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6p31,72399
13j(S)-1-methyl-3-(1-(methyl-sulfonyl)pyrrolidin-3-yl)-5-pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6q31,92413
13k(S)-7-methyl-9-(1-(methyl-sulfonyl)piperidine-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6u31,93428

EXAMPLE 14

(2R)-2-[2-(5-Cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propane acid

To a suspension of compound of example 1 (65 mg, 018 mmol) in dioxane (1.6 ml) and H2O (0.8 ml) at 0°C was added LiOH-H2O (15 mg, 0.36 mmol). The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 26 hours. The pH of the solution was adjusted to 5 by adding 10% aqueous HCl. The solvent was removed under vacuum and the obtained solid was suspended in Et2O (10 ml) and concentrated. The obtained solid substance was washed with water (2×5 ml), hexane (3 ml) and Et2O (2×5 ml) to give 57 mg of the desired product (91%).

LC-MS (method 1): tR=13,59 min; m/z=350 (MH+).

Following the procedure similar to that described in example 14, but using the appropriate initial matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodt (min)m/z
(ΜH+)
14a(2S)-2-[2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propane acidExample 1i113,59350
14b(S)-2-(8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-yl)propane acidExample 3E31,10325

EXAMPLE 15

(2R)-2-[2-(5-Cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-N-(2,2,2-trifluoroethyl)propanamide

To a solution of HOBt·H2O (31 mg, 0.20 mmol) and TEM (0,068 ml, 0.49 mmol) in THF (1 ml) was added the compound of example 14 (70 mg, 0.20 mmol). After 15 minutes, was added EDC·HCl (40 mg, 0,21 mmol) and 2,2,2-triftormetilfullerenov (14.6 mg, 0.11 mmol) and the resulting mixture was stirred at room temperature for 3.5 days. Then, the mixture was quenched using H2O (5 ml) and extracted using EtOAc (3×15 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of MeOH/CH2Cl2

LC-MS (method 1): tR=Ones was 15.34 min; m/z=431 (MH+).

Following the procedure similar to that described in example 15, but using the appropriate initial matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
15A(2R)-2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-methylpropanamideExample 14 and N-methylamine1Of 13.62363
15b(2S)-2-[2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-3-methyl-N-(2,2,2-trifluoroethyl)butanamide(2S)-2-[2-(5-cyanopyridine-[1,5-a]pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-3-methylbutanoate acid (1) and 2,2,2-triptorelin32,08459
15c(R)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2-hydroxyethyl)-PR�paramid Example 2-aminoethanol3Of 1.35393

391
15d(R)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(cyclopropylmethyl)-propanamideExample 14 and dihydro-methanamine31,75403
15e(R)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2-(dimethylamino)ethyl)-propanamideExample 14 and N1,N1-dimethylated-1,2-diamine31,48420
15f(R)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-ethylpropaneExample 14 and N-ethylamine31,57377
15g(R)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-isopropylparabenExample 14 and N-Isopropylamine31,70
15h(R)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N,N-dimethylpropanamideExample 14 and N,N-dimethylamine31,53377
15i(S)-2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2,2,2-trifluoroethyl)propanamideExample 14a and 2,2,2-triptorelin31,72431

15j(S)-N-methyl-2-(8-oxo-2-(pyrazolo-[1,5-a]-pyridin-3-yl)-7H-purin-9(8H)-yl)-propanamideExample 14b and N-methylamine3Of 1.35338
15k(S)-N,N-dimethyl-2-(8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)-propanamideExample 14b and N,N-dimethylamine51,90352
(1) Obtained as in example 14, but using HCl/Dioxane 4M/H2O (1:1) instead of LiOH·H2Oh, and meth�Lowy ester L-valine, hydrochloride as the starting material.

EXAMPLE 16

3-(7-(2-Methoxyethyl)-8-oxo-9-(tetrahydro-2H-Piran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To the solution of compound of example 1 (50 mg, 0.14 mmol) in DMF (8 ml) was added 55-65% NaH dispersion in mineral oil (6 mg, 0,15 mmol) and the resulting solution was stirred at room temperature for 10 minutes. Was then added 2-bromatology ether (to 0.032 ml, 0.34 mmol) and the reaction mixture was stirred at 50°C for 14.5 hours. The reaction mixture was quenched using H2O (10 ml) and extracted using EtOAc (3×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of EtOAc/hexane with increasing polarity, to obtain 36 mg of the desired compound (62% yield).

LC-MS (method 1): tR=16,17 min; m/z=420 (MH+).

Following the procedure similar to that described in example 16, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC method tR(min)m/z
(ΜH+)
16A(S)-3-(9-(1-(2-cyanoacetyl)piperidine-3-yl)-7-(2-dimethylamino)ethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril2-bromo-N,N-dimethylated-amine and example 1b (1)21,95499
16b(S)-3-(7-(2-dimethylamino)ethyl)-8-oxo-9-(piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril2-bromo-N,N-dimethylated-amine and example 1b (2)21,83432
16c7-(2-dimethylamino)ethyl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-7H-purin-8(9H)-he2-bromo-N,N-dimethylated-amine and example 321,921408
16d3-(7-(2-dimethylamino)ethyl)-8-oxo-9-(tetrahydro-2H-Piran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril2-bromo-N,N-dimethylated-amine and example 1114,79 433

16e3-(7-(2-dimethylamino)ethyl)-9-(8-ferroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl) pyrazolo[1,5-a]pyridin-5-carbonitril2-bromo-N,N-dimethylated-amine and example 1R42,12499
16f3-(9-(8-ferroman-4-yl)-7-(2-methoxyethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril2-bromacil-methyl ester and example 1R42,20486
16g3-(9-(8-ferroman-4-yl)-7-(3-hydroxypropyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril3-bromopropane-1-ol and example 1p41,96486
16h(S)-3-(3-(1-(2-dimethylamino)ethyl)-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrile2-bromo-N,N-dimethylated-amine and example 2A (1)41,73 473
16i(S)-3-(3-(1-(2-methoxyethyl)-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrile2-bromacil-methyl ester and example 2A (1)41,92460

16j(S)-3-(3-(1-the cyclopropylmethyl)-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrile(methyl bromide) cyclopropane and example 2A (1)42,08456
(1) a procedure was followed similar to that described in example 6 (cleavage of tert-butoxycarbonyl) and 7 (formation of an amide).
(2) follow the procedure for the cleavage of tert-butoxycarbonyl as in example 6

EXAMPLE 17

3-(7-(2-Hydroxyethyl)-8-oxo-9-(tetrahydro-2H-Piran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

a) 3-(7-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-oxo-9-(tetrahydro-2H-Piran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To the solution of compound of example 1 (50 mg, 0.14 mmol) in DMF (8 ml) was added 55-65% of NaH disper�Oia in mineral oil (6 mg, Of 0.15 mmol). The resulting solution was stirred at room temperature for 10 minutes. Was then added (2-bromoethoxy)-tert-butyldimethylsilyl (to 0.074 ml, 0.34 mmol) and the reaction mixture was stirred at 50°C for 14.5 hours. The reaction mixture was quenched using H2O (10 ml) and extracted using EtOAc (3×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of hexane/EtOAc with increasing polarity, to obtain 55 mg of the desired compound (76% yield).

(b) Specified in the header connection

To a solution of the compound obtained in the previous section (55 mg, 0.10 mmol), in THF (5 ml) was added 1M solution of TBAF in THF (0.14 ml, 0.14 mmol) and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched using H2O (10 ml) and extracted using EtOAc (3×10 ml) and CH2Cl2(2×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of MeOH/EtOAc with increasing polarity, to obtain 39 mg of the desired compound (91% yield).

LC-MS (method 1: t R=To 14.13 min; m/z=406 (MH+).

Following the procedure similar to that described in example 17, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
17A(S)-3-(9-(1-(2-cyanoacetyl)piperidine-3-yl)-7-(2-hydroxyethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 1b (1)11,68472

17b(S)-3-(7-(2-hydroxyethyl-8-oxo-9-(piperidine-3-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitridedExample 1b (2)11,55405
17c3-(9-(8-ferroman-4-yl)-7-(2-hydroxyethyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 1R 115,99472
(1) a procedure was Followed similar to that described in example 6 (cleavage of tert-butoxycarbonyl) and 7 (formation of an amide).
(2) follow the procedure for the cleavage of tert-butoxycarbonyl as in example 6

EXAMPLE 18

3-(9-Tetrahydro-2H-Piran-4-yl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a suspension of the compound obtained in example 1, section d, (100 mg, 0,30 mmol) in EtOH (1 ml) was added PTS monohydrate (5.7 mg, 0,03 mmol) and triethylorthoformate (1 ml). The reaction mixture was heated in a microwave oven CEM Explorer at 123°C and 270 Watts for 30 minutes. It was then evaporated to dryness. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of MeOH/EtOAc with increasing polarity, to obtain 81 mg of the desired compound (79% yield).

LC-MS (method 1): tR=14,56 min; m/z=346 (MH+).

Following the procedure similar to that described in example 18, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min) m/z
(ΜH+)
18a3-(8-methyl-9-tetrahydro-2H-Piran-4-yl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 1 section d and triethylorthoformate1To 14.77360
18b3-(9-(4,4-diverticulosis)-8-methyl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilTriethylorthoformate and 3-(5-amino-4-(4,4-diverticulosis-amino)pyrimidine-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril (1)22,17394
18c3-(9-(1,1-dioxotetrahydrofuran-3-yl)-8-methyl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilTriethylorthoformate and 3-(5-amino-4-(1,1-dioxalate-hydration-3-yl)aminopyrimidine-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrile (2)2The 1.65394
18d5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(tetrahydro-2H-Piran-4-yl)-3H-imidazo[4,5-b]pyridinReference example 2g and triethylorthoformate3 1,85320

18e(S)-tert-butyl-3-(5-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylateReference example 2g and triethylorthoformate32,33444
18f(S)-tert-butyl-3-(5-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylateReference example 2h and triethylorthoformate32,57458
18g2-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3-(tetrahydro-2H-Piran-4-yl)-3H-imidazo[4,5-b]pyridinReference example 2h and triethylorthoformate31,92334
18PM3-(9-(TRANS-4-hydroxycyclohexyl)-8-methyl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilReferential example 2j and triethylorthoformate31,7034

18i(S)-tert-butyl-3-(5-pyrazolo[1,5-a]pyridin-3-yl-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylateReference example 2d and triethylorthoformate31,77386
(1) obtained in example 1e, section d
(2) obtained in example 1f, section d

EXAMPLE 19

3-(3-(Tetrahydro-2H-Piran-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a suspension of the compound obtained in example 2, section d (to 33.6 mg, 0.1 mmol), in EtOH (1.5 ml) was added citric acid (2 mg, 0.1 mmol) and triethylorthoformate (340 μl, 2 mmol). The reaction mixture was heated in a microwave oven CEM Explorer at 145°C and 270 Watts for 2.5 hours. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of hexane/acetone with increasing polarity, to obtain 14.2 mg of the desired product (41% yield).

LC-MS (method 3): tR=Of 1.76 min; m/z=345 (MH+).

Following the procedure similar to that described in example 19, but using the appropriate initial matter, received the following connection:

Example NameThe original substanceThe HPLC methodtR(min)m/z
(ΜH+)
19a(S)-3-(3-(1-Reference example52,22386

acetylpiperidine-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitril2f

EXAMPLE 20

3-(2-Methyl-3-(tetrahydro-2H-Piran-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a solution of the compound obtained in example 2, section d (56.4 mg, 0,169 mmol) in EtOH (1.5 ml) was added PTS monohydrate (3,21 mg, 0,017 mmol) and triethylorthoformate (547 mg, 3,37 mmol). The reaction mixture was heated in a microwave oven CEM Explorer at 145°C and 270 Watts for 2.5 hours. The crude residue was chromatographically to flash the system with silica gel (ISCO Rf) using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain the desired product (15% yield).

LC-MS (method 3): tR =To 1.79 min; m/z=of 359.5 (MH+).

EXAMPLE 21

3-(8-(1-Methyl-1H-imidazol-2-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a solution of the compound obtained in example 1, section d, (100 mg, 0,30 mmol) in AcOH (0,025 ml) and of DMA (2.5 ml) was added 1-methyl-1H-imidazol-2-carbaldehyde (46 mg, 0,42 mmol). The reaction mixture was stirred in a sealed tube at 140°C for 19 hours. The crude mixture was quenched using H2O (10 ml), was extracted using EtOAc (3×10 ml) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of hexane/EtOAc with increasing polarity, to obtain 40 mg of the desired compound (31% yield).

LC-MS (method 1): tR=16,436 min; m/z=426 (MH+).

Following the procedure similar to that described in example 21, but using the appropriate initial matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
21A3-(8-(pyrimid�n-5-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril Example 1 section d and pyrimidine-5-carbaldehyde41,67424
21b3-(9-(8-ferroman-4-yl)-8-(pyrimidine-5-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilReference example 2E and pyrimidine-5-carbaldehyde116,34490
21c3-(9-(8-ferroman-4-yl)-8-(1-methyl-1H-imidazol-2-yl)-9H-purin-2-yl) pyrazolo[1,5-a]pyridin-5-carbonitrilReference example 2E and 1-methyl-1H-imidazol-2-carbaldehyde118,4492

21d2-(pyrazolo[1,5-a]pyridin-3-yl)-8-(1H-pyrrol-2-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purinReference example 2C and 1H-pyrrol-2-carbaldehyde32,15386
21e8-(5-methylthiophene-2-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purinReference note�R 2C and 5-methylthiophene-2-carbaldehyde 32,52417
21f8-(5-methyl-1H-imidazol-2-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purinReference example 2C and 1-methyl-1H-imidazol-2-carbaldehyde32,05401
21g2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-8-(2,2,2-trifluoroethyl)-9H-purinReference example 2C and 3,3,3-triptocaine32,22403
21h8-(1H-pyrazol-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purinReference example 2C and 1H-pyrazole-3-carbaldehyde31,83387
21i8-(1-methyl-1H-pyrrol-2-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purinReference example 2C and 1-methyl-1H-imidazol-2-carbaldehyde32,33400

21j2-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-8-yl) - thiazolReference example 2C and thiazol-2-carbaldehyde32,43404
21k2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-8-(thiophene-2-yl) -9H-purinReference example 2C and thiophene-2-carbaldehyde32,32403
21l(S)-3-(9-(1-acetylpiperidine-3-yl)-8-(pyrimidine-5-yl)-9H-purin-2-yl) pyrazolo[1,5-a]pyridin-5-carbonitrilReferential example 2, and pyrimidine-5-carbaldehyde31,8465
21m(S)-tert-butyl 3-(2-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylateReference example 2D and acetaldehyde32,60433

EXAMPLE 22

3-[8-(Ethylamino)-9-tetrahydro-2H-Piran-4-in-purin-2-yl]pyrazolo[1,5-a]pyridin-5-carbonitril

To a suspension of the compound obtained in example 1, section d (100 mg, 0,30 mmol), in CH2Cl2(2 ml) was added ethylisothiocyanate (0,042 ml, 0.48 mmol), EDC·HCl (171 mg, 0,89 mmol) and DIPEA (0.25 ml, 1.49 mmol). The reaction mixture was heated in a microwave oven CEM Explorer at 80°C and 150 Watt for 30 minutes. It was then evaporated to dryness. The thus obtained crude product was chromatographically on silica gel, using as eluent a mixture of MeOH/EtOAc with increasing polarity, to obtain 42 mg of the desired compound (36% yield).

LG-MS (method 1): tR=15,64 min; m/z=389 (MH+).

Following the procedure similar to that described in example 22, but using the appropriate initial matter, received the following connections:

3-(8-ethylamino)-9-(8-ferroman-4-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril
ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
22A3-(8-(pyridin-3-ylamino)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilExample 1 section d, pyridine-3-isothiocyanate116,20438
22bReference example 2E and utilizatio-cyanate1Is 17.07455
22c3-9-(8-ferroman-4-yl)-8-(pyridin-3-ylamino)-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilReference example 2E and pyridine-3-isothiocyanate1Gained 17.22504

EXAMPLE 23

8-Cyclopentyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin

To a solution of the compound of reference example 2c (0.05 g, 0.16 mmol) in DMF (1 ml) was added cyclopentanecarboxaldehyde (0,018 ml, 0.17 mmol) and sodium bisulfite (0.030 g, 0.29 mmol). The reaction mixture was stirred at 130°C for 6 hours. The solvent was evaporated and the crude residue was chromatographically to flash the system with silica gel (ISCO Companion), using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain 37 mg of the desired product (60% yield).

LC-MS (method 3): tR=2,40 min; m/z=389 (MH+).

Following the procedure similar to that described in example 23, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
23a(S)-3-(9-(1-acetylpiperidine-3-yl)-8-ethyl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilReferential example 2 and Propionaldehyde52,42415

23b(S)-3-(9-(1-acetylpiperidine-3-yl)-8-isopropyl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilReferential example 2 and Isobutyraldehyde52,57429
23c(S)-3-(9-(1-acetylpiperidine-3-yl)-8-methyl-9H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilReferential example 2 and acetaldehyde31,78401
23d8-cyclopropyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin Reference example 2C and cyclopropane-carbaldehyde32,05361

EXAMPLE 24

(S)-3-(1-Acetylpiperidine-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he

To the solution of compound of example 6g (250 mg, of 0.65 mmol) in pyridine (10 ml) was added acetyl chloride (0,92 ml, 1.3 mmol). The reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated and the crude residue was chromatographically to flash the system with silica gel (SP1 biotage AB), using as eluent a mixture of EtOAc/MeOH with increasing polarity, to obtain 196 mg of the desired product (78% yield).

LC-MS (method 4): tR=Of 1.66 min; m/z=391 (MH+).

Following the procedure similar to that described in example 24, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
24A(S)-1-methyl-3-(1-Jaloliddin-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-he Example 6g and pualeilani42,10433
24b(S)-3-(1-(4-fluorobenzoyl)peridin-3-yl)-1-methyl-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and 4-fluorobenzoyl chloride42,11472
24c(S)-1-methyl-3-(1-Propionaldehyde-3-yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-2(3H)-heExample 6g and propionyl chloride4To 1.79405

EXAMPLE 25

(S)-1-(3-(1-Methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile

To a solution of 1-cyano-1-cyclopropanecarbonyl acid (65 mg, of 0.58 mmol) in DMF (7 ml) was added DIEA (0,31 ml, 1.7 mmol), the compound of example 6g (248 mg, 0,64 mmol) and HBTU (266 mg, 0,70 mmol). The reaction mixture was stirred at room temperature over night. The solvent was evaporated and the crude residue was chromatographically to flash the system with silica gel (SP1 biotage AB), using as eluent a mixture of EtOAc/MeOH with increasing polarity, to obtain the desired compounds�ia with a quantitative yield.

LC-MS (method 4): tR=1,92 min; m/z=442 (MH+).

Following the procedure similar to that described in example 25, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
25A9-(1-isobutylpyrazine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6d and isobutyric acid41,59405
25b9-(1-(2-(dimethylamino)acetyl)piperidine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6d and 2-(dimethylamino)-acetic acid4To 1.34421

EXAMPLE 26

(S)-Methyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate

To the solution of compound of example 6 (200 mg, 0,26 mmol) in DMF (2.6 ml) was added methylchloroform (27 mg, 0.28 mmol) and DIPEA (0,068 ml, 0.39 mmol). The reaction semipermissive at room temperature over night. The reaction mixture was evaporated under reduced pressure, was dissolved in CH2Cl2and washed three times with saturated aqueous solution of NaHCO3. The combined organic phases were dried over MgSO4and concentrated to dryness. The crude residue was chromatographically to flash the system with silica gel (ISCO Combiflash) using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain 36 mg of the desired product (32% yield).

LC-MS (method 5): tR=2,37 min; m/z=419 (MH+).

Following the procedure similar to that described in example 26, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
26a(S)-ethyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylateExample 6 and tilhar-formate52,63433
26b(S)-isobutyl 3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-�CSR-7H-purin-9(8H)-yl)piperidine-1-carboxylate Example 6 and isobutyl-chloroformate52,82461

5
26c(S)-3-(2-(5-cyanopyridyl[1,5-5a]pyridine-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-isopropylpiperazine-1-carboxamideExample 6 and isopropyl-isocyanate52,33446
26d(S)-N-tert-butyl-3-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-piperidine-1-carboxamideExample 6 and tert-utilitzant52,52460
26e(S)-ethyl-9-(1-(2-cyanoacetyl)piperidine-3-yl)-8-oxo-2-pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purine-7-carboxylateExample 7f and tilhar-formate52,62475
26f(S)-3-(3-(7-acetyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)-piperidine-1-yl)-3-oxopropanenitrileExample 7f and acetyl chloride2,60445
26g(S)-9-(1-acetylpiperidine-3-yl)-7-methyl-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-8(9H)-heExample 6u and acetyl chloride31,80392

26h(S)-N-isopropyl-3-(1-methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)-piperidine-1-carboxamideExample 7P and isopropyl-isocyanate41,85434
26i(S)-3-(3-(1-acetyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-1H-imidazo[4,5-b]pyridin-3(2H)-yl)-piperidine-1-yl)-3-oxopropanenitrileExample 7P and acetyl chloride42,01444
26j(S)-ethyl-3-(1-(2-cyanoacetyl)-piperidine-3-yl)-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxylateExample 7P and tilhar-formate41,97 474

EXAMPLE 27

(S)-3-(9-(1-(1-Cyanocyclohexane)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

Following the procedure similar to that described in example 25, but using HATU instead of HBTU, and the compound of example 6 instead of the compound of example 6g, was obtained the desired compound (30% yield).

LC-MS (method 3): tR=To 1.87 min; m/z=454 (MH+).

Following the procedure similar to that described in example 27 but using the appropriate initial matter, received the following connection:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
27A(S)-3-(9-(1-(1-hydroxycyclopent-carbonyl)piperidine-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitrilThe compound of example 6 and hidroxizina-propanganda acid31,7455

EXAMPLE 28

(R)-3-(9-(1-Hydroxypropan-2-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To the solution of compound of example 14 (60 mg, 0.17 mmol) in THF (10ml) at 0°C was added a complex of 1M THF.borane in the form of a solution in THF (0,69 ml, 0,69 mmol). The reaction mixture was stirred at room temperature overnight, quenched with the aid of MeOH (10 ml) and the reaction mixture was evaporated under reduced pressure. The crude residue was chromatographically to flash the system with silica gel (ISCO Combiflash) using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain 4 mg of the desired product (7% yield).

LC-MS (method 3): tR=2,02 min; m/z=336 (MH+).

EXAMPLE 29

(S)-3-(3-(2-(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9-yl)piperidine-1-yl)-3-oxopropanenitrile

a) (S)-tert-Butyl 3-(2-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9-yl)piperidine-1-carboxylate

Following the procedure similar to that described in example 18, but using the compound of reference example 2A instead of the compound obtained in example 1, section d, was obtained the desired compound (10% yield).

LC-MS (method 3): tR=2.53 min; m/z=434 (MH+).

b) (S)-2-(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9-(piperidine-3-yl)-9H-parigidownload

Following the procedure similar to that described in example 6, but using the compound obtained in the previous section, was obtained the desired compound (quantitative yield).

LC-MS (method 3): tR=1,7 min; m/z=334 (MH+).

(c) Specified in the header connection

Following the procedure similar to that described in example 7, but using the compound obtained in the previous section, was well received�lemoe compound (57% yield).

LC-MS (method 3): tR=1,78 min; m/z=401 (MH+).

EXAMPLE 30

1-(4-(2-(Pyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9-yl)piperidine-1-yl)alanon

a) 9-(piperidine-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-parigidownload

Following the procedure similar to that described in example 29 section a and b, but using the compound obtained in reference example 2b instead of the compound of reference example 2a, was obtained the desired compound (10% yield).

(b) Specified in the header connection

Following the procedure similar to that described in example 24, but using the compound obtained in the previous section, was obtained the desired compound (quantitative yield).

LC-MS (method 4): tR=1.35 min; m/z=362 (MH+).

EXAMPLE 31

(S)-(9-(1-(2-Cyanoacetyl)piperidine-3-yl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methyl acetate

a) (S)-tert-Butyl 3-(7-(acetoxymethyl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate

Following the procedure similar to that described in example 4, but using the compound obtained in example 3b instead of the compound of example 1 and Bromeliaceae instead of methyliodide, was obtained the desired compound (83% yield).

LC-MS (method 3): tR=2.72 min; m/z=508 (MH+).

b) (S)-(8-Oxo-9-(piperidine-3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methylacetylene

Following the procedure similar to that described in example 6, but used�using the connection obtained in the previous section, was obtained the desired compound (quantitative yield).

LC-MS (method 3): tR=1.80 min; m/z=408 (MH+).

(c) Specified in the header connection

Following the procedure similar to that described in example 7, but using the compound obtained in the previous section, was obtained the desired compound (36% yield).

LC-MS (method 3): tR=1.82 min; m/z=475 (MH+).

Following the procedure similar to that described in example 31, but using the appropriate initial matter, received the following connection:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
31A(S)-3-(1-(2-cyanoacetyl)piperidine-3-yl)-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl acetateThe compound of example 7R41,84474

EXAMPLE 32

(R)-3-(9-(1-Hydroxypropan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To the solution of compound of example 28 (20 mg, 0,06 mmol) in AcN (2 ml) and DMF (0.5 ml) was added ACS�d silver(I) (28 mg, 0,12 mmol) and methyliodide (0,006 ml, 0.09 mmol). The reaction mixture was stirred at room temperature over night. The reaction mixture was filtered through a layer of celite® and the solvent was evaporated under reduced pressure. The crude residue was chromatographically to flash the system with silica gel (ISCO Combiflash) using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain 6 mg of the desired product (29% yield).

LC-MS (method 3): tR=To 1.75 min; m/z=350 (MH+).

EXAMPLE 33

2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-8-amine

To a solution of the compound of reference example 2c (144 mg, 0.46 mmol) in EtOH (4 ml) was added cyanogenmod (147 mg, of 1.39 mmol). The reaction mixture was stirred at 70°C overnight. The reaction mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed three times with a saturated aqueous solution of NaHCO3. The combined organic phases were dried over MgSO4and concentrated to dryness. The crude reaction mixture was used for next step without further purification.

LC-MS (Method 3): tR=1,53 min; m/z=336 (MH+)

EXAMPLE 34

1-(2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-8-yl)pyrrolidin-2-he

To a suspension of the compound of example 33 (25 mg, of 0.075 mmol) in DMF (1.5 ml) was added DIPEA (0.04 ml, 0.22 mmol) and 4-bromobutyrate (0.01 ml, 0,082 mmol�). The reaction mixture was stirred at room temperature over night. The solvent was evaporated to dryness and received 1.7 mg specified in the title compound (yield 6%) after purification using preparting HPLC.

LC-MS (method 3): tR=1.82 min; m/z=404 (MH+)

Following the procedure similar to that described in example 34, but using in each case corresponding to the source of matter, received the following connections:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z(ΜH+)
34aN-(2-pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-8-yl)-isobutyramideExample 33 and isobutyrate31,97406
34bN-(2-pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-8-yl)-propionamideExample 33 and propionate31,77392
34cN-(2-PI�azolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-Piran-4-yl)-9H-purin-8-yl)acetamide Example 33 and acetyl chloride31,60378

EXAMPLE 35

3-(9-(TRANS-4-Hydroxycyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

a) 3-(9-(TRANS-4-(tert-butyldimethylsilyloxy)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

To a suspension of compound of example 1o (584 mg, 1,55 mmol) in DMF (15 ml) was added imidazole (265 mg, 3,89 mmol) and tert-BUTYLCARBAMATE (281 mg, 1.86 mmol). The reaction mixture was stirred at room temperature over night. The solvent was evaporated to dryness, the mixture was dissolved in CH2Cl2and washed three times with water. The combined organic phases were dried over MgSO4and concentrated to dryness. The crude reaction mixture was used for next step without further purification.

LC-MS (method 3): tR=3.38 min; m/z=490 (MH+)

b) 3-(9-(TRANS-4-(tert-butyldimethylsilyloxy)cyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridin-5-carbonitril

Following the procedure similar to that described in example 5, but using the compound obtained in the previous section, was obtained the desired compound (72% yield).

LC-MS (method 2): tR=3,67 min; m/z=504 (MH+).

(c) Specified in the header connection

To the suspension .. �t, obtained in the previous section (246 mg, 0,488 mmol) in AcN (10 ml) at 0°C was added 1M solution of TBAF in THF (0,73 ml, 0,73 mmol). The reaction mixture was stirred at room temperature over night. The solvent was evaporated to dryness, the mixture was dissolved in EtOAc and washed three times with water. The combined organic phases were dried over MgSO4and concentrated to dryness. The crude residue was chromatographically to flash the system with silica gel (ISCO Combiflash) using as eluent a mixture of CH2Cl2/MeOH with increasing polarity, to obtain 77 mg of the desired product (40% yield).

LC-MS (method 3): tR=To 1.82 min; m/z=390 (MH+).

EXAMPLE 36

2-(2-(5-Cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2,2,2-trifluoroethyl)acetamide

a) 2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)acetic acid

Following the procedure similar to that described in example 14, but using the compound obtained in example 1n instead of the compound of example 1a, was obtained the desired connection.

LC-MS (method 3): tR=1,05 min; m/z=336 (MH+).

(b) Specified in the header connection

Following the procedure similar to that described in example 15 but using the compound obtained in the previous section, and 2,2,2-triptorelin, got the desired connection.

LC-MS (method 3): tR=1,065 min; m/z=417 (MH+).

Following the procedure similar to that described in example 36, but using�yn corresponding to the source of the substance, received the following connection:

ExampleNameThe original substanceThe HPLC methodtR(min)m/z
(MH+)
36A2-(2-(5-cyanopyridyl[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-ethylacetamideN-ethylamine31,40363

EXAMPLE 37

2-(Imidazo[1,2-a]pyridin-3-yl)-7-methyl-9-(tetrahydro-2H-Piran-4-yl)-7H-purin-8(9H)-he

a) 2-Chloro-N-4-(tetrahydro-2H-Piran-4-yl)pyrimidine-4,5-diamine

Following the procedure similar to that described in example 1, section d, but using the compound obtained in example 1, section a, instead of the compound obtained in example 1, section c, was obtained the desired compound (quantitative yield).

LC-MS (method 1): tR=6,73 minutes; m/z=229 (MH+).

b) 2-Chloro-9-(tetrahydro-2H-Piran-4-yl)-7H-purin-8(9H)-he

Following the procedure similar to that described in example 1, part e, but using the compound obtained in the previous section, instead of the compound obtained in example 1, section d, was obtained the desired compound (83% yield).

LC-MS (method 1): tR=Made 7.16 interest min; m/z=254 (MH+).

) 2-chloro-7-methyl-9-(tetrahydro-2H-Piran-4-yl)-7H-purin-8(9H)-he

Following the procedure similar to that described in example 5, but using the compound obtained in the previous section, instead of the compound obtained in example 3b, was obtained the desired compound (58% yield).

LC-MS (method 1): tR=7,51 min; m/z=268 (MH+).

(d) Specified in the header connection

To a suspension of the compound obtained in the previous section (30 mg, 0.11 mmol) in EtOH (0.5 ml) and dioxane (1 ml) was added imidazo[1,2-a]pyridine (16 mg, 0.13 mmol), triphenylphosphine (5,8 mg, 0,02 mmol), potassium carbonate (3.1 mg, 0,22 mmol) and palladium acetate(II) (2.5 mg, 0.01 mmol). The reaction mixture was heated in a microwave oven CEM Explorer at 110°C for 10 minutes and at 90°C for 3 hours. The reaction mixture was filtered through a layer of celite® and the solvent evaporated. The sample was purified using preparative HPLC.

LC-MS (method 4): tR=1.55 min; m/z=351 (MH+).

EXAMPLE 38

Inhibition of JAK3 activity

Inhibition of kinase activity of JAK3 was determined in 384-well analytical microplates using the set of Z'-Lyte®Kinase Assay kit-Tyr 6 Peptide kit supplied by Invitrogen (Ref: PV4122), in accordance with the manufacturer's instructions.

In the final volume of 10 μl per well of 2.5 μl of the product for the study, dissolved in 4% DMSO (the final concentration of the product tested of 0.1-10000 nm) was incubated with 0.3 mg/ml of the catalytic domain of human JAK3 (amino acid followers�nost 281-1124), 2 μm peptide substrate Z'-Lyte®Tyr 6 and 4 μm ATP; all components were dissolved in 50 mm pH 7.5 Hepes buffer, 10 mm magnesium chloride(II), 1 mm EGT and 0.01% Brij®35. The reaction was started by adding the indicated 4 μm ATP; after incubation for 1 hour at 25°C was added 5 ál of reagent exhibiting Z'-Lyte® Tyr 6 and the mixture is incubated for 1 hour at 25°C. was Then carried out quantitative determination of phosphorylation in each well using a Safire2®tablet reader to opredeleniya fluorescence from the company Tecan.

Compounds 1-1b, 1d-1j, 1n-1p, 1s, 2, 2e, 3-3e, 3h-3i, 4, 4b-5i, 5s, 6-6b, 6d-6f, 6x, 7-7d, 7f-16a and 16c-17a, 17c-19, 20-29, 31-37 showed over 50% inhibition of JAK3 activity at 1 μm in this analysis.

EXAMPLE 39

The inhibition of the activity of JAK2

Inhibition of kinase activity of JAK2 was determined in 384-well analytical microplates using the set of Z'-Lyte®Kinase Assay kit-Tyr 6 Peptide kit supplied by Invitrogen (Ref: PV4122), in accordance with the manufacturer's instructions.

In the final volume of 10 μl per well of 2.5 μl of the product for the study, dissolved in 4% DMSO (the final concentration of the product tested of 0.1-10000 nm) was incubated with 0.5 mg/ml of the catalytic domain of human JAK2, 2 μm peptide substrate Z'-Lyte®Tyr 6 and 16 μm ATP; all components were dissolved in 50 mm pH 7.5 Hepes buffer, 10 mm magnesium chloride(II), 1 mm EGT and 0.01% Brij®35. The reaction was started put�m adding the specified 16 μm ATP; after incubation for 1 hour at 25°C, was added 5 ál of reagent exhibiting Z'-Lyte® Tyr 6 and the mixture is incubated for 1 hour at 25°C. was Then carried out quantitative determination of phosphorylation in each well using a Safire2®tablet reader to opredeleniya fluorescence from the company Tecan.

Compounds 1-1b, 1e-1g, 1n-1p, 1s, 2, 2e, 3, 3b, 3d, 3e, 4, 4c, 5, 5a, 5b, 5e, 5f, 5h, 5i, 5s, 7-7c, 7f-7n, 7p, 7r-7u, 8-8c, 8d, 8f-8h, 9a, 9b, 9c, 9f, 9g, 9i, 9k, 9m-9s, 10a, 10b, 10e, 10h, 10i, 10k, 101, 10m, 10n, 13b-13k, 15-15b, 15f, 15h, 15i, 15k, 16, 16a, 16d-16f, 17-17c, 18a, 18b, 18d-18i, 19, 20, 21A-21d, 21g-21i, 21k, 22-23, 23d, 24, 24a, 24b, 24c, 25, 26, 26a, 26c, 26d, 26e, 26f, 26g, 27, 27a, 29, 31, 33, 34, 34b, and 35-36A showed over 50% inhibition of JAK2 activity at 1 μm in this analysis.

EXAMPLE 40

The definition of clearance in human liver

A single concentration (1 μm in buffer pH 7,4) test compounds were incubated with liver microsomes for 0, 10, 30 and 60 minutes at 37°C (0.4 mg protein/ml). The degree of metabolism in liver was measured using LC-MS/MS as a reduction of the peak area of the parent compound and expressed as a characteristic clearance.

Several compounds of the present invention were tested in this analysis.

EXAMPLE 41

Analysis of cytotoxicity in cells Hep G2

Alamar blue (AB) was used to assess the possible toxicity of the test compounds on cells of the hepatocyte carcinoma (HepG2). Cells (20,000 cells/well) to�was litererally in 96-well plates in the presence of compounds at various concentrations (1-20 μm), containing 0.2% DMSO, for 72 hours at 37°C. After addition of AB fluorescence was measured. The calculated value EC50defined as the concentration of a compound that leads to lower AB fluorescence equal to 50% of the control.

Several compounds of the present invention were tested in this analysis.

1. The compound of formula I or II

where
And is the carbon and represents nitrogen or a is a nitrogen and b is a carbon;
W represents CH or N;
R1and R2, independently, represent hydrogen, C1-4alkyl, Halogens1-4alkyl, -CN;
R3represents C1-4alkyl, R9-Cl-4alkyl, Cy1where Cy1optionally substituted by one or more substituents R10;
R4represents hydrogen, C1-4alkyl, Rl2R7N-C0alkyl, where one of R7and R12represents hydrogen and the other represents C1-4alkyl or a group R13choice of C1-5of alkyl, Cy2-C0alkyl;
R5represents hydrogen;
R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16And CO0alkyl, Cy1;
R 7represents hydrogen or C1-4alkyl;
R9represents halogen, -CN, -CONR7R12, -COR13That CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12;
R10represents C1-4alkyl or R9-C0-4alkyl;
R11represents C1-4alkyl, halogen, -CN, -NR7R14;
R12represents hydrogen or R13;
R13represents C1-5alkyl, hydroxys1-4alkyl, tsianos1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2optionally substituted by one or more substituents R11;
R14represents hydrogen or C1-4alkyl;
R16represents C1-4alkyl, Halogens1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl or cyanos1-4alkyl;
Cy1represents a monocyclic carbocyclic unsaturated or saturated ring selected from C3-C6cycloalkyl, phenyl, or a saturated monocyclic 4-6-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring containing an oxygen atom as heteroatom,which may be substituted by a group R 11where the specified ring is connected to the rest of the molecule through any available atom, and where one or more ring atoms or S optionally oxidized to form CO or SO2; and
Cy2is a monocyclic saturated carbocyclic ring selected from C3-C6cycloalkyl, or aromatic monocyclic 4 to 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N and S, or an unsaturated 10-membered bicyclic heterocyclic ring containing an oxygen atom as heteroatom, which may be substituted by a group R11where the specified ring is connected to the rest of the molecule through any available atom, or N;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1 of formula II.

3. The compound according to any one of claims. 1 and 2, in which a represents nitrogen and is the carbon.

4. The compound according to any one of claims. 1 and 2, in which R1represents hydrogen or-CN.

5. The compound according to claim 4, in which R1represents N.

6. The compound according to any one of claims. 1 and 2, in which R2represents hydrogen.

7. Connection according to claims. 1 and 2, wherein Cy1in R3is a monocyclic saturated carbocyclic ring, representing the C3-C6cyclea�Kil, or a saturated monocyclic 5-6-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N and S, where the specified ring is connected to the rest of the molecule through any available atom, and where one or more ring atoms or S optionally oxidized to form CO or SO2; and where specified Cy1optionally substituted by one or more substituents R10.

8. The compound according to claim 1, wherein R3is piperidinyl or pyrrolidinyl, which are optionally substituted by one or more substituents R10.

9. The compound according to claim 8, in which R3is a piperidine-3-yl or pyrrolidin-3-yl, which are optionally substituted by one or more substituents R10.

10. The connection according to claim 9, in which R3is a cycle of formula
or

11. The compound according to claim 10, wherein R3is a cycle of formula Cy1a.

12. The compound according to claim 11, in which Cy1ahas (S) stereochemistry.

13. The compound according to claim 10, wherein R3is a cycle of formula Cy1b.

14. The compound according to claim 10, wherein R10is an R9-C0-4alkyl, i.e., where R10is an R9.

15. The compound according to claim 11, in which R10 is an R9,and R9represents-COR13or-SO2R13.

16. The compound according to claim 1 or 2, wherein R13represents C1-4alkyl or cyanos1-4alkyl.

17. The compound according to claim 16, in which R13is methyl, isopropyl or cyanomethyl.

18. The compound according to claim 1, wherein R6represents hydrogen, C1-4alkyl, C1-4alkoxyl1-4alkyl, hydroxys1-4alkyl, R12R7N-C1-4alkyl, R16And CO0alkyl, Rl6CO2-C0-4alkyl, Cy1.

19. The compound according to claim 1 or 2, wherein R6represents C1-4alkyl.

20. The connection according to claim 19, in which R6is methyl or ethyl.

21. The compound according to claim 18, in which R6represents hydrogen or C1-4alkyl.

22. The compound according to claim 1, which is an (S)-3-(3-(1-methyl-2-oxo-5-(pyrazolo-[1,5-a]pyridin-3-yl)-1H-imidazo-[4,5-b]pyridin-3(2H)-yl)piperidine-1-yl)-3-oxopropanenitrile or its pharmaceutically acceptable salt.

23. Pharmaceutical composition having the properties of JAKs inhibitor containing the compound according to any one of claims. 1-22 or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.

24. The compound according to claim 1 or its pharmaceutically acceptable salt for use in �ERPII as a drug for the treatment of diseases, mediated by JAKs.

25. The compound according to claim 1 or its pharmaceutically acceptable salt for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3.

26. The compound according to claim 1 or its pharmaceutically acceptable salt for the treatment or prophylaxis of a disease selected from asthma and chronic obstructive pulmonary disease (COPD).

27. The compound according to claim 1 or its pharmaceutically acceptable salt for use in treating or preventing asthma or chronic obstructive pulmonary disease (COPD).



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to anhydrous crystalline vinflunine salts of general formula (I) prepared with 1 or 2 equivalents of a pharmaceutically acceptable inorganic or organic acid. . In formula (I) [The acid] represents hydrobromic, lactic or fumaric acid for a group of water-soluble crystalline salts, as well as para-toluenesulphonic, benzoic, mandelic and para-hydroxybenzoic acid for a group of relatively water-insoluble crystalline salts.

EFFECT: preparing the anhydrous crystalline vinflunine salts.

8 cl, 8 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of vinflunine ditartrate, production method thereof and use thereof in therapy, especially for cancer pathology treatment.

EFFECT: high stability and wide variety of galenic forms.

8 cl, 3 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivative of purinylpyridinylamino-2,4-difluorophenylsulphonamide of formula 1 and its pharmaceutically acceptable salt. Compounds have properties of inhibiting Raf-kinase super activity and can be applied for prevention and treatment of diseases, mediated by activity of Raf-kinase, such as cancer, in particular melanoma. In formula 1 R stands for methyl; ethyl; propyl; isopropyl, butyl, isobutyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C5-C6aryl, unsubstituted or substituted with one or more substituents, selected from the group, which consists of chlorine, fluorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, fluoromethoxy, difluorimethoxy and trifluoroethoxy; C5-C12heteroaryl, which consists of one or two rings, non-substituted or substituted with one or more substituents, selected from the group, which consists of chlorine, fluorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tret- butoxycarbonyl and dioxolanyl; C5-C6heterocycloalkyl, non-substituted or substituted with one or more substituents, selected from the group, which consists of chlorine, fluorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl; or C5-C6aryl-linear or branched C1-C6alkyl, non-substituted or substituted with one or more substituents, selected from the group, which consists of chlorine, fluorine, bromine, nitro, methyl, ethyl, propyl, isopropyl, butyl and isobutyl, and heteroaryl and heterocycloalkyl contain in ring one or more heteroatoms, selected from the group, which consists of N, O and S. Invention also relates to methods of obtaining formula 1 compounds.

EFFECT: improvement of characteristics.

15 cl, 3 tbl, 51 ex 1 dwg

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.

SUBSTANCE: invention refers to medicine, namely to psychiatry and drug addiction, and may be used for detoxification-infusion therapy of the patients used psychotropic cannabis products. That is ensured by the infusion intravenous drop-by-drop sequential administration of drugs. A mixture containing 5% glucose 200 ml, 25% magnesium sulphate 10 ml and 4% potassium chloride 10 ml are administered. That is combined with the additional bolus administration of 5% vitamin B1 2 ml. That is followed by introducing a mixture containing 0.9% normal saline 200 ml and 20% piracetam 10 ml. That is added with the bolus administration of 5% vitamin B6 10 ml. Then, a mixture containing rheopolyglucin 200 ml, 5% ascorbic acid 5 ml and 1% nicotinic acid 1 ml is administered. Then, a mixture containing 0.9% normal saline 200 ml and 2.4% aminophylline 5 ml is administered. The procedure is performed twice a day for 10 days.

EFFECT: method provides the higher therapeutic effectiveness and reduced length of the therapy, as well as the presented method is reproducible easily.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to using a purine derivatives for preparing drug preparations for treating chronic lymphocytic leukaemia and polycystic kidneys.

EFFECT: invention provides preparing the compounds possessing higher activity on lymphocytic leukaemia and polycystic kidneys.

8 cl, 3 dwg, 1 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new heteroaryl compounds of general formula (I) and their pharmaceutically acceptable salts possessing the properties of protein kinase inhibitor, such as mTOR, IKK-2, Tyk2, Syk-kinase. In formula (I) R1 represents substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl, specified in phenyl, substituted or unsubstituted 5-6-member heteroaryl with 1-3 nitrogen atoms in a cycle specified in pyridine, pyrazole, indole, indazole, triazole, benzimidazole, 2-(1H-imidazo-[4,5-b]pyridine, substituted or unsubstituted 5-7- member cycloalkyl or substituted or unsubstituted heterocycloalkyl specified in pyrrolidinyl; -X-A-B-Y- taken together form -N(R2)CH2C(O)NH-, -N(R2)C(O)CH2NH-, -N(R2)C(O)NH-, -N(R2)C=N- or -C(R2)=CHNH-; L represents a direct bond, NH or O; R2 represents substituted or unsubstituted C1-8alkyl, substituted or unsubstituted aryl specified in phenyl, tetrahydronaphthalene, unsubstituted 5-7- member mono- or 8- member bicycloalkyl; and R3 and R4 independently represent H or C1-8alkyl. The substitutes in the substituted groups are specified in one or more halogen, C1-8alkyl, hydroxyl, amino, nitro, thiol, C1-4alkyl thioether, cyano, carboxyl, C1-4alkyl ester, halogen alkyl, C6cycloalkyl or heteroaryl specified in pyridyl, triazole, O-lower alkyl, aryl specified in phenyl, phenyl-lower alkyl, CO2CH3, CONH2, OCHF2, CF3 or OCF3 groups wherein CONH2 group may be substituted by cyclohexyl.

EFFECT: compounds can find application for treating or preventing cancer, inflammatory pathological conditions, metabolic pathological conditions.

24 cl, 8 dwg, 2 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: disclosed agent is a xanthine derivative of formula 1

, where R1 denotes CH3, R2 denotes CH3; R3 denotes halogens: F,Cl, Br, I; R4 denotes hydrogen; R1 denotes CH3, R2 denotes CH3; R3 denotes hydrogen, halogens: F, Cl, Br, I; R4 denotes CH2COOH; R1 denotes hydrogen, R2 denotes CH3; R3 denotes halogens: F, Cl, Br, I; R4 denotes CH3. The preferred compounds of the said agent are 8-chlorotheophylline, 8-bromotheophylline and theophylline-7-acetate. The invention also relates to a method of slowing down proliferation of tumour cells and a method of inducing differentiation in mouse melanoma B16-F10 cells. Each of the methods involves addition of an effective amount of the said agent in an effective amount, preferably in amount of 1 mM.

EFFECT: improved properties of the derivatives.

8 cl, 4 tbl, 12 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which inhibit HIV replication, of formula (I) , its pharmaceutically acceptable additive salt; or stereochemically isomer form, where -a1=a2-a3=a4-represents bivalent radical of formula -CH=CH-CH=CH- (a-1); -b1=b2-b3=b4 -represents bivalent radical of formula -CH=CH-CH=CH- (b-1); n represents 0; m represents 1, 2; -A-B- represents bivalent radical of formula -CR5=N- (c-1); -N=N- (c-2); -CH2-CH2- (c-3); -CS-NH- (c-4); -CH=CH- (c-6); R1 represents hydrogen; R2a represents cyano; R3 represents cyano-substituted C1-6alkyl; cyano-substituted C2-6lkenyl; each of R4 independently represents halogen or C1-6alkyl; Q represents hydrogen or C1-6alkyl; R5 represents hydrogen, C1-6alkyl, aryl, pyridyl, thienyl, furanyl, amino, mono- or di(C1-4alkyl)amino, where aryl represents phenyl. Invention also relates to pharmaceutical composition, application and method of obtaining compounds.

EFFECT: obtaining novel compounds, which inhibit HIV replication.

5 cl, 25 dwg, 7 tbl, 16 ex

Novel compounds // 2395511

FIELD: chemistry.

SUBSTANCE: present invention relates to novel xanthine derivatives of general formula (I) and their pharmaceutically acceptable salts which have HM74A receptor activity, which can be used in therapy for treating diabetic dyslipidemia, combined dyslipidemia, heart failure, hypercholesteremia, atherosclerosis, arteriosclerosis, hypertriglyceridemia, type II sugar diabetes, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic kidney disease, peripherical vascular disease or stroke. In compounds of formula (I) , R1 is hydrogen or methyl; R2 is unsubstituted H-C4-6 alkyl; and R3 is chlorine.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on the said novel xanthine derivatives.

15 cl, 54 ex

FIELD: medicine, pharmacology, organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) promoting the defecation. Also, invention relates to a pharmaceutical composition containing these compounds and a method for promoting defecation and a method for treatment or relief of constipation. Proposed compounds possess the enhanced effectiveness.

EFFECT: valuable medicinal properties of pharmaceutical composition.

14 cl, 11 tbl, 55 ex

FIELD: organic chemistry, neurology, medicine.

SUBSTANCE: invention relates to a new medicinal agent used in treatment of feeble-mindedness comprising a derivative of 2-aryl-8-oxodihydropurine, namely, a derivative of 2-aryl-8-oxodihydropurine that comprises acetamide group at position 7 or 9 of purine ring. Invention proposes compounds of formulae (Ia) and (Ib) wherein radicals X1, Y1, R12, R13, R22, R23, R32, R42 and R43 have the corresponding values, or their pharmaceutically acceptable acid-additive salt. Also, invention proposes using compounds of the formulae (Ia) and (Ib) or their pharmaceutically acceptable acid-additive salt for preparing a medicinal agent used in treatment or prophylaxis of feeble-mindedness wherein feeble-mindedness represents deterioration of the teaching process, dysmnesia, dysmnesia-based disorientation, mental dysfunction, Alzheimer's disease, cerebrovascular feeble-mindedness and/or senile feeble-mindedness, and in treatment or prophylaxis of higher cerebral dysfunction. Invention provides the development of a medicinal preparation for prophylaxis or treatment of feeble-mindedness symptoms associated with diseases that can induce feeble-mindedness and higher cerebral dysfunction.

EFFECT: valuable medicinal properties of agents.

12 cl, 3 tbl, 5 ex

Ethinyl derivatives // 2553461

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I), their pharmaceutically acceptable salts, tautomers or stereoisomers. In formula R1 represents benzimidazolyl optionally substituted by C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, dimethylaminoC1-4alkyl or oxo group; benzioxazolyl optionally substituted by C1-4alkyl or amino group; benzotriazolyl optionally substituted by C1-4alkyl; dihydrobenzisothiazol-1,1-dionyl; pyrimidyl; dihydroisoquinolinonyl optionally substituted by oxo group; imidazopyridyl; indazolyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, tetrahydropyranylamino, piperidinylamino, halogen, trifluoromethyl or amino group; indolinyl optionally substituted by C1-4alkyl, hydroxyC1-4alkyl, carboxylate or oxo group; isoindolinyl optionally substituted by C1-4alkyl, aminoC1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or oxo group; phenyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, trifluoromethyl, carbamoyl, methylcarbamoyl, piperidinylcarbamoyl, methylpiperidinylcarbamoyl, aminoC1-4alkyl, carboxyl, amino, dialkylamino, imidazolyl, pyrrolidin-2-one, triazolyl, morpholinyl, C1-4alkylcarbonylamino, C1-4alkoxyC1-4alkoxy or hydroxyC1-4alkyl; pyrazolopyridyl optionally substituted by C1-4alkyl; pyridyl optionally substituted by C1-4alkyl, C1-4alkoxy, halogen, cyano, hydroxy, amino, morpholinyl, carbamoyl, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkoxy, aminoC1-4alkylamino, hydroxypiperidinyl, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, pyrrolidinylC1-4alkylamino, pyrrolidinylC1-4alkoxy; pyrrolopyridinyl optionally substituted by oxo group; quinolinyl optionally substituted by amino or hydroxy group; or triazolopyridyl substituted by C1-4alkyl. The other radical values are presented in the patent claim. The invention also refers to individual compounds, to a pharmaceutical composition, possessing kinase inhibitory activity and containing an effective amount of the compound of the invention, to a method for kinase inhibition in a cell, to a method of treating or preventing inflammatory conditions, immunological conditions, allergic conditions, rheumatic conditions, cancer, and neuroinflammatory diseases.

EFFECT: there are prepared new compounds possessing Syk, FLT3, JAK1, JAK2 inhibitory activity.

21 cl, 1 tbl, 133 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5,6-dihydropyrrolo[2,1-a]isoquinoline derivatives 1-4 having the general structural formula: , where 1 - R=CH3, 2 - R=CH2CH3, 3 - R=CH2CF3, 4 - R=CH(CH3)2, characterised by that 6,7-diethoxy-3,4-dihydro-1-(3,4-diethoxybenzoyl)isoquinoline is mixed with methyl propiolate and methane, or ethanol, or 2,2,2-trifluoroethanol, or isopropanol and stirred at temperature of +50°C, the precipitate obtained at the end of the reaction and after removing reagents, is crystallised in ether.

EFFECT: method of producing derivatives which can be used as intermediate compounds when producing biologically active compounds.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to dihydroazol compounds of formula (I) wherein R1 means a C1-C6alkyl or C1-C6haloalkyl; X means a phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C12alkyls, C3-C10cycloalkyls, C1-C12haloalkyls, C2-C12alkenyls, C2-C12haloalkenyls, C1-C12alkinyls or C1-C12haloalkynyls; A1 means hydrogen, and A2 means CR7R8; G means G-1 or G-2; B1, B2, B3, B4 and B5 independently mean N or C-R9; Y means Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8 or Y-9 (as it is presented in the patent claim); R2, R3 independently mean hydrogen, C1-C12alkyl, C1-C12haloalkyl, thio-C1-C12alkyl, C1-C12alkylthio-C1-C12alkyl, hydroxy-C1-C12alkyl, C1-C12alkoxy-C1-C12alkyl, C2-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl, C3-C10cycloalkyl; R4 independently means hydrogen, C1-C12alkyl, C1-C12haloalkyl, thio-C1-C12alkyl, C1-C12alkylthio-C1-C12alkyl, hydroxy-C1-C12alkyl, C1-C12alkoxy-C1-C12alkyl, C2-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl, C2-C12haloalkynyl or C3-C10cycloalkyl; R7 and R8 independently mean hydrogen, C1-C12alkyl or C1-C12haloalkyl; R9 means hydrogen, halogen, C1-C12alkyl, C1-C12haloalkyl, C1-C12alkenyl, C2-C12haloalkenyl, C2-C12alkynyl or C2-C12haloalkynyl; each R10, R11, R12 and R13 independently means hydrogen, C1-C12alkyl or C1-C12haloalkyl; or R10 together with R11 form =O, =S or =NR2; or R12 together with R13 form =O, =S or =NR2; n=1. The invention also refers to compositions for treating or preventing endoparasitic infections or ectoparasitic invasions in animals and for protecting crops, plants, planting stock or timber against pests, to a method of treating or preventing endoparasitic infections or ectoparasitic invasions in animals, to a method for protecting crops and growing plants against pest attacks or invasions, to a method for preventing or controlling a pest invasion on site, and to using the compounds of formula (I).

EFFECT: compounds of formula (I) applicable for preventing or treating endoparasitic infections or ectoparasitic invasions in animals, and also as pesticides

30 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, including: i) opening of epoxy cycle of Compound 3 by means of methylamine with obtaining compound 4, ii) separation of Compound 4 by means of chiral acid, selected from L-(-)-malic acid and L-(-)-pyroglutamic acid with obtaining Compound 5A or 5B, or iii protection of secondary amine of Compound 5A or 5B with tert-butoxycarbonyl protective group with obtaining compound 6 iv) methylation of free hydroxyl group of Compound 6 with methylating agent, v) removal of protection from amino groups by means of monohydrate of p-toluenesulphonic acid with obtaining Compound 8 and vi) interaction of Compound 8 with compound 10 with the following obtaining (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid.

EFFECT: method improvement.

29 cl, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

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