Pyrid-2-ones applicable as protein kinase inhibitors of tec family for treating inflammatory, proliferative and immunologically mediated diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to compounds applicable as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions containing the compounds of the invention and methods of using the compositions in the treatment of various disorders. The invention also provides methods of making compounds of the invention and intermediates applicable in these ways.

The LEVEL of TECHNOLOGY

The search for new therapeutic agents in recent years has helped better understanding of the structure of enzymes and other biomolecules associated with diseases. One of the important classes of enzymes that have been the subject of extensive research, are protein kinases.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of many processes, signal transmission within the cell (See, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II,Academic Press, San Diego, CA: 1995). Protein kinases are considered to be descended from a common ancestral gene due to the conservatism of its structure and catalytic function. Almost all kinases contain similar catalytic domain size of 250-300 amino acids. Kinases can be categorized into families depending on the substrate, which is neither phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc). Were identified sequence motifs that, in General, correspond to each of these families of kinases (See, for example, Hanks, S.K., Hunter, T.,FASEB J.1995, 9, 576-596; Knighton et al.,Science1991, 253, 407-414; Hiles et al.,Cell1992, 70, 419-429; Kunz et al.,Cell1993, 73, 585-596; Garcia-Bustos et al.,EMBO J. 1994, 13, 2352-2361).

In General, protein kinases mediate intracellular signaling, affecting the transfer of phosphoryla from nucleosidase to protein-acceptor, which is involved in the signaling pathway. These acts phosphorylation act as molecular switches that can cause or regulate the biological function of the target protein. These acts of phosphorylation ultimately initiated in response to a variety of extracellular and other incentives. Examples of such incentives include external and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (such as interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α)and growth factors (e.g. granulocyte-macrophage colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimulus may affect one or more cellular responses associated with cell growth, migration, differences vcoi, the secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

Many diseases are related to improper cellular responses triggered by protein kinases-mediated events, as described above. These diseases include, without limitation, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormonal disorders. Thus, in the field of medicinal chemistry was undertaken significant effort to find inhibitors of protein kinases, which are effective as therapeutic agents.

The TEC family preceptory tyrosinekinase plays a Central role in signaling through antigen receptors such as the TCR, BCR and Fcε receptors (reviewed in Miller A, et al., Current Opinion in Immunology 14;331-340 (2002)). Kinase of the TEC family, required for activation of T-cells. Three members of the TEC family, Itk, Rlk and TEC are activated during transcription by the interaction of antigen receptor in T-cells and transmit signals during the transcription effectors, including PLC-γ. Destruction of Itk in mice leads to reduced proliferation, induce vannoy T-cell receptor (TCR), and to the secretion of cytokines IL-2, IL-4, IL-5, IL-10 and IFN-γ (Schaeffer et al, Science 284; 638-641 (1999), Fowell et al., Immunity 11;399-409 (1999), Schaeffer et al Nature Immunology 2,12; 1183-1188 (2001)). Immunological symptoms of allergic asthma is reduced in mice Itk-/-. Pneumonia, eosinophilic infiltration and mucus formation is significantly reduced in Itk-/- mice in response to provocation OVA allergen (Mueller et al., Journal of Immunology 170: 5056-5063 (2003)). Itk was also involved in atopic dermatitis. It was reported that this gene had a higher level of expression in the T cells of peripheral blood in patients with moderate and/or severe atopic dermatitis than in control patients or patients with mild atopic dermatitis (Matsumoto et al, International archives of Allergy and Immunology 129; 327-340 (2002)).

Splenocytes of mice Rlk-/- secrete half of the IL-2 produced by the wild-type animals in response to the inclusion of TCR (Schaeffer et al, Science 284; 638-641 (1999)), whereas the combined destruction of Itk and Rlk in mice results in complete inhibition of TCR-induced responses, including proliferation and production of cytokines IL-2, IL-4, IL-5 and IFN-γ (Schaeffer et al Nature Immunology 2,12; 1183-1188 (2001)), Schaeffer et al, Science 284; 638-641 (1999)). In T-cells, deficient Itk/Rlk, impacts on the intracellular signaling after activation TCR; production of Inositol triphosphate, mobilization of calcium, activation of map kinase, and activation of the transcription factors NFAT and AP-1 are all reduce the tion (Schaeffer et al., Science 284; 638-641 (1999), Schaeffer et al. Nature Immunology 2,12; 1183-1188 (2001)).

Kinase of the TEC family also necessary for the development and activation of B-cells. Patients with mutations in Btk have a strong lock on the development of B-cells, which leads to the almost complete absence of B-lymphocytes and plasma cells, greatly reduced levels of Ig and complete inhibition of the humoral response to the secondary antigens (reviewed in Vihinen et al. Frontiers in Bioscience 5:d917-928). Mouse, deficient in Btk also have a reduced number of peripheral b cells and reduced levels of IgM and IgG3. The deletion of Btk in mice has a strong effect on the proliferation of b cells induced by anti-IgM, and inhibits immune responses to thymus-independent type II antigens (Ellmeier et al., J Exp Med 192:1611-1623 (2000)).

Tec kinases also play a role in the activation of mast cells through the high-affinity IgE receptor (FcεRI). Itk and Btk is expressed in mast cells and activated cross-linking FcεRI (Kawakami et al, Journal of Immunology; 3556-3562 (1995)). Murine mast cells, deficient in Btk have reduced degranulation and the reduced production of proinflammatory cytokines after cross-linking with FcεRI (Kawakami et al. Journal of leukocyte biology 65:286-290). The Btk deficiency also leads to reduction of the effector functions of macrophages (Mukhopadhyay et al, Journal of Immunology; 168, 2914-2921 (2002)).

Accordingly, there is a high need to develop compounds applicable as and the of gibilaro protein kinases. In particular, it would be desirable to develop compounds that are used as inhibitors of TEC family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases, particularly given the inadequate treatments currently available for most disorders associated with their activation.

The INVENTION

It was found that the compounds and pharmaceutically acceptable compositions of the present invention are effective as inhibitors of protein kinases. In certain embodiments of the implementation of these compounds are effective as inhibitors of TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases. These compounds have the formula I, as defined here, or are their pharmaceutically acceptable salt.

These compounds and their pharmaceutically acceptable compositions suitable for treatment or prophylaxis of various diseases, disorders or conditions including, including autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases. The composition is also applicable in the ways of prevention of thrombin-induced platelet aggregation. Compounds provided in accordance with the present invention are also applicable for the study of kinases in biological and ecologicheskih phenomena; to study the intracellular transmission of signals mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

The present invention provides methods of making compounds of the present invention and intermediates applicable in these ways.

DETAILED description of the INVENTION

The present invention describes compounds of Formula I:

or their pharmaceutically acceptable salt, where

each R3and R4independently is H, halogen or C1-4-aliphatic group, optionally substituted with halogen, C1-2-aliphatic group, OCH3, NO2, NH2CN, NHCH3, SCH3or N(CH)2;

R2is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R2optionally substituted JR;

each X1and X2independently is-C(O)-, -NR - or-SO2-where one of X1or X2is-NR -, and the other of X1or X2 is-C(O)- or-SO 2-;

R represents H, unsubstituted C1-6-aliphatic group;

R1represents-T-Q;

T is a bond or C1-6-aliphatic group in which up to three methylene units of the chain are optionally and independently replaced by G or G', where G is-NR5-, -O-, -S-, -SO-, SO2-, -CS - or-CO-; G' is cyclopropyl, C≡C or C=C; T necessarily replaced by the Jt;

Q independently is hydrogen, C1-6-aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q is optionally substituted JQ;

R5is optionally substituted by R, C6-10-aryl, C3-10-cycloaliphatic group, a 5-14-membered heteroaryl or 5 to 14-membered heterocyclic group; or two groups R5together with the atom(s)to which they are bound, form an optionally substituted 3-7-membered monocyclic or 8-14 membered bicyclic ring;

optional substituents JRI , JTand JQdefined here.

In certain variant of the x implementation of the present invention, provided that

when R2represents a 4-pyridyl or 3-pyridyl, R3represents H, X1represents-NR-, R is H, and X2represents-C(O)-; then

a) R1is not CH(CH3)OC(=O)CH3; CH2OC(=O)CH3; or CH2C(=O)CH3;

b) R1is not C1-6-alkyl or O(C1-6-alkyl);

when R2is a 4-pyridium, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-, then

a) when T is a bond, Q is not the stands, imidazole, OCH3or H;

b) when T is-CH2-, Q is not 3-OH-phenyl, 4-OH-phenyl, 4-pyridium, 3-NO2-phenyl, HE, -O(C=O)CH3or-C(=O)CH3;

c) when T is-CH(CH3)-, Q is not - OC(=O)CH3;

d) when T is-CH2CH2-, Q is not 2-pyridium or-COOH;

e) when T is CH(CH3) (=O)-, Q is CH3;

when R2is a 4-pyridium, R3is H, R4is not H, X1is-NR-, R is H, and X2is-C(O)-, then

a) when T is a bond, Q is CH3;

b) R1is not CH(CH3) (=O)CH3;

when R2is 2,4-pirimidinom, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-, then

a) R1n what is stands, NHCH3or-NHC(=O)NH2;

when R2is a 4-pyridium, R3and R4are H, X1is-NR-, R is H, and X2is-SO2-then

a) when T is a bond, Q is an optionally substituted C6-10-aryl or C5-10-heteroaryl;

when R2is a 4-thiazolyl, R3is H, R4is CH3X1is-C(O)-, X2is-NR-, R is H, then

a) when T is-CH2CH2-, Q is N(CH3)2;

when R2is unsubstituted phenyl, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-,

when T is C1-aliphatic group, where 1 link methylene chain is replaced by G; G is-NR5-; and R5is H, then Q is not 2,6-di-isopropylphenyl;

when R2is unsubstituted phenyl, R3is H, R4is CH3X1is-C(O)-, X2is-NR-, R is H, then

a) when T is a bond, Q is CH3or CH2CH3;

b) when T is-CH2CH2-, Q is not unsubstituted phenyl or N(CH2CH3)2;

c) when T is-CH2CH2CH2-, Q is N(CH2CH3)2;

d) R1is not NH2;

the hen R 2is unsubstituted phenyl, R3is H, R4is CH3X1is-NR-, R is H, X2is-C(O)-, then

a) when T is-O-CH2-, Q is not unsubstituted phenyl,

when R2is a 4-OCH3-phenyl, R3is H, R4is CH3X1is-NR-, R is H, X2is-C(O)-, then

a) when T is a bond, Q is CH3;

when R2is a 6-membered heteroaryl 2 astami; R3is H, stands or ethyl; R4is stands or ethyl; X1is-NR-, R is H, X2is-C(O)-, then

a) R1is CH3;

when X1is-C(O)-, X2is-NR-, R is H, then R1is not H or stands;

when R2is, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-, then R1is CH3;

when R2is unsubstituted phenyl, R3and R4are H, X1is-C(O)-, X2is-NR-, R is H, then

R1is not.

Other embodiments of the present invention provided that

when R2is a 4-pyridium, 3-pyridium or; R is H, X1is-NR-, R is H, and X2is-C(O)-; then

a) R1is not H, C1-6-alkyl, O(C1-6-alkyl), CH(CH3)OS(=O)CH3or imidazole;

b) when T is-CH2-, Q is not 3-OH-phenyl, 4-OH-phenyl, 4-pyridium, 3-NO2-phenyl, HE, OS(=O)CH3or-C(=O)CH3;

c) when T is-CH2CH2-, Q is not 2-pyridium or-COOH;

when R2is 2,4-pirimidinom, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-, then

a) R1is not the stands, NHCH3or-NHC(=O)NH2;

when R2is a 4-pyridium, R3and R4are H, X1is-NR-, R is H, and X2is-SO2-then

a) when T is a bond, Q is an optionally substituted C6-10-aryl or C5-10-heteroaryl;

when R2is a 4-thiazolyl, R3is H, R4is CH3X1is-C(O)-, X2is-NR-, R is H, then

a) when T is-CH2CH2-, Q is N(CH3)2; when R2is optionally substituted by phenyl, R3is H, X1is-NR-, R is H, and X2is-C(O)-, then

a) when T is C1-aliphatic group, where 1 methylene unit of the chain is replaced by n is G; G is-NR5-; and R5is H, then Q is not 2,6-di-isopropylphenyl;

b) when T is-O-CH2-, Q is not unsubstituted phenyl;

c) when T is a bond, Q is CH3;

when R2is unsubstituted phenyl, R3is H, X1is-C(O)-, X2is-NR-, R is H, then

a) when T is a bond, Q is CH3or CH2CH3;

b) when T is-CH2CH2-, Q is not unsubstituted phenyl or N(CH2CH3)2;

c) when T is-CH2CH2CH2-, Q is N(CH2CH3)2;

d) R1is not NH2or,

when R2is a 6-membered heteroaryl 2 astami; R3is H, stands or ethyl; R4is stands or ethyl; X1is-NR-, R is H, X2is-C(O)-, then R1is CH3;

when X1is-C(O)-, X2is-NR-, R is H, then R1is not H or stands.

Compounds of the present invention include compounds described in General above and further illustrated by the classes, subclasses, and species disclosed here. The following definitions used herein shall be used, unless specified otherwise. In accordance with the purposes of the present is the first invention, the chemical elements are identified in accordance with the Periodic table of Elements, the CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, General principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March''s Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which is hereby incorporated by reference.

As described herein, compounds of the invention can be optionally substituted by one or more substituents, such as shown in the above General or as specific classes, subclasses, and species of the invention. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In General, the term "substituted", whether prior to the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure on the radical of a specified substituent. Unless otherwise indicated, the group, which is optionally substituted, may have a substituent at each substitutable position of the group, and when more than one position in any given structure can be replaced by more than one Deputy, selected from a specified group, the Deputy may be either the same or different in each position. Combinations of substituents, estimated in accordance with the present invention are preferably those that result in the formation of stable is whether chemically plausible connection. The term "stable", as used here, refers to compounds that are not substantially altered when subjected to conditions necessary for their production, detection, and preferably their separation, purification, and use for one or more purposes, disclosed here. In some embodiments, implementation, stable compound or chemically probable connection are such compounds which do not significantly change during storage at 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term "optionally interrupted" refers to the replacement of one atom within alkylidene chain another atom. Unless otherwise specified, the second atom can replace the first atom in any position, including the end atoms. For example, C1-3is an alkyl chain, optionally interrupted by-O-, can form-OCH2CH3, -CH2-OCH3or CH2CH2OH. Unless otherwise specified, the end groups are associated with hydrogen on the terminal side.

Used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or which contains one or more units of unsaturation and the and monocyclic hydrocarbon or bicyclic hydrocarbon, which is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to here as "carbocyclic", "cycloaliphatic" or "cycloalkyl"), which has a single attachment point to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the implementation of the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, implementation of the aliphatic groups contain 1-8 aliphatic carbon atoms. In again other variants of implementation of the aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, the implementation of the aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, the implementation of "cycloaliphatic" (or "carbocyclic" or "cycloalkyl") refers to monocyclic C3-C8the hydrocarbon or bicyclic C8-C12the hydrocarbon which is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single attachment point to the rest of the molecule, where any individual ring in the specified bicyclic ring system has 3-7 members. On the walking aliphatic groups include, in addition, linear or branched, substituted or unsubstituted alkyl, alkeline, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkeneamine.

It should be clear that the ring system may be linearly condensed, bridged or spirocyclohexane.

Used herein, the term "heteroaromatics" means aliphatic group in which one or two carbon atoms are independently replaced by one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and enable "heterocycles", "heterocyclyl", "heterocyclizations" or "heterocyclic" group.

Used herein, the term "heterocycle", "heterocyclyl", "heterocyclizations" or "heterocyclic" means non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring atoms are independently selected heteroatom. In some embodiments, implementation of the "heterocycle", "heterocyclyl", "heterocyclizations" or "heterocyclic" group has from three to fourteen members in the ring, from which one or more member of the new ring are heteroatoms, independently selected from oxygen, sulfur, nitrogen or phosphorus and each ring in the system contains 3-7 members.

The term "heteroatom" means one or more atoms of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the Quaternary form of any basic nitrogen or a substituted nitrogen heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

Used herein, the term "unsaturated" means that the group has one or more units of unsaturation.

Also used herein, the term "CNS" or "touchily" refers to an alkyl group as defined previously, is attached to the main carbon chain through an oxygen atom ("CNS") or sulfur ("touchily").

The terms "haloalkyl", "haloalkyl" and "haloalkoxy" means alkyl, alkenyl or alkoxyl, depending on the circumstances, substituted by one or more halogen atoms. The term "halogen" means F, Cl, Br or I.

The term "aryl"used alone or as part of a larger molecule, as in "aralkyl", "arakaki" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having a total of from five to cityrad the Athi members in the ring, where at least one ring in the system is aromatic and where each ring in the system contains 3-7 members. The term "aryl" may be used interchangeably with the term "aryl ring".

The term "heteroaryl", used alone or as part of a larger molecule, as in "heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic ring systems having a total of from five to fourteen members in the ring, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains 3-7 members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Aryl (including Uralkaliy, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heteroaromatics and the like) group may contain one or more substituents. Suitable substituents (e.g. JRI , JTand JQ) on the unsaturated carbon atom aryl or heteroaryl group selected from halogen; -R°; C1-6-alkyl, optionally substituted by R°, in which up to three methylene units of the chain are optionally and independently replaced by-NR°-, -O-, -S-, -SO-, SO2- or-WITH - the chemically stable environment; -OCF3; -SCF2; C1-4-haloalkyl; -CH2-halogen; C6-10-aryl, which is optionally substituted by R°; 5-12-membered heteroaryl, optionally substituted by R°; 3-12-membered heterocyclic ring, optionally substituted by R°; -O(Ph), optionally substituted by R°; -CH=CH(Ph), optionally substituted by R°; -CH≡CH(Ph), optionally substituted by R°, -C1-6-alkyl-(5 to 12-membered heterocyclyl), optionally substituted by R°; -C1-6-alkyl-(C6-10-aryl), optionally substituted by R°, -C1-6-alkyl-(5-10-membered heteroaryl), optionally substituted by R°; C3-10-cycloaliphatic group, optionally substituted by R°; -C1-6-alkyl-(C3-10-cycloaliphatic) group, optionally substituted by R°; -(C1-6-alkyl)-OR°, optionally substituted by R°; -(C1-6-alkyl)-N(R°)2not necessarily replaced with R°; -(C1-6-alkyl)-SR°, optionally substituted by R°; -NO2; -CN; -OR°; -SR°; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°)R°; -C(NR°)R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°; -N(or SIG°)R°; -C(=NH)-N(R°)2; -P(O)2R°; -PO(R°)2; -OPO(R°)2; and -(CH2)0-2NHC(O)R IS.

Each R° is independently selected from hydrogen, NH2, NH(C1-4-aliphatic) groups, - N(C1-4-aliphatic)2group, halogen, HE, O(C1-4-aliphatic) groups, NO2CN, CO2H, CO2(C1-4-aliphatic) groups, - O(halo-C1-4-aliphatic) groups, halo-C1-4-aliphatic group, optionally substituted C1-6-aliphatic group in which up to 2 methylene units optionally replaced by O, N or S, optionally substituted 5-8-membered heterocyclyl, unsubstituted 5-6-membered heteroaryl, unsubstituted 3-6-membered cycloaliphatic group, unsubstituted phenyl, unsubstituted-O(Ph), unsubstituted-CH2(Ph), unsubstituted-CH2(5-7-membered heterocyclyl) or unsubstituted-CH2(5-6-membered heteroaryl); or, notwithstanding the definition above, two independent R°, on the same Deputy or different substituents, taken together with the atom(s)to which each R° group, forms an optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Optional substituents on the aliphatic group of R°, or the ring formed by the 2 R° groups selected from NH2, NH(C1-4-aliphatic) g is PI, N(C1-4-aliphatic)2group, halogen, C1-4-aliphatic group, IT is, O(C1-4-aliphatic) groups, NO2CN, CO2H, CO2(C1-4-aliphatic) groups, - O(halo-C1-4-aliphatic) groups, and halo-C1-4-aliphatic groups, where each of the preceding C1-4-aliphatic groups of R° is unsubstituted.

Aliphatic or heteroaromatics group or non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents (e.g. JRI , JTand JQ) on the saturated carbon of an aliphatic or heteroaromatics group or non-aromatic heterocyclic ring are selected from those mentioned above for the unsaturated carbon aryl or heteroaryl group and additionally include the following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), =NH and =NR*where each R*independently selected from hydrogen and optionally substituted C1-6-aliphatic group. Optional substituents on the aliphatic group of R*selected from NH2, NH(C1-4-aliphatic) groups, - N(C1-4-aliphatic)2group, halogen, C1-4-aliphatic group, IT is, O(C1-4-aliphatic) groups, NO2CN, CO2H, CO2(C1-4-aliphatic) g is PI, O(halo-C1-4-aliphatic) groups, and halo-(C1-4-aliphatic) groups, where each of the preceding C1-4-aliphatic groups of R*is unsubstituted.

Optional substituents (e.g. JRI , JTand JQ) on the non-aromatic nitrogen heterocyclic ring or on the nitrogen heteroaryl ring selected from R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2and-NR+SO2R+; where R+represents hydrogen, optionally substituted C1-6-aliphatic group, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph), optionally substituted -(CH2)2(Ph); optionally substituted-CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, having from one to four heteroatoms independently selected from oxygen, nitrogen and sulfur, or, notwithstanding the definition above, two independent R+at the same Deputy or different substituents, taken together with the atom(s)to which each R+group, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloaliphatic ring, in the with 0-3 heteroatom, independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+selected from NH2, NH(C1-4-aliphatic) groups, - N(C1-4-aliphatic)2group, halogen, C1-4-aliphatic group, IT is, O(C1-4-aliphatic) groups, NO2CN, CO2H, CO2(C1-4-aliphatic) groups, - O(halo-C1-4-aliphatic) groups, and halo-(C1-4-aliphatic) groups, where each of the preceding C1-4-aliphatic groups of R+is unsubstituted.

The term "alkylidene chain" refers to a straight or branched carbon chain, which may be fully saturated or have one or more units of unsaturation, and has two points of connection to the rest of the molecule in which one or more methylene groups can be optionally and independently replaced by a group, including, including, CO, CO2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO2, NRCONR, SO, SO2, NRSO2, SO2NR, NRSO2NR, O, S, or NR.

As described above, in some embodiments, implementation, two independent R° (or R+or any other variable similarly defined here), taken together with the atom(s)associated with each variable, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Typical rings that are formed when two independent R° (or R+or any other variable similarly defined here) taken together with the atom(s)associated with each variable, include, inter alia: (a) two independent R° (or R+or any other variable similarly defined here)that are associated with the same atom and are taken together with that atom to form a ring, for example, N(R°)2where both R° are taken together with the nitrogen atom to form piperidine-1-silt, piperazine-1-silt or morpholine-4-silt group; and b) two independent R° (or R+or any other variable similarly defined here)that are associated with different atoms and are taken together with these two atoms to form a ring, for example where a phenyl group is substituted at two positions OR°these two provisions of R° are taken together with the oxygen atoms to which they are linked to form a condensed 6-membered oxygen-containing ring:. It will be understood that a variety of other rings can be formed when two independent R° (or R+or any other variable similarly defined here) taken together with the atom(s)associated with each variable is I, and that the examples described above are not intended to limit the invention.

Unless otherwise stated, structures depicted herein, is also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) isomers on double bond, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds are included in the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are included in the scope of the invention. Additionally, unless otherwise stated, structures depicted herein, is also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon13C - or14C-enriched carbon are included in the scope of the present invention. Such compounds are applicable, for example, as analytical tools or probes in biological tests.

Unless otherwise stated, structures depicted herein, is also intended, stabillity N-oxide derivative or pharmaceutically acceptable salt of each of the compounds of formula I.

According to one of embodiments of the invention, T represents C1-3-aliphatic group, optionally interrupted by zero or one group G, where G is selected from O, NR5and S.

In some embodiments, the implementation of T represents-C1-2-aliphatic-G group, where G is O or NR5and G associated with Q in a chemically stable environment. In other embodiments, the implementation of G associated with X2in a chemically stable environment. In some embodiments, the implementation of T represents a C1-3-aliphatic group, optionally interrupted by zero groups G.

In some embodiments, the implementation of T represents a C1-3-aliphatic group, optionally interrupted by zero or one group G'. In other embodiments, the implementation of T represents a C1-3-aliphatic group, optionally interrupted by zero or one group G or G'.

In some embodiments, the implementation of T represents a-CH2-; in other embodiments, the implementation of the T represents the relationship.

According to one variant of the invention, each R3and R4independently is H. In some embodiments, implementation and R3and R4represent H.

According to some variants of implementation of R2is a 5-8-membered minociclina not necessarily replace the i.i.d. 5 groups J R. In certain embodiments of the implementation of R2is a 5-6-membered aryl or heteroaryl, optionally substituted 5 JRgroups. In other embodiments, implementation of R2is a 5-6-membered heteroaryl, optionally substituted 5 groups JRpreferably R2represents a 6-membered heteroaryl having 1 or 2 nitrogen atom, where R2optionally substituted 5 groups JR.

In some embodiments, the implementation of R2represents a C3-8-cycloaliphatic group, optionally substituted five JRgroups. In other embodiments, implementation of R2represents a C3-8-cycloalkyl, optionally substituted groups JRin up to five groups. In certain embodiments of the implementation of R2represents a C3-8-cycloalkenyl, optionally substituted groups JRin up to five groups. In other embodiments, implementation of R2is cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl, optionally substituted groups JRin up to five groups.

In some embodiments, the implementation of R2is a pyridine ring, optionally substituted 5 groups JR. In some embodiments, the implementation of R22 is a feast is denila, 3-pyridium or 4-pyridium, optionally substituted groups JRin up to five groups. In certain embodiments of the implementation of R2represents a pyrimidine ring, optionally substituted by groups JRin up to five groups. In some embodiments, the implementation of R2is 2,4-pyrimidinyl. In other embodiments, implementation of R2represents a 5-membered heteroaryl ring, optionally substituted by groups JRin up to five groups. In some embodiments, the implementation of R2is thiophene or pyrazole, optionally substituted groups JRin up to five groups. In some embodiments, the implementation of R2represents phenyl, optionally substituted 5 groups JR.

In some embodiments, the implementation of R2optionally substituted 5 groups JR; in other embodiments, implementation of the 3 groups JR; in another implementation options 0 or 1 group JR.

In some embodiments, implementation of the present invention JRselected from C1-6-alkyl, C6-10-aryl, -C1-6-alkyl-C6-10-aryl, C1-4-haloalkyl, -OR°, -N(R°)2, -SR°, 3-12-membered heterocyclyl, -(C1-6-alkyl)-OR°, -(C1-6-alkyl)-N(R°)2, -(C1-6-alkyl)-SR°, -C(O)OR°, -NR°COR°, -COR°, -CON(R°)2, -SO2R°, SO 2N(R°)2and C1-6-alkyl, in which up to three methylene units of the chain are independently replaced by-NR°-, -O-, -S-, -SO-, SO2or WITH - in a chemically stable environment.

In certain embodiments of the implementation of the JRselected from oxo or =NH.

In other embodiments, implementation of the JRrepresents-OR°, -N(R°)2, -SR°, NO2CN, -(C1-6-alkyl)-OR°, -(C1-6-alkyl)-N(R°)2or -(C1-6-alkyl)-SR°.

In some embodiments, the implementation of each of the JRindependently selected from a 5-8-membered, optionally substituted heterocyclyl, optionally replaced by-NR(C1-4-alkyl)N(R°)2not necessarily replaced by-NR(C1-4-alkyl)OR°, -N(R°)2or optionally substituted-NH(5-6-membered heterocyclyl). In certain embodiments of the implementation of the JRrepresents-NH(C1-4-alkyl)N(R°)2; in other embodiments, implementation-NH(C1-4-alkyl)other° or-NH(C1-4-alkyl)NH2; In some embodiments, the implementation is-NR(CH2CH2)N(R°)2; In other embodiments, implementation of the JRrepresents-N(CH3)CH2CH2N(R°)2;

In other embodiments, the implementation of each of the JRindependently selected from optionally substituted-NH(5-6-membered heterocyclyl).

In certain embodiments of the implementation of each of the JRis a 5-6-membered, heterotic the sludge, containing 1-2 nitrogen atom. In some embodiments, the implementation of 5-6-membered heterocyclyl selected from pyrrolidine, piperidine or piperazine.

In some embodiments, the implementation of the JRoptionally and independently substituted R°.

In one embodiment of the present invention, each X1and X2independently is-C(O) -, or-NR-, where one of X1or X2is a-NR-, and the other of X1or X2is-C(O)-.

In some embodiments, implementation of the X1is-C(O)-, and X2is-NR-.

In other embodiments, implementation of the X1is-NR-, and X2IS-C(O)-.

In one of the embodiments of the present invention Q is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In certain embodiments of the realization of Q is C6-10-aryl, C3-10-cycloaliphatic group, a 5-14-membered heteroaryl or a 5-14-membered heterocyclyl. In other embodiments, the implementation of Q is C6-10-aryl or a 5-14-membered heteroaryl. the another options exercise of Q is a 5-6-membered aryl or heteroaryl. In some embodiments, the implementation of Q is a 5-8-membered heterocyclyl; in certain embodiments of the implementation - 5-6-membered heterocyclyl; in certain embodiments the implementation of Q is phenyl.

In some embodiments, implementation of the present invention Q is substituted by the groups JQin up to 5 groups, where JQrepresents CN, C1-6-alkyl, C6-10-aryl, -C1-6-alkyl-C6-10-aryl, C1-4-haloalkyl, -OR°, -N(R°)2, -SR°, -(C1-6-alkyl)-OR°, -(C1-6-alkyl)-N(R°)2, -(C1-6-alkyl)-SR°, -C1-6-alkyl-(C3-10-heterocyclyl), -C(O)OR°, -NR°COR°, -COR°, -CON(R°)2, -SO2R°, -SO2N(R°)2or C1-6-alkyl, in which up to three methylene units optionally and independently replaced by-NR°-, -O-, -S-, -SO-, SO2or WITH - in a chemically stable environment.

In some embodiments, the implementation of the JQselected from C1-6-alkyl, CN, C1-4-haloalkyl, -OR°, -N(R°)2, - SR°, -(C1-6-alkyl)-OR°, -(C1-6-alkyl)-N(R°)2, -(C1-6-alkyl)-SR°, C6-10-aryl, -C1-6-alkyl-C6-10-aryl, C3-10-cycloaliphatic group, -C1-6-alkyl-(C3-10-cycloaliphatic) group, a C3-10-heterocyclyl, -C1-6-alkyl-(C3-10-heterocyclyl), -C(O)OR°, -NR°COR°, -COR°, -CON(R°)2, -SO2R°, -SO2N(R°)2or C1-6-alkyl, in which up to three METI anovich links optionally and independently replaced by-NR°-, -O-, -S-, -SO-, SO2-, -CO-, cyclopropyl, C≡C or C=C in a chemically stable environment; each JQoptionally and independently substituted R°.

In some embodiments, implement, JQis-SO2N(R°)2, -SO2R°, -NR°C(O)OR°, -C≡C-R°, -C=C-R°, - phenyl, -O-Ph, -O-CH2Ph, C5-6-heteroaryl, C3-7-heterocyclyl or C3-7-cycloaliphatic group.

In certain embodiments of the implementation of the JQrepresents CN, C1-6-alkyl, -CF3, -OCF3, -OR°, -N(R°)2, -SR°, -CH2-halogen, -SCF2, -(C1-6-alkyl)-N(R°)2C6-aryl, C5-6-heteroaryl, -C(O)OR°, -NR°COR°, -COR° or - CON(R°)2.

In some embodiments, the implementation of R2optionally substituted groups JQin up to five groups; in other embodiments, the implementation of the groups JQin up to three groups; in another implementation options 0 or 1 group JQ.

In some embodiments, the implementation of R° is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, tert-butyl, HE, halogen, -CH2-pyrrolidine, COCH3, -(C1-4-alkyl)0-1-O(C1-4-alkyl), -(C1-4-alkyl)0-1-O(C1-4-alkyl)HE, -(C1-4-alkyl)0-1-NH(C1-4-alkyl), -(C1-4-alkyl)0-1-N(C1-4-alkyl)2or -(C1-4-alkyl)0-1-NH2.

In kotoryj options exercise of the variables correspond depicted in Table I the compounds.

Accordingly, typical examples of the compounds of formula I are presented in Table I.

Table I

Compounds of the present invention can be obtained by standard methods known to experts in the art for analogous compounds, as illustrated in accordance with the General scheme below, and examples of the preparation, which are listed below.

Scheme I

Reagents and conditions(a) Pyridine, CT, 16 hours.

In Scheme I above shows a General way of synthesis, which is used to obtain the compounds 3a of the present invention, when R1corresponding to the description sdesign formula 3a can be obtained by the reaction of amrinona 1 with an acid chloride in pyridine according to stage (a) of Scheme I. The reaction can be used a variety of acid chlorides.

Compounds I-1 to I-67 and I-82 I-85 were obtained according to standard methods described in Scheme I.

Scheme II

Reagents and conditions(a) NMP, xs(R°)2NH, 160°C, 2 hours, microwave radiation.

Scheme II above shows a General way of synthesis, which is used to obtain the compounds 3b of the present invention, when R° is described here. The compounds of formula 3b can be obtained by the reaction of I-20 with excess amine in NMP according to stage (a) of Scheme II. The reaction can be used in a variety of amines.

Compound I-68 to I-81 were obtained according to standard methods described in Scheme II.

Scheme III

Reagents and conditions: (a) MeI, Ag2CO3, CHCl3, CT, 48 hours; (b) bis(pinacolato)diboron, Pd(OAc)2, KOAc, DMF, 85°C, 3 h; (c) R2-Hal, Pd(Pph3)4, aq. Na2CO3, toluene, EtOH, boiling under reflux, for 4 hours.

Scheme III above shows a General way of synthesis, which is used to obtain the compounds 7 of the present invention, when R2matches the description given here. The original connection 4, which can be obtained according to the method described by Warner et al., J. Med. Chem. 1994, 37, 3090, is methylated according to the on the stage (a) of Scheme II. The compound of formula 6 is formed in the reaction of iodide with 5 bis(pinacolato)diboron in the presence of palladium as catalyst. The formation of derivatives of 7 occurs as a result of processing derivative broowaha ether 6-halide R2-Hal in the presence of palladium as catalyst when using the ways of combination Suzuki, well known in the prior art. The reaction can be used in a variety of substituted halides R2-Hal.

Scheme IV

Reagents and conditions(a) aq. HCl, 1,4-dioxane, boiling under reflux, 30 min; (b) H2, 10% Pd/C, MeOH, EtOAc, 2 hours; (c) Pyridine, CT, 16 hours.

Scheme IV above shows a General way of synthesis, which is used to obtain the connection 10 of the present invention, when R1and R2correspond to the description given here. Demethylation 7 in acidic medium leads to the formation of 8, with which unsecured according to stage (b). Finally, the compounds of formula 10 can be obtained by the interaction of the derivative 9 with the acid chloride of 2 in pyridine. The reaction can be used a variety of acid chlorides 2.

Scheme V

Reagents and conditions(a) H2, 10% Pd/C, MeOH, EtOAc, 2 hours; (b) Pyridine, CT, 16 hours; (c) aq. HCl, 1,4-dioxane, boiling under reflux, 30 minutes.

Scheme V above shows another General way of synthesis, which is used to obtain the connection 10 of the present invention, when R1and R2correspond to the description given here. The intermediate compound (11), obtained by removing the protection of amines 7, react with the acid chloride of 2 in pyridine. The reaction can be used a variety of acid chlorides 2. After demethylation intermediates 12 in an acidic environment, formed pyridone 10.

Scheme VI

Reagents and conditions(a) H2Pd(OH)2A /C, MeOH, CT, 5 hours; (b) Et3N, DCM, CT, 10 minutes; (c) R2-Hal, Pd(Pph3)4, aq. Na2CO3, toluene, EtOH, boiling under reflux, 4 h; (d) aq. HCl, 1,4-dioxane, boiling under reflux, 30 minutes.

Scheme VI above shows another General way of synthesis, which is used to obtain the connection 10 of the present invention, when R1and R2correspond to the description given here. Intermediate compound 13 obtained by removing protection from amine 6, reacts with the acid chloride of 2, resulting in the formation of compounds of formula 14. The reaction can be used a variety of acid chlorides 2. A downcast 12 is achieved by processing Baranovich ether derivatives 14 halide R2-Hal in the presence of palladium as katal is congestion, when using methods of combining Suzuki, well known in the prior art. The reaction can be used in a variety of substituted halides R2-Hal. After demethylation intermediates 12 in an acidic environment, formed pyridone 10.

Scheme VII

Reagents and conditions(a) NMP, xs(R°)2NH, 160°C, 2 hours, microwave radiation.

Scheme VII above shows a common way of synthesis, which is used to obtain connections 16 of the present invention, when R2and R° correspond to the description given here. The compounds of formula 16 can be prepared by the reaction of the compound 15 with excess amine in NMP according to stage (a) Scheme VII. The reaction can be used in a variety of amines.

Compounds II-1 to II-182 were obtained according to standard methods described in Schemes III, IV, V, VI and VII.

Scheme VIII

Reagents and conditions(a) HOBt, DMAP, EDC, THF, CT, 16 hours.

Scheme VIII above shows the General path of synthesis, which is used to obtain connections 19 of the present invention, when R, R1and R2correspond to the description given here. The parent compound 17 can be obtained by methods substantially similar to that described in the literature (Churchet al.J. Org. Chem. 1995,60, 3750). Connection formula obtained according to stage (a) of scheme VIII.

Compounds III-1 to III-54 were obtained according to the standard method described in Scheme VIII.

Scheme IX

Reagents and conditions(a) Pyridine, 0°C, 2 hours

Scheme IX above shows the General path of synthesis, which is used to retrieve the connection 21 of the present invention, when R1and R2correspond to the description given here. The compounds of formula 21 can be obtained by the reaction of derivatives 9 sulphonylchloride 20 in pyridine. The reaction can be used in a variety of sulphonylchloride 20.

Compound IV-1 was obtained according to the standard method described in Scheme IX.

The present invention also provides compounds that can be used as an intermediate in the synthesis of compounds of the present invention. Additionally, the present invention provides methods for use of these intermediates in obtaining the compounds of the present invention.

Specifically, the connection 22 can be used as an intermediate compound in the production method of compound 23. Compound 23 can then be converted into a compound of formula I.

Scheme X

where:

R10represents an amino-protective group;

R11represents H or C1-6-alkyl GroupWise R 10and R11together with the nitrogen atom to which they are bound, form an amino-protective group;

R12is hydroxylamino group; and

R2corresponds here to the description.

In one embodiment, the compound 22 is reacted with an appropriate compound comprising R2under appropriate reaction conditions, resulting in a connection 23. An example of a suitable connection, including R2is R2-X, where X is an appropriate leaving group such as halogen. The appropriate reaction conditions are the conditions combinations that allow you to form a connection between bronovil ether (or Bronevoy acid) and R2-X. Appropriate leaving group and the corresponding conditions for the combination of well-known experts in the art (see, for example, March, above).

Compound 23 can be obtained by processing the derived broowaha ether 22 halide R2-Hal in the presence of palladium as catalyst when using the methods of combination, which are known in the prior art, for example, when using a combination of Suzuki.

In Scheme XI shows the example of using a combination Suzuki in the method of the present invention. In Scheme XI, R10is a Cbz group, R11 is hydrogen, and R12is a methyl group. However, it should be understood that in the reaction depicted in Scheme XI, can be used in connection 22 instead of compound 6 and compound 23 instead of compound 7.

Scheme XI

(a) R2-Hal, Pd(Pph3)4, aq. Na2CO3, toluene, EtOH, boiling under reflux.

Compound 23 can also be obtained by processing the derived broowaha ether 22 nitrogen-containing saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring (as described in the definition of R2), by reaction through the nitrogen atom in the ring, in the presence of copper as catalyst, for example, using the methods of combination, which are known in the prior art (see, Chernick et al.J. Org. Chem. 2005, 1486), which leads to the connection 23 (in which R2is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having at least one heteroatom is nitrogen; or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having at least one heteroatom is nitrogen, and R2optionally substituted JR). In Scheme XII illustrates the copper-mediated conditions by the combination of the way altoadige invention. In Scheme XII, R10is a Cbz group, R11is hydrogen, and R12is a methyl group. However, it should be understood that in the reaction presented in Scheme XII, may be used in connection 22 instead of compound 6 and compound 23 instead of compound 7.

Scheme XII

(a) Cu(OAc)2Et3N, O2CH2Cl2, count, 20 p.m.

In the method of the present invention, the compound 23 (and similar compounds, such as compound 7) is converted to the compound of formula I by methods known to experts in this field, including, among others, are described here. In specific embodiments, implementation, removes the hydroxyl-protective group in compound 23, and is then removed and the amino-protective group. Educated amine reacts with the corresponding R1-containing intermediate compound, resulting in a compound of formula I. the purpose of familiarization with specific examples of the specified variant implementation, see Scheme IV and Scheme IX. In Scheme IV R10is a Cbz group, R11is hydrogen, and R12is a methyl group. However, it should be understood that in the reaction depicted in Scheme IV may be used for the connection 23 instead of compound 7.

In another embodiment, deleted amino-protective group in compound 23, and then education is asisa amine reacts with the corresponding R 1-containing intermediate compound, resulting in obrawatsa compound X. Compound of formula I produced by removal of the protective hydroxyl group in compound X. To get acquainted with the specific example of the specified version of the implementation see Diagram V Diagram V R10is a Cbz group, R11is hydrogen, and R12is a methyl group. However, it should be understood that in the reaction depicted in Scheme V may be used for connection of X instead of compound 11 and compound XX instead of the connection 12.

In the variants of implementation, where X1represents-NR-, amino-protective group, R11can be a group, R1-X2-. As you might guess, in such scenarios, the implementation is not necessary to remove the amino-protective group and replace it with R1-containing group. Accordingly, to obtain the compound of formula I, compound 23 was supposed to react under conditions suitable for removal of the hydroxyl-protective group in the resulting compound of formula (I). In the variants of implementation, where R1C(=O)-group is incompatible with the formation of broowaha ether, baranovy ether could be formed by a group of R10which is Cbz, and then the Cbz group could be replaced by R1-containing group after education the project broowaha ether. With the purpose of acquaintance with the specific example of the specified version of the implementation see Scheme VI. In Scheme VI, R10(compound 14) is an R1C(=O)-, R11is hydrogen, and R12is a methyl group. However, it should be understood that in the reaction depicted in Scheme VI may be used in connection 22 instead of compound 6.

Alternative, R1023 can be converted to R1-X2-. Thus, the functional group in the R10could be converted into the desired R1-containing group. Then the hydroxyl-protective group to be removed, the result would have been obtained compound of formula I. the purpose of familiarization with specific examples of the specified variant implementation, see Scheme II and Scheme VII.

The connection 22 may be obtained by methods known to experts in this field, including, among other things, the methods disclosed here. In one embodiment, imprisone 24 reacts under the conditions required for the formation of broowaha ether 22 (Scheme XIII). With the purpose of acquaintance with concrete examples of these conditions, see Scheme III. In Scheme III, R10is a Cbz group, R11is hydrogen, and R12is a methyl group. However, it should be understood that in the reaction depicted in Scheme XII, may be used in connection 22 instead of compound 6I connection 23 instead of compound 7.

Scheme XIII

You need to understand that instead of using broowaha ester 22 in the process of the present invention can be used corresponding baronova acid (Scheme XIV). Baronova acid could be used as the starting material or formed in place. Compound 25 can be obtained by standard methods, including, inter alia, the conversion broowaha ester 22 in Bronevoy acid 25.

Scheme XIV

Protective groups protect functional amino and hydroxyl groups from the interaction at conversion conditions broowaha ester or acid group, R2. Specialists in the art will know of many amino-protective groups and the hydroxyl-protective groups. Examples of such protective groups can be found in T.W. Greene and P.G.M. Wutz, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, Inc. (1999) and more early editions of this book, and J.W.F. McOmie, "Protective Groups in Organic Synthesis", Plenum Press (1973).

In certain embodiments of the implementation of R10represents-C(O)R13or-C(O)OR13where:

R13is:

unsubstituted C1-6-alkyl,

C1-6-alkyl, substituted C6-C10the aryl or

C6-C10-aryl, where each C6-C10-aryl optionally Sames the n-halogen, -CN, -NO2, -N(R14)2, unsubstituted C1-6the alkyl or
-CF3; and

R14is H or unsubstituted C1-6-alkyl.

Preferably, R10represents Cbz (carbobenzoxy) or Boc (tert-butoxycarbonyl).

In certain embodiments of the implementation of R11is hydrogen.

In certain embodiments of the implementation of R12is C1-6-alkyl. Preferably, R12is stands or ethyl.

In a preferred embodiment, R10represents Cbz (carbobenzoxy) or BOC (tert-butoxycarbonyl); R11is hydrogen; and R12is stands.

Although certain typical embodiments of listed and described here above, it should be understood that the compounds of the invention can be obtained according to methods described in General above, using appropriate starting compounds, the methods typically available to a person skilled in the technical field.

As has been disclosed here, the present invention provides compounds that are inhibitors of protein kinases, and thus the present compounds are applicable for the treatment of diseases, disorders and conditions, including without limitation, autoimmune, inflammatory, proliferative or hyperproliferative disease or immunologists who Eski-mediated disease. Accordingly, in another aspect of the present invention, are provided pharmaceutically acceptable compositions, where these compositions contain any of the compounds described herein, and optionally contain a pharmaceutically acceptable carrier, excipient or base. In certain embodiments of the implementation of the above composition further optionally contain one or more additional therapeutic agent. Such additional therapeutic agents include, without limitation, agent for the treatment of autoimmune, inflammatory, proliferative, hyperproliferative diseases, or immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS).

You should also understand that some of the compounds of the present invention can exist in free form for treatment, or, where necessary, in the form of their pharmaceutically acceptable derivative. According to the present invention, pharmaceutically acceptable derivative includes, without limitation, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon introduction of a needy patient is able to be transformed, directly or indirectly, in connection castes otherwise described or its metabolite or residue.

Used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of a thorough medical examination, suitable for use in contact with the tissues of humans and lower animals without increased toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit ratio of risk. "Pharmaceutically acceptable salt" means any non-toxic salt or salt of ester compounds of the present invention that, when administered to the recipient is capable of converting, either directly or indirectly, in the compound of the present invention or inhibitore active metabolite or residue. Used herein, the term "inhibitore active metabolite or residue" means that a metabolite or residue also is an inhibitor of a kinase of the TEC family of protein kinases (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk).

Pharmaceutically acceptable salts are well known in the prior art. For example, S. M. Berge et al describes pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, used here as a reference. Pharmaceutically acceptable salts of the compounds of the present invention include the salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic salts to recognize the possible acids are salts of an amino group, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or formed using other methods used in the prior art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-econsultant, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate, and the like, Salts derived from appropriate bases include alkali metal salts, alkaline earth metal, ammonium and N+(C1-4-alkyl)4. The present image is the buy also involves the quaternization of any basic nitrogen-containing groups of the compounds disclosed here. Water - or oil-soluble or dispersible products may be obtained by such quaternization. Typical salts of alkaline or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations, Quaternary ammonium, and amines formed using counterions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention optionally contain a pharmaceutically acceptable carrier, excipient or base, which, when used here, includes any and all solvents, diluents, or other liquid basis, dispersing or suspendresume additives, surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid carriers, lubricants, etc. that are appropriate for specific dosage forms. Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the preparation of pharmaceutically acceptable compositions, as well as known methods for producing media. Except that the environment of any usual wear the El is incompatible with the compounds of the invention, in particular causing any undesirable biological effect or otherwise interacting adverse manner with any other component(s) of the pharmaceutically acceptable composition, it is assumed that its use is included in the scope of the present invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, without limitation, ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins, for example, serum human albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, disodium hydrogen phosphate, potassium phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-co-polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; excipients such as cocoa butter and suppozitornyj waxes; oils such as peanut oil, cottonseed oil; safflower m the words; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic; ringer's solution; ethyl alcohol and phosphate buffer solutions, such non-toxic compatible lubricants as sodium lauryl sulfate and magnesium stearate in the composition can also contain coloring agents, releasing agents, covering agents, sweeteners, flavoring and aromatic agents, preservatives and antioxidants, in depending on the decision of the developer compositions.

In certain embodiments of the implementation of the composition contains an effective amount of a compound according to paragraph 1 of the claims, and a pharmaceutically acceptable carrier, excipient or base. In a specific embodiment, the compound is present in an amount necessary for measurable inhibition of protein kinases a TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk).

The present invention also provides a pharmaceutical composition obtained by mixing the compounds of the present invention and a pharmaceutically acceptable carrier, excipient or base,as well as a method of obtaining a pharmaceutical composition, comprising mixing the compound of the present invention and a pharmaceutically acceptable carrier, excipient or base.

In another aspect, cosob of treating or reducing the severity of disease due to a TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is provided by the introduction of an effective amount of a compound or pharmaceutically acceptable composition comprising the compound to a patient in need. The methods can be used the compound of Formula I, or any other compound of the present invention:

or their pharmaceutically acceptable salt, where

each R3and R4independently is H, halogen or C1-4-aliphatic group, optionally substituted with halogen, C1-2-aliphatic group, OCH3, NO2, NH2CN, NHCH3, SCH3or N(CH)2;

R2is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and R2optionally replaced by a group JR;

every X 1and X2independently are-C(O)-, -NR - or-SO2-where one of X1or X2represents-NR-, and the other of X1or X2is-C(O)- or-SO2-;

R represents H, unsubstituted C1-6-aliphatic group;

R1is-T-Q;

T is a bond or C1-6-aliphatic group in which up to three methylene units of the chain are optionally and independently replaced by G or G', where G is-NR5-, -O-, -S-, -SO-, SO2-, -CS - or-CO-; G' is cyclopropyl, C≡C or C=C; T is optionally replaced by a group JT;

Q independently is hydrogen, C1-6-aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q is optionally replaced by a group JQ; and

R5is optionally substituted by R, C6-I0-aryl, C3-10-cycloaliphatic group, a 5-14-membered heteroaryl or a 5-14-membered heterocyclyl; or two groups R5together with the atom(s)to which they are attached, form a optionally Sames the TES 3-7-membered monocyclic or 8-14 membered bicyclic ring;

where the optional substituents JRI , JTand JQdefined here.

In certain embodiments of the implementation of the present invention an "effective amount" of a compound or pharmaceutically acceptable composition is that amount effective against the disease, mediated by a TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk). Compounds and compositions, according to the method of the present invention, can be entered using any amount and any route of administration effective for treating or reducing the severity of the disease, mediated by a TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk). The exact required amount will vary depending on patient race, age and General condition of the patient, severity of infection, specific substances, its method of administration, etc. of Compounds of the invention preferably are prepared in a composition in unit dosage form for ease of administration and standard dosage. The expression "unit dosage form"as used here, refers to a physically discrete unit of matter suitable for treatment of the patient. However, it should be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of a thorough medical examination. Specific UB is the tier of the effective dose for any particular patient or organism will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific connections in use; some used the composition; the age, body weight, General health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific connections in use; the duration of the treatment; drugs used in combination or coincident with a specific used by the connection, as well as factors known in the medical art. Used herein, the term "patient" means an animal, preferably a mammal, and most preferably human.

Pharmaceutically acceptable compositions of the present invention can be waiti people and other animals orally, rectally, parenterally, intracisternally, intrawaginalno, administered intraperitoneally, locally (powders, ointments or drops), buccal, in the form of an oral or nasal sprays or similar, depending on the severity of infection, which is treated. In certain embodiments of the implementation of the compounds of the invention can be entered orally or parenterally at dosages from about 0.01 mg/kg to about 50 mg/kg, and preferably, from about 1 mg/kg to about 25 mg/kg of body weight of the patient per day, one or more times a day to obtain the desired t is rapeutically effect.

Liquid dosage forms for oral administration include, without limitation, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the prior art, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, oil from germinated seeds, olive, castor and sesame), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include excipients, such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavoring and aroma additives.

Injectable preparations, for example, sterile injectable aqueous or oil suspensions can be produced in accordance with the prior art, using suitable dispersing or wetting agents and suspendresume agents. The sterile injectable preparation can also be sterilisation solution the suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Acceptable bases and solvents may be used water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspendida environment. This purpose can be any soft fixed oils, including synthetic mono - or diglycerides. In addition, in the preparation of injection preparations are fatty acids such as oleic acid.

Injectable compositions can be sterilized, for example, by filtration through a filter that retains bacteria or by adding sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To extend the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved using a liquid suspension of crystalline or amorphous material with poor water solubility. The speed of absorption of connection depends on speed of dissolution, which, in itsturn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral input forms the connection is achieved by dissolution or suspension of the compounds in oil-based. Injectable form depot is produced by obtaining microencapsulating matrix compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, you can control the rate of release of connection. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Injectable form depot also get through the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal injection preferably represent suppositories, which can be obtained by mixing the compounds of the present invention with suitable, not irritating eccipienti or carriers such as cocoa butter, polyethylene glycol or suppozitornyj wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms DL the oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or dry diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum, (c) water-retaining additives, such as glycerol, d) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, starch potato or tapioca starches, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders, such as paraffin, f) absorption accelerators, such as Quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used as excipients in soft and hard floor is built gelatin capsules, using such excipients as lactose or milk sugar and high molecular weight glycols and other Solid dosage forms as tablets, pills, capsules, pills and granules can be obtained with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical preparations. They may not necessarily include silencers and can also represent the composition, so that only the active component(s) will be released, or preferentially, in a certain part of the intestinal tract, optionally deferred. Examples of impregnating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as excipients in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight glycols, etc.

The active compounds can also be in microencapsulating form with one or more excipients as noted above. Solid dosage forms as tablets, pills, capsules, pills and granules can be obtained with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical preparations. In such solid dosage forms, the active compound may be added, at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include, as is customary, additional substances, in addition to inert diluents, for example, tabletiruemye lubricants and other tabletiruemye auxiliary additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also include a buffering agent. They may not necessarily include silencers and can also represent the composition, so that only the active component(s) will be released, or preferentially, in a certain part of the intestinal tract, optionally deferred. Examples of impregnating compositions which can be used include polymeric substances and waxes.

Dosage forms for local or transdermal injection of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, which may be required. Ophthalmic composition, ear drops and eye drops are also considered as included in the scope of the present invention. Additionally, the present invented the e is considering the use of transdermal patches, which have the added advantage of providing controlled flow connection in the body. Such dosage forms can be prepared by dissolving or distribution of the compound in a suitable medium. To increase revenues compounds through the skin can also be used amplifiers absorption. Speed can be controlled either with the use of regulating the speed of the membrane, or distributing the compound in a polymer matrix or gel.

As generally described above, the compounds of the invention are applicable as inhibitors of protein kinases. In one embodiment, compounds and compositions of the invention are inhibitors of one or more kinases TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly applicable for treating or reducing the severity of the disease, condition or disorder, which disease, condition or disorder involved the activation of one or more kinases TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk). When activation of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) involved in a specific disease, condition or disorder, the disease, condition, or disorder may also be referred to as "a disease mediated by a TEC family (e.g., T is C, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk)or symptom of the disease. Accordingly, in another aspect, the present invention provides a method of treating or reducing the severity of the disease, condition or disorder where activation of one or more kinases TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) involved in a painful condition.

Also, not wishing to be bound by any particular theory, the compounds and compositions, particularly applicable for treating or reducing the severity of the disease, condition or disorder, which disease, condition or disorder involved the activation of Itk kinase, and are in particular applicable for the selective inhibition of Itk relatively Btk and Rlk (see, Examples 14-16 and 18).

The potency of the compound used in this invention as an inhibitor of a kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), can be evaluated byin vitro,in vivoor in cell lines. Testsin vitroinclude assays to determine inhibition fosforiliruyusciye activity or ATPase activity of activated kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk). Additional testsin vitroquantitatively assess the ability of the inhibitor to bind the kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk). The binding of the inhibitor can be measured by tagging inhibitor radioactive metal is Oh before linking, highlight the complex Inhibitor/a TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) and determine the amount of bound radioactive label. Alternatively, the binding of the inhibitor can be determined by conducting a competition experiment where new inhibitors are incubated with the kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), associated with the famous radio.

Used herein, the term "measurable inhibit" means a measurable change in the activity of the kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) between the sample comprising the above composition and a kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk), and an equivalent sample comprising the kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) in the absence of a specified composition.

Used herein, the term "state-mediated tyrosine kinases TEC family" means any disease or other painful condition in which a TEC kinase family known to play a role. Such conditions include, without limitation, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically mediated diseases including rejection of implanted organs or tissues and Acquired Syndrome Immunodeficita (AIDS).

For example, state-mediated tyrosine kinases the EU family, include diseases of the respiratory tract, including, without limitation, chronic obstructive airway disease, including asthma, such as bronchial, allergic, hereditary, acquired and dust, particularly chronic or running asthma (for example, Hyper-reactive Airways at a late stage of asthma and bronchitis. Additionally, diseases, mediated by tyrosine kinases TEC family include, without limitation, such conditions as inflammation of the nasal mucosa, including acute rhinitis, allergic, acrotiri rhinitis and chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and rhinitis medication; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrupulously rhinitis, seasonal rhinitis, including nervous rhinitis (hay fever) and vasomotor rhinitis, sarcoidosis, lung farmer's and similar diseases, pneumovirus and idiopathic interstitial pneumonia.

Condition mediated by tyrosine kinases TEC family, also include diseases of bones and joints, including, without limitation, rheumatoid arthritis (pannus formation), the seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and the disease Reiter), Behcet's disease, Sjogren syndrome, and the system exclusive sclerosis.

Condition mediated by a kinase of the TEC family also includes skin diseases and disorders, including, without limitation, psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic dermatitis, lichen planus, bladderwort, the bullous disease, bullous bullosa, urticaria, angioedema, vasculitis, erythema, dermal eosinophilia, uveitis, alopecia alopecia and vernal conjunctivitis.

Condition mediated by tyrosine kinases TEC family, also include diseases and disorders of the gastrointestinal tract, including, without limitation, brunobeast disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food allergies, which cause effects not related to the bowel, for example, migraine, rhinitis and eczema.

Condition mediated by tyrosine kinases TEC family, also include diseases and disorders of other tissues and systemic disease, including, without limitation, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, malignant gravis, diabetes type I, nephrotic syndrome, eosinophilic fasciitis, Hyper-IgE syndrome, lepromatous leprosy, syndrome Cesari and idiomatics the th thrombocytopenic purple, restenosis after angioplasty, tumours (for example, leukemia, lymphoma), arthrosclerosis and systemic lupus erythematosus.

Condition mediated by tyrosine kinases TEC family, also include allograft rejection, including, without limitation, acute and chronic allograft rejection after, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea, as well as chronic disease graft-versus-host.

It should also be understood that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered simultaneously, before or after one or more other preferred therapy or medical intervention. A particular combination of therapies (treatment or surgery) for use in the combination mode will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It should also be understood that the applied therapy can achieve desired effect for the same disorder (for example, the compound of the invention can be administered simultaneously with another agent used to treat the same disorder), or they may have reached the ut different effects (for example, control of any adverse effects). Used herein, additional therapeutic agents that are normally administered to treat or prevent a specific disease or condition, known as "relevant disease or condition treated".

Additional therapeutic agents that can be used in the methods of the present invention include, without limitation, agents for the treatment of autoimmune, inflammatory, proliferative, hyperproliferative diseases, or immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS), where the additional therapeutic agent is appropriate for the disease being treated; and the additional therapeutic agent is administered together with a specified composition in the form of a single dosage form or separately from the specified composition as part of a complex dosage forms.

For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, without limitation, for example, other therapies or anticancer agents that mo is ut be used in combination with anticancer agents of the present invention, include surgery, radiotherapy (just a few examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF)to name a few), hyperthermia and cryotherapy, agents to reduce any side-effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabin, gemcitabine), spun poisons (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoanatabine (carmustin, lomustin), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, Leopold, flutamide and megestrol), Gleevec™, adriamycin, dexamethasone and cyclophosphamide. In order to get acquainted with more comprehensive discussion of updated cancer therapies see http://www.nci.nih.gov/FDA-approval is different cancer drugs in http://www.fda.gov/cder/cancer/ druglistframe.htm, and The Merck Manual, Seventeenth ed. 1999, the entire contents of which is incorporated herein by reference.

Other examples of agents which are inhibitors of the present invention can be combined include, without limitation: drugs for treatment of Alzheimer's disease, for example, Aricept® Exelon®; agents for treating Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirol, pramipexol, parlodel, pergolid, trihexyphenidyl and amantadine; agents for treating multiple sclerosis (MS)such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; medications for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, quetiapine, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazin; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazin; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, blockers of ion channels, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, the urine is pension funds, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, protivoanemicheskoe agents and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositions of the present invention, will not be higher than the amount that normally would have introduced into the composition, including specified therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent now disclosed compositions is in the range from about 50% to 100% of the amount normally present in a composition comprising the specified agent as the sole therapeutically active agent.

The compounds or pharmaceutically acceptable compositions of the present invention may also be included in compositions for coating implantable medical devices such as prostheses, artificial valves, vascular implants, stents and catheters. Accordingly, the present invention in another aspect includes a composition for coating an implantable device containing the compound of nastoyascheevremya, as described in General above and in classes and subclasses here, and a carrier suitable for coating of specified implanted device. In another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention, as described in General above and in classes and subclasses here, and a carrier suitable for coating of specified implanted device.

Vascular stents, for example, was used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices, run the risk of a blood clot or platelet activation. These adverse effects can be prevented or mitigated by pre-coating device pharmaceutically acceptable composition comprising an inhibitor of kinases. Suitable coatings and the General preparation of coated implantable devices are described in Patents US 6099562; 5886026 and 5304121. Coatings are typically biocompatible polymeric materials, such as hydrogel polymer polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating optionally can be further covered with a suitable top layer of ferrosilicon, polysaccharides, polyethylene glycol, FOS is olpidem or combinations thereof, to give the compositions of the properties of a controlled release.

Another aspect of the invention relates to the inhibition of the activity of a TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) in a biological sample or patient, and this method includes the introduction of the patient, or contacting the specified biological sample with a compound of formula I or a composition comprising the specified connection. Used herein, the term "biological sample" includes, without limitation, cell cultures or extracts; biopsy material obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

The inhibition activity of the kinase of the TEC family (e.g., TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) in a biological sample is applicable for a variety of purposes known to the person skilled in the art. Examples of these objectives include, inter alia, blood transfusion, organ transplantation, storage of Biologicals and biological tests.

EXAMPLES

Used herein, the term "Rt(min)" refers to retention time HPLC, in minutes, associated with the connection. Unless otherwise indicated, the HPLC method used to obtain the specified retention time is as follows:

Column: ACE 5 C8, 15 cm x 4,6 the m nutria.

Gradient: 0-100% acetonitrile+methanol (50:50) (20 mm Tris-phosphate, pH 7.0).

Flow rate: 1.5 ml/min

Detection: 225 nm.

Example 1

4-tert-Butyl-N-(6-oxo-1,6-dihydro-[3,4']bipyridinyl-5-yl)-benzamide I-11

Amrinon (200 mg, 1.07 mmol) was suspended in pyridine (5 ml)was then added 4-tert-butylbenzoate (209 μl, 1.07 mmol). The reaction mixture was stirred over night at room temperature. The solid precipitate was filtered and washed with MeOH, the resulting target compound as a pink solid (33 mg, yield 9%). MS (ES+) m/e=348.1H NMR (DMSO-d6) δH was 1.43 (9H, s), EUR 7.57 to 7.62 (4H, m), 7,81 (1H, s), 7,88 (2H, d), 8,59 (2H, d), 8,78 (1H, d), to 9.32 (1H, s), was 12.61 (1H, s).

Example 2

N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridine-3-yl)-4-(piperidine-1-yl)benzamide I-68

4-Bromo-N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridine-3-yl) benzamide (30 mg, of 0.081 mmol) of I-20 was placed in a test tube for microwave oven, equipped with a stirrer. Was added NMP (0.75 ml)and then added piperidine (1.5 ml). The reaction vessel was heated at 160°C for 2 hours in a microwave oven. After cooling the solution and excess piperidine were removed in vacuum. The crude compound was recrystallized from methanol, the resulting target compound as a white solid which CSOs substances (13 mg, yield 43%). MS (ES+) m/e=375.1H NMR (DMSO-d6) δH 1,54-of 1.65 (6H, m), 3,30-to 3.38 (4H, m), 7,02 (2H, d), to 7.61 (2H, d), 7,72-7,80 (1H, m), 7,78 (2H, d), 8,59 (2H, d), 8,77 (1H, d), 9,13 (1H, s), to 12.58 (1H, users).

A number of other compounds of Formula I was obtained by methods generally similar to those described here. Characterization data for these compounds are shown in Table I-a below and includes HPLC, LC/MS (observed) and data1H NMR.

Data1H NMR are shown in Table I below, in which data1H NMR were obtained at 400 MHz in deuterated DMSO, unless otherwise indicated, and as specified, consistent with the structure. The numbers of the Compounds correspond to the numbers of the compounds listed in Table 1.

Table 1-a
The characteristic data of Selected Compounds of Formula I
Connection # I-M+1 (OBS)RT (min)1H-NMR
12927,5(CDCl3) 7,02-the 7.65 (6H, m), 7.95 is-to 7.99 (2H, m), 8,69-to 8.70 (2H, m), 9,11 (1H, users), 9,16 (1H, users), 11,43 (1H, users)
23227,7 of 3.85 (3H, s), 7,10 (2H, d), to 7.61 (2H, d), 7,80 (1H, s), to 7.93 (2H, d), 8,58 (2H, d), is 8.75 (1H, m), 9.28 are (1H, s), 12,60 (1H, s)
33067,5of 3.85 (2H, s), 7,19-7,34 (5H, m), 7,52 (2H, d), of 7.70 (1H, s), 8,54 (1H, d), 8,72 (1H, s), 9,58 (1H, s), 12,45 (1H, s)
42988,11,25-1,40 (5H, m), 1,64 (1H, userd), 1,72 (2H, userd), of 1.80 (2H, userd), 2,60-to 2.67 (1H, m), 7,55 (2H, d), 7,71 (1H, s), 8,55 (2H, d), 8,72 (1H, s), 9,18 (1H, s), 12,40 (1H, users)
53408,2a 4.86 (2H, s), 7,58-the 7.65 (4H, m), 7,83 (1H, s), of 7.97 (2H, m), 8,59 (2H, m), 8,76 (1H, s), 9,44 (1H, s), 12,63 (1H, users)
63208,7to 1.22 (3H, t), 2,70 (2H, HF), 7,41 (2H, d), to 7.61 (2H, d), 7,81 (1H, d), 7,87 (2H, d), 8,58 (2H, d), 8,77 (1H, d), was 9.33 (1H, s), br12.62 (1H, users)
73428,7a 7.62-of 7.69 (4H, m), to 7.84 (1H, s), 8,02 (2H, t), 8,10 (1H, d), 8,16 (1H, d), 8,59-to 8.62 (3H, m), 8,82 (1H, s), 9,59 (1H, s), 12,65 (1H, s)

83068,0is 2.40 (3H, s), 7,37 (2H, d), 7,86 (2H, d), 8,01 (2H, d), of 8.09 (1H, s), is 8.75 (2H, d), 8,83 (1H, d), 9,39 (1H, s), 12,88 (1H, s)
93177,4a 7.62 (2H, d), 7,87 (1H, s), of 8.04 (2H, d), 8,11 (2H, d), 8,59 (2H, d), 8,72 (1H, s), 9,72 (1H, s), 12,63 (1H, s)
103349,2of 0.91 (3H, t), of 1.62 (2H, m)of 2.64 (2H, t), 7,38 (2H, d), to 7.61 (2H, d), 7,81 (1H, s), 7,87 (2H, d), 8,59 (2H, d), 8,77 (1H, d), was 9.33 (1H, s), was 12.61 (1H, s)
123689,37,44 (1H, t), 7,53 (2H, t), 7,63 (2H, d), to 7.77 (2H, d), to 7.84 (1H, d), 7,88 (2H, d), with 8.05 (2H, d), at 8.60 (2H, d), 8,79 (1H, d), for 9.47 (1H, d), 12,64 (1H, users)
133068,2to 2.41 (3H, s), 7,44-of 7.48 (2H, m), 7,74 for 7.78 (2H, m), 8,21-of 8.25 (3H, m), 8,82-8,86 (3H, m), 9,41 (1H, s), 13,02 (1H, s)
143368,3of 1.37 (3H, t), of 4.12 (2H, q), 7,19 (1H, d), 7,44-7,51 (3H, m), to 7.61 (2H, d), 7,83 (1H, d), 8,59 (2H, d), a total of 8.74 (1H, d), 9,37 (1H, s), was 12.61 (1H, s)
153748,67,60-to 7.84 (3H, m), 8,05 compared to 8.26 (5H, m), 8,76-8,84 (3H, m), 9,73 (1H, s)13,00 (1H, s)
16376 9,07,66 (1H, d), 7,72 (1H, t), to 7.93 (1H, s), 8,02 (1H, d), to 8.20 (2H, d), compared to 8.26 (1H, s), 8,81-8,83 (3H, m), 9,78 1H, s), 12,99 (1H, s)
173908,8of 4.00 (3H, s), the 7.43 (1H, d), 8,14-8,28 (5H, m), a total of 8.74-8,82 (3H, m), of 9.75 (1H, s), 12,93 (1H, users)
183769,07,55-EUR 7.57 (2H, m), 8,09-8,11 (2H, m), 8,18-8,19 (2H, m), 8,23 (1H, m), 8,81-8,83 (3H, m), to 9.66 (1H, s), 12,97 (1H, s)
193208,02,79 of 2.92 (4H, m), 7,18 (1H, m), 7,28-7,30 (4H, m), 8,13-to 8.14 (3H, m), 8,75-8,79 (2H, m), 8,87 (1H, s), for 9.64 (1H, s), 12,82 (1H, s)
203728,6to 7.61 (2H, DD), to 7.77 (2H, d), to 7.84 (1H, d), of 7.90 (2H, d), 8,58 (2H, DD), 8,73 (1H, d), 9,52 (1H, s), was 12.61 (1H, users)
213508,7of 1.30 (6H,s), and 4.75 (1H, m), 7,07 (2H, d), to $ 7.91 (2H, d), 8,20-8,21 (3H, m), 8,82-8,86 (3H, m), to 9.32 (1H, s), 12,98 (1H, s)
223849,37,11-to 7.15 (4H, m), 7,25 (1H, m), 7,45-7,49 (2H, m), 7,94-8,02 (4H, m), of 8.09 (1H, s), 8,70-8,82 (2H, m), 8,82 (1H, m), 9,40 (1H, s), 12,86 (1H, s)
23 3328,5of 1.31 (1H, m)to 1.48 (1H, m), is 2.37 (1H, m), and 2.79 (1H, m), 7,16-7,22 (3H, m), 7,28-to 7.32 (2H, m), 8,12-to 8.14 (3H, m), 8,80 (2H, d), 8,87 (1H, m), 9,99 (1H, s), 12,81 (1H, s)
2437410,3of 1.27 (1H, m), 1,40-1,49 (4H, m), 1,72 (1H, m), 1,80-to 1.82 (4H, m)2,60 (1H, m), 7,41-7,44 (3H, m), 7,86-7,92 (6H, m), 8,79 (1H, s), was 9.33 (1H, s)12,70 (1H, s)
253267,77,40-to 7.67 (6H, m), 7,83 (1H, s), 8,59 (2H, d), 8,80 (1H, d), 9,67 (1H, s), and 12.6(1H, s)
262936,17,58-7,63 (3H, m), 7,86 (1H, s), 8,31 (1H, d), 8,59 (2H, d), a total of 8.74 (1H, d), 8,78 (1H, d), 9,10 (1H, s), 9,74 (1H, s), and 12.6 (1H, s)
273268,4to 7.61-the 7.65 (4H, m), to 7.84 (1H, d), 7,98 (2H, d), 8,58 (2H, d), 8,73 (1H, d), 9,52 (1H, s), br12.62 (1H, users)
284266,7of 2.93 (3H, s), 3,17 (3H, s), a 7.62 (2H, d), to 7.77 (1H, d), a 7.85 (2H, d), to 7.93 (2H, d), of 8.27 (1H, s), 8,59 (2H, d), is 8.75 (1H, d), a 9.60 (1H, s), was 12.61 (1H, users)
292937,4a 7.62 (2H, d), 7,74 (1H, m), 7,83 (1H, m), 8,13 (1H, m), to 8.20 (1H, m), at 8.60 (2H, d), 8,78 (1 is, d)of 8.92 (1H, d), of 10.76 (1H, s), 12,68 (1H, s)
303277,1to 7.61 (2H, DD), of 7.70 (1H, d), 7,86 (1H, d), a 8.34 (1H, DD), 8,58 (2H, d), 8,71 (1H, d), 8,93 (1H, d), 9,87 (1H, s), 12,60 (1H, users)
31327-to 7.35 (1H, m), of 7.70 (2H, m), 7,80 (2H, m), of 8.00 (1H, s), 8,68 (2H, m), of 8.90 (1H, s), 9,80 (1H, m)
32327-at 7.55 (2H, m), of 7.70 (1H, m), of 7.90 (2H, users), with 8.05 (1H, users), to 8.70 (2H, m), of 8.90 (1H, s), 9,80 (1H, m)
33327-at 7.55 (1H, m), the 7.65 (2H, m), of 7.90 (2H, m), of 8.09 (1H, s), a total of 8.74 (3H, m), and 9.7 (1H, s)
34297-of 7.23 (1H, m), of 7.90 (1H, s), with 8.05 (1H, s), to 8.20 (3H, m), is 8.75 (1H, s), 8,80 (2H, m), to 9.57 (1H, s)
35281-to 6.75 (1H, m), 7,35 (1H, m), of 7.90 (2H, m), with 8.05 (2H, m), to 8.70 (2H, m), is 8.75 (1H, s), 9,23 (1H, s)
36377-the 7.65 (1H, m), 8,15 (2H, m), to 8.20 (1H, m), 8,80 (2H, m), cent to 8.85 (1H, s), 10,00 (1H, s) of 7.75 (2H, m)
37316-of 7.60 (2H, s), 7,76 (1H, m), a 7.85 (1H, s), 8,10 (1H, m), of 8.25 (1H, m), to 8.41 (1H,C)8,58 (2H, m), is 8.75 (1H, s), 9,85 (1H, s)
38369-(CD3OD) 3,20 (3H, s), 7,20 (1H, s), of 7.70 (1H, s), 8,20-8,40 (6H, m), to 8.70 (2H, d), 8,80 (1H, d)
39310-7,40 (2H, m), 8,10 (2H, m), to 8.20 (3H, m), 8,80 (3H, m), a 9.60 (1H, s)
403728,6rate of 7.54 (1H, t), 7,58-the 7.65 (2H, m), 7,80-7,88 (2H, m), 794 (1H, d), 8,13 (1H, s), 8,57-8,63 (2H, m), 8,73 (1H, s), 9,62 (1H, s)
41335--
42359--
43360-7,80 (1H, m), 8,00 (1H, m), 3,18 (2H, m), of 8.25 (3H, m), 8,80 (3H, m), 9,85 (1H, s)

44309-7,42 (2H, m), 7,55 (2H, m), the 7.65 (1H, m), 7,80 (1 is, C)8,00 (1H, m), at 8.60 (2H, m), of 8.90 (1H, s)to 9.70 (1H, m)
453358,0to 3.02 (6H, s), to 6.80 (2H, d), 7,60 (2H, DD), 7,75-7,80 (3H, m), 8,58 (2H, d), 8,77 (1H, d), 9,11 (1H, s), 12,57 (1H, users)
46398-(CDCl3) 5,20 (2H, s), 7,10 (3H, d), to 7.50 (5H, m), 8,00 (3H, m), to 8.70 (2H, d), 9,10 (2H, d)
47307-6,70 (2H, d), 7,40 (2H, d), 7,60 (2H, m), of 8.00 (1H, s), 8,40 (2H, d), and 8.50 (1H, s), 9,50 (1H, s)
48348-of 2.10 (3H, s), 7,60 (2H, d), of 7.70 (3H, m), of 7.90 (2H, d), at 8.60 (2H, d), 8,80 (1H, s), of 9.30 (1H, s), 10,30 (1H, s)
49348-of 2.10 (3H, s)to 7.50 (1H, m), 7,60 (3H, s), 7,80 (1H, s), of 7.90 (2H, d), to 8.20 (1H, s), at 8.60 (2H, d), 8,80 (1H, s), of 9.30 (1H, s), and 10.20 (1H, s)
50372-of 9.00 (1H, s), to 8.70 (1H, s), at 8.60 (2H, d), 7,80 (2H, d), of 7.75 (2H, d), 7,60 (2H, d), 7,40-to 7.50 (3H, m), 7,30 (1H, t), 2,70 (3H, s)
51382-7,10 (1H, d), was 7.45 (2H, d), to 7.50(3H, m), 7,60 (2H, m), of 7.70 (2H, d), 7,80 (1H, d), at 8.60 (2H, d), to 8.70 (1H, d), of 9.30 (1H, s)
52376--
53358--
54373--
55---
56256-0,80 (4H, m), of 2.20 (1H, m), of 7.90 (2H, m), 7,95 (1H, s), to 8.70 (2H, m), 8,78 (1H, s), of 9.75 (1H, s)
57311-at 7.55 (1H, m), of 7.90 (2H, m), 8,10 (1H, m), 8,40 (2H, m), to 8.70 (2H, m), for 9.90 (1H, s), and 10.0 (1H, s)
58359-the 7.43 (1H, m), the 7.65 (1H, m), a 7.85 (3H, m), with 8.05 (1H, m), of 8.25 (1H, m), 8,70 (4H, m), of 8.95 (1H, users), and 10.20 (1H, s)
59311-the 7.65 (1H, s), 7,80 (1H, m), 7,92 (2H, m), 8,10 (1H, users), to 8.45 (1H, m), is 8.75 (3H, m), for 9.90 (1H, s)
60 324-of 1.35 (3H, t), of 2.20 (3H, s), of 4.45 (2H, HF), to 6.80 (1H, s), 7,95 (2H, m), with 8.05 (1H, users), to 8.70 (3H, m), 9,20 (1H, s)
61409--
62--are 3.90 (3H, s), make 6.90 (1H, d), 7,40 (2H, d), to 7.50 (1H, s), of 7.90 (2H, d), of 8.00 (1H, s), to 8.70 (2H, d), 8,80 (1H, s), 9,20 (1H, s), 9,80 (1H, s)
63327-2,60 (2H, s)6,70 (1H, s), of 8.00 (1H, s), 8,10 (2H, d), at 8.60 (1H, s), 8,80 (2H, d)
64254-of 3.00 (3H, s), 7,80 (1H, s), 7,95 (1H, s), of 8.00 (2H, d), and 8.50 (1H, s), to 8.70 (2H, d)
65359-of 1.30 (3H, t), 2,80 (2H, HF), to 6.80 (1H, s), 7,10 (1H, m), 7,40 (2H, d), to 7.50 (1H, s), 7,60 (2H, d), 7,80 (1H, m), at 8.60 (2H, d), 11,40 (1H, s)
66407-of 1.50 (9H, s), 7,40 (1H, m)to 7.50 (1H, d), 7,60 (2H, d), of 7.70 (1H, m), 7,80 (1H, s), 8,10 (1H, s), at 8.60 (2H, d), 8,80 (1H, s), of 9.30 (1H, s), a 9.60 (1H, s)
67412- of 3.80 (2H, s), 5,20 (2H, s), make 6.90 (1H, m), 7,10 (1H, d), 7,20-7,30 (5H, m), 7,40 (2H, d), to 7.50 (2H, d), of 7.70 (1H, s), at 8.60 (2H, d), to 8.70 (1H, s), a 9.25 (1H, s)
693618,81,96 is 2.00 (4H, m), 3,29-to 3.35 (4H, m), 6,63 (2H, d), 7,60 (2H, d), of 7.75-7,79 (3H, m), 8,58 (2H, d), 8,77 (1H, d), the remaining 9.08 (1H, s), 12,45 (1H, users)
703907,4of 2.23 (3H, s), 2,43-2,48 (4H, m), 3,28-to 3.34 (4H, m), 7,05 (2H, d), 7,60 (2H, d), 7,76-to 7.84 (3H, m), 8,58 (2H, d), 8,77 (1H, d), 9,16 (1H, s), to 12.58 (1H, users)
713766,32,81-of 2.86 (4H, m), 3,20-3,26 (4H, m), 7,02 (2H, d), 7,60 (2H, d), of 7.75-of 7.82 (3H, m), 8,58 (2H, d), 8,77 (1H, d), with 9.14 (1H, s)
723917,1to 1.38 to 1.48 (2H, m), 1,76-of 1.84 (2H, m), 3.00 and-of 3.07 (2H, m), 3,66 is 3.76 (3H, m), to 4.73 (1H, users), 7,03 (2H, d), 7,54 (2H, d), of 7.75 (2H, d), a 7.85 (1H, d), charged 8.52 (2H, d), 8,68 (1H, d), 9.28 are (1H, users)
733777,53,25 be 3.29 (4H, m), 3.72 points-of 3.77 (4H, m), 7,06 (2H, d), 7,60 (2H, DD), 7,78 (1H, d), of 7.82 (2H, d), 8,58 (2H, DD), 8,76 (1H, d), 9,18 (1H, s), 12,56 (1H, users)
744767,0of 0.95 (6H, t), 2,39-2,56 (12H, m), 3,2-3,39 (4H, m), 7,03 (2H, d), 7,60 (2H, d), of 7.75-of 7.82 (3H, m), 8,58 (2H, d), 8,77 (1H, d), to 9.15 (1H, s)
754446,81,47-to 1.59 (2H, m), 1,63 is 1.86 (4H, m), 1,92 e 2.06 (2H, m), 2,89 (2H, t), 3,26-3,39 (5H, m), 3,82-3,98 (2H, m), 7,06 (2H, d), 7,60 (2H, d), 7,76-of 7.82 (3H, m), 8,59 (2H, d), 8,77 (1H, d), to 9.15 (1H, s), to 12.58 (1H, users)
763899,5the 1.44-1,49 (4H, m), 1.70 to 1.77 in (4H, m), 3,50 of 3.56 (4H, m), 6,79 (2H, d), to 7.59 (2H, d), 7,73-to 7.77 (3H, m), to 8.57 (2H, d), 8,76 (1H, d), the remaining 9.08 (1H, s)
774497,8was 1.69 (2H, quintet), a 2.36 (2H, t), up 3.22 (3H, s), 3.27 to 3,38 (10H, m),? 7.04 baby mortality (2H, d), 7,60 (2H, d), 7,76-of 7.82 (3H, m), 8,58 (2H, d), 8,76 (1H, d), 9,16 (1H, s)12,42 (1H, PTS. users)
783906,41,74-of 1.81 (2H, m), 2,62 (2H, t), 2,85 (2H, t), 3,29-3,37 (2H, m), 3,53 (2H, t), 3,61 (2H, t), for 6.81 (2H, d), to 7.59 (2H, d), 7,72-7,76 (3H, m), 8,58 (2H, d), 8,77 (1H, d), 9,07 (1H, s)
793926,5by 1.68 (2H, m), and 2.14 (6H, s)to 2.29 (2H, t)to 3.09 (2H, dt), 6,41-6,48 (1H, m), 6,63 (2H, d), 7,50-rate of 7.54 (2H, m), 7,66 (2H, d), 7,82-7,86 (1H, m), 8,46-8,51 (2H, m), 8,63-8,68 (1H, m), of 9.21 (1H, users)
803646,0 of 1.63 (2H, m)to 2.65 (2H, t), of 3.13 (2H, dt), of 6.50 (1H, t), of 6.65 (2H, d), 7,58 (2H, d), to 7.68 (2H, d), 7,76 (1H, d), to 8.57 (2H, d), is 8.75 (1H, d), 9,05 (1H, s)
814647,02,50-of 2.58 (6H, m), 3.25 to be 3.29 (4H, m), 3,42 (2H, t), 3.46 in-to 3.52 (2H, m), of 3.56 (2H, t), to 4.62 (1H, users),? 7.04 baby mortality (2H, d), 7,60 (2H, d), to 7.77-of 7.82 (3H, m), 8,58 (2H, d), 8,76 (1H, d), 9,17 (1H, s)
823917,43,19 (4H, m), 3.5 to 4.0 (hidden protons), 4,43 (2H, s), to 7.67-7,71 (2H, m), of 7.97 (2H, m), 8,04-8,10 (3H, m), a total of 8.74-8,82 (3H, m), of 9.51 (1H, s), 12,87 (1H, users)
833906,4(DMSO+D2O) to 3.00 (4H, m), up 3.22 (4H, m), a 4.03 (2H, s), 7,58 (2H, d), of 7.96 (2H, d), 8,09-to 8.12 (3H, m), 8,69 (2H, d), 8,79 (1H, s)
843926,7(D2O) of 2.68 (3H, s), 2,77 (3H, s), 3,43-3,51 (4H, m)to 4.41 (2H, s), 7,58 (2H, d), of 7.90 (2H, d), of 8.04 (1H, m), of 8.09 (2H, m), at 8.60 (2H, m), to 8.70 (1H, m)
854066,7(D2O) of 2.08 (2H, m)2,60 (3H, s), 2,73 (3H, s), 2,98 (2H, m), 3,19 (2H, m), 4,35 (2H, m), 7,55 (2H, m), 7,88 (2H, m), 8,01-8,10 (3H, m), 8,59-8,69 (3H, m)

Example 3

Benzyl ester (5-iodine-2-methoxypyridine-3-yl)carbamino the second acid

Benzyl ester (5-iodine-2-oxo-1,2-dihydropyridines-3-yl)carbamino acid (3,68 g, 9,94 mmol) was dissolved in chloroform (50 ml) at room temperature under nitrogen in the dark (wrapped in foil). Then was added silver carbonate (3,70 g, 13,2 mmol) and itmean (6.2 ml, and 99.4 mmol). Reactional the mixture was allowed to mix at room temperature for 48 hours. Of silver salts were removed by filtration through zletovo substrate, washed with a large amount of chloroform, and the filtrate was concentrated in vacuum. The residue was purified column chromatography, resulting target compound as a white solid (3,14 g, yield 82%). MS (ES+) m/e=385.1H NMR (CDCl3) δH of 3.97 (3H, s), 5,23 (2H, s), to 7.15 (1H, users), 7,35-7,47 (5H, m), of 8.00 (1H, s)8,64 (1H, users).

Example 4

Benzyl ether [2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-3-yl]carbamino acid

Benzyl ester (5-iodine-2-methoxypyridine-3-yl)carbamino acid (1 g, 2.6 mmol), bis(pinacolato)diboron (727 mg, of 2.86 mmol), KOAc (766 mg, 7,81 mmol) and Pd(OAc)2(18 mg, 3 mol.%) were suspended in anhydrous DMF (20 ml). The mixture was degirolami slow stream of bubbles of nitrogen flow through the system for 30 minutes and then was heated at 85°C for 3 hours. The reaction was cooled to room t is mperature and diluted with water. The reaction mixture was extracted with EtOAc (×3), dried over MgSO4was filtered and concentrated in vacuum. Purification of column chromatography gave the target compound as a white solid (501 mg, 50% yield). MS(ES+) m/e=385.1H NMR (DMSO-d6) δH of 1.34 (12H, s), a 4.03 (3H, s), of 5.24 (2H, s), to 7.15 (1H, users), 7,34-7,46 (5H, m), 8,21 (1H, s), 8,63 (1H, users).

Example 5

Benzyl ether [2-methoxy-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]carbamino acid

Benzyl ether [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-3-yl]carbamino acid (377 mg, 0.98 mmol), 4-chloro-2-dimethylpyrimidin (171 μl, about 1.47 mmol) and Pd(Pph3)4(113 mg, 10 mol.%) were dissolved in a mixture of toluene (15 ml) and EtOH (3 ml). Then was added Na2CO3(717 mg, 6,77 mmol) in water (6 ml), after which the reaction mixture was heated at the boil under reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and was extracted with EtOAc (×3). The combined organic extracts were dried over MgSO4filtered and concentrated in vacuum. The residue was absorbed by the silica gel column and purified by chromatography, resulting target compound in the form of a yellowish-white solid (261 mg, 70% yield). MS(ES+) m/e=83. 1H NMR (DMSO-d6) δH to 2.67 (3H, s), 4.09 to (3H, s), at 5.27 (2H, s), 7,30-7,47 (7H, m), 8,54 (1H, d), 8,67 (1H, s), 9,01 (1H, users).

Example 6

Benzyl ester of [5-(2-methylsulfonylamino-4-yl)-2-oxo-1,2-dihydropyridines-3-yl]carbamino acid II-3

Benzyl ether [2-methoxy-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]carbamino acid (20 mg, 0.05 mmol)was dissolved in a mixture of 1,4-dioxane (1 ml) and water (300 μl). Then added concentrated HCl (100 ml), after which the reaction mixture was heated at the boil under reflux for 30 minutes. The reaction mixture was cooled to room temperature and added water. The precipitate was isolated by filtration and dried under vacuum, resulting target compound as yellow solid (12.9 mg, yield 67%). MS (ES+) m/e=369.1H NMR (DMSO-d6) δH of 2.56 (3H, s), 5,20 (2H, s), 7,38-7,46 (5H, m), 7,60 (1H, d), 8,10 (1H, userd), 8,56 (1H, d), 8,61 (1H, s), 8,69 (1H, s), to 12.52 (1H, userd).

Example 7

2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-3-ylamine

Benzyl ether [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-3-yl]carbamino acid (506 mg, 1,32 mmol) was dissolved in methanol (10 ml). Next was added Pd(OH)2coal (51 mg, 10 mol.%), then the reaction mass was degenerous is nitrogen. Then, the nitrogen atmosphere was replaced by hydrogen, and the reaction mixture was stirred at room temperature for 5 hours. The remainder of the palladium was removed by filtration through zletovo substrate and washed with a large quantity of methanol. The filtrate was concentrated in vacuo, the resulting target compound in the form of a yellowish-white solid (319 mg, yield 97%). MS (ES+) m/e=251.1H NMR (DMSO-d6) δH 1,27 (N, C), 3,88 (3H, s), 4,89 (2H, users), 7,13 (1H, s), to 7.64 (1H, s).

Example 8

4-tert-Butyl-N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-3-yl]benzamide

2-Methoxy-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyridine-3-ylamine (319 mg, 1.28 mmol) was dissolved in dichloromethane (5 ml). Then added triethylamine (117 μl, of 1.40 mmol) and 4-tert-butylbenzoate (274 μl, of 1.40 mmol)and the reaction mass was stirred at room temperature for 10 minutes. The crude mixture was absorbed on silica gel and purified column chromatography, resulting in the target connection in the form of a yellowish-white solid (274 mg, yield 52%). MS (ES+) m/e=411.1H NMR (CDCl3) δH of 1.36 (12H, s)of 1.39 (9H, s), 4,10 (3H, s), 7,55 (2H, d), 7,86 (2H, d), of 8.28 (1H, s), at 8.36 (1H, users), 9,07 (1H, s).

Example 9

4-tert-Butyl-N-[-methoxy-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]benzamide

4-tert-Butyl-N-[2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine-3-yl]benzamide (274 mg, 0.67 mmol), 4-chloro-2-dimethylpyrimidin (116 μl, 1.00 mmol) and Pd(Pph3)4(77 mg, 10 mol.%) dissolved in a mixture of toluene (10 ml) and EtOH (2 ml). Then was added Na2CO3(488 mg, 4.61 mmol) in water (4 ml), after which the reaction mixture was heated at the boil under reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted EtOAc (×3). The combined organic extracts were dried over MgSO4filtered and concentrated in vacuum. The residue was absorbed on silica gel and purified column chromatography, resulting target compound as a yellow solid (120 mg, yield 44%). MS (ES+) m/e=409.1H NMR (CDCl3) δH of 1.40 (9H, s), 2,69 (3H, s), 4,17 (3H, s), 7,41 (1H, d), EUR 7.57 (2H, d), 7,87 (2H, d), to 8.45 (1H, users), 8,56 (1H, d), 8,76 (1H, d), 9,46 (1H, d).

Example 10

4-tert-Butyl-N-[5-(2-methylsulfonylamino-4-yl)-2-oxo-1,2-dihydropyridines-3-yl]benzamide II-4

4-tert-Butyl-N-[2-methoxy-5-(2-methylsulfonylamino-4-yl)pyridine-3-yl]benzamide (120 mg, 0.29 mmol) was dissolved in a mixture of 1,4-dioxane (6 ml) and water (1.2 ml). Added concentrated HCl (600 ml), after which the reaction mixture was heated at boiling with inverse x is Hladilnika within 30 minutes. Then the reaction mixture was cooled to room temperature and added water. The precipitate was isolated by filtration and dried under vacuum. The crude solid was purified flash chromatography, the resulting target compound in the form of a yellowish-brown solid (29 mg, yield 25%). MS (ES+) m/e=395.1H NMR (DMSO-d6) δH of 1.33 (9H, s), 2,58 (3H, s), to 7.59 (2H, d), to 7.64 (1H, d), 7,88 (2H, d), 8,21 (1H, s), 8,58 (1H, d), 9,11 (1H, s), of 9.30 (1H, s), 12,72 (1H, users).

Example 11

N-(1,2-dihydro-5-(2-(methylamino)pyrimidine-4-yl)-2-oxopyridine-3-yl)-4-(piperidine-1-yl)benzamid II-40

4-Bromo-N-(2-methoxy-5-(2-(methylamino)pyrimidine-4-yl)pyridine-3-yl)benzamide (50 mg, 0,121 mmol) was placed in a test tube for microwave oven equipped with a stirrer. Then was added NMP (1.5 ml) and piperidine (1.5 ml). The reaction vessel was heated at 160°C for 2 hours in a microwave oven. After cooling, the solvent and excess piperidine were removed in vacuum. The crude compound was recrystallized from methanol, the resulting target compound as a white solid (22 mg, yield 45%). MS (ES+) m/e=405.1H NMR (DMSO-d6) δH 1,54-to 1.61 (6H, m), 2,85 (3H, users), 3,28-to 3.36 (4H, m), 6,95 for 7.12 (4H, m), to 7.77 (2H, d), of 8.00 (1H, s), of 8.27 (1H, d), of 9.02 (1H, users), which is 9.09 (1H, s), of 12.53 (1H, users).

A number of other joint is of Formula II was obtained by means in General, similar to those described here. Characterization data for these compounds are shown in Table II-A below and includes HPLC, LC/MS (observed) and data1H NMR.

Data1H NMR are shown in Table II-A below, in which data1H NMR were obtained at 400 MHz in deuterated DMSO, unless otherwise specified, and as established, are consistent with the structure. The numbers of the Compounds correspond to the numbers of the compounds listed in Table 1.

Table II-A
The characteristic data of Selected Compounds of Formula II
Connection # IIM+1 (OBS)RT (min)1H-NMR
13219,5of 5.26 (2H, s), 7,28-7,51 (11H, m), a 7.85 (1H, s), 8,56 (1H, s), 12,49 (1H users)
22918,97,33 to 7.62 (9H, m), 7,95 (2H, m), 8,71 (1H, s), 9,36 (1H, s), 12,34 (1H, users)
3Cm. Example 6
4Cm. Example 10
54329,8to 1.38 (9H, s), 3,80-4,14 (8H, osirm), 6,85 (1H, d), 7,16 (1H, d), 7,54 (2H, d), 7,60 (1H, t), 7,88 (2H, d), 7,94 (1H, users), to 8.94 (2H, users), 9,01 (1H, s), 9.28 are (1H, s), 12,47 (1H, userd)
639110,4of 1.33 (9H, s), 3,11 (6H, s), 6,62 (1H, userd), 7,00 (1H, d), 7,58 (3H, d), 7,88 (3H, d), 9,05 (1H, users), 9,27 (1H, users), 12,45 (1H, users)
73779,8of 1.33 (9H, s), 2.91 in (3H, s)6,94 (1H, userd), was 7.36-7,46 (1H, m), 7,53-of 7.69 (3H, m), 7,88 (3H, d), of 8.90 (1H, users), 9,36 (1H, users), 12,56 (1H, users)
8365-(CDCl3) to 1.25 (9H, s), 7,05 (2H, m), 7,25 (1H, s), was 7.45 (2H, d), to 7.50 (2H, d), a 7.85 (2H, d), of 8.95 (1H, s), 9,05 (1H of user., C)
9391-(Meon-d4) to 1.35 (1H, m)of 1.47 (4H, m), of 1.80 (1H, m), 1,90 (4H, m), 2,62 (1H, m), to 7.15 (2H, m), 7,40 (3H, m), 7,55 (2H, m), of 7.90 (2H, d), cent to 8.85 (1H, s)
10362-of 1.31 (9H, s), to 6.80 (2H, m), 7,30 (3H, m), 7,55 (3H, m), of 7.85 (2H, m), of 6.65 (1H, m), of 9.30 (1H, users)
11 372-of 1.33 (9H, s), 7,58 (2H, m), of 7.75 (2H, m), 7,80 (1H, d), a 7.85 (4H, m), to 8.70 (1H, s), 9,40 (1H,users)

12353-of 1.33 (9H, s), 7,05 (2H, m), 7,18 (1H, m), 7,30 (1H, m), 7,55 (2H, m), 7,60 (1H, s), 7,83 (2H, m), and 8.50 (1H, m), to 9.45 (1H,users)
13392-of 1.30 (9H, s), 7,55 (3H, m), 7,80 (1H, users), of 7.90 (4H, m), 8,30 (2H, m), 8,80 (1H, s), of 9.30 (1H, s)
143789,5of 1.33 (9H, s), 2.91 in (3H, users), 7,14 (1H, users), to 7.59 (2H, d), 7,88 (2H, d), 8,17 (1H, users), 8,29 (1H, d), 9,07 (1H, users), of 9.30 (1H, s)12,70 (1H, users)
15351-of 1.33 (9H, s), 3,85 (3H, s), 7,40 (1H, s), 7,60 (2H, d), the 7.65 (1H, s), a 7.85 (2H, d), of 8.00 (1H, s), and 8.50 (1H, s), of 9.30 (1H, users)
16426-of 1.32 (9H, s), 7,33 (1H, s), EUR 7.57 (2H, d), the 7.65 (1H, m), 7,78 (2H, d), of 7.90 (4H, m), is 8.75 (1H, s), of 9.30 (1H, s)
173789,2(S) 3,01 (3H, s), make 6.90 (1H, s), 7,60 (2H, d), 7,88 (2H, d), and 8.0 (1H, d)to 8.34 (1H, s), 8,81 (1H, s), which 9.22 (1H, s), to 12.58 (1H, users)
183929,6of 1.32 (9H, s), 3,30 (6H, s), 7,16 (1H, s), to 7.59 (2H, d), of 7.90 (2H, d), 8,18 (1H, d), 8,73 (1H, s), 8,80 (1H, s), 9,40 (1H, s), 12,99 (1H, users)
19520the 10.1to 1.19 (3H, t), of 1.32 (9H, s)of 1.46 (2H, m), a 1.96 (2H, m), 2,85-3,10 (2H, m), 3,92-4,10 (6H, m), 7,33 (1H, users), 7,58 (2H, d), 7,88 (2H, d), 8,32 (3H, m), 9,06-9,16 (1H, m), 9,29 (1H, s), 12,87 (1H, s)
204219,4of 1.32 (9H, s), 2,62 (3H, m), 3,19 (2H, m), 3,74 (2H, m), 7,32 (1H, users), to 7.59 (2H, d), 7,89 (2H, d), 8,17 (1H, PTS. users), of 8.37 (1H, users), 8,87 (2H, PTS. users), the remaining 9.08 (1H, s), was 9.33 (1H, s), 12,87 (1H, users)

td align="center"> the 10.1
2139210,0of 1.33 (9H, s), 3,23 (6H, s), 7,16 (1H, users), 7,58 (2H, d), 7,88 (2H, d), 8,19 (1H, users), to 8.34 (1H, d), 9,12 (1H, s), 9,29 (1H, s)12,70 (1H, users)
223929,8to 1.21 (3H, t), of 1.32 (9H, s), 3,50 (3H, osirm), 7,31 (1H, userd), 7,58 (2H, d), 7,88 (2H, d), 8,30 (1H, s), 8,31 (1H, users), the remaining 9.08 (1H, s), 9,31 (1H, s), 12,86 (1H, users)
23406to 1.24 (6H, d), of 1.33 (9H, s), of 4.12 (2H, osirm), from 7.24 (1H, users), 7,58 (2H, d), 7,88 (2H, d), compared to 8.26 (1H, users), 8,29 (1H, d), 9,06 (1H, s), 9,31 (1H, s), 12,82 (1H, users)
2445410,3of 1.32 (9H, s), of 4.66 (2H, users), 7,22-to 7.35 (4H, m), 7,49 (1H, users), to 7.59 (2H, d), 7,89 (2H, d), of 8.28 (1H, users), 8,32 (1H, users), 9,10 (1H, users), 9,31 (1H, s), 12,84 (1H, users)
25433the 9.7of 1.33 (9H, s), up 3.22 (4H, osirm), Android 4.04 (4H, osirm), 7,19 (1H, d), to 7.59 (2H, d), 7,88 (2H, d), 8,14 (1H, userd), 8,43 (1H, d), 8,93 (1H, users), 9,04 (1H, s), 9,31 (1H, s), 12,71 (1H, userd)
263489,6was 7.45 (1H, t), 7,58 (2H, d), a 7.85 (2H, d), 7,94-of 8.04 (3H, m), 8,65 (1H, d), 9,04 (1H, s), 9,31 (1H, s),
2751910,4of 1.20 (3H, t), of 1.32 (9H, s), 1,96-of 2.05 (2H, m), 2.95 and-of 3.12 (2H, m), 3,30-to 3.36 (2H, m), 3,90-4,06 (5H, m+kV), 6,37 (1H, d), 6,52 return of 6.58 (1H, m), 6,85 (1H, d), 7,40 (1H, t), EUR 7.57 (2H, d), 7,76-to 7.84 (1H, m), 7,84 (1H, d), 9,07 (1H, s), 9,20 (1H, s)
284489,5of 1.32 (9H, s), 1,76-of 7.82 (2H, m), 2,07-of 2.20 (2H, m), of 3.07 (2H, osirm), 3,33-3,39 (2H, m), 4,10 (1H, m), 7,29 (1H, users), 7,49 (2H, d), 7,88 (2H, d), of 8.27 (1H, users), to 8.34 (1H, s), 9,01-9,23 (1H, ears the mkm), 12,82 (1H, users)
294489,5of 1.32 (9H, s), 1,61-2,07 (4H, m), 2,82-2,99 (2H, osirm), 3,19 (1H, m), 3,39 (1H, m), is 4.21 (1H, m), 7.23 percent (1H, users), to 7.59 (2H, d), 7,89 (2H, d), 8,08-of 8.28 (2H, osirm), 8,35 (1H, s), 9,06 (1H, s), 12,79 (1H, users)
304339,5of 1.32 (9H, s)2,07 (1H, m), of 2.25 (1H, m), or 3.28 (2H, m), 3,37 (1H, m), 3,47 (1H, m), 4,55 (1H, m), 7,25 (1H, s), to 7.59 (2H, d), 7,88 (2H, d), 8,16 (1H, s), 8,35 (1H, d), the remaining 9.08 (1H, s), 9,14-9,26 (1H, osirm), of 12.76 (1H, users)
314339,5of 1.32 (9H, s), is 2.09 (1H, m), and 2.27 (1H, m), with 3.27 (2H, m), 3,39 (1H, m), of 3.45 (1H, m), of 4.49 (1H, m), 7,28 (1H, s), to 7.61 (2H, d), 7,88 (2H, d), 8,19 (1H, s), at 8.36 (1H, d), 9,12 (1H, s), 9,14-a 9.35 (1H, osirm), 12,80 (1H, users)
324479,81,22-of 1.30 (2H, m)of 1.33 (9H, s), 1,86-of 1.95 (2H, m), of 2.51-2,60 (2H, m), 2.91 in-of 2.97 (2H, m), 3.75 to of 3.85 (1H, m), 6.35mm (1H, d), 6,47 (1H, d), 6,83 (1H, d), of 7.36 (1H, t), to 7.59 (2H, d), 7,80 (1H, s), a 7.85 (2H, d), of 9.02 (1H, s), which 9.22 (1H, s),
334339,5of 1.32 (9H, s), 3,23 (4H, s), of 4.05 (4H, s), of 7.36 (1H, s), to 7.59 (2H, d), 7,89 (2H, d), by 8.22 (1H, s)8,71 (1H, s), 8,96 (1H, s), a 9.35 (1H, s), 9,38 (1H, users), 12,86 (1H, users)
34 3499,4of 1.32 (9H, s), to 7.59 (2H, d), 7,88 (2H, d), 7,98 (1H, d), by 8.22 (1H, s), 8,76 (1H, d), 9,17 (2H, d), of 9.30 (1H, s), 12,71 (1H, users)
354209,1of 1.35 (9H, s)to 2.65 (3H, s), 3,16-of 3.25 (2H, m), 3,63-3,70 (2H, m), 7,03 (1H, d), 7,60 (2H, d), of 7.90 (2H, d), 8,80-8,95 (2H, m), of 9.00 (1H, s), to 9.32 (1H, s)
36409the 10.1of 1.33 (9H, s), is 2.37 (3H, s)to 2.55 (3H, s), 7,55 (2H, d), of 7.69 (1H, s), a 7.85 (2H, d), 8,48 (1H, s), 8,78 (1H, s), a 9.25 (1H, s),
37311-of 5.17 (2H, s), 7,35 (7H, m), a 7.85 (2H, users), 8,10 (1H, s)of 8.37 (1H,users)
384218,7of 1.32 (9H, s), 2,58-2,60 (3H, m), 3,13 is 3.15 (2H, m), 3.75 to 3,76 (2H, m)6,94 (1H, users), to 7.59 (2H, d), 7,89 (2H, d), 8,11 (1H,users), 8,69 (1H, s), 8,84 (1H, s), 8,93 (2H, users), 9,36 (1H, s), is 12.85 (1H, users)
394338,7of 1.32 (9H, s)to 1.99 (1H, m), of 2.38 (1H, m), and 3.16 (1H, m), 3,30 (1H, m), 3,37 (1H, m), 3,52 (1H, m), with 4.64 (1H, m), 6,93 (1H, s), to 7.61 (2H, d), 7,88 (2H, d), of 8.09 (1H, users), 8,69 (1H, s), cent to 8.85 (1H, s), was 9.33 (2H, users), 9,36 (1H, s), 12,82 (1H, users)
41424of 1.31 (9H, s), and 2.83 (3H, s), of 6.49 (1H, s), 7,46-to 7.61 (3H, m), 7,81-7,98 (3H, m), of 8.90 (1H, users), 9,27 (1H, s), 12,48 (1H, users)
42376the 9.7of 1.31 (9H, s), 2,11 (3H, s), of 4.95 (2H), 6,41-6,51 (2H, m), 6.89 in (1H, m), 7,05 (1H, s), 7,58 (2H, m) a 7.85 (2H, m), 8,32 (1H, s), a 9.25 (1H)
4339010,2of 1.36 (9H, s), of 2.15 (3H, s)to 2.67 (3H, m), of 5.55 (1H, m), 6,36-6,51 (2H, m), 6,97 (1H, m), was 7.08 (1H, s), 7,58 (2H, m) a 7.85 (2H, m), 8,35 (1H, s), a 9.25 (1H)
4439110,5of 1.31 (9H, s), 2,22 (3H, in), 3.75 (3H, s), is 6.78-6.89 in (2H, m), 7.18 in-7,22 (2H, m, 7,58 (2H, m), a 7.85 (2H, m), 8,35 (1H, s), 9,29 (1H)

454608,61,55-1,65 (6H, m), of 1.94 (1H, m), 2,24 (1H, m), 3,11 (1H, m), 3.27 to be 3.29 (2H, m), 3,29-to 3.35 (4H, m), 3,44 (1H, m), a 4.53 (1H, m), PC 6.82 (1H, s), 7,02 (2H, d), to 7.77 (2H, d), 7,86-7,94 (2H, m), and 8.50 (1H, s), 8,96-8,99 (2H, m), 9,10 (1H, s), 12,51 (1H, users)
464058,91,50-1,60 (6H, m), 2,84 (3H, users), 3,31-to 3.34 (4H, m), of 6.75 (1H, s), 7,02 (2H, d), 7,39 (1H, users), to 7.77 (2H, d), 7,92 (1H,users), 8,42 (1 H, s), of 8.95 (1H, s), which is 9.09 (1H, s)to 12.44 (1H, users)
4049,51,55-1,65 (6H, m), 3,30-3,37 (4H, m), and 2.83 (3H, s), 6,33 (1H, d), 6.48 in-6,59 (1H, users), at 6.84 (1H, d), of 7.00 (2H, d), the 7.43 (1H, t), 7,72-7,80 (3H, m), of 9.00 (1H, s), 9,06 (1H, s),
48432the 10.1to 1.21 (6H, d), 1,55-to 1.63 (6H, m), 3,30-to 3.38 (4H, m), 3,99-4.09 to (1H, m), 6,33 (1H, d), 6,38 (1H, d), 6,76 (1H, d), of 6.99 (2H, d), of 7.36 (1H, t), 7,72 for 7.78 (3H, m), 8,93 (1H, s), 9,05 (1H, s)
49430the 10.10,40-0,46 (2H, m), of 0.67 to 0.75 (2H, m), 1,55-of 1.64 (6H, m), 2,49-to 2.57 (1H, m), 3,30-to 3.38 (4H, m), 6,50 (1H, d), to 6.80 (1H, s)6,91 (1H, d), of 7.00 (1H, d), 7,49 (1H, t), 7,71-7,79 (3H, m), 8,97 (1H, s), 9,05 (1H, C)
5048010,31,55-of 1.64 (6H, m), 3,30-to 3.38 (4H, m), a 4.53 (2H, d), 6,37 (1H, d), 7,83 (1H, d), of 7.00 (2H, d), 7,15-7,22 (2H, m), 7,25-7,33 (2H, m), 7,35-7,44 (3H, m), 7,70-to 7.77 (3H, m), 8,96 (1H, s), 9,05 (1H, s)
514478,71,53-of 1.64 (6H, m), is 2.30 (3H, s), 2,63-2,70 (2H, m), 3,30-3,44 (6H, m), 6.35mm (1H, d), 6,45-of 6.52 (1H, m), to 6.80 (1H, d), of 7.00 (2H, d), 7,38 (1H, t), 7,70 for 7.78 (3H, m), of 8.95 (1H, s), 9,05 (1H, s)
524229,8of 1.59 (6H, users), of 2.54 (3H, s), 3,23 (4H, users), 7,01 (2H, d), of 7.36 (1H, users), 7,71 (2H, is), with 8.33 (1H, users), 8,39 (1H, users), 8,84 (1H, users), 9,39 (1H, users)
5343210,2of 1.30 (6H, d), to 1.60 (6H, users), the 2.46 (4H, users), 3,10 (1H, m), and 3.31 (3H, s), 7,02 (2H, d), 7,60 (1H, s), to 7.77 (2H, d), 8,10 (1H, userd), 9,11 (2H, users d), was 12.61 (1H, userd)
5437710,3of 1.34 (9H, s), 3,85 (3H, s)6,91 (1H, m), 7,10-7,16 (2H, m), of 7.36 (1H, m), 7,58 (3H, m), 7,89 (2H, m), 8,71 (1H, s), of 9.30 (1H)
55362the 9.7of 1.31 (9H, s)to 2.55 (3H, s), 7,41 (1H, s), 7,56 (2H, m), 7,89 (3H, m), 8,40 (1H, s), 8,70-8,78 (2H, m), 9,35 (1H)
564059,1of 1.62 (6H, m), 2,90 (3H, m), 6,34 (1H, d),? 7.04 baby mortality (2H, d), 7,38 (1H, osirm), of 7.75 (2H, d), of 8.09 (2H, m), the remaining 9.08 (1H, s), which 9.22 (1H, s), 12,35 (1H, s)
57420the 9.7to 1.79 (3H, t), a 2.01 (6H, users), 3,70 (4H, users), 4,82 (2H, m), the 7.43 (2H, d), of 7.96 (1H, m), 8,19 (2H, d), 8,56 (1H, users), 8,96 (1H, m), 9,50 (2H, d), 13,06 (1H, users)
584629,4of 1.53 (6H, m), 2,77 (6H, m), 4,20-4,50 (6H, m), 4,60-4,80 (2H, m), 7,05 (2H, m), 7,35 (1H, m), 7,73 (1H, m), to 7.99 (1H, m), of 8.27 (1H, m), 9,05 (2H, m), 32 (1H, users), to 9.93 (1H, users), 12,91 (1H, users)
594358,61,55-1,65 (6H, m), 3.33 and is 3.40 (6H, m), of 3.54 (2H, m), 4,58 (1H, users), 6,90-7,02 (4H, m), 7,76 (2H, d), 7,98 (1H, s), compared to 8.26 (1H, s), 8,99 (1H, s), the remaining 9.08 (1H, s), 12,50 (1H, users)

604488,91,50-of 1.65 (6H, m), of 2.34 (3H, s), 2.77-to 2,90 (2H, m), 3,24 is 3.40 (4H, m), 4,30-and 4.40 (2H, m), 6,60 (1H, m), 6,93-7,05 (2H, m), 7,26-to 7.35 (1H, m), of 7.64-7,80 (3H, m), 7,89 (1H, s), 8,97 (1H, s), 9,10 (1H, s)
61476the 9.7of 1.56 (6H, m), 2,46 (3H, hidden signal), 2,85 (6H, m), 3,20-of 3.60 (6H, m), of 3.97 (2H, m), 6,98-7,11 (2H, m), 7,73 (2H, users), of 8.04 (1H, users), to 8.34 (1H, users), 9,07 (2H, users), 9,26 (1H, users), 12,6 (users)
623929,6of 1.30 (9H, s), measuring 2.20 (3H, s), 2,80 (3H, d), 6,91 (1H, userd), 7,55-to 7.61 (3H, m), a 7.85 (2H, d), 8,16 (1H, s), is 8.75 (1H, s), 9,26 (1H, s)
634488,7to 1.60 (6H, m), 2,62 (3H, s), and 3.16 (2H, m)to 3.33 (4H, m), 3,62 (2H, m), 7,01 (1H, d), 7,10 (1H, d), 7,16 (1H, t), to 7.77 (2H, d), of 8.04 (1H, m), with 8.33 (1H, d), 8,58 (2H, m), 9,06-of 9.09 (2H, m), USD 12.6 (1H, d)
64322 7,62,82-2,89 (3H, m), of 6.99 (1H, d), 7,11 (1H, d), 7,53-to 7.67 (3H, m), 7,94 (2H,d), with 8.05 (1H, s), of 8.27 (1H, d), 9,04 (1H,s), a 9.35 (1H, s), to 12.58 (1H, d),
654629,1of 1.59 (6H, m), 2,32 (3H, s)to 2.67 (3H, s)3,18 (2H, m), 3,35-of 3.60 (4H, m), of 3.78 (2H, m), 7,00-7,10 (3H, m), 7,76 (2H, d), 8,03 (1H, s), with 8.33 (1H, d), 9,07 (2H, m)
664339,8to 1.21 (3H, t)to 1.59 (6H, m), of 2.54 (2H, m), 2,85 (3H, s), 3,39 (4H, osirm), PC 6.82 (1H, s), 7,01 (2H, d), of 7.75 (2H, d), of 8.09 (1H, s), of 8.95 (1H, s)
674268,8of 2.86 (3H, users), 7,01 (1H, d), 7,12 (1H, d), 7,60 (2H, DD), 7,66-7,76 (1H, m), 7,79 (2H, d), 7,88 (2H, d), 8,06-to 8.12 (3H, m), of 8.28 (1H, d), 9,05 (1H, s), of 9.55 (1H, s), 12,60 (1H, s)

6837610,0of 1.35 (9H, s), of 2.86 (3H, s), to 6.95 (1H, m), 7,18 (2H, m), 7,39 (1H, m), 7,54 (1H, s), to 7.61 (2H, d), 7,92 (2H, d), 8,72 (1H, s), 9,31 (1H, s)
69403the 9.7was 1.58 (6H, s), a 2.71 (3H, s)to 3.36 (4H, m), of 6.45 (1 H, m), 6,65-6,72 (2H, m), 6,98 (2H, d), 7,11 (1H, t), 7,37 (1H, s), of 7.75 (2H,d), 8,67 (1H, s)
7044 9,01,53-of 1.62 (6H, m), 3,30-3,42 (4+2H, 2×m), 3,51-of 3.60 (2H, m), 4.72 in (1H, t), 6,38 (1H, d), 6,53 (1H, t), to 6.80 (1H, d), of 6.99 (2H, d), 7,37 (1H, t), 7,72 for 7.78 (3H, m), of 8.92 (1H, s), 9,06 (1H, s)
714489,61,54-of 1.65 (6H, m), with 3.27 (3H, s), 3,30-3,37 (4H, m), 4,46-4,55 (4H, m), 6,2 (1H, d), 6,63 (1H,
t), 6,85 (1H, d), 7,01 (2H, d), 7,41 (1H, t), 7,72-of 7.82 (3H, m), 8,99 (1H, s), 9,06 (1H, s)
72403-(CDCl3) of 1.7 to 1.2 (6H, m), of 1.85 (4H, m)to 2.55 (1H, m), of 3.80 (3H, s), make 6.90 (2H, d), to 7.15 (2H, m), 7,30 (2H, d), 7,40 (2H, d), a 7.85 (2H, d), of 8.95 (1H, users), 9,05 (1H, users)
7339610,2of 1.3 (9H, s), and 2.3 (3H, s), and 7.3 (1H, d), and 7.4 (1H, s), and 7.6 (2H, d), and 7.8 (1H, d), and 7.9 (2H,d), and 8.6 (1H, s)
743899,1of 1.6 (6H, s), and 3.4 (4H, m), 7,0 (2H, osirm), 7,2 (1H, osirm), 7,4-7,6 (4H, m), 7,8 (2H, d), and 8.7 (1H, s)
754469,1of 1.6 (6H, s), 2,6 (3H, s), 3,1 (2H, m), 3,3 (4H, m), 3,4 (2H, m), and 6.6 (1H, m), 6,8 (2H, m), 7,0 (2H, m), 7,2 (1H, t), and 7.4 (1H, s), 7,8 (2H, m), and 8.6 (1H, s), and 9.1 (1H, s)
764498,6 of 1.59 (6H, users), 2,49 (5H, users), to 3.33 (4H, users), a 4.53 (2H, users), 7,00 (2H, userd), 7,63 (1H, users), of 7.75 (2H, users), 8,17 (1H, users), to 8.57 (1H, users), the remaining 9.08 (2H, userd)
774066,3to 2.85 (3H, s), 3,17-3,20 (4H, m), 3,44-to 3.50 (4H, m), 6,97 (1H, d), 7,05 for 7.12 (3H, m), a 7.85 (2H, d), 8,01 (1H, s), of 8.27 (1H, d), of 9.02 (1H, users), to 9.15 (1H, s),
784487,7a 1.01 (6H, d), 2,53 at 2.59 (4H, m), 2,66-2,69 (1H, m), 2,85 (3H, users), 3,26-to 3.36 (4H, m), 6,97 (1H, d), 7,03 (2H, d), to 7.09 (1H, d), 7,78 (2H, d), of 8.00 (1H, s), of 8.27 (1H, d), 9,03 (1H, s), 9,10 (1H, s), 12,51 (1H, users)
794787,81,63 is 1.75 (2H, m), 2,30-to 2.41 (2H, m), 2,82-2,90 (4H, m), up 3.22 (3H, s), 3,28-3,39 (6H, m), 6,94 for 7.12 (4H, m), 7,79 (2H, d), of 8.00 (1H, s), of 8.27 (1H, d), 9,03 (1H, s), 9,11 (1H, s), of 12.53 (1H, d)
804747,91,66-of 1.73 (4H, m), 1,89-of 2.09 (4H, m), 2,31-of 2.54 (4H, m), 2.57 m) of 2.68 (2H, m), is 2.88 (3H, users), 3,11-3,19 (1H, m), 3,39-of 3.48 (1H, m), 3,91-to 3.99 (1H, m), of 6.66 (2H, d), 6,97 (1H, d), 7,10 (1H, d), to 7.77 (2H, d), 7,99 (1H, s), of 8.27 (1H, d), 9,03 (2H,s), 12,49 (1H, users)
814487,1is 2.05 (3H, s), 2,85 (3H, s), 3,28 is 3.40 (4H, m), 3,56-3,61 (4H, m), 6,97 (1H, d), 7,02-7,11 (3H, m), 7,81 (2H, d), 8,01 (1H, s), compared to 8.26 (1H, d), 902 (1H, C), 9,12 (1H, s), to 12.52 (1H, users)
823866,5of 1.02 (9H, s), 2,82 (3H, s), 3,35-3,39 (8H, m), 6.90 to (1H, m), 7,05 (1H, m), 7,86 (2H, m), 8,24 (1H, m), 8,68 (1H, m), 12,38 (1H, users)
83379-of 1.31 (9H, s), is 2.05 (2H, m), 2,35 (2H, m), of 2.72 (2H, m), 6,17 (1H, s), 7,55 (2H, m), 7,60 (1H, m), 7,88 (2H, m), 8,65 (1H, s), a 9.25 (1H, users)
84382--

85392-(CDCl3) 1,70 of 1.50 (6H, m), is 2.05 (2H, m), 2.40 a (2H, m)2,60 (2H, m)of 3.25 (4H, m), 6.35mm (1H, s), make 6.90 (2H, m), 7,30 (1H, s), 7,80 (2H, m), of 8.90 (2H, d)
86407-to 1.60 (6H, s), of 1.80 (4H, m), of 2.45 (4H, m)to 3.35 (4H, m), 6.35mm (1H, s), 7,00 (2H, m), 7,25 (1H, m), of 7.75 (2H, m), to 8.70 (1H, s), 9,10 (1H, s)
87378-(CDCl3) 1,50-1,70 (6H, m)of 2.50 (2H, m), 2,90 (2H, m), 3,30 (4H, m), to 6.43 (s, 1H), 6,85 (2H, m), 7,35 (1H, s), 7,80 (2H, m), of 8.90 (2H, d)
88365 (CDCl3) to 1.25 (9H, s), 7,05 (2H, m), 7,25 (1H, s), was 7.45 (2H, d), to 7.50 (2H, d), a 7.85 (2H, d), of 8.95 (1H, s), 9,05 (1H, users)
89394-to 1.60 (8H, m), of 1.85 (3H, m), of 2.20 (2H, m)of 3.25 (4H, m), 4,30 (1H, users), equal to 6.05 (1H, s), 6,85 (2H, m), 7,00 (1H, s), of 7.75 (2H, m), 8,80 (1H, m), of 8.90 (1H, m)
90364--
91496--
92406--
934339,6to 1.21 (3H, t)to 1.60 (6H, m), of 2.54 (2H, HF), 2,87 (3H, s), 3.3V (4 hidden proton), 6,17 (1H, s), 7,02 (2H, d), to 7.77 (2H, d), 8,07 (1H, s), of 9.21 (1H, s)
944009,5to 1.60 (6H, m), 3.3V (4 hidden proton), 7,02 (2H, d), of 7.70 (1H, d), to 7.77 (2H, d), of 8.09 (1H, d), 8,39 (1H, s), 8,84 (1H, d), 9,13 (1H, d)
954619,41,52-of 1.62 (6H, m), is 2.30 (3H, s), 2,70 (2H, t), of 3.05 (3H, s), 3,24-to 3.36 (4H, m), 3,61 (2H, t), 6,51 (1H, d), of 6.90 (1H, d), 6,97 (2H, d), 7,47 (1H, t), 7,70 (2, d), a 7.85 (1H, s), 9,03 (1H, s), 9,05 (1H, s)

965039,3of 0.93 (6H, t), 1,55-1,60 (6H, m), 1,62-1,71 (2H, m), 2,38-of 2.54 (6H, m), 3.25 to 3,37 (6H, m), 6,32 (1H, d), 6,57-6,63 (1H, m), to 6.80 (1H, d), of 7.00 (2H, d), 7,37 (1H, t), 7,71-7,80 (3H, m), of 8.95 (1H, s), 9,03 (1H, C)
974289,2is 2.88 (3H, users), to 5.21 (2H, s), to 7.09 (1H, d), 7,17 (2H, d), 7,30-of 7.48 (5H, m), 7,92 (2H, d), to 8.12 (1H, users), of 8.28 (1H, d), 9,03 (1H, users), a 9.25 (1H, s), 12,65 (1H, users)
984129,4to 2.85 (3H, users), Android 4.04 (2H, s), 6,97 (1H, d), to 7.09 (1H, d), 7,16-7,34 (5H, m), 7,42 (2H, d), 7,86 (2H, d), of 8.04 (1H, s), of 8.25 (1H, d), of 9.02 (1H, users), 9.28 are (1H, users)
994009,2of 1.59 (6H, m), 3.3V (4 hidden proton), 7,02 (2H, d), 7,76 for 7.78 (3H, m), 8,54 (1H, s), to 8.70 (1H, d), to 8.94 (1H, s), 9,07 (1H, d)
1003776,12,77 (4H, t), of 3.57 (4H, t), to 6.88 (1H, d), 7,60 (2H, d), 7,78 (1H, d), of 8.00 (1H, DD), to 8.57 (2H, d), 8,68 (1H, d), 8,73 (1H, d)
1014759,11,56-to 1.63 (6H, m), equal to 1.82 (3H), 3,22 be 3.29 (2H, m), 3,30-3,37 (6H, m), 6,36 (1H, d), 6,63 (1H, t), of 6.99 (2H, d), 7,41 (1H, t), 7,73 (2H, d), 7,81 (1H, s), 7,95 (1H, t), of 9.00 (1H, s), 9,07 (1H, s)
1024139,5to 1.60 (6H, users), to 3.34 (4H, users), 6,60 (1H, d), 7,03 (3H, t), was 7.08 (1H, t), 7,14 (1H, d), 7,16 (1H, d), of 7.36 (1H, d), to 7.77 (2H, d), 8,79 (1H, d)
103503the 9.7of 0.91 (6H, m)to 1.59 (6H, m), 2,40-2,60 (6H, m), 3.04 from (3H, s), 3,30 is-3.45 (4H, m), the 3.65 (2H, m), 6.48 in (1H, m)6,91 (1H, m), 7,01 (2H, d), 7,44 (1H, m), 7,75-7,781 (3H, m), 9,03 (2H, d), 12,30 (1H, users)

104487the 9.7to 1.60 (6H, m), 1,87 is 1.91 (2H, m), 2,02 (2H, m)and 3.15 (2H, m), 3,28-3,30 (4H, m), 3.43 points-of 3.46 (2H, m), 3,53 of 3.56 (4H, m), of 6.45 (1H, d), 6,91 (1H, users), 6,97-7,10 (2H, m), 7,49 (1H, m), 7,75-7,81 (3H, m), 9,07-9,12 (2H, m), of 9.51 (1H, users), 12,35 (1H, m)
1054879,21,29-to 1.38 (2H, m)to 1.60 (6H, m), 1.91 a-2,03 (4H, m), 2,90-of 2.93 (2H, m), 3,24-of 3.25 (2H, m), 3,30-to 3.34 (5H, m), to 6.43 (1H, d), 6,901 (1H, d), 6,97-7,03 (2H, m), 7,44 (1H, m), 7,75 for 7.78 (3H, m), 8,15 (1H, d), 8,49 (1H, d), 9,06-remaining 9.08 (2H, m), 12,48 (1H, users)
1064439,3to 1.60 (6H, m), 2,84-2,87 (2H, m), 3,30-to 3.50 (4H, m), 3,56-of 3.60 (2H, m), of 6.45 (1H, d)and 6.2 (1H, d), 7,01-7,05 (3H, m), of 7.48 (1H, m), 7,76 (2H, m), 7,81 (1H, d), of 9.00 (1H, d), 9,07 (1H, s), 12,30 (1H, s)
1073946,01,78 is 1.86 (2H, m), 2,65-2,70 (2H, m), 2,85-only 2.91 (3H, m), 3,18 (1,4H, t), 3,30 (0,6H, t), to 6.67 (2H, d), 7,06 (1H, d), 7,72 (2H, d), 8,03-of 8.09 (1H, m), of 8.28 (1H, d), 9,01 (1H, s), 9,02-9,06 (1H, m)
1084769,60,85-0,95 (6H, m)and 1.51-of 1.62 (6H, m), 1,65-to 1.77 (1H, m), 2,82-2,90 (1H, m), 3,24-to 3.35 (4H, m), 4,06-to 4.15 (1H, m), 4,25-to 4.33 (1H, m), of 6.68 (1H, d), of 7.00 (2H, d), 7,31 (1H, d), 7,66-7,76 (3H, m), 7,87 (1H, s), of 9.02 (1H, s), 9,06 (1H, s)
10941310,0to 1.60 (6H, users)at 3.25 (4H, users), of 6.52 (1H, d), 7,01-7,10 (4H, m), of 7.36 (2H, d), to 7.64 (1H, d), of 7.75 (2H, d), 8,65 (1H, d)
1104829,9to 1.60 (6H, users), the 3.35 (4H, users), 7,02 (2H, d), to 7.50 (1H, s), 7,78 (2H, d), 7,83 (1H, s), to 8.41 (1H, s), of 8.47 (1H, users), 9,01 (1H, users)
1114339,9of 1.65-1.77 in (6H, m), 2,65 (6H, s), 3,40-to 3.50 (4H, m), at 6.84 (1H, d), 7,06 (1H, d), 7,14 (2H, d), of 7.36 (1H, s), 7,66 (1H, t), a 7.85-of 7.90 (3H, m), 9,07 (1H, s), 9,18 (1H, s)
1124619,1of 1.07 (6H, s), 153-1,62 (6H, m), 3,23-3,37 (6H, 2×m), to 6.43 (1H, d), 6,47 (1H, t), to 6.80 (1H, d), of 6.99 (2H, d), 7,37 (1H, t), 7,72 (2H, d), 7,76 (1H, s), 8,98 (1H,s), 9,04 (1H, s)
1133908,6to 1.60 (6H, users), to 3.34 (4H, users), between 6.08 (1H, userd), 6,38 (1H, d), at 6.84 (1H, s), 7,02 (2H, d), 7,72-to 7.77 (3H, m), 8,01 (1H, d), of 8.95 (1H, s)
1144059,1to 1.60 (6H, m), 2,87 (3H, s), 3.3V (4 hidden proton), 7,02 (2H, d), 7,76 (2H, d), 7,78 (1H, s), of 7.90 (1H, d), 8,08 (1H, s), 8,98 (1H, d)
1154049,2to 1.60 (6H, s), 2,47 (3H, s)to 3.34 (4H, s), to 6.57 (1H, s), of 6.68 (1H, d), 7,02 (2H, d), to 7.59 (1H, s), of 7.75 (2H, d), of 7.97 (1H, d), 8,66 (1H, s)
116389the 9.7to 1.60 (6H, s), is 2.37 (3H, s)to 3.35 (4H, s), 7,02 (2H, d), 7,12 (1H, d), 7,66 (1H, s), 7,76 (2H, d), 7,89 (1H, d), cent to 8.85 (1H, d), 9,12 (1H, s)
11745810,51,46-and 1.54 (2H, m), 1,57 is 1.60 (8H, m), 1,68 is 1.70 (2H, m), 1,96-2,02 (2H, m)to 3.35 (4H, m), is 4.15 (1H, m), 6,37 (1H, m), 6,56 (1H, m), PC 6.82 (1H, d), 7,02 (2H, d), 7,41 (1H, m), 7,75-7,80 (3H, m), 8,98 (1H, s), 9,07 (1H, s), with 12.3 (1H, s)
1183788,6to 1.60 (6H, s)to 3.35 (4H, s)to 3.64 (3H, s), 701 (3H, m), 7,28 (1H, s), of 7.75 (3H, m), scored 8.38 (1H, d)
11951710,00,86 (3H, d), of 0.94 (3H, d), 1,45-1,55 (2H, m), 1,52-of 1.64 (6H, m)of 1.65 and 1.75 (1H, m), to 2.57 (3H, d), 3,32-of 3.42 (4H, m), 4,29-to 4.38 (1H, m), of 6.45 (1H, d), 6,65-6,74 (1H, m), for 6.81 (1H, d), of 7.00 (2H, d), 7,40 (1H, t)7,72-,82 (4H, m), 8,89 (1H, s), the remaining 9.08 (1H, s)
120501the 9.70,95-1,10 (3H, m), 1,53 is 1.75 (9H, m), 1,78-to 2.65 (4H, m), 2,85-3,18 (3H, m), 3,30-3,37 (4H, m), 3,55-3,68 (1H, m), 6,38 (1H, d), a 6.5-6,85 (1H, m), 7,00 (2H, d), 7,37 (1H, t), 7,69 for 7.78 (3H, m), 8,93 (1H, s), 9,04 (1H, s)
1214058,9to 1.60 (6H, s)to 3.34 (4H, s), 4,60 (2H, s), 7,02 (2H, d), 7,34 (1H, d), 7,63 (1H, d), 7,76 (2H, d), of 7.82 (1H, t), to 7.93 (1H, d), of 9.02 (1H, s)
1223488,32,87 (3H, users), 6,98 (1H, d), 7,35-7,47 (4H, m), EUR 7.57 (1H, d), the 7.65 (2H, d), 8,02 (1H, s), of 8.27 (1H, d), 9,20 (1H, users), 9,62 (1H, s)
1234349,3to 1.60 (6H, m), 2,80 (6H, 2s), 3.3V (4 hidden proton), equal to 6.05 (1H, s)6,41 (1H, users), 6,89 (1H, users), 7,02 (2H, d), to 7.77 (2H, d), a 7.85 (1H, s), 8,88 (1H, s)
1244329,21,54-to 1.63 (6H, m), 2,85 3H, (C)at 3.25 is 3.40 (4H, m), 7,00 (2H, d), 7,70-of 7.82 (4H, m), to $ 7.91 (1H, t), of 8.40 (1H, s)8,89 (1H, s)
1254188,9to 1.60 (6H, s), of 2.38 (3H, s)to 3.35 (4H, s), 3,86 (2H, s), 7,02 (2H, d), 7,32 (1H, d), 7,66 (1H, d), 7,79 (2H, d), of 7.82 (1H, t), of 7.96 (1H, d), 9,06 (1H, d)
1264066,22,78-2,86 (7H, m), 3,19-3,24 (4H, m), of 6.73 (1H, s), 7,02 (2H, d), 7,34 (1H, users), to 7.77 (2H, d), 7,98 (1H, users), to 8.41 (1H, s)of 8.92 (1H, users), 9,16 (1H, s)
127501the 10.11,55-1,60 (10H, m)1,70 (3H, s)to 1.99 (2H, m), 2,32 (4H, m)and 3.15 (1H, m)to 3.34 (4H, m), 6.35mm (1H, d), 6,63 (1H, s), at 6.84 (1H, d), 7,02 (2H, d), 7,40 (1H, m), 7,76 for 7.78 (3H, m), 8,99 (1H, s), the remaining 9.08 (1H, ), 12,30 (1H, s)

1284889,91,19 of 1.28 (2H, m)to 1.60 (6H, m), 1,67 is 1.70 (4H, m), 1,88 is 1.91 (2H, m), 3,23-3,37 (5H, m), 3,86-3,88 (2H, m), 6.48 in (1H, s), to 6.88 (1H, m), 7,03 (2H, d), 7,49 (1H, m), 7,60-7,80 (4H, m), 8,96 (1H, s), which is 9.09 (1H, C), 12,40 (1H, s)
1294479,1of 1.16 (3H, d), 1,53-to 1.63 (6H, m), 2,55-by 2.73 (2H, m), 3.25 to 3.40 in (4H, m), 3,85-of 3.96 (1H, m), 6.35mm (1H, d), PC 6.82 (1H, d), 7,01 (2H, d), 7,39 (1H, t), 7,70-7,80 (3H, m), 8,97 (1H, s)
1309,4-
1314787,3-
1324769,80,93-0,98 (6H, m)to 1.60 (6H, m), of 1.78 (1H, m)to 2.94 (1H, m)to 3.34 (4H, m), 4,18 (1H, m), 4,36 (1H, m), 6,70 (1H, d), 7,02 (2H, d), of 7.36 (1H, d), 7,73-7,89 (3H, m), of 7.90 (1H, s), 9,04 (1H, s), which is 9.09 (1H, )
133490the 10.10,96 is 0.99 (9H, m)to 1.60 (6H, m), 2,96 (1H, m), 3,32-to 3.34 (4H, m), 4,13 (1H, m), with 4.64 (1H, m), of 6.75 (1H, m), 7,02 (2H, d), 7,38 (1H, d), 7,71 for 7.78 (3H, m), of 7.90 (1H, d), 9,06-remaining 9.08 (2H, m)
1344487,71,10 (2H, m), 1,48-of 1.78 (5H, m), 2.40 a-2,47 (2H, m), 2,85 (3H, m), 2,89 (2H, m), 4,10 (2H, m), of 6.31 (1H, m), 6,52 (NH), 6,85 (1H, m), to 7.09 (2H, m), 7,42 (1H, t), 7,81-to $ 7.91 (3H, m), of 9.00 (1H, s), 9,12 (1H, )
1354346,3of 1.28 (6H, d), was 2.76 (2H, t), with 2.93 (3H, s), 3,34-to 3.52 (2H, m), 4,08 (2H, d), 6,85 (1H, s), to 7.15 (2H, d), a 7.85 (2H, d), 7,94 (1H, users), 8,59 (1H, users), cent to 8.85 (1H, users), of 9.21 (1H, s), 12,69 (1H, users)
1364747,61,84-of 2.20 (8H, m), with 2.93 (3H, s), 3,06-to 3.52 (6H, m), 3,57-3,68 (1H, m), 3,78-3,86 (1H, m),4,18-to 4.28 (1H, m), 6,77 (2H, d), at 6.84 (1H, users), 7,83 (2H, d), to 7.93 (1H, users), 8,58 (1H, users), 8,87 (1H, users), 9,11 (1H, s)
1374036,22,34-2,39 (2H, m), 2,84 (3H, s), of 2.92 (2H, t), 3,30-of 3.42 (2H, m), 6,40 (1H, s), 6,74 (1H, s), 7,60 (2H, d), 7,89 (2H, d), of 7.96-8,08 (1H, m), to 8.41 (1H, s)of 8.92 (1H, users), 9,38 (1H, s)
1384497,42,38-to 2.42 (4H, m)to 2.67 (6H, m), of 2.81 (3H, m), 4,14 (2H, m), 6.35mm (1H, m), 6,51 (NH), 6.89 in (1H, m), 7,10 (2H, m), 7,45 (1H, t), a 7.85-a 7.92 (3H, m), 8,98 (1H, s), 9,11 (1H, s)
1394066,5(eOD) to 3.02 (3H, s), 3,37 (4H, t), of 3.60 (4H, t), 7,16 (2H, d), 7,78 (1H, s), 7,95 (2H, d), of 7.97 (1H, d), with 8.05 (1H, s),of 9.21 (1 H,d)
1403759,31,55-of 1.62 (6H, m), 3.25 to 3.40 in (4H, m), 6,98 (2H, d), 7,16-7,22 (1H, m), 7,71-7,80 (4H, m), 7,95 (1H, s), 8,54-to 8.57 (1H, m), of 9.00 (1H, s)
1414629,0to 1.1 (6H, m), and 1.6 (6H, s), a 3.2 and 3.4 (6H, m)to 7.0 (3H, m), 7,7-7,8 (2H, m), 7,8-7,9 (2H, m), with 8.0 and 8.1 (1H, s), and 9.0 (1H, m), and 9.1 (1H, s)
1424496,81,21-of 1.36 (2H, m), 1,72 (3H, m)and 1.83 (2H, m), 2.71 to 2,85 (5H, m), 3,10 (2H, m), 4,11 (2H, m), of 6.75 (1H, s), 7,10 2H, m), 7,39 (NH), to $ 7.91 (2H, m), to 8.45 (1H, s), of 8.95 (1H, users), which 9.22 (1H, s)
1434497,21,18-of 1.30 (2H,m), 1,69-of 1.85 (5H, m), 2,68 (2H, m), of 2.86 (3H, m), 3,11 (2H, m), 4,13 (2H, m), to 7.09 (2H, m), 7,12 (NH), 7,80 (1H, m), of 7.90 (3H, m), 8,10 (1H, m), of 9.00 (1H, s), of 9.21 (1H, s)
1443795,82,81-2,82 (4H, m), 3,19-is 3.21 (4H, m), 3,61 (3H, s), 6.89 in (1H, s), 7,02 (2H, d), 7,33 (1H, s), to 7.64 (1H, s), of 7.75 (2H, d), 8,31 (1H, s), 9,26 (1H, s)
1454748,0-

/tr>
1464206,7,1,74-to 1.82 (2H, m), 2.63 in (2H, t), 2,82-2,90 (5H, m), 3,53 (2H, t), 3,61 (2H, t), for 6.81 (2H, d), 7,08-7,16 (1H, m), 7,73 (2H, d), 7,80 (1H, s), 7,86 (1H, d), of 8.09 (1H, s), of 9.00 (1H, d)
1474217,61,85-of 2.08 (4H, m), is 2.88 (3H, d), 3,09-3,18 (1H, m), 3,20 of 3.28 (1H, m), 3,40-to 3.52 (2H, m), 3,78-a-3.84 (1H, m), 6,70 (2H, d), 7,07-to 7.15 (1H, m), 7,76 (2H, d), 7,80 (1H, s), 7,87 (1H, d), of 8.09 (1H, s), of 9.00 (1H, d)
1484506,7of 2.44 (2H, t), to 2.55 (4H, t), is 2.88 (3H, d), 3,26-3,37 (4H, m), of 3.54 (2H, t),? 7.04 baby mortality (2H, d), 7,08-7,14 (1H, m), 7,78 (2H, d), 7,80 (1H, s), 7,88 (1H, d), 8,10 (1H, s), of 9.00 (1H, d), 9,12 (1H, s)12,42 (1H, users)
1494789,11,04 is 1.13 (3H, m), 1,50-of 1.62 (6H, m), 3,78-of 3.85 (1H, m), 3,63-a 3.83 (1H, m), 4,10-4,34 (2H, 2×m), 6,54-of 6.61 (1H, m), 7,01 (2H, d), 7,21 (1H, t), 7,66 (1H, t), 7,71 (2H,d), 8,01+8,11 (1H, 2×s), of 8.90 (1H,)
1504889,81,37 was 1.43 (2H,m), 1,50-1,66 (12H,m), 1,70-1,80 (2H, m), 3,22-to 3.36 (4H, m), 4,18 (2H, s), 6,60 (1H, d), 7,01 (2H, d), 7,20 (1H, d), the 7.65 (1H, t), 7,73 (2H, d), 8,02 (1H, s), cent to 8.85 (1H, s)
1514629,6of 0.96 (3H,t), 1,30-1,40 (1H, m), 1,55-1,60 (6H, m), 2.95 and-to 3.02 (1H, m), 3,30-to 3.36 (4H, m), 4,10-4,27 (2H, m), 6,70 (1H, d), 7,01 (2H,d), 7,32 (1H, d), 7,70 for 7.78 (4H, m), 7,86 (1H, s), 9,01 (1H, s)
152490the 10.10,86 (3H, t), of 0.95 (3H, d), 1,13-1,25 (1H, m), 1,47 is 1.60 (8H, m), 2.95 and-a 3.01 (1H, m), 3,30 is 3.40 (4H, m), 4,10-4,20 (1H, m), 3,38 is-3.45 (1H, m), 6,70 (1H, d), of 7.00 (2H, d), 7,33 (1H, d), 7,70-a 7.85 (3H, m), of 7.90 (1H, s), 9,05 (1H, s)
1534357,01,41-of 1.52 (2H, m), a 1.96 (2H, m)to 2.13 (1H, m), 2,89 (3H, m), 3,01 (4H, m), of 3.97 (2H, m), to 7.09 (2H, m), 7,11 (1H, s), 7,81 (1H, s), 7,94 (3H, m), 8,16 (1H, s), of 9.00 (1H, s), 9,24 (1H, s)
154469 8,2of 1.65 and 1.75 (4H, m), 1,94-of 2.09 (4H, m), 2,41 is 2.51 (4H, m), 2,61-2,62 (2H, m), and 3.16 (1H, m), 3,42 (1H, m), 3,93 (1H, m), to 6.67 (2H, d), 7,72 (2H, d), 7,88 (1H, d), 8,35 (1H, m), 8,54 (1H, d), 8,76 (1H, d), 8,97 (1H, d), 9,42, (1H, d)
1554207,52,35-2,52 (4H, m), 2,62-of 2.86 (3H, m), 2,87 (3H, s), 3,28-of 3.48 (4H, m), 7,07 (2H, d), 7,80 (1H, s)of 7.82 (2H, d), 7,89 (1H, d), 8,10 (1H, s), of 9.00 (1H, d), with 9.14 (1H, s), 12,45 (1H, d)
1564497,81,12-1,24 (2H, m)to 1.38 (2H, HF), 1,56 was 1.69 (1H, m), 1,74 (2H, d), 2,80 (2H, t), 2,87 (3H, s), of 3.46 (2H, t), 3,91 (2H, d), 7,02 (2H, d), 7,08-7,14 (1H, m), 7,76 (2H, d), 7,80 (1H, s), 7,88 (1H, d), of 8.09 (1H, (C), of 9.00 (1H, d)
1574347,71,15-of 1.26 (2H, m)of 1.75 (2H, m), of 1.78 (1H, m), 2,85 (3H, m), 2,98 (2H, m), 3,40 (2H, m)to 3.89 (2H, m), 6,32 (1H, m), 6,55 (NH), 6.89 in (1H, m), to 7.09 (2H, m), 7,42 (1H, m), a 7.85 (1H, s), to $ 7.91 (2H, m), 9,00 (1H, s), of 9.21 (1H, s)
1584506,8of 2.45 (4H, m), 2,71 (2H, m), of 2.81 (4H, m), 2,89 (3H, m), 4,18 (2H, m), 7,08 for 7.12 (3H, m), 7,80 (1H, s), to $ 7.91 (3H, m), 8,10 (1H, s), 8,97 (1H, s), a 9.25 (1H, s)
1594049,01,55-to 1.63 (6H, m), of 2.72 (3H, s), 3.25 to 3.40 in (4H, m), 6,97 (1H, s), 7,01 (2H, d), 7,51 (1H, s), of 7.75 (2H, d), 7,86 (1H, s), 7,95 (1H, s), 8,51 (1H, is)
1604307,9of 2.8-3.0 (7H, m), and 3.1 (4H, m), 6,7 (1H, s)to 7.0 (2H, m), 7,1-7,2 (1H, m), 7,2-7,3 (1H, s), 7,7-7,8 (2H, m), and 7.9 (1H, m), and 9.0 (1H, m), and 9.1 (1H, s)
1614017,2the 2.8 and 2.9 (4H, m), 3,2-3,3 (4H, m), 7,0 (2H, m), and 7.7 (1H, m), 7,8 (2H, m), with 8.0 and 8.1 (1H, m), and 8.4 (1H, s), and 8.8 (1H, m), and 9.1 (2H, m)
1624346,71,84-of 1.94 (2H, m), 1,98-2,07 (2H, m), is 2.88 (3H, s), 3,02-3,10 (2H, m), 3,30-of 3.42 (2H, m), 3,48-of 3.54 (2H, m), 3,56-of 3.64 (2H, m), of 6.75 (2H, d), 7,76 (2H, d), 7,81 (1H, s), 7,88 (1H, d), 8,10 (1H, s), of 9.00 (1H, d)
1634206,41,47 is 1.58 (2H, m), 1,90-to 1.98 (2H, m), is 2.88 (3H, s), 2,90-of 3.00 (2H, m), 3,24 is 3.40 (1H, m), 3.95 to as 4.02 (2H, m), was 7.08 (2H, d), 7,81 (2H, d), of 7.82 (1H, s), of 7.90 (1H, d), 8,11 (1H, s), of 9.02 (1H, d)
1644227,62,87 (6H, s), is 2.88 (3H, s), 3,03 (3H, s), 3,24-3,30 (2H, m), 3.75 to-3,81 (2H, m), of 6.90 (2H, d), 7,81 (1H, s)of 7.82 (2H, d), 7,89 (1H, d), 8,10 (1H, s), of 9.00 (1H, d)
1654316,82,87 (3H, s), of 2.92 (2H, t), of 3.43 (2H, t)6,70 (2H, d), to 7.50 (1H, s), 7,72 (2H, d), 7,81 (1H, s), 7,87 (1H, d), of 8.09 (1H, s), 8,97-9,01 (2H, m), 9,03 (1H, s), 12,43 (1H, d)
1664347,92,14-of 2.26 (2H, m), is 2.88 (6H, s), 2,90 (3H, s), 3,30-of 3.64 (3H, m), 3.72 points-of 3.78 (1H, m), 3,98-4,08 (1H, m), 6.73 x (2H, d), 7,81 (1H, s),to 7.84 (2H, d), 7,89 (1H, d), 8,10 (1H, s), 9,01 (1H, d)
1674367,41,86 is 1.96 (2H, m), 2,78 (6H, s), is 2.88 (3H, s), a 3.01 (3H, s), 3,07-3,14 (2H, m), 3,49 (2H, t), at 6.84 (2H, d), 7,79 (2H, d), 7,81 (1H, s), 7,88 (1H, d), 8,10 (1H, s), of 9.00 (1H, d)

1684457,12,04 (2H, quintet), 2,87 (3H, s), 3,06 (2H, t), 4,14 (2H, t), only 6.64 (2H, d), to 7.15 (1H, s), 7,40 (1H,s), 7,71 (2H, d),7,81 (1H, s), 7,86 (1H, d), of 8.09 (2H, s), of 9.00 (1H, d), of 9.02 (1H, s)
1694056,92,79-2,84 (7H, m), 3,16-3,24 (4H, m), 6,41 (1H, m), is 6.54 (1H, s), of 6.66 (1H, d), 7,02-7,03 (2H, m), 7,74 (2H, d), to $ 7.91 (1H, d), 8,56 (1H, d), 9,39 (1H, d)
1704356,5is 1.51 (2H, m), a 1.88 (2H, m), is 2.09 (1H, m), 2,78-of 2.86 (5H, m), 3,21 (2H, m), of 3.95 (2H, m), 6,78 (1H, s), 7,11 (2H, m), 7,45 (1H, users), to 7.93 (2H, m), to 8.45 (1H, s), 8,96 (1H, s), 9,23 (1H, s)
1714909,21,68 is 1.75 (4H,m), 1,90-2,12 (4, m), 2,35-to 2.65 (6H, m), 2,70 (3H, s), of 3.10-3.20 (1H, m), 3,40-3,50 (1H, m), 3,90-to 3.99 (1H, m), 6,27 (1H, d), 6,45-6,55 (2H, m), 6,70 (2H, d), 7,43-to 7.61 (2H, m), of 7.75 (2H, d), 8,68 (1H, s)
1724737,91,70-1,80 (4H, m), 1,98-2,07 (4H, m), 2,401-2,49 (2H, m), 2,61-2,62 (2H, m), 2,80 (3H, s), 3,16-3,17 (2H, m), 3,42-3,44 (2H, m), of 3.95 (1H, m), of 6.52 (1H, d), to 6.58 (1H, s), 6,66-6,70 (3H, m), a 7.62 (1H, d), 7,76 (2H, d), of 7.97 (1H, d), 8,67 (1H, d), 9,16 (1H, s)
1734166,33,00 was 3.05 (4H, m), 3,29-3,39 (4H, m), 6,69 (1H, d), was 7.08 (2H, d), to 7.84 (2H, d), 7,86-of 7.90 (1H, m), of 7.96 (1H, d), is 8.75 (1H, s), 9,14-9,18 (2H, m), 12,08 (1H, users)
1744648,81,55-1,70 (6H, m), 3,30-3,53 (4+2H, m), 4,13-of 4.25 (2H, m), to 4.62-4.72 in (1H, m), of 6.71 (1H, d), 7,03 (2H, d), 7,33 (1H, d), 7,70-7,80 (3H, m), 7,88 (1H, s), of 9.00 (1H, s), 9,07 (1H, s)

1754888,4to 1.21 (3H, t), 1,71 (4H, users), 1,91-2,07 (4H, m), 2,33-to 2.40 (1H, m), 2,61 of 2.68 (4H, m), 3,12-3,19 (1H, m)to 3.35 (3H, s), 3,38-of 3.46 (1H, m), 3,93-of 3.97 (1H, m), to 6.67 (2H, d), 7,11-7,14 (1H, m), 7,76 (1H, s), 7,78 (2H, d), a 7.85 (1H, d), 8,07 (1H, s), 8,97 (1H, d)
1765008,60,41 (2H, users), 0,78 (2H, userd), 1,71 (3H, users), 1,81 is 2.9 (7H, osirm), to 2.65 (2H,users), and 3.16 (1H,users), to 3.36 (3H,s),of 3.45 (1H, users), a 3.87-of 3.97 (1H, m), of 6.68 (2H, userd), 7,78 (2H, users), 7,88 (1H, s), 7,92 (1H, s), 8,21 (1H, s), of 9.00 (1H, s), 9,06 (1H, s)
1774637,11,41 is 1.58 (6H, osirm), at 1.91 (2H, osirm), of 2.38 (4H, m) 2,90 (3H, m)to 3.35 (4H,m), 4,11 (2H,m), 7,07-7,15 (NH and 2H, m), 7,82 (1H, s), of 7.96 (3H, m), 8,13 (1H, s), 9,01 (1H, s), 9,27 (1H, s)
1784737,5at 1.91 (4H, m), 2,04 (4H, m), 2,50 is 2.51 (2H, m), was 2.76 (3H, s), 3,15-up 3.22 (2H, m), 3.45 points-to 3.49 (2H, m), the 3.65 (1H, m), 3,80 (1H, m), 4,24 (1H, m), the 6.06 (1H, m), is 6.78 (2H, d), 6,97 (1H, m)to 7.50 (1H, m), 7,81 (2H,d), to 7.93 (1H, m), of 7.97 (1H, m), 8,67 (1H, m), 9,12 (1H, s), 10,02 (1H, users)
1794979,0of 1.65 and 1.75 (4H, m), 1.85 to 2.05 is (6H, m), 2,50-2,60 (3H, m)of 2.75 (3H, d), is 3.08-3,19 (1H, m), 3,35 is-3.45 (2H, m), 3,85-to 3.92 (1H, m), 6,27-6,34 (1H, m), 6,63 (2H, d), of 6.75 (1H, s)6,94 (1H, s), to 7.09 (1H, s)of 7.48 (1H, s), of 7.75 (2H, d), 8,63 (1H, s), 9,04 (1H, s)

1805428,81,71 (4H, users), 1,94-2,19 (4H, m), 2,38 is 2.51 (4H, m), 2,61 of 2.68 (2H, m), 3,16-3,18 (1H, m), 3,44-3,47 (1H, m), 3,92-of 3.95 (1H, m), 4,20-4,32 (2H, m), to 6.67 (2H, d), 7,71 (1H, ushort), 7,76 (2H, d), 7,83 (1H, s), 7,98 (1H, s), 8,21 (1H, s)of 8.92 (1H, s)to 9.15 (1H, s)
181 4216,6to 1.45 (2H, m)to 1.98 (2H, m), 2,61 (2H, m) 2,95 (3H, m)of 3.00 (2H, m), 4,55 (2H, m), 7,10-7,15 (NH and 2H, m), 7,86 (1H, s), 7,95 (3H, m), 8,15 (1H, s), of 9.02 (1H, s), 9.28 are (1H, s)
1824657,7of 1.95 (2H, m), 2,39 (4H, m), 2,89 (3H, m) to 3.35 (2H, m)and 3.59 (4H, m), of 4.12 (2H, m), 7,08-7,14 (3H, m), 7,80 (1H, s), 7,89 (3H, m), 8,10 (1H, s), 8,99 (1H, s), 9,24 (1H, s)

Example 12

Phenylamide 2-oxo-5-phenyl-1,2-dihydropyridines-3-carboxylic acid (III-1

To a solution of 2-oxo-5-phenyl-1,2-dihydropyridines-3-carboxylic acid (44 g, 0.20 mmol) in tetrahydrofuran (5 ml) were sequentially added aniline (20 µl, 0.23 mmol), hydroxybenzotriazole (30 mg, 0.23 mmol), dimethylaminopyridine (27 mg, 0.23 mmol) and EDC (43 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel, using as eluent DCM containing 10% MeOH, resulting target compound was obtained as a white solid (20 mg, yield 34%). MS (ES+) 291. δH (DMSO-d6) to 7.2 (3H, m), and 7.9 (1H, t), and 8.5 (1H, d), or 8.6 (2H, m), and 9.3 (1H, s).

A number of other compounds of Formula III was obtained by methods generally similar to those described here in Example 12. The characteristic data of these compounds Pref is found in Table III-A below and includes HPLC, LC/MS (observed) and data1H NMR.

Data1H NMR are shown in Table III-A below, in which data1H NMR were obtained at 400 MHz in deuterated DMSO, unless otherwise specified, and as established, are consistent with the structure. The numbers of the Compounds correspond to the numbers of the compounds listed in Table 1.

Table III-A
The characteristic Data of Selected Compounds of Formula III
Connection # III-M+1 (OBS)RT (min)1H-NMR
23058,64,56 (2H, d), 7,28 (1H, m), 7,34-7,37 (5H, m), 7,46 (2H, t), a 7.62 (2H, d), of 8.06 (1H, s), 8,66 (1H, d), and 10.20 (1H, ushort), 12,86 (1H, users)
33067,44,51 (2H, d), 7,20-7,40 (5H, m), 7,60 (2H, d), 8,40 (1H, m), 8,50-to 8.70 (3H, m), 11,10 (1H, users)
43349,21H NMR (DMSO) 1,19-1,25 (6H, m), 2,80 of 2.92 (1H, m), 7,19-7,29 (2H, m), 7,58-7,66 (2H, m), 7,70-7,76 (2H, m), 8,35-to 8.40 (1H, m), 8,58-8,65 (2H, m), 8,78-8,83 (1H, m), 12,08 (1H, users), 13,22 (1 is, users),
53489,6of 1.29 (9H, s), 7,39 (2H, d), 7,63 (2H, d), 7,73 (2H, d), 8,39 (1H, d), 8,61 (2H, d), 8,81 (1H, d), 12,10 (1H, users), 13,24 (1H, users),

63207,62,84 (2H, t)to 3.58 (2H, HF), 7,18-7,34 (5H, m), 7,65-of 7.69 (2H, m), 8,29 (1H, d), to 8.57-8,61 (2H, m), to 8.70 (1H, d), 9,78 (1H, ushort), 13,0 (1H, users),
73208,8of 1.18 (3H, t), at 2.59 (2H, HF), 7,21 (2H, d), a 7.62 (2H, d), 7,73 (2H, d), 8,39 (1H, d), 8,61 (2H,d), 8,80 (1H, d), 12,10 (1H, users), 13,20 (1H, users),
83718,9EUR 7.57 (2H, d), 7.68 per to 7.75 (4H, m), to 8.41 (1H, d), 8,61 (2H, d), 8,81 (1H, d), 12,20 (1H, s), 13,30 (1H, users),
93849,3of 6.96-to 7.18 (5H, m), 7,32-7,46 (2H, m), 7,62-7,81 (4H,m), 8,35-to 8.45 (1H, m), 8,56-8,66 (2H, m), 8,77-8,84 (1H, m), 12,19 (1H, users),
103349,2to 1.22 (6H, d), 2,83-2,96 (1H, m), 6,98? 7.04 baby mortality (1H, m), 7.24 to 7,33 (1H, m), 7,51-to 7.61 (2H, m), 7.68 per for 7.78 (2H, m), 8,35-to 8.40 (1H, m), 8,59-8,64 (2H, m), 8,78-8,84 (1H, m), 12,02 (1H, users)/td>
11322-(300 MHz) of 3.75 (3H, s), to 6.95 (2H, d), to 7.64 (2H, d), 7,72 (21H, m), at 8.36 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 11,92 (1H, s)
12322-(300 MHz) of 3.77 (3H, s), 6,7 (1H, d), 7,16 (1H, d), 7,27 (1H, t), 7,47 (1H, s), 7,72 (2H, d), 8,39 (1H, s), at 8.60 (2H, d), 8,79 (1H, d), 12,20 (1H, s)13,0 (1H, users)
13336-(300 MHz) of 1.33 (3H, d), 4,7 (1H, HF), and 5.2 (1H, users), 7,13 (1H, d), of 7.36 (1H, t), a 7.62 (1H, d), to 7.64 (1H, s), 7,71 (2H, d), 8,40 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 12,23 (1H, s), and 13.2 (1H, users)
14336-(300 MHz) of 3.85 (3H, s), 4,50 (2H, d), 6,91 (1H, t), 7,02 (1H, d), 7,30-7,22 (2H, m), to 7.67 (2H, DD), 8,29 (1H, d), 8,59 (2H, d), 8,71 (1H, d), of 10.09 (1H, t)
15384-(300 MHz) 6,83-6,79 (1H, m), 7,08-7,05 (2H, m), 7,28-to 7.18 (2H, m), 7,47-7,39 (3H, m), to 7.59 (1H, t), of 7.70 (2H, DD), with 8.33 (1H, d), at 8.60 (2H, DD), 8,78 (1H, d), 12,11 (1H, users), 13,24 (1H, users)
16352-(300 MHz) 3,76 (3H, s), with 3.79 (3H, s), to 6.95 (1H, d), 7,20 (1H, DD), was 7.45 (1H, d), 7,72 (2H, DD), of 8.37 (1H, d), 8,61 (2H, d, 8,81 (1H, d), 11,95 (1H, users)
17334-(300 MHz) of 1.84 (2H, quintet), of 2.64 (2H, t)to 3.34 (2H, HF), 7,31-to 7.15 (5H, m), 7,94 (2H, d), 8,39 (1H, d), 8,68 (2H, d), 8,78 (1H, d), to 9.70 (1H, t), 13,16 (1H, users)
18410-(300 MHz) 2,31 (2H, kV)of 3.25 (2H, t), a 4.03 (1H, t), 7,17 (2H, t), 7,35-7,28 (8H, m), to 7.67 (2H, DD), of 8.28 (1H, d), 8,58 (2H, DD), 8,67 (1H, d), made up 9.77 (1H, t), 12,90 (1H, users)
19396-(300 MHz) of 7.48 (1H, d), 7,79-of 7.55 (8H, m), 7,89 (1H, d), 8,23 (1H, s), 8,40 (1H, d), at 8.60 (2H, d), 8,80 (1H, d), 12,40 (1H, users), 13,0 (1H, users)
20350-(300 MHz) 2,82 (2H, HF), 3,53 (2H, q), with 3.79 (3H, s), 6.87 in (1H, t), of 6.96 (1H, d), 7.23 percent-7,16 (2H, m), to 7.67 (2H, d), of 8.27 (1H, d), 8,59 (2H, d), 8,69 (1H, d), to 9.70 (1H, t),12,90 (1H, users)
21334-(300 MHz) of 1.25 (3H, d), and 3.0 (1H, Sextus,), 3,55-to 3.49 (2H, m), 7,34-to 7.18 (5H, m), 7,66 (2H, d), compared to 8.26 (1H, d), 8,58 (2H, d), 8,68 (1H, d), 9,74 (1H, t), 12,86 (1H, users)
22286-(300 MHz) 0,92-to 0.88 (6H, m), 1,10 (3H, d), of 1.76 (1H, Sextus,), 3,9 (1H, Sextus,), to 7.67 (2H, d), of 8.27 (1H, d), 8,59 (2H, d), to 8.70 (1H, d), 9,73 (1H, d), 12,94 (1H, users)
23382-(300 MHz) of 3.95 (2H, s)to 7.0 (1H, d), 7,32-7,19 (5H, m), 7,56 (1H, s), 7,58 (2H, d), 7,71 (2H, d), scored 8.38 (1H, d), 8,61 (2H, d), 8,79 (1H, d), 12,10 (1H, users), 13,20 (1H, users)
24256-(300 MHz) of 0.55-0,49 (2H, m), 0.79, which is to 0.70 (2H, m), 2,90-2,84 (1H, m), to 7.67 (2H, DD), of 8.27 (1H, d), 8,59 (2H, d), 8,68 (1H, d), 9,68 (1H, s), 12,98 (1H, users)
25313-(300 MHz) 9,79 (1H, s), to 8.70 (1H, d), 8,59 (2H, d), of 8.28 (1H, d), to 7.67 (2H, d), of 3.48 (2H, t), 2,79-2,69 (6H, m), 1,80-to 1.60 (4H, m)
26328-(300 MHz) 1,58-of 1.24 (10H, m), 3,30 (2H, s), 4,39 (1H, s), to 7.68 (2H, d), of 8.28 (1H, d), 8,59 (2H, DD), 8,71 (1H, d), 9,84 (1H, t), 12,89 (1H, users)
27312-(300 MHz) of 1.57 was 1.43 (10H, m), 1,91-of 1.85 (2H, m), 4.04 the-3,99 (1H, m), 7,66 (2H, DD), of 8.28 (1H, d), 8,59 (2H, DD), 8,68 (1H, d), 9,82 (1H, d), 12,40 (1H, users)
28350-(300 MHz) and 2.79 (1H, DD), to 2.94 (1H, DD), 3.45 points-of 3.32 (2H, m), 4,17 (1H, d), of 4.95 (1H, is IRS), 7,26-7,19 (5H, m), 7,66 (2H, DD), of 8.28 (1H, d), 8,58 (2H, d), 8,68 (1H, d), 9,82 (1H, d), 12,20 (1H, users)
29348-(300 MHz) of 1.24 (9H, s), 7,17 (1H, d), 7,30 (1H, t), 7,53 (1H, d), 7,73 (2H, d), 7,74 (1H, s), scored 8.38 (1H, d), 8,61 (2H, d), 8,82 (1H, d), 12,07 (1H, users), 13,19 (1H, users)
30272-(300 MHz) of 0.82 (3H, t), of 1.10 (3H, d), 1,52-of 1.40 (2H, m), 3,89-a 3.83 (1H, m), the 7.65 (2H, d), 8,30 (1H, d), to 8.57 (2H, d), 8,65 (1H, d), to 9.91 (1H, d)

31332-(300 MHz) of 1.30-1,25 (2H,m), 2,11-2,05 (1H, m), 3,05-2,99 (1H, m), 7,33-7,17 (5H, m), to 7.67 (2H, DD), 8,30 (1H, d), 8,59 (2H, DD), 8,69 (1H, d), to 9.91 (1H, d), 13,01 (1H, users)
32336-(300 MHz) 3,44 (1H, DD), 3,66 (1H, DD), was 4.76 (1H, DD), 5,63 (1H, users), 7,41-7,22 (5H, m), 7,63 (2H, d), 8,32 (1H, d), 8,55 (2H, d), to 8.62 (1H, d), 10,29 (1H, s), 12,80 (1H, users)
33336-(300 MHz) of 3.45 (1H, DD), 3,66 (1H, DD), was 4.76 (1H, DD), 5,62 (1H, users), 7,41-7,22 (5H, m), the 7.65 (2H, d), 8,30 (1H, d), to 8.57 (2H, d), 8,65 (1H, d), 10,12 (1H, s), 12,80 (1H, users)
34-(300 MHz) of 1.20 (3H, d), 1,84-to 1.77 (2H, m), 2,66-2,61 (2H, m), a 4.03-3,98 (1H, m), 7,30-7,16 (5H, m), to 7.67 (2H, DD), 8,29 (1H, d), 8,58 (2H, DD), to 8.70 (1H, d), 9,76 (1H, d), of 12.8 (1H, users)
35348-(300 MHz) of 1.20 (3H, d), 1,84-to 1.77 (2H, m), 2,66-2,60 (2H, m), 4,05-of 3.96 (1H, m), 7,30-7,14 (5H, m), 7,68 (2H, DD), 8,30 (1H, d), 8,59 (2H, d), 8,71 (1H, d), to 9.70 (1H, d), 13,0 (1H, users)
36270-(300 MHz) of 0.23 to 0.18 (2H, m), 0,48 at 0.42 (2H, m), 1.04 million-of 0.95 (2H, m), 3,19 (2H, d), to 7.67 (2H, DD), of 8.28 (1H, d), 8,59 (2H, DD), to 8.70 (1H, d), 9,79 (1H, t), 12,96 (1H, users)
37310-(300 MHz) 1,51-1,10 (7H,m), 1,80-of 1.74 (1H, m), 2,29-2,19 (2H, m), 3,81-3,70 (1H, m), 7,66 (2H, d), of 8.27 (1H, d), 8,59 (2H, d), 8,67 (1H, d), of 9.75 (1H, d)
38400-(300 MHz) 7,43-7,24 (7H, m), 7,79-7,71 (4H, m), 8,40 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 12,24 (1H, s), 13,25 (1H, users)
39350-(300 MHz) of 1.46 (3H, d), 3,74 (3H, s), 5,10 (1H, Quint,), 6,91 (2H, d), 7,30 (2H, d), to 7.67 (2H, d), of 8.27 (1H, d), 8,59 (2H, d), to 8.70 (1H, d), 10,10 (1H, d)
40 327-(300 MHz) of 1.52-of 1.24 (6H, m), 2,47-to 2.40 (6H, m), of 3.43 (2H, t), to 7.68 (2H, d), 8,30 (1H, d), 8,59 (2H, DD), to 8.70 (1H, d), 9,81 (1H, t)
41336-(300 MHz) 3,41-to 3.34 (1H, m), 3.72 points-3,61 (1H, m), 4.72 in-4,70 (1H, DD), 5,63 (1H, d), 7,41-7,22 (5H, m), the 7.65 (2H, d), 8,30 (1H, d), to 8.57 (2H, d), 8,65 (1H, d), 10,11 (1H, users)
423777,23.04 from-3,14(4H, m), 3,70-with 3.79 (4H, m), 6,98 (2H, d), to 7.59 (2H, d), 7,71 (2H, d), of 8.37 (1H, d), 8,61 (2H, d), 11,91 (1H, users), 13,20 (1H, users)
433747,21,10-1,90 (10H, m), 2,40-of 2.56 (1H, m), 7,22 (2H, d), a 7.62 (2H, d), 7,72 (2H, d), 8,39 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 12,10 (1H, users)
443758,81,48 by 1.68 (6H, m), 3,05-3,15 (4H, m), 6,93 (2H, d), 7,56 (2H, d), 7,72 (2H, d), at 8.36 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 11,90 (1H, s), 13,20 (1H, users)
453368,1of 1.31 (3H, t)to 4.01 (2H, q), 6,94 (2H, d), a 7.62 (2H, d), 7,72 (2H, d), 8,39 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 11,99, 13,25 (1H, users)
463907,1 of 2.23 (3H,s), 2,43-of 2.50 (4H, m), is 3.08-3,14 (4H, m), to 6.95 (2H, d), to 7.59 (2H, d),7,72 (2H, d), of 8.37 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 11,92 (0,5H, C)
474047,1of 1.03 (3H, t), of 2.38 (2H, HF), 2,45-of 2.54 (4H, m), 3,06-3,14 (4H, m), to 6.95 (2H, d), 7,58 (2H, d), 7,72 (2H, d), scored 8.38 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 12,00 (0,4H, C)

483066,33,39 (3H, s), 7,10-7,39 (5H, m), 7,46-of 7.60 (2H, m), 7,80-8,02 (2H, m), 8,48-8,56 (2H,m), 12,10 (0,1H, users)
493206,9of 2.20 (3H, s), 3,30 (3H, s), 7,00-7,20 (4H, m), 7,50 to 7.62 (2H, m), a 7.85-8,02 (2H, m), 8,49 at 8.60 (2H, m), 12,10 (0,2H, users)
503208,8of 1.20 (3H, t), 2,61 (2H, HF), 6,98 (1H, userd), 7,25-to 7.32 (1H, m), 7,51-of 7.60 (2H, m), 7,72 (2H, d), 8,39 (1H, d), 8,61 (2H, d), 8,81 (1H, d), 12,02 (1H, s), 13,26 (0,8H, users)
513068,32,31 (3H, s)6,94 (1H, d), 7.23 percent-7,29 (1H, m), of 7.48-to 7.59 (2H, m), 7,72 (2H, d), 8,39 (1H, d), 8,61 (2H, d), 8,81 (1H, d), 12,02 (0,5H, C)
523916,71,40-of 1.57 (2H, m), 1,76-to 1.87 (2H, m) 2,75-of 2.86 (2H, m), 3,43-3,68 (3H, m), 4,70 (1H, d), to 6.95 (2H, d), 7,56 (2H, d), 7,73 (2H, d), of 8.37 (1H, d), 8,61 (2H, d), 8,80 (1H, d), 11,90 (1H, s), 13,20 (0,6H, users)
534769,1of 1.42 (9H, s), 3,02-3,10 (4H, m), 3,41-to 3.50 (4H, m), 6,98 (2H, d), 7,60 (2H, d), 7,71 (2H, d), scored 8.38 (1H, d), 8,61 (2H, d), 8,80 (1H, D11,93 (0,6H, C)
543766,22,81-of 2.97 (4H, m), 3.00 and-of 3.12 (4H, m), 6.89 in-6,99 (2H, m), 7,52 to 7.62 (2H, m), the 7.65 to 7.75 (2H, m), scored 8.38 (1H, users), 8,55-to 8.62 (2H, m), is 8.75 (1H, users), 12,15 (0,6H, users)

Example 13

N-(6-Oxo-l,6-dihydro-[3,4']bipyridinyl-5-yl)benzosulfimide-IV-1

Amrinon (100 mg, of 0.53 mmol) was suspended in pyridine (2 ml), then added dropwise at 0°C was added benzosulphochloride (75 μl, 0.59 mmol). The reaction mixture was stirred for 2 hours. Then the pyridine was removed in vacuum. To the crude mixture was added MeOH, after which the solid was filtered and washed a large amount of MeOH, resulting target compound was obtained as a pale yellow solid (100 mg, yield 57%). MS (ES+) m/e=328.1H NMR (DMSO-d6) δH 7,51 (2H, DD), 7,54-7,58 (2H, m), to 7.61-the 7.65 (1H, m), of 7.75 (2H, DD), of 7.90 (2H, DD), 8,56 (2H, DD), 9,78 (1H, users), of 12.33 (1H, users).

Example 14: analysis of the Inhibition of ITK:

Compounds were the rotestirovana on their ability to inhibit Itk using analysis on the inclusion of radioactive phosphate. The analysis was performed in a mixture of 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 0.01% of BSA and 1 mm DTT. The final substrate concentration was 15 μm [γ-33P]ATP (400 MCI33P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 2 μm peptide (protein SAM68 D332-443). The analysis was performed at 25°C in the presence of 30 nm Itk. The original analytical buffer solution was prepared using all of the above reagents except for ATP and test the target compounds. 50 ál of solution was added to 96-well plate, and then added 1.5 ál of DMSO solution containing serial dilution of the test compound (typically starting from a final concentration of 15 µm with 2 multiples of serial dilutions) in the twofold repetition (the final concentration of DMSO of 1.5%). The tablet is pre-incubated for 10 minutes at 25°C, after which the reaction was initiated by adding 50 μl of [γ-33P] ATP (final concentration of 15 μm).

The reaction was stopped after 10 minutes by adding 50 ál of the mixture THU/ATP (20%THU, 0.4 mm ATP). 96-well plate Unifilter GF/C (Perkin Elmer Life Sciences, Cat no. 6005174) pre-treated with 50 μl of water Milli Q before you add the entire reaction mixture (150 μl). The tablet was washed with 200 ál of water Milli Q, and then 200 ml of a mixture THU/ATP (5%THU, 1 mm ATP). Then the washing cycle was repeated 2 more times. After drying, the hole was added to 30 μl of liquid from interazioni mixture Optiphase 'SuperMix' (Perkin Elmer) for scintillation counting (liquid scintillation counter 1450 Microbeta, Wallac).

Data IC50 were calculated using nonlinear regression data analysis of initial velocities, using the software package Prism (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

The analysis was performed in a mixture of 20 mm MOPS (pH 7.0), 10 mm MgCl2, 0,1% BSA and 1 mm DTT. The final concentration of substrate in the analysis was 7.5 μm [γ-33P] ATP (400 MCI33P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 3 μm peptide (protein SAM68 D332-443). The analysis was performed at 25°C in the presence of 50 nm Itk. The original analytical buffer solution was prepared using all of the above reagents except for ATP and test the target compounds. 50 ál of solution was added to 96-well plate, and then added 2 ál of DMSO solution containing serial dilution of the test compound (typically starting from a final concentration of 50 μm with 2 multiples of serial dilutions) in the twofold repetition (the final concentration of DMSO 2%). The tablet is pre-incubated for 10 minutes at 25°C, after which the reaction was initiated by adding 50 μl of [γ-33P] ATP (final concentration of 7.5 μm).

The reaction was stopped after 10 minutes by addition of 100 ml of 0,2M phosphoric acid+0.01% of TWEEN 20. Advance 96-nocny plashet for screening with phosphocellulose filter (Millipore, Cat no. MAPHN0B50) will prefix is Ino was treated with 100 μl of 0,2M phosphoric acid+0.01% of TWEEN 20 before adding 170 μl of the mixture to stop the analysis. The plate was washed 4×with 200 μl of 0,2M phosphoric acid+0.01% of TWEEN 20. After drying in the hole was added to 30 μl of liquid scintillation mixture Optiphase 'SuperMix' (Perkin Elmer) for scintillation counting (liquid scintillation counter 1450 Microbeta, Wallac).

Data Ki(approx) were calculated using nonlinear regression data analysis of initial velocities, using the software package Prism (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

In General, the compounds of the invention are effective for inhibiting ITK. Preferred compounds showed Ki below 0.1 μm in the analysis include radioactive labels (I-68, I-71, I-4, 1-77, I-81, II-14, II-17, II-20, II-22, II-23, II-28, II-9, II-30, II-31, II-35, II-40, II-46, II-51, II-58, II-63, II-64, II-65, II-66, II-77, II-78, II-79, II-80, II-81, II-97, II-107 II-112 II-114 II-115 II-126 II-129 II-130 II-131 II-134 II-135 II-136 II-138 II-139 II-142 II-143 II-145 II-146 II-147 II-148, II-153 II-155 II-156 II-157 II-158 II-159 II-160, II-162 II-163 II-164, II-165 II-166 II-167 II-168 II-169 II-170, II-171 II-172, II-177 II-178 II-179 II-181 II-182, III-42, III-44, III-46, III-47, III-52, III-54). Preferred compounds showed Ki between 0.1 μm and 1 μm in the analysis include radioactive labels (I-5, I-10, I-11, I-20, I-1, I-22, I-27, I-45, I-46, I-47, I-69, I-72, I-73, I-75, I-2, I-83, I-84, I-85, II-4, II-7, II-15, II-21, II-32, II-34, II-38, II-39, II-41, II-43, II-45, II-47, II-52, II-56, II-57, II-59, II-60, II-61, II-62, II-69, II-70, II-71, II-75, II-76, II-83, II-85, II-87, II-95, II-98, II-99, II-100, II-101, II-104, II-105, II-108 II-120 II-121, II-123 II-124 II-132 II-133 II-137 II-140 II-144 II-149 II-150 II-151 II-152 II-154 II-161 II-174, II-175, II-176, III-4, III-5, III-7, III-8, II-11, III-16, III-43, III-45).

Example 15: analysis of the Inhibition of ITK (UV):

Compounds were tested for their ability to inhibition of Itk using standard analysis of enzyme binding (Fox et al., Protein Sci., (1998) 7, 2249).

Analyses were carried out in a mixture of 20 mm MOPS (pH 7.0), 10 mm MgCl2, 0,1% BSA, 1 mm DTT, 2.5 mm of phosphoenolpyruvate, 300 μm NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase. The final concentration of substrate in the analysis was 100 μm ATP (Sigma Chemicals) and 3 μm peptide (biotinylated SAM68 D332-443). Analyses were performed at 25°C and in the presence of 100 nm Itk.

The original analytical buffer solution was prepared using all of the above reagents except for ATP and test the target compounds. 60 ál of solution was added to 96-well plate, and then added 2 ál of DMSO solution containing serial dilution of the test compound (typically starting from a final concentration of 15 μm). The tablet is pre-incubated for 10 minutes at 25°C, after which the reaction was initiated by adding 5 μl of ATP. The initial reaction rate were determined using a tablet reader (Molecular Devices SpectraMax Plus after 10 minutes. Data IC50 and Ki were calculated using nonlinear regression analysis using the software package Prism (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego Caliph is rnia, USA).

In General, the compounds of the invention are effective for inhibiting ITK. Preferred compounds showed Ki below 0.1 μm in the analysis of enzyme binding (I-70, I-76, I-78, I-79, I-80). Preferred compounds showed Ki between 0.1 μm and 1 μm of the dual enzyme analysis (I-5, I-10, I-11, I-69, I-82, I-83, I-84, II-4, II-7, II-41).

Example 16: analysis of the Inhibition of BTK:

Compounds were tested for their ability to inhibit Btk using analysis on the inclusion of radioactive phosphate at Vertex Pharmaceuticals. Analyses were performed in a mixture of 20 mm MOPS (pH 7.0), 10 mm MgCl2, 0,1% BSA and 1 mm DTT. The final substrate concentration was 15 μm [γ-33P]ATP (200 MCI33P ATP/mmol ATP, Amersham Pharmacia Biotech, Amersham, UK/Sigma Chemicals) and 2 μm peptide (protein SAM68 D332-443). The analysis was performed at 25°C in the presence of 25 nm Btk. The original analytical buffer solution was prepared using all of the above reagents except the peptide and the test target compound. 75 ál of solution was added to 96-well plate, and then added 2 ál of DMSO solution containing serial dilution of the test compound (typically starting from a final concentration of 15 μm) in the twofold repetition (the final concentration of DMSO 2%). The tablet is pre-incubated for 15 minutes at 25°C, after which the reaction was initiated by the user is receiving 25 μl of the peptide to a final concentration of 2 μm). Indicator background was determined by adding 100 ml of 0,2M phosphoric acid+0.01% of TWEEN to control wells containing the original analytical buffer and DMSO prior to initiating peptide.

The reaction was stopped after 10 minutes by addition of 100 ml of 0,2M phosphoric acid+0.01% of TWEEN 20. Advance 96-hole plashet for screening with phosphocellulose filter (Millipore, Cat no. MAPHN0B50) pre-treated with 100 μl of 0,2M phosphoric acid+0.01% of TWEEN 20 before adding 170 ml of a mixture to stop the analysis. Plashet was washed with 4×200 μl of 0,2M phosphoric acid+0.01% of TWEEN 20. After drying in the hole was added to 30 μl of liquid scintillation mixture Optiphase 'SuperMix' (Perkin Elmer) for scintillation counting (liquid scintillation counter 1450 Microbeta, Wallac).

After exclusion of the mean background values for all data points, the data Ki (approx) were calculated using nonlinear regression analysis using the software package Prism (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

In General, the compounds of the invention, including compounds in Table 1, are effective for inhibition of Btk. Preferred compounds showed Ki above 0.5 μm in the analysis include radioactive labels (II-43, II-61, II-114 II-149). Preferred compounds showed Ki below 0.5 μm in the analysis include radioactive labels (II-51, II-58, II-61, II-63, II-77, II-78, II-80, II-11).

Example 17: analysis of the Inhibition of BTK (AlphaScreen™):

Compounds were tested for their ability to inhibit Btk using phosphotyrosine analysis AlphaScreenTMat Vertex Pharmaceuticals. The test was performed in a mixture of 20 mm MOPS (pH 7.0), 10 mm MgCl2, 0,1% BSA and 1 mm DTT. The final concentration of substrate in the analysis was 50 μm ATP (Sigma Chemicals) and 2 μm peptide (biotinylated SAM68 D332-443). The analysis was performed at 25°C in the presence of 25 nm Btk. The original analytical buffer solution was prepared using all of the above reagents except the peptide and the test target compound. of 37.5 ál of solution was added to 96-well plate, and then added 1 ál of DMSO solution containing serial dilution of the test compound (typically starting from a final concentration of 15 μm) in the twofold repetition (the final concentration of DMSO 2%). The tablet is pre-incubated for 15 minutes at 25°C, after which the reaction was initiated by addition of 12.5 μl of the peptide to a final concentration of 2 μm). Indicator background was determined by adding 5 μl of 500 mm EDTA to control wells containing the original analytical buffer and DMSO to initiate using Biotin-SAM68.

The reaction was stopped after 30 minutes by 225-fold dilution of the reaction in MOPS buffer (20 mm MOPS (pH 7.0), 1 mm DTT, 10 mm MgCl 2, 0,1% BSA)containing 50 mm EDTA to bring the final concentration of peptide to 9 nm.

AlphaScreen reagentsTMwere prepared according to the manufacturer's instructions (AlphaScreenTMset for phosphotyrosine analysis (P-Tyr-100), PerkinElmer catalog number 6760620C). With dimmed lights and 20 μl of reagents AlphaScreenTMwere added to each well of the white half of the 96-hole tablet (Corning Inc. - COSTAR 3693) with 30 µl stopped diluted in kinase reactions. The plates were incubated in the dark for 60 minutes before reading on a tablet reader Fusion Alpha (PerkinElmer).

After exclusion of the mean background values for all data points, the data Ki (approx) were calculated using nonlinear regression analysis using the software package Prism (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

Example 18: an Analysis of Inhibition RLK:

Compounds were tested for their ability to inhibition Rlk using standard analysis of enzyme binding (Fox et al., Protein Sci., (1998) 7, 2249). Analyses were carried out in a mixture of 20 mm MOPS (pH 7.0), 10 mm MgCl2, 0,1% BSA and 1 mm DTT. The final concentration of substrate in the analysis was 100 μm ATP (Sigma Chemicals) and 10 μm peptide (Poly Glu:Tyr 4:1). The analysis was performed at 30°C and in the presence of 40 nm Rlk. The final concentrations of the components of the system enzyme binding amounted to 2,5mm of phosphoenolpyruvate, 300 μm NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

The original analytical buffer solution was prepared using all of the above reagents except for ATP and test the target compounds. 60 ál of solution was added to 96-well plate, and then added 2 ál of DMSO solution containing serial dilution of the test compound (typically starting from a final concentration of 7.5 μm). The tablet is pre-incubated for 10 minutes at 30°C, after which the reaction was initiated by adding 5 μl of ATP. The initial reaction rate were determined using a tablet reader (Molecular Devices SpectraMax Plus after 10 minutes. Data IC50 and Ki were calculated using nonlinear regression analysis using the software package Prism (GraphPad Prism version 3,0cx for Macintosh, GraphPad Software, San Diego California, USA).

In General, the compounds of the invention are effective for inhibiting RLK. Preferred compounds showed Ki greater than 1 μm in the analysis of enzyme binding (I-5, I-11, I-71, I-74, II-7, II-15, II-17, II-38, II-41, II-46, II-47, II-65, II-75, II-83, II-85, II-87, II-114 II-115 II-143 II-148 II-149 II-159, II-160, II-163 II-164, II-166 II-168 II-171 II-178 II-179, III-4, III-5). Preferred compounds showed Ki below 1 μm in the analysis of enzyme binding (II-14, II-28, II-29, II-30, II-31, II-35, II-40, II-77, II-78, II-79, II-80, II-81, II-112).

While has been described a number of embodiments us Otsego of the invention, it is obvious that presents basic examples can be modified to provide other embodiments that use the compounds and methods of the present invention. Thus, it should be understood that the scope of the present invention should be defined by the attached claims rather than specific implementation options, which were presented as examples.

1. The compound of the formula I

or its pharmaceutically acceptable salt,
where each R3and R4is H;
R2is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms, represents a nitrogen atom or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-5 heteroatoms, represents nitrogen; and R2optionally replaced by a group JR;
each X1and X2independently is-C(O)-, -NR - or-SO2-where one of X1or X2represents-NR-, and the other of X1or X2is-C(O)- or-SO2-;
R represents H;
R1is-T-Q;
T is a bond or C1-6-aliphatic chain, in which up to two methylene units of the chain it is interesting and independently replaced by G or G', where G is-O -, and G' is cyclopropyl or C=S;
Q independently is hydrogen, C1-6-aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-2 heteroatoms independently selected from nitrogen or oxygen; and Q is optionally replaced by a group JQ;
Deputy JRand JQon the unsaturated carbon atom aryl or heteroaryl group selected from halogen; -R°; C1-6-alkyl, optionally substituted by a group R°, in which up to three methylene units of the chain are optionally and independently replaced by-NR°-, -O-, -S-, -SO-, SO2-, -CO-, cyclopropyl, With a≡C or C=C in a chemically stable environment; -F3; -SCF2;1-4-haloalkyl; CH2-halogen; C6-10-aryl, optionally substituted with R°; 5-12-membered heteroaryl, optionally substituted with R°; 3-12-membered heterocyclic ring, optionally substituted with R°; -O(Ph)optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -CH≡CH(Ph), optionally substituted with R°; -C1-6-alkyl-(3-12 membered GE is eroticline), optionally substituted with R°; -C1-6-alkyl-(C6-10-aryl), optionally substituted with R°; -C1-6-alkyl-(5-10-membered heteroaryl), optionally substituted with R°; With3-10-cycloaliphatic group, optionally substituted with R°; -C1-6-alkyl-(C3-10-cycloaliphatic group), optionally substituted with R°; - (C1-6-alkyl)-OR°, optionally substituted with R°; -(C1-6-alkyl) -N(R°)2, optionally substituted with R°; - (C1-6-alkyl)-SR°, optionally substituted with R°; -NO2; -CN; -OR°; -SR°; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°)R°; -C(NOR°)R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2; -P(O)2R°; -PO(R°)2; -OPO(R°)2; and -(CH2)0-2NHC(O)R°;
each R° is independently selected from hydrogen, NH2, NH(C1-4-aliphatic) groups, N(C1-4-aliphatic)2group, halogen, HE, (C1-4-aliphatic) groups, NO2CN, CO2N, CO2(C1-4-aliphatic) groups, O (halo-C1-4-aliphatic) groups, halo-C1-4-aliphatic group is s, optionally substituted C1-6-aliphatic group in which up to 2 methylene units optionally replaced by O, N or S, 5-8-membered heterocyclyl, unsubstituted 5-6-membered heteroaryl, unsubstituted 3-6-membered cycloaliphatic group, unsubstituted phenyl, unsubstituted-O(Ph), unsubstituted-CH2(Ph), unsubstituted-CH2(5-7-membered heterocyclyl) or unsubstituted-CH2(5-6 membered heteroaryl);
optional substituents on the aliphatic group of R° is selected from CO2(C1-4-aliphatic) groups, where each of the preceding C1-4-aliphatic groups of R° is unsubstituted;
Deputy JRon a saturated carbon of an aliphatic group selected from NH(C1-4-aliphatic) groups =O, =NOH;
Deputy JRand JQon the non-aromatic nitrogen heterocyclic ring or on the nitrogen heteroaryl ring selected from R+, -N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2and-NR+SO2R+; where R+represents hydrogen, optionally substituted C1-6-aliphatic group, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph), optionally alseny -(CH 2)2(Ph); optionally substituted-CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, having from one to four heteroatoms independently selected from oxygen, nitrogen and sulfur, or, notwithstanding the definition above, two independent R+at the same Deputy or different substituents, taken together with the atom(s)to which each R+group, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; optional substituents on the aliphatic group or the phenyl group ring R+selected from NH2, -NH(C1-4-aliphatic) groups, -N(C1-4-aliphatic)2group, halogen, C1-4-aliphatic group, IT is, -O(C1-4-aliphatic) groups, -NO2, -CN, -CO2H, -CO2(C1-4-aliphatic) groups, -O(halo-C1-4-aliphatic) groups, and halo-(C1-4-aliphatic) groups, where each of the preceding C1-4-aliphatic groups group R+is unsubstituted;
provided that
when R2is a 4-pyridium or 3-pyridium, R3is N, X1is-NR-, R is H, and X2is-C(O)-; then
a) R1 is not CH(CH3)OS(=O)CH3; CH2OS(=O)CH3or CH2C(=O)CH3;
b) R1is not C1-6-alkyl or O(C1-6-alkyl);
when R2is a 4-pyridium, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-, then
a) when T is a bond, Q is not the stands, imidazole or N;
b) when T is-CH2-, Q is not 3-HE-phenyl, 4-HE-phenyl, 4-pyridium, 3-NO2-phenyl, HE or-C(=O)CH3;
c) when T is-CH2CH2-, Q is not 2-pyridium;
when R2is 2,4-pirimidinom, R3and R4are H, X1is-NR-, R is H, and X2is-C(O)-, then
a) R1is not the stands;
when R2is a 4-pyridium, R3and R4are H, X1is-NR-, R is H, and X2is-SO2-then
a) when T is a bond, Q is an optionally substituted C6-10-aryl or C5-10-heteroaryl;
when X1is-C(O)-, X2is-NR-, R is H, then R1is not H or stands.

2. The compound according to claim 1, where T is a C1-3-aliphatic group, optionally interrupted by one group G, where G is O.

3. The compound according to claim 1, where T is-C1-2-aliphatic-group, where G is the tsya About, moreover, G is associated with Q in a chemically stable environment.

4. The compound according to claim 1, where T is a C1-3-aliphatic group.

5. The compound according to claim 1, where T is a C1-3-aliphatic group, optionally interrupted by one group G'.

6. The compound according to claim 1, where T is-CH2-.

7. The compound according to claim 1, where T is the link.

8. The compound according to claim 1, where R2is a 5-8-membered monticola, optionally substituted groups JRup to five groups.

9. The connection of claim 8, where R2is3-8-cycloaliphatic group, optionally substituted groups JRup to five groups.

10. The connection according to claim 9, where R2is3-8-cycloalkyl group optionally substituted by groups JRup to five groups.

11. The connection according to claim 9, where R2is3-8-cycloalkenyl group optionally substituted by groups JRup to five groups.

12. Connection to item 11, where R2is cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl, optionally substituted groups JRup to five groups.

13. The connection of claim 8, where R2is a 5-6-membered aryl or heteroaryl, optionally substituted groups JRup to ATI groups

14. The connection indicated in paragraph 13, where R2is a 5-6-membered heteroaryl, optionally substituted by groups of the IRup to five groups.

15. The connection 14, where R2is a 6-membered heteroaryl comprising 1 or 2 nitrogen atom; R2is optionally substituted by groups of the IRup to five groups.

16. The connection indicated in paragraph 15, where R2is a pyridine ring, optionally substituted by groups JRup to five groups.

17. Connection P16, where R2is 2-pyridinyl, optionally substituted groups JRup to five groups.

18. Connection P16, where R2is 3-pyridinyl, optionally substituted by groups of the IRup to five groups.

19. Connection P16, where R2is 4-pyridinyl, optionally substituted by groups of the IRup to five groups.

20. The connection indicated in paragraph 15, where R2is a pyrimidine ring, optionally substituted by groups JRup to five groups.

21. Connection claim 20, where R2is 2-4 pyrimidinyl, optionally substituted groups JRup to five groups.

22. The connection 14, where R2is 5-membered heteroaryl ring, optionally substituted by groups JRup to five groups.

23. Connected the e on p.22, where R2is a thiophene ring, optionally substituted by groups JRup to five groups.

24. Connection p.22, where R2is a pyrazol ring, optionally substituted by groups JRup to five groups.

25. The connection indicated in paragraph 13, where R2is phenyl, optionally substituted groups JRup to five groups.

26. The connection according to claim 9, where each group JRselected from oxo or =NOH.

27. The connection indicated in paragraph 13, where each group JRselected from C1-6-alkyl, C6-10-aryl, -C1-6-alkyl-C6-10-aryl, C1-4-haloalkyl, -OR°, -N(R°)2, -SR°, NO2CN, 3-12-membered heterocyclyl, - (C1-6-alkyl)-OR°, - (C1-6-alkyl)-N(R°)2- (C1-6-alkyl) -SR°, -C(O)OR°, NR°COR°, -COR°, -CON(R°)2, -SO2R°, -SO2N(R°)2or1-6-alkyl, in which up to three methylene units of the chain are independently replaced by-NR°-, -O-, -S-, -SO-, SO2or WITH - in a chemically stable environment; and each group JRindependently and optionally substituted by a group R°.

28. Connection item 27, where each group JRindependently and optionally substituted by a group of R° is selected from-OR°, -N(R°)2, -SR°, - (C1-6-alkyl)-OR°, - (C1-6-alkyl) -N(R°)2or - (C1-6-alkyl)-SR°.

29. Connection item 27, where each group JRindependently select the on from optionally substituted 5-8-membered heterocyclyl, optionally replaced by-NR(C1-4-alkyl)N(R°)2not necessarily replaced by-NR(C1-4-alkyl)OR°, -N(R°)2or optionally substituted-NH(5-6-membered heterocyclyl).

30. The connection clause 29, where each group JRindependently selected from optionally substituted-NH(5-6-membered heterocyclyl).

31. Connection item 30, where 5-6-membered heterocyclyl contains 1-2 nitrogen atom.

32. Connection p, where 5-6-membered heterocyclyl selected from pyrrolidine, piperidine or piperazine.

33. Connection pop, where X1is C(O), and X2is NR.

34. The compound according to claim 1, where X1is NR, and X2is S(O).

35. Connection p or 34, where Q is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system containing 0-2 heteroatoms independently selected from nitrogen or oxygen.

36. Connection p, where Q is a C6-10-aryl, C3-10-cycloaliphatic group, a 5-14-membered heteroaryl or a 5-14-membered heterocyclyl.

37. Connection p, where Q is a C6-10-aryl or a 5-14-membered heteroaryl.

38. The connection clause 37, where Q t is aetsa 5-6-membered aryl or heteroaryl.

39. Connection § 38, where Q is phenyl.

40. Connection p where Q is a substituted groups JQup to 3 groups, and each group of JQselected from CN, C1-6-alkyl, C1-4-haloalkyl, -OR°, -N(R°)2, -SR°, -(C1-6-alkyl)-OR°, -(C1-6-alkyl)-N(R°)2-(C1-6-alkyl)-SR°, With6-10-aryl, -C1-6-alkyl-C6-10-aryl, C3-10-cycloaliphatic group, -C1-6-alkyl-(C3-10-cycloaliphatic group)3-10-heterocyclyl, -C1-6-alkyl-(C3-10-heterocyclyl), -C(O)OR°, -NR°COR°, -COR°, -CON(R°)2, -SO2R°, -SO2N(R°)2or C1-6-alkyl, in which up to three methylene units optionally and independently replaced by-NR°-, -O-, -S-, -SO-, SO2-, -CO-, cyclopropyl, With a≡C or C≡C bonds chemically stable in the environment; and each group JQoptionally and independently substituted by a group R°.

41. Connection p, where each group JQis-SO2N(R°)2, -SO2R°, -NR°C(O)OR°, -C≡C-R°, -C=C-R°, - phenyl, -O-Ph, -O-CH2Ph5-6-heteroaryl,3-7-heterocyclyl or3-7-cycloaliphatic group.

42. Connection p, where each group JQis CN, C1-6-alkyl, -CF3, -OCF3, -OR°, -N(R°)2, -SR°, -CH2-halogen, -SCF2, - (C1-6-alkyl)-N(R°)2With6-aryl, C5-6-heteroaryl, -C(O)OR°, -R°COR°, -COR° or-CON(R°)2.

43. Connection p, where R° is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, tert-butyl, HE, halogen, -CH2-pyrrolidine, PINES3, -(C1-4-alkyl)0-1-O(C1-4-alkyl), -(C1-4-alkyl)0-1-O(C1-4-alkyl)HE, -(C1-4-alkyl)0-1-NH(C1-4-alkyl), -(C1-4-alkyl)0-1-N(C1-4-alkyl)2or -(C1-4-alkyl)0-1-NH2.

44. A compound selected from the following:
































































.

45. A compound selected from the following:


















































46. Pharmaceutical composition having inhibitory activity against the kinase family of TES containing compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or base.

47. Method of inhibiting kinase activity of a TEC family (e.g. TEC, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk):
(a) the patient; or
(b) in a biological sample,
moreover, this method includes the introduction of a specified patient or contacting the specified biological sample with a compound according to claim 1.

48. The method according to p, where the method comprises inhibiting the activity of Itk kinase.

49. The compound of formula 22

where R10is an amino-protecting group;
R11is N or C1-6is an alkyl group, or R10and R11together with the nitrogen atom to which they are bound, form an amino-protective group;
R12is a hydroxyl-protecting group.

50. The method of obtaining the compounds of formula I, including the Mering interaction of the compounds of formula 22 with a connection R 2- X, where X is an appropriate leaving group, to obtain compounds of formula 23

where R10is an amino-protecting group;
R11is N or C1-6is an alkyl group, or R10and R11together with the nitrogen atom to which they are bound, form an amino-protective group;
R12is a hydroxyl-protecting group; and
R2I , JRand R0have the meanings indicated in claim 1.



 

Same patents:

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oxazolidinone derivatives covered by general graphic formula (I) and to their pharmaceutically acceptable salts. In formula (I) R1, R2, R3 and R4 are independently chosen from a group including -H and halogen; A is chosen from a group including R5 and R6 are independently chosen from a group including -H, -F, -CI, -Br, -OH, alkyl(C1-C6), haloalkyl(C1-C6), alkoxygroup(C1-C6); R7 is chosen from a group including -H, alkyl(C1-C6); either R7 and R5 or R6 taken together form a cycle of 2 carbon atoms and include 1 group chosen from O which in turn can be substituted by one substitute chosen from alkyl(C1-C6); R12 is chosen from a group including -H, -COR14, -CSR14, -COOR14; R14 is chosen from a group including alkyl (C1-C6), cycloalkyl(C3-C6), alkenyl(C2-C6), R16, R17 and R18 represent -H; R21 is chosen from a group including -H, alkyl(C1-C6); X is chosen from a group including O, S, and Y is chosen from a group including O, S, SO, SO2, and NR12; and optional substitutes of alkyl(C1-C6) groups can represent one or two groups chosen from the following: -OR21, -CN.

EFFECT: invention refers to methods for preparing the compounds of the invention, to application of oxazolidinone derivatives for preparing a drug for treating bacterial infections and to a pharmaceutical composition for treating bacterial infections, including a therapeutically effective amount of the compound of the invention.

36 cl, 10 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound 3-{[5-(azetidine-1-ylcarbonyl)pyrazine-2-yl] oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazine-5-yl)benzamide or to its pharmaceutically acceptable salt. Also, it refers to a pharmaceutical composition for treating insulin-independent diabetes or obesity containing said compound.

EFFECT: there is produced and described a new compound which can be effective in treating insulin-independent diabetes and obesity.

5 cl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

where there are R3/R3', R4/R4' and R5/R5' where at least one of either R4/R4' or R5/R5' always represents a fluorine atom, and the other radical values are disclosed in the description.

EFFECT: making the compounds which are γ-secretase inhibitors, and can be effective in treating Alzheimer's disease or advanced cancers, including but not limited to carcinoma of uterine cervix and breast carcinoma and malignant tumours of hematopoietic system.

15 cl, 3 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of formula I in which cycle A represents unsaturated carbocycle with double bonds, which is selected from phenyl or naphtyl; 1 can take value from 1 to 3; m can take value 0, 2 or 3; n can take value 0 or 2; R1 represents a hydrogen atom, (C1-3)alkyl group; R2 represents(C1-6)alkyl group, which is possibly substituted with substituent, selected from C6-cycloalkyl, monocyclic heteroaryl, selected from thiophene, aryl group, selected from phenyl, in form of base or salt of bonding with an acid. Invention also relates to pharmaceutical composition, based on formula I compound, to application of formula I compound for obtaining medication, to method of obtaining formula I compound and to application of formula compound for obtaining formula 1 compound.

EFFECT: obtained are novel isoquinoline and benzo[h]isoquinoline derivatives, possessing properties of antagonists of histamine type H3 receptor.

9 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 2-quinolyloxazoles of formula (I) or pharmaceutically acceptable salts thereof, having PDE4 inhibiting properties, a pharmaceutical composition based on said compounds and use thereof to prepare a medicinal agent which inhibits inflammatory cell recruitment in respiratory tracts. , where is , X is O, R1 is alkyl, R3 and R4 are independently selected from H, R5 and R6 are independently selected from a group comprising H, alkyl, hydroxyalkyl, t equals 1 or 2. Values of substitutes R7-R11, R13 are given in the formula of invention.

EFFECT: high efficiency of using the composition.

24 cl, 1 dwg, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) or pharmaceutically acceptable salts thereof, in which X is or ; Y is H; Z is -C(O)-; R1 and R3 each independently denotes H or (C1-C4) alkyl; R2 and R4 each independently denotes , , or ; R5 denotes H or (C1-C6) alkyl; R8 and R9 each independently denote (C1-C6) alkyl; and Q is H.

EFFECT: possibility of use in stimulating the growth hormone in a subject based on the said compounds.

49 cl, 2 tbl, 57 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds described by formula in which radical and symbol values are specified in the patent claim, and their pharmaceutically acceptable salts. These compounds inhibit tompomyosine-related kinases (Trk), and can find application in treating a malignant growth, such as breast cancer, rectal cancer and prostate cancer. Also, the invention relates to a method for producing these compounds, a based pharmaceutical composition and to methods of application thereof.

EFFECT: preparation of the pharmaceutical composition which can find application in treating a malignant growth.

18 cl, 134 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where R2 denotes H, [(C1-C6) alkylene]0-1-R'; R3 denotes H; R4 denotes H, halogen or (C1-C6) alkyl; R5 denotes H or halogen; R6 denotes H, (C1-C8) alkyl, R', (C1-C6) alkylene-R'; R7 and R8 independently denote H, halogen, (C1-C6) alkyl, O-(C1-C6) alkyl, R'; R9 denotes (C1-C6)alkyl; n equals 0 or 1; L denotes O or O-(C1-C6)alkylene; where R' denotes (C3-C8) cycloalkyl; (C5-C10)heterocyclyl, which denotes an aromatic or saturated mono- or bicyclic ring system which, besides a carbon atom, includes one or more heteroatoms such as nitrogen, oxygen and sulphur atoms; or (C6-C10) aryl; where in the heterocyclyl is unsubstituted or substituted with (C1-C6)alkyl, and the aryl is unsubstituted or substituted with a halogen, (C1-C4)alkyl, -O-(C1-C4)alkyl, SO2- (C1-C4) alkyl or N[(C1-C4) alkyl]2; and where in groups R4, R6 and R7 the alkyl can be halogenised in one or more positions; or pharmaceutically acceptable salts and/or stereo isomer forms thereof. The invention also relates to use of formula (I) compounds, as well as a medicinal agent.

EFFECT: obtaining novel biologically active compounds having Rho-kinase inhibiting activity.

21 cl, 320 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

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