Azaindoles, useful as inhibitors of jak and other proteinkinases

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

 

The present invention relates to inhibitors of protein kinases. The invention relates also to pharmaceutical compositions comprising compounds of the invention and methods of using the compositions in the treatment of various disorders.

In recent years, the search for and study of new therapeutic agents to a greater extent aim at a better understanding of the structure of enzymes and other biomolecules associated with diseases. One of the important classes of enzymes, which was and remains a subject of extensive research, is a protein kinase.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control or regulation of many processes of signal transduction in the cell (see, Hardie, G. and Hanks, S.The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). It is believed that protein kinases have evolved from a simple ancestral gene due to conservation of their structure and catalytic function. Almost all kinases contain similar 250-300 amino acid catalytic domain. Kinases can be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc). The identified motifs sequences, which typically correspond to each of these families of kinases (see, for example, anks, 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).

Usually protein kinases mediate intracellular signaling through the implementation of the transfer of phosphoryla from nucleosidase to a protein acceptor, which is involved in the signaling pathway. These cases phosphorylation acts as a molecular on/off switch, which can modulate or regulate the biological function of a protein target. These cases phosphorylation ultimately run in response to many extracellular and other incentives. Examples of such stimuli include environmental signals and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial ergotoxin and H2About2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)and growth factors (for example, granulocytic macrophage-colony stimulating factor

(GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimulus can affect one or more cellular responses associated with cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis by regulirovanie cell cycle.

Many diseases are associated with abnormal cellular responses triggered mediated by protein kinase events or circumstances described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and related hormones of the disease. Accordingly, in medicinal chemistry, considerable efforts are directed to the detection of inhibitors of protein kinases, which are effective as therapeutic agents.

Janus kinases (JAK) are a family of tyrosinekinase consisting of JAK1, JAK2, JAK3 and TYK2. JAK play a crucial role in cytokines alarm. Downstream downstream substrates of JAK family kinases include signal transducer and activator of transcription (STAT) proteins. JAK/STAT signaling is involved in mediating many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, lateral to the lateral amyotrophic sclerosis and multiple sclerosis, as well as in solid and hematologic malignancy, such as leukemia and lymphoma. Reviewed by f is rmaceuticals intervention in the JAK/STAT path [ Frank Mol. Med.5, 432-456 (1999) & Seidel, et al.,Oncogene19, 2645-2656 (2000)].

JAK1, JAK2 and TYK2 are expressed ubiquitously, whereas JAK3 is predominantly expressed in hematopoietic cells. JAK3 is associated exclusively with the gamma-chain of normal cytokine receptor (γwith) and is activated by IL-2, IL-4, IL-7, IL-9 and IL-15. It has been shown indeed that the proliferation and survival of murine breast cancer cells induced by IL-4 and IL-9, dependent on JAK3 - and γwith-alarm [Suzuki et al.,Blood96, 2172-2180 (2000)].

Joining of immunoglobulin (Ig) E receptor with high affinity for sensitization of breast cancer cells leads to the release of proinflammatory mediators, including a number of vasoactive cytokines, resulting in acute allergic or immediate (type I) hypersensitivity reactions [Gordon et al.,Nature346, 274-276 (1990) & Galli,N. Engl. J. Med.,328, 257-265 (1993)]. Established the crucial role of JAK3 in mediated IgE receptor response the reaction of breast cells in vitro and in vivo [Malaviya, et al,Biochem. Biophys. Res. Commun.257, 807-813 (1999)]. In addition, it was also reported on the prevention of hypersensitivity reactions type I, including anaphylaxis mediated by activation of breast cancer cells through inhibition of JAK3 [Malaviya et al,J. Biol. Chem.274, 27028-27038 (1999)]. Penetration into the target cells of the mammary gland JAK3 inhibitors mod is lonavala the degranulation of the cells of the mammary gland in vitro and prevented mediated IgE receptor/antigen anaphylactic reactions in vivo.

In a recent study described a successful hit the target JAK3 for immune suppression and acceptance of the allograft. This study demonstrated a dose-dependent survival of cardiac allograft Buffalo on the recipients Wistar Furth after the introduction of JAK3 inhibitors, indicating the ability to control unwanted immune responses and disease graft-versus-host [Kirken,Transpl. Proc.33, 3268-3270 (2001)].

Mediated IL-4 STAT-phosphorylation was meant to be a mechanism involved in early and late stages of rheumatoid arthritis (RA). Characteristic of the disease is sverrehelena proinflammatory cytokines in RA, the synovium and synovial fluid. It was demonstrated that mediated IL-4 activation of the IL-4/STAT path is mediated through the Janus kinase (JAK 1 and 3) and that associated with IL-4 JAK kinases expressed in the RA synovium [Muller-Ladner, et al.,J. Immunol.164, 3894-3901 (2000)].

Hereditary lateral to the lateral amyotrophic sclerosis (FALS) is a devastating neurodegenerative disorder that affects approximately 10% of ALS patients. The degree of survival of FALS mice was increased after treatment JAK3 specific inhibitor. This suggests that JAK3 plays a role in FALS [Trieu, et al.,Biochem. Biophys. Res. Commun.267, 22-25 (2000)].

Signal transductor and activator of transcription is ion (STAT) proteins are activated along with other JAK kinases family. The results of recent studies suggest the possibility of intervention in the JAK/STAT signaling pathway by targeting the JAK kinase family of specific inhibitors for the treatment of leukemia [Sudbeck, et al.,Clin. Cancer Res.5, 1569-1582 (1999)]. It was demonstrated that JAK3 specific compounds inhibit count of clonogenic growth JAK3-expressing cell lines DAUDI, RAMOS, LC1; 19, NALM-6, MOLT-3 and HL-60.

TEL/JAK2 fusion proteins induced in animal models of myeloproliferative disorders, and hematopoietic cell lines introduction TEL/JAK2 has resulted in activation of STAT1, STAT3, STAT5 and tsitogeneticheskogo growth [Schwaller, et al.,EMBO J.17, 5321-5333 (1998)].

Inhibition of JAK3 and TYK2 were eliminated trainferrovie STAT3 and inhibited cell growth of mycosis fungoides, a form of cutaneous T-cell lymphoma. These results allowed to talk about the complicity of JAK kinases family in constitutively activated JAK/STAT path, which is present in mushroom avium [Nielsen et al.,Proc. Nat. Acad. Sci. USA.94, 6764-6769 (1997)]. Similarly, it was demonstrated that STAT3, STAT5, JAK1 and JAK2 significantly activated in T-cell lymphoma mice, characterized in the initial stage of LCK by overexpression, thus additionally involving the JAK/STAT path in abnormal growth of cells [Yu, et al.,J. Immunol.159, 5206-5210 (1997)]. In addition, mediated IL-6 activation of STAT3 blocked inhibitor the JAK, citing the sensitivity of myeloma cells to apoptosis [Catlett-Falcone, et al.,Immunity10, 105-115 (1999)].

One of the interest of the families of kinases is Rho-associated-handed superhelix forming protein serine/threonine kinase (ROCK), which, it is believed, is an effector of Ras-related small GTPase Rho. ROCK family includes p160ROCK (ROCK-1) (Ishizaki et al.,EMBO J.1996, 15, 1885-1893) and ROKα/Rho-kinase/ROCK-II (Leung et al.,J. Biol. Chem.1995, 270, 29051-29054; Matsui et al.,EMBO J.1996, 15, 2208-2216; Nakagawa et al.,FEBS Lett.1996, 392, 189-193), protein kinase PKN (Ammano et al.,Science1996, 271, 648-650; Watanabe et al.,Science1996, 271, 645-648), and citron and citronins (Madaule et al.,Nature,1998, 394, 491-494; Madaule et al.,FEBS Lett.1995, 377, 243-248). It was shown that the ROCK family of kinases involved in many functions, including Rho-induced formation of actin stress fibers and focal adhesion (Leung et al.,Mol. Cell Biol.1996, 16, 5313-5327; Amano et al.,Science,1997, 275, 1308-1311; Ishizaki et al.,FEBS Lett.1997, 404, 118-124) and nistorescu myinfosafe (Kimura et al.,Science,1996, 273, 245-248), platelet activation (Klages et al.,J. Cell. Biol.,1999, 144, 745-754), reduction of smooth muscle aorta different stimuli (Fu et al.,FEBS Lett.,1998, 440, 183-187), thrombin-induced response of smooth muscle cells of the aorta (Seasholtz et al.,Cir. Res.,1999, 84, 1186-1193), hypertrophy of cardiomyocytes (Kuwahara et al.,FEBS Lett.,1999, 452 314-318), contraction of bronchial smooth muscle (Yoshii et al.,Am. J. Respir. Cell Mol. Biol.,1999, 20, 1190-1200), reduction of smooth muscles and the cytoskeleton reorganizatio second cells (Fukata et al.,Trends in Pharm. Sci.2001, 22, 32-39), activation Alhamdulillah anionic channels (Nilius et al.,J. Physiol.,1999, 516, 67-74), the retraction of neuritis (Hirose et al.,J. Cell. Biol.,1998, 141, 1625-1636), chemotaxis of neutrophils (Niggli et al,FEBS Lett.,1999, 445, 69-72), wound healing (Nobes and Hall,J. Cell. Biol.,1999, 144, 1235-1244), tumor invasion (Itoh et al.,Nat. Med.,1999, 5, 221-225) and transformation of cells (Sahai trust et al.,Curr. Biol.,1999, 9, 136-145).

More specifically, ROCK involved in various diseases and disorders, including hypertension (Satoh et al.,J. Clin. Invest.1994, 94, 1397-1403; Mukai et al.,FASEB J.2001, 15, 1062-1064; Uehata et al.,Nature1997, 389, 990-994; Masumoto et al.,Hypertension,2001, 38, 1307-1310), spasm of cerebral vessels (Sato et al.,Circ. Res.2000, 87, 195-200; Miyagi et al.,J. Neurosurg.2000, 93, 471-476; Tachibana et al.,Acta Neurochir (Wien)1999, 141, 13-19), coronary artery spasm (Shimokawa et al.,Jpn. Cir. J.2000, 64, 1-12; Kandabashi et al.,Circulation2000, 101, 1319-1323; Katsumata et al.,Circulation1997, 96, 4357-4363; Shimokawa et al.,Cardiovasc. Res.2001, 51, 169-177; Utsunomiya et al.,J. Pharmacol.2001, 134, 1724-1730; Masumoto et al.,Circulation2002, 105, 1545-1547), bronchial asthma (Chiba et al.,Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol.1995, 11, 351-357; Chiba et al.,Br. J. Pharmacol.1999, 127, 597-600; Chiba et al.,r. J. Phartmacol.2001, 133, 886-890; Iizuka et al.,Eur. J. Pharmacol.2000, 406, 273-279), premature birth (Niro et al.,Biochem. Biophys. Res. Commun.1997, 230, 356-359; Tahara et al.,Endocrinology2002, 143, 920-929; Kupittayanant et al.,Pflugers Arch.2001, 443, 112-114), erectile dysfunction (Chitaley et al.,Nat. Med.2001, 7, 119-122; Mills et al.,J. Appl. Physiol.2001, 91, 1269-1273), glaucoma (Honjo et al.,Arch. Ophthalmol.2001, 1171-1178; Rao et al.,Invest. Ophthalmol. Vis. Sci.2001, 42, 1029-1037), cell proliferation of vascular smooth muscle (Shimokawa et al.,Cardiovasc. Res.2001, 51, 169-177; Morishige et al.,Arterioscler. Thromb. Vasc. Biol.2001, 21, 548-554; Eto et al.,Am. J. Physiol. Heart Circ. Physiol.2000, 278, H1744-H1750; Sawada et al.,Circulation2000, 101, 2030-2023; Shibata et al.,Circulation2001, 103, 284-289), myocardial hypertrophy (Hoshijima et al.,J. Biol. Chem.1998, 273, 7725-77230; Sah et al.,J. Biol. Chem.1996, 271, 31185-31190; Kuwahara et al.,FEBS Lett.1999, 452, 314-318; Yanazume et al.,J. Biol. Chem.2002, 277, 8618-8625), malignoma (Itoh et al.,Nat. Med.1999, 5, 221-225; Genda et al.,Hepatology1999, 30, 1027-1036; Somlyo et al.,Biochem. Biophys. Res. Commun.2000, 269, 652-659), ischemia/reperfusion-induced damage (Ikeda et al.,J Surgical Res.2003, 109, 155-160; Miznuma et al.Transplantation2003, 75, 579-586), endothelial dysfunction (Hernandez-Perera et al.,Circ. Res.2000, 87, 616-622; Laufs et al.,J.Biol. Chem.1998, 273, 24266-24271; Eto et al.,Circ. Res.2001, 89, 583-590), Crohn's disease and colitis (Segain et al.Gastroenterology2003, 124(5), 1180-1187), trigeminus transformation (Fournier et al.J. Neurosci 2003, 23, 1416-1423), disease Raynaud (Shimokawa et al.J. Cardiovasc. Pharmacol.2002, 39, 319-327), angina (Utsunomiya et al.Br. J. Pharmacol.2001, 134, 1724-1730; Masumoto et al.,Circulation2002, 105, 1545-1547; Shimokawa et al.,J. Cardiovasc. Pharmacol.,2002, 40, 751-761; Satoh et al.,Jpn. J.Pharmacol.,2001, 87, 34-40), Alzheimer's disease (Zhou et al.,Science2003, 302, 1215-1218), benign hyperplasia of the prostate (Rees et al., J. of Urology, 2003, 170, 2517-2522) and atherosclerosis (Retzer et al.FEBS Lett.2000, 466, 70-74; Ishibashi et al.Biochim. Biophys. Acta2002, 1590, 123-130). Accordingly, it would be valuable to the development of ROCK inhibitors of kinases as therapeutic agents for the treatment of disorders involved in ROCK kinase pathway.

Aurora proteins represent a family of three highly related serine/threonine kinases (called Aurora-A, -B and-C), which are essential to progress through the mitotic phase of the cell cycle. In particular Aurora-A plays a crucial role in the maturation and segregation of centrosomes, the formation of the mitotic spindle and accurate segregation of chromosomes. Aurora-B is a chromosomal protein-"the passenger," which plays a Central role in regulating the separation of chromosomes at metaphase tablet, control of spun Assembly and for proper completion of cytokinesis.

Overexpression of Aurora-A, -B or-C was observed in several human tumors, including adenocarcinomas of the colon, ovarian, stomach and invasi the aqueous flow. In addition, amplification of AURKA locus, which encodes Aurora-A is correlated with poor prognosis for patients with carcinoma breast cancer without lymph nodes. It was further shown that overexpression of Aurora-A transforms fibroblasts mammals, giving rise aneuploidy cells containing multipolar spindles.

A number of studies have demonstrated that depletion or inhibition of Aurora-A or-B in cancer human cell lines using siRNAs, dominant negative or neutralizing antibodies destroys progressing through mitosis with accumulation of cells 4N DNA, and in some cases this is accompanied by endocapillary and cell death.

Protein kinases are attractive and tested targets for new therapeutic agents to treat a range of human diseases, and examples include Gleevec and Tarceva. Aurora kinases are particularly attractive due to their Association with numerous cancers of the person and the role they play in the promotion of cell proliferation data of cancer cells (Harrington et al.,Nature Med.,2004, 10: 262-267).

Accordingly, there is a great need to develop inhibitors of JAK, ROCK and Aurora, preferably JAK-3, ROCK and Aurora A, protein kinases that are useful in the treatment of various diseases or conditions associated with the asset is of JAK, ROCK and Aurora, particularly given the inadequate treatments currently available for most of these disorders.

BRIEF description of the INVENTION

It was found that the compounds of this invention and pharmaceutically acceptable salts are effective as inhibitors of JAK, ROCK and Aurora kinases. In some embodiments of these compounds are effective as inhibitors of JAK3, ROCK and Aurora kinases. These compounds have the General formulaI:

or are their pharmaceutically acceptable salts, where R1, R2, R3, R4X1X2X3, R5and x have the meanings given below and in the sections of this specification.

These compounds and pharmaceutical compositions based on them are useful for the treatment or prevention of many disorders, including but not limited to, heart disease, diabetes, Alzheimer's disease, disorders associated with immunodeficiency, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases and viral diseases. The compositions are also useful in the methods of prevention the prevention of cell death and hyperplasia and, therefore, can be used for treatment or prevention of reperfusion/ischemia in stroke, heart attacks and hypoxia bodies. The compositions are also useful in the prevention thrombinantithrombin platelet aggregation. The compositions are particularly useful for disorders such as chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocyte leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, but not limited to, ovarian cancer, breast cancer and endometrial cancer), liver disease, including hepatic ischemia, heart disease, such as myocardial infarction and congestive heart failure, pathologic immune conditions, involving the activation of T cells, and neurodegenerative disorders.

DETAILED description of the INVENTION

1. A General description of the compounds of the invention:

The present invention relates to compounds of the formulaI:

or their pharmaceutically acceptable salts, where

R1is T-R' or-Si(R')3;

R2, R3and R4each independently represents halogen, CN, NO2V-R';

X1X2and X3each independently represents N or CH, where the hydrogen atom of the group SN optionally substituted by a group R5;

<> x is equal to 1, 2, 3 or 4;

each of R5is independently halogen, CN, NO2or U-R';

T, V and U each independently represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units of the chain are optionally and independently replaced by-NR'-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-,

-COCO-, -CONR'-, -NR'r CO-, -NR'r CO2-, -SO2NR'-, -NR'r SO2-, -CONR'NR'-, -NR'r CONR'-,

-OCONR'-, -NR'r NR'-, -NR'r SO2NR'-, -SO-, -SO2-, -PO-, -PO2-, or-POR'-; and

each R' is independently hydrogen or optionally substituted group selected from C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur. In some cases, two R', which form a number of the TSO, are on the same substituent (for example, R1, R2, R3, R4or one of R5the Deputy and form a monocyclic or bicyclic ring. In other embodiments, two R' are two substituents (for example, two R5the deputies) and may form a bicyclic condensed ring with a ring that is attached to R5the deputies. However, the two groups R' do not form a tricyclic ring, whether they are associated with one Deputy or two separate deputies.

In some embodiments for compounds described directly above:

a. if R1is substituted cyclopentyl, x is 1, X1and X3are CH, then X2is not a group C-R5in which R5represents fluorine or OMe;

b. if R2and R3are simultaneously H, and R1and R4independently selected from H and Me, x is 1, X1and X3are CH, then X2is not C-R5where R5is OMe, NO2or fluorine;

c. if R1, R2, R3and R4are simultaneously H, x is 1, R5is-Se, NH2or optionally substituted NH-piperidine, and X1and X2represent N, then X3is not a CH group;

d. if R2, R3and R4present one is temporarily H, X1X2and X3represent CH, and two R5form a fused optionally substituted bicyclic ring with the ring to which they are attached, then R1is CH2CH2N(Me)2;

that is, if R2and R3are simultaneously H, R4represents NH2and X1X2and X3are CH, then R1is not substituted phenyl;

f. if R2, R3and R4are simultaneously H, then R1is not Si(R')3;

g. if R1, R2and R4are simultaneously H, and (i) X2and X3represent CH or CR5or (ii) any one of X1X2or X3is N, then R3is not phenyl or phenyl substituted O-phenyl or N(Me)2.

2. Connections and definitions

The compounds of this invention include compounds described above and further illustrated by the classes, subclasses, and species disclosed herein. In the sense, as they are used in the description, you should use the following definitions, unless otherwise stated. For the purposes of this invention, the chemical elements are identified in the description in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. In addition to this General principle is organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. March, J., John Wiley & Sons, New York: 2001, the entire content of which is included in this description by reference to them.

As described in the description, the compounds of the invention can be optionally substituted by one or more substituents, such as illustrated above, or as shown by the examples of particular classes, subclasses, and species according to the invention. It should be understood that the phrase “optionally substituted” is used interchangeably with the expression “substituted or unsubstituted”. Usually the term “substituted”, whether preceded him, the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical named specifically deputies. Unless otherwise specified, optionally substituted group may have a substituent at each substitutable position of the group, and when in any given structure in more than one position may be substituted by more than one Deputy, selected from a specified group, the substituent at each position can be either the same or different from each other. Combinations of substituents covered by this invention are preferably those that result in the formation of a stable or chemically feasible with the joining. The term “stable”, as used in the description refers to compounds, which essentially do not change when exposed to the conditions in which it becomes possible the reception, protection and preferably their isolation, purification, and use for one or more of the purposes described in the description. In some embodiments stable compound or chemically feasible compound is a compound that essentially does not change when stored at 40°C or less, in the absence of moisture or other chemically reactive conditions, at least during the week.

The term “aliphatic” or “aliphatic group”, as used in the description refers to remotemachine (i.e. unbranched) or branched, saturated or unsaturated hydrocarbon chain that is completely saturated or which contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to in the description as “carbocycle”, “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), which has one attachment point to the remainder of the molecule. Unless otherwise specified, aliphatic what groups contain 1-20 aliphatic carbon atoms. In some embodiments of the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments aliphatic groups contain 1-8 aliphatic carbon atoms. In additional embodiments of the aliphatic groups contain 1-6 aliphatic carbon atoms, and in accordance with other embodiments of the aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments “cycloaliphatic” (or “carbocycle”, or “cycloalkyl”refers to monocyclic3-C8the hydrocarbon or bicyclic8-C12the hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, and which has one attachment point to the remainder of the molecule, in which any individual ring in the specified bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkeline, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaromatics”used in the description means an aliphatic group in which one or two carbon atoms are independently replaced by one or more of color is Yes, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle”, “heterocyclyl”, “heterocyclizations” or “heterocyclic” group.

The term “heterocycle”, “heterocyclyl”, “geterotsiklicheskikh” or “heterocyclic”as used in the description refers to non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring members are an independently selected heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocyclizations” or “heterocyclic” group has from three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen or phosphorus and each ring in the system contains 3-7 ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternion the 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, pyrrolidine the (e)).

The term “unsaturated”as used in the description means that the fragment has one or more links of ninasimone.

The term “alkoxy” or “thioalkyl”used in the description refers to an alkyl group, as defined previously, is attached to the main carbon chain through an oxygen atom (“alkoxy”) or sulfur (“thioalkyl”).

The terms “haloalkyl”, “haloalkyl and haloalkoxy” denotes alkyl, alkenyl or alkoxy which may be substituted by one or more halogen atoms. The term “halogen” means F, Cl, Br or I.

The term “aryl”used alone (as is) or as part of a larger fragment as in “aralkyl”, “arakaki”, or “aryloxyalkyl” refers to monocyclic, bicyclic and tricyclic ring systems having a total number of five to fourteen ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3-7 ring members. The term “aryl” may be used interchangeable with the term “aryl ring”. The term “aryl” also refers to a heteroaryl ring systems, as defined below.

The term “heteroaryl used one (as is) or as part of a larger fragment as in “heteroalkyl” or “heteroaromatics”, refers to monocyclic, bicyclic and tricycle the mini-ring systems, with a total number of five to fourteen ring members, where at least one ring in the system is aromatic, at least one ring contains one or more heteroatoms, and where each ring in the system contains 3-7 ring members. The term “heteroaryl” may be used interchangeable with the term “heteroaryl ring” or the term “heteroaromatic(th)”.

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heteroaromatics and the like) group may contain one or more substituents, and thus may be “optionally substituted”. Unless otherwise noted above and herein, suitable substituents on the unsaturated carbon atom aryl or heteroaryl group are generally selected from halogen; -R°; -OR°; -SR°; phenyl (Ph), optionally substituted by R°; -O(Ph), optionally substituted by R°; -(CH2)1-2(Ph), optionally substituted by R°; -CH=CH(Ph), optionally substituted by R°; 5-6-membered heteroaryl or heterocyclic ring, optionally substituted by R°;

-NO2; -CN; -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(ON(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°)2or -(CH2)0-2NHC(O)R°, where each independent of R° is selected from hydrogen, optionally substituted C1-6aliphatic group, an unsubstituted 5-6-membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or-CH2(Ph), or, notwithstanding the preceding definition, two independent R°, on the same substituent or different substituents, taken together with the atom(s), which are attached to each R° group, forming 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 of the aliphatic group of R° is selected from NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), (haloids1-4aliphatic group) or keloids1-4aliphatic group, where each of the above With1-4aliphatic groups groups of R° is unsubstituted.

Aliphatic and and heteroaromatics group, or non-aromatic heterocyclic ring may contain one or more substituents and thus can be “optionally substituted”. If above not otherwise specified, suitable substituents at the saturated carbon of an aliphatic or heteroaromatics group or non-aromatic heterocyclic ring selected from the substituents listed 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), or =NRwhere each Rindependently selected from hydrogen or optionally substituted C1-6aliphatic group.

If above not otherwise specified, the optional substituents at nitrogen non-aromatic heterocyclic ring is usually 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+1)2, -C(=NH)-N(R+)2or-NR+SO2R+where R+represents hydrogen, optionally substituted C1-6aliphatic group, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph),optionally substituted-(CH2)1-2(Ph); optionally substituted-CH=CH(Ph);or unsubstituted 5-6-membered heteroaryl or heterocyclic ring having from one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or, notwithstanding the preceding definition, two independent R+at the same substituent or different substituents, taken together with the atom(s), which are attached to each R+group, form a 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 of the aliphatic group or the phenyl ring of the group R+selected from-NH2, -NH(C1-4aliphatic group), -N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, -OH, -O(C1-4aliphatic group), -NO2, -CN, -CO2H, -CO2(C1-4aliphatic group), -O(Halogens1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above With1-4aliphatic groups group R+is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbon chain, which may be fully saturated or have one or bol is e link ninasimone and has two attachment points to the remainder of the molecule.

The term “protective group”used in the description refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In some embodiments, the protective group has one or more, or preferably all, of the following characteristics: (a) reacts selectively in good yield, giving a protected substrate that is stable with respect to the reactions occurring in one or more other reactive sites; and (b) is selectively removed in good yield by reagents that do not affect the regenerated functional group. Examples of protective groups are described in detail Greene, T.W., Wuts, P.G. in the work “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999, the contents of which are incorporated in this description by reference. The term “nitrogen protecting group”used in the description refers to agents that are used to temporarily block one or more desired reactive nitrogen sites in a multifunctional compound. Preferred nitrogen protecting groups all have the characteristics described for the example above, and some examples of nitrogen protecting groups are also described in detail in Chapter 7 Greene, T.W., Wuts, P.G. in the work “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New Yrk: 1999, the contents of which are incorporated in this description by reference.

As described above, in some embodiments, two independent R° (or the

R+, R, R' or any other variable similarly defined in the description) taken together with the atom(s)to which they are attached, form a 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.

Examples of rings that are formed when two independent R° (or R+, R, R' or any other variable similarly defined in the description) taken together with the atom(s), which are attached to each variable, include, but are not limited to, the following: a) two independent R° (or R+, R, R' or any other variable similarly defined in the description)that are attached to the same atom and are taken together with the atom forming a ring, for example N(R°)2where both of R° are taken together with the nitrogen atom, form a piperidine-1-ilen, piperazine-1-ilen, or morpholine-4-ilen group; and b) two independent R° (or R+, R, R' or any other variable similarly defined in the description)that are attached to different atoms and are taken together with both of those atoms to form a ring, for example, when anilina group is substituted by two of R° the two R° are taken together with the oxygen atoms to which they are attached, form a fused 6-membered oxygen-containing ring:. Obviously it is clear that you can produce many other rings, when two independent R° (or R+, R, R' or any other variable similarly defined in the description) taken together with the atom(s), which are attached to each variable, and that the examples detailed above are not intended to be perceived as restrictive.

Unless otherwise stated, there is also aware that the structure shown in the description, 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 with double bonds, and (Z)- and (E)conformational isomers. Therefore, the scope of the invention includes a single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of these compounds. Unless otherwise specified, the scope of the invention includes all tautomeric forms of the compounds of the invention. In addition to this also meant that, unless otherwise stated, structures depicted in the description, include compounds that differ only in Pris is tsteam 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 carbon13With or14C-enriched carbon are covered by the scope of the invention. Such compounds are useful, for example, as analytical tools or samples or probes in biological assays.

3. Examples of compounds

As described in General above, R1is T-R', or is a group-Si(R')3.In some embodiments, when R1is T-R', T represents optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-O-, -S-, -NR'-, -OCO-, -COO-, -SO2- or-CO-, and R' represents hydrogen, C1-C4-alkyl, or optionally substituted 5 - or 6-membered aryl or heteroaryl group. In other embodiments, R1, R' can be, in addition,1-C4-aliphatic group. In other embodiments, when R1is-Si(R')3, R' represents hydrogen, C1-C4is alkyl or optionally substituted 5 - or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R1is bodoro is, With1-C4-alkyl, -COR', -SO2R' or-Si(R')3. In other embodiments, R1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-toluensulfonyl (Ts), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or triethylsilyl (TES). Examples R1groups are also depicted in tables 1 and 2, presented in the description.

As described in General above, R2, R3and R4each independently represents halogen, CN, NO2or V-R'. In some embodiments, R2, R3and R4each independently represents hydrogen, R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH2)3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2OR', -O(CH2)3OR', -O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3N(R')2or-O(CH2)4N(R')2. In other embodiments, R2, R3and R4each independently represents Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or optionally substituted group selected from C1-C4-alkyl, C1-C4alkyloxy, 3-8-clenn the th 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 other embodiments, R2, R3and R4each represents hydrogen. In other embodiments, one of R2, R3or R4represents hydrogen. In other embodiments two of R2, R3or R4represent hydrogen. In other embodiments, R2and R4both represent hydrogen, and R3represents halogen, CN, NO2or V-R'. In other embodiments, R2and R4both represent hydrogen, and R3is optionally substituted group selected from 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 other embodiments, R2and R4both represent hydrogen, and R3is optional what about the substituted 5 - or 6-membered saturated, partially unsaturated or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R2and R4both represent hydrogen, and R3is optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl or oxadiazolyl. In other embodiments, when R1, R2and R4represent hydrogen, then R3is not optionally substituted phenyl. In other embodiments, when R1, R2and R4represent hydrogen, then R3is not aryl, heteroaryl, carbocyclic or heterocyclic ring. Examples R2, R3and R4groups also include groups shown in tables 1 and 2.

As described above, R2, R3and R4, each independently, is optionally substituted by the group, and in some embodiments, R2, R3and R4each optionally and independently substituted (R6)zwhere z is equal to 0-5, and R6is =O, =NR, =S, halogen, -CN, -NO2or Z-R”, where Z represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by what the group-NR”-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a 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. In other embodiments, z is 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2 OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR”(CH2)4'OR”. In some embodiments, R6may additionally be a group-NR”CH(CH3R”. In other embodiments, z is 1, 2 or 3, and each of R6is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), -CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the foregoing phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic Additional examples R 6groups are depicted in table 1.

As described in General above for compounds of the formulaI,X1X2and X3each independently represents N or CH, where the hydrogen atom of the group SN optionally replaced by a group of R5. In some embodiments two of X1X2or X3represent N, and one of the other X1X2or X3is CH, where the hydrogen atom of the group SN optionally replaced by a group of R5. In some other embodiments, one of X1X2or X3represents N and the remaining two of X1X2or X3represent CH, where the hydrogen atom of the group SN optionally replaced by a group of R5. In other embodiments, each of X1X2or X3is CH, where the hydrogen atom of the group SN optionally replaced by a group R5. In some other example embodiments, the compounds have one of formulasI-A, I-B, I-CorI-D:

In other embodiments compounds have the formulaI-E:

As described in General to compounds of the formulaIabove, x is 1, 2, 3 or 4; and each of R5is independently halogen, CN, NO2or U-R', where each U is independently represents a bond or optionally substituted C1-C6 alkylidenes a circuit in which up to two methylene units of the chain are optionally and independently replaced by-NR'-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR'-,

-NR'r CO-, -NR'r CO2-, -SO2NR'-, -NR'r SO2-, -CONR'NR'-, -NR'r CONR'-, -OCONR'-, -NR'r NR'-, -NR'r SO2NR'-, -SO-, -SO2-, -PO-, -PO2-, or-POR'-; and each R' is independently hydrogen or optionally substituted C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur. In some embodiments each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2) 2N(R')2, -CONR(CH2)3N(R')2, -CONR(CH2)4(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2IT)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2)3Or SIG' or-NR'(CH2)4Or SIG'. In some embodiments, R5can also be a group-NR'r CH(CH3)R', -NR'r CH(CF3)R', -NR'r CH(CH3)C(O)OR', -NR'r CH(CF3)C(O)OR', -NR'r CH(CH2CH3)R', -NR'r CH2C(O)N(R')2, -NR'r CH(CH3)C(O)N(R')2, -NR'r CH(CF3)C(O)N(R')2, -NR'r CH(CH2CH3)C(O)N(R')2, -NR'r CH(CH(CH3)2C(O)N(R')2, -NR'r CH(C(CH3)3)C(O)N(R')2, -NR'r CH(CH2CH(CH3)2)C(O)N(R')2, -NR'r CH(CH2OR9)C(O)N(R')2or-NR'r CH(CH2CH2N(Me)2)C(O)N(R')2. In some examples of embodiments x is 1, 2 or 3, and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2or-NR'(CH2)2N(R')2. In other embodiments x is 1, 2 or 3, and the least one of R5is-OR'. In other embodiments x is 1, 2 or 3, and at least one of R5represents halogen. In other embodiments x is 1, 2 or 3, and at least one of R5is-NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r CH(CH2OH)R', -NR'r CH(CH2OMe)R', -NR'r CH(CH2Ot)R', -NR'r CH(CH2OCF3)R', -NR'r CH(CH2CH2OH)R', -NR'r CH(CH2CH2OMe)R', -NR'r CH(CH2CH2Ot)R', -NR'r CH(CH2CH2OCF3)R', -NR'r CH(CH3)C(O)or SIG', -NR'r CH(CF3)C(O)OR', -NR'r CH(CH3)C(O)N(R')2, -NR'r CH(CF3)C(O)N(R')2, -NR'r CH(CH2CH3)C(O)N(R')2, -NR'r CH(CH2OH)C(O)N(R')2, -NR'r CH(CH2OMe)C(O)N(R')2, -NR'r CH(CH2Ot)C(O)N(R')2or-NR'r CH(CH2OCF3)C(O)N(R')2where R' represents optionally substituted C1-C4aliphatic group; -NHCH2C(O)other', -NHCH(CH3)C(O)other', -NHCH(CH2CH3)C(O)other', -NHCH(CH(CH3)2)C(O)other', -NHCH(C(CH3)3C(O)other', -NHCH(CH2CH(CH3)2)C(O)other', -NHCH(CH2OH)C(O)other', -NHCH(CH2OMe)C(O)other' or-NHCH(CH2CH2N(Me)2)C(O)other', where R' represents optionally substituted C1-C4aliphatic group; -other', -NH(CH2)R', -NH(CH2)2R', -NHCH(CH3)R', -NHCH2C(O)other', -NHCH(CH3)C(O)other', -NHCH(CH2CH3)C(O)other', -NHCH(CH(CH3)2)C(O)other', -NHCH(C(CH3)3)C(O)other', -NHCH(CH2CH(CH3)2)C(O)other', -NHCH(CH2/sub> OH)C(O)other', -NHCH(CH2OMe)C(O)other' or-NHCH(CH2CH2N(Me)2)C(O)other', where R' represents optionally substituted C1-C4aliphatic group; -NHCH(CH3)R', where R' is optionally substituted phenyl; H, halogen, CH3, CF3, COOH, COOMe or or', where R' represents a C1-C4aliphatic group.

According to other embodiments x is 1, 2 or 3, and at least one of R5represents optionally substituted C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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 other embodiments x is 1 or 2, and each of R5is independently halogen, R', CN, -CH2CN, -(CH2)2CN, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, -COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2 NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -CH2NR'r COR', or -(CH2)2NR'R COR'. In other embodiments, R5represents CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In other embodiments each of R5is independently hydrogen, halogen, CN, -CH2CN, -(CH2)2CN, NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C1-C4-alkyl), -SO2NH2, -SO2N(C1-C4-alkyl), NH2, -N(C1-C4-alkyl), -OH, -O(C1-C4-alkyl), -CH2OH, -CH2O(C1-C4-alkyl), or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen.

As described in General, for compounds of the formulaIabove, R5optionally substituted (R7)ywhere y is 0-5, and R7is =O, =NR, =S, halogen, -CN, -NO2or W-R”, where W represents the tie is or optionally substituted C 1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-,

-NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-,

-NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a 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. In other embodiments y is 0, 1, 2 or 3, and each of R7is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”,

-NR”COR”, -NR”COOR”, -CON(R')2, -SO 2N(R')2, -CONR”(CH2)2N(R')2,

-CONR”(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3'OR”

-O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR”or-NR”(CH2)4'OR”. In some embodiments, R7can also be a group-NR'r CH(CH3)R'. In other embodiments y is 1, 2 or 3, and each of R7is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), -CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the foregoing phenyl, benzyl and C1-C6the alkyl groups is independently and it is certainly replaced by(Oh), and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic. Additional examples R7groups are depicted in table 1.

In other embodiments x is 1, 2 or 3; at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R', or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments R' is hydrogen, C1-C6alkyl, neobyazatel is substituted by 1-3 R 7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from the

where y and R7described in General and in the sections above.

In other embodiments, R' can be the groupxLviiwhere y and R7described in General and in the sections above.

In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from the

where y and R7described in General and in the sections above.

Some additional subgroups of compounds of General formulaIinclude:

I the compounds of formula I-A:

where R1, R2, R3, R4, R5and x, each described in General above and in the subgroups described above and here.

In some of the which embodiments of the compounds of the formula I-A:

and.R1is

i. T-R', where T represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-O-, -S-, -NR'-, -OCO-, -COO-, -SO2- or-CO-, and R' represents hydrogen, C1-C4-alkyl, or optionally substituted 5 - or 6-membered aryl or heteroaryl group, or

ii. -Si(R')3where R' represents hydrogen, C1-C4-alkyl, or optionally substituted 5 - or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur;

b. R2, R3and R4each independently represents hydrogen, R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH2)3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3N(R')2or-O(CH2)4N(R')2; where R2, R3and R4each optionally substituted (R6)zwhere z is equal to 0-5, and R6is =O, =NR, =S, halogen, -CN, -NO2, or Z-R”, where Z represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units of the chain are optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen, or sulfur; and

C. each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2 R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR'(CH2)4(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2)3Or SIG' or-NR'(CH2)4Or SIG', where R5optionally substituted (R7)ywhere y is 0-5, and R7is =O, =NR, =S, halogen, -CN, -NO2or W-R”, where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2-,

-OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated or fully replaced Susanne 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; or two R” taken together with the atom(s)to which they are attached, form a 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.

In other embodiments of the compounds of the formulaI-A:

and.R1represents hydrogen, C1-C4-alkyl, -COR', -SO2R' or-Si(R')3;

b. R2, R3and R4each independently represents Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or optionally substituted group selected from C1-C4-alkyl, C1-C4alkyloxy, 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 completely is using unsaturated bicyclic ring system, having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4OR”;

C. each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2) 3N(R')2, -CONR'(CH2)4(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2)3Or SIG' or-NR'(CH2)4Or SIG', where R5optionally substituted (R7)ywhere y is 0, 1, 2 or 3, and each of R7is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, NR”(CH 2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR”(CH2)4'OR”.

In other embodiments for compounds of formula I-A and subsets described directly above, R1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-toluensulfonyl (Ts), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or triethylsilyl (TES).

In other embodiments of the compounds of the formulaI-Aand subsets described directly above, R2, R3and R4each represents hydrogen. In still other embodiments, one of R2, R3or R4represents hydrogen. In other embodiments two of R2, R3or R4represent hydrogen. In other embodiments, R2and R4both represent hydrogen, and R3represents halogen, CN, NO2or V-R'. In other embodiments, R2and R4both represent hydrogen, and R3is optionally substituted group selected from 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, to the of Sloboda or sulfur. In other embodiments, R2and R4both represent hydrogen, and R3represents an optionally substituted 5 - or 6-membered saturated, partially unsaturated or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R2and R4both represent hydrogen, and R3is optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl or oxadiazolyl. In other embodiments, R3selected from H, Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(R')2, -NO2, -OR', -CON(R')2, -COOR', -OH, -SR', -C(R')2Or SIG', -N(R')COR', -N(R')C(O)OR', -SO2NH2, -SO2N(R')2or optionally substituted group selected from C1-C4-aliphatic group1-C4alkyloxy or=C-C1-C4-aliphatic group. In an additional embodiment, R2and R4both represent hydrogen, and R3selected from the immediately preceding list.

In other embodiments of the compounds of the formulaI-Aand subsets described directly above, R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 1, 2 or 3, and each of R6is n is dependent F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

In some examples of embodiments of the compounds of the formulaI-A,and subsets described directly above, x is 1, 2 or 3, and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2or-NR'(CH2)2N(R')2. In other embodiments x is 1, 2 or 3, and at least one of R5is-OR'. In other embodiments x is 1, 2 or 3, and at least one of R5is-NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'. According to other embodiments x is 1, 2 or 3, and at least one of R5is optional Zam is placed With 1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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 other embodiments of the compounds of the formulaI-Andand subsets described directly above, R5optionally substituted (R7)ywhere y is 1, 2 or 3 and each of R7is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic. In other embodiments of the compounds of the formulaI-And and subsets described directly above, x is 1, 2 or 3; at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 gets is of rotoma, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments x is 1 and compounds have the General formulaI-A-i:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and R5represents-N(R')2, -NR'r CH(CH2OH)R',

-NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R',

-NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially nenas is fastened or fully unsaturated bicyclic ring system, having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents-N(R')2. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

With the according to other embodiments x is equal to 1, and compounds have the General formulaI-A-ii:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and R5represents-N(R')2, -NR'r CH(CH2OH)R',

-NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents-N(R')2. In some embodiments for each of the subgroups described above, R' before the hat hydrogen, With1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2, R3and R4each represents hydrogen, and provided compounds of General formulaI-A-iii:

where x is 1, 2 or 3; and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, long is correctly substituted (R 7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2, R3and R4each is hydrogen and x is equal to 1, and are provided compounds of General formulaI-A-iv:

where R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, Rsup> 2, R3and R4each represents hydrogen, x is equal to 1, and are provided compounds of General formulaI-A-v:

where R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each represents hydrogen, and provided compounds of General formulaI-A-vi:

where R3is optionally substituted group selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially nenas is fastened or fully unsaturated bicyclic ring system, having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; x is 1, 2 or 3; and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments for compounds described directly above, R3represents an optionally substituted 5 - or 6-membered saturated, partially unsaturated or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R3is optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl Il is oxadiazolyl. As described in General above, R3optionally substituted (R6)z. In some embodiments, where z is equal to 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR”(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4'OR”.

According to other embodiments, R1, R2, R3and R4each is hydrogen and x is equal to 1, and are provided compounds of General formulaI-A-vii:

where R3is optionally substituted group selected from a 3-8-membered saturated, partially unsaturated or fully ninasimone the monocyclic ring, having 0-3 heteroatoms selected independently 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; R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments for compounds described directly above, R3represents an optionally substituted 5 - or 6-membered saturated, partially unsaturated or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R3is optionally substituted ring, you the security of phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl or oxadiazolyl. As described in General above, R3optionally substituted (R6)z. In some embodiments, where z is equal to 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4'OR”.

According to other embodiments, R1, R2, R3and R4each is hydrogen and x is equal to 1, and are provided compounds of General formulaI-A-viii:

where R3 is optionally substituted group selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments for compounds described directly above, R3represents an optionally substituted 5 - or 6-membered saturated, partially unsaturated or fully narasiman the ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R3is optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl or oxadiazolyl. As described in General above, R3optionally substituted (R6)z. In some embodiments, z is 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4'OR”.

Some additional subgroup is of soedinenii General formula I include the

II. The compounds of formula I-C:

where R1, R2, R3, R4, R5and x, each described in General above and in the subgroups described above and here.

In some embodiments for compounds of formula I:

A. R1is

i. T-R', where T represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-O-, -S-, -NR'-, -OCO-, -COO-, -SO2- or-CO-, and R' represents hydrogen, C1-C4-alkyl, or optionally substituted 5 - or 6-membered aryl or heteroaryl group, or

ii. -Si(R')3where R' represents hydrogen, C1-C4-alkyl, or optionally substituted 5 - or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur;

b. R2, R3and R4each independently represents hydrogen, R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH2)3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3 N(R')2or-O(CH2)4N(R')2; where R2, R3and R4each optionally substituted (R6)zwhere z is equal to 0-5, and R6is =O, =NR, =S, halogen, -CN, -NO2or Z-R”, where Z represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen the oxygen is a or sulfur; and

C. each of R5is independently hydrogen, halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -CH2NR'r COR', or -(CH2)2NR'r COR', where R5optionally substituted (R7)ywhere y is 0-5, and R7is =O, =NR, =S, halogen, -CN, NO2or W-R”, where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-,

-O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-and each of R” PR is dstanley independently hydrogen or optionally substituted C 1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a 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.

In other embodiments of the compounds of the formulaI-From:

A. R1represents hydrogen, C1-C4-alkyl, -COR', -SO2R' or-Si(R')3;

b. R2, R3and R4each independently represents Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or an optionally substituted group selected from C1-C4-alkyl, C1-C4alkyloxy, 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring, Meuse is about 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; where R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR”(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4OR'; each of R5is independently-CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2 NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R', where R5optionally substituted (R7)ywhere y is 0, 1, 2 or 3, and each of R7is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR”(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR”(CH2)4'OR”.

In other embodiments of the compounds of the formulaI-and subsets described directly above, R1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-toluensulfonyl (Ts), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or triethylsilyl (TES).

In other embodiments of the compounds of the formulaI-and what of thrupp, described directly above, R2, R3and R4each represents hydrogen. In other embodiments, one of R2, R3or R4represents hydrogen. In other embodiments two of R2, R3or R4represent hydrogen. In other embodiments, R2and R4both represent hydrogen, and R3represents halogen, CN, NO2or V-R'. In other embodiments, R2and R4both represent hydrogen, and R3is optionally substituted group selected from 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 other embodiments, R2and R4both represent hydrogen, and R3represents an optionally substituted 5 - or 6-membered saturated, partially unsaturated or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In other embodiments, R2and R4both represent hydrogen, and R3is optionally substituted ring selected from phenyl, pyridyl,pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl or oxadiazolyl.

In other embodiments of the compounds of the formulaI-and subsets described directly above, R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 1, 2 or 3, and each of R6is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

In some examples of embodiments of the compounds of the formulaI-and subsets described directly above, x is 1, 2 or 3, and at least one of R5represents halogen, CN, -CH2CN, -(CH2)2CN, NO2, -CH2NO2, -(CH2)2NO2, -CONH 2, -CON(C1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), NH2, -N(C1-C4alkyl), -OH, -O(C1-C4alkyl), -CH2OH, -CH2O(C1-C4alkyl) or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen. In other embodiments x is 1, 2 or 3 and at least one of R5is-OR'.

In other embodiments of the compounds of the formulaI-and subsets described directly above, R5optionally substituted (R7)ywhere y is 1, 2 or 3 and each of R7is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cilice the transition.

According to other embodiments x is equal to 1, and the compounds have the General formulaI-C-i:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and R5represents halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -CH2NR'r COR', or -(CH2)2NR'r COR', and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring systems which, having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents CN, -CH2SP, -(CH2)2JV-NO2, -CH2NO2, -(CH2)2NO2, OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

According to other embodiments x is equal to 1, and the compounds have the General formulaI-C-ii:

where R1, R23and R4have the meanings described in General above and herein, and R5represents halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -CH2NR'r COR', or -(CH2)2NR'r COR', and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optional the tion substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents CN, -CH2SP, -(CH2)2JV-NO2, -CH2NO2, -(CH2)2NO2, OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

According to other embodiments each of R5is independently-CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. According to other embodiments each of R5is independently hydrogen, halogen, CN, -CH2CN, (CH 2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), -NH2, -N(C1-C4alkyl), -OH, -O(C1-C4alkyl), -CH2OH, -CH2O(C1-C4alkyl) or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen, where R5optionally replaced with 0-3 R7.

According to other embodiments x is equal to 2 and the compounds have the General formulaI-S-iii:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and each of R5is independently halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(C 2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -CH2NR'r COR', or -(CH2)2NR'r COR', and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents CN, -CH2SP, -(CH2)2JV-NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic us is pregnant partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

According to other embodiments each of R5is independently-CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. According to other embodiments each of R5is independently hydrogen, halogen, CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), NH2, -N(C1-C4alkyl), -OH, -O(C1-C4alkyl), -CH2OH, -CH2O(C1-C4alkyl), or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen, and where R5optionally replaced with 0-3 R7.

According to other embodiments, R1, R2, R3and R4each is hydrogen and x is equal to 1, and provide the tsya compounds of the formula I-C-iv:

where R5represents halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -CH2NR'r COR', or -(CH2)2NR'r COR', and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered n is Susanne, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents CN, -CH2SP, -(CH2)2JV-NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

According to other embodiments each of R5is independently-CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. According to other embodiments each of R5is independently hydrogen, halogen, CN, -CH2CN,-(CH 2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), -NH2, -N(C1-C4alkyl), -OH, -O(C1-C4alkyl), -CH2OH, -CH2O(C1-C4alkyl) or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen, and where R5optionally replaced with 0-3 R7.

According to other embodiments, R1, R2, R3and R4each represents hydrogen, x is 1 and compounds have the General formulaI-To-v:

where R5represents halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2) 2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -CH2NR'r COR', or -(CH2)2NR'r COR', and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents CN, -CH2SP, -(CH2)2JV-NO2, -CH2NO2, -(CH2)2NO2, OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated Kohl is about, having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

According to other embodiments each of R5is independently-CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. According to other embodiments each of R5is independently hydrogen, halogen, CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), -NH2, -N(C1-C4alkyl), OH, -O(C1-C4alkyl), -CH2OH, -CH2O(C1-C4alkyl) or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen, and where R5optionally replaced with 0-3 R7.

According to other embodiments, R1, R2, R3and R4each represents hydrogen, x is 2 and the compounds have the General formulaI With vi:

where each of R5is independently halogen, R', CN, -CH2SP, -(CH2)2SP, NO2, -CH2NO2, -(CH2)2NO2, -CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR', -O2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, -NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', -NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2, -CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -CH2NR'r COR', or -(CH2)2NR'r COR', and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially replaced susannae or fully unsaturated monocyclic or bicyclic ring, having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents CN, -CH2SP, -(CH2)2JV-NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii), described above.

According to other embodiments each of R5is independently-CN, -CH2CN, -(CH2)2CN, -NO2, -CH2NO2, -(CH2)2NO2, -OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'. According to other embodiments each of R5is independently hydrogen, halogen, CN, -CH2CN, -(CH2)2CN, NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C 1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), NH2, -N(C1-C4alkyl), -OH, -O(C1-C4alkyl), -CH2OH, -CH2O(C1-C4alkyl) or optionally substituted 5 - or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen, where R5optionally replaced with 0-3 R7.

Typical examples of the compounds of formula I are summarized in table 1.

Table 1

Examples of compounds of the formula I:

Some additional subgroups of compounds of formula I include the

The compounds of formula I-A:

where R1, R2, R3, R4, R5and x each has the values described above.

In some embodiments of the compounds of the formulaI-In:

A. R1is

i. T-R', where T represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-O-, -S-, -NR'-, -OCO-, -COO-, -SO2- or-CO-, and R' represents hydrogen, C1-C4is alkyl or optionally substituted 5 - or 6-members of the ing aryl or heteroaryl group, or

ii. -Si(R')3where R' represents hydrogen, C1-C4is alkyl or optionally substituted 5 - or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur;

b. R2, R3and R4each independently represents hydrogen, R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r C(O)OR', -NR'r COCH2R', -NR'r CO(CH2)2R', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH2)3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3N(R')2or-O(CH2)4N(R')2; where R2, R3and R4each optionally substituted (R6)zwhere z is equal to 0-5, and R6is =O, =NR, =S, halogen, -CN, -NO2or Z-R”, where Z represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-and each of R” p is ecstasy independently hydrogen or optionally substituted C 1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen, or sulfur; and

C. each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR(CH2)4N(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH 2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2)3Or SIG' or-NR'(CH2)4Or SIG', where R5optionally substituted (R7)ywhere y is 0-5, and R7is =O, =NR, =S, halogen, -CN, NO2or W-R', where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially replaced susannae or fully unsaturated monocyclic or bicyclic ring, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In other embodiments of the compounds of the formulaI-B

A. R1represents hydrogen, C1-C4-alkyl, -COR', -SO2R' or-Si(R')3;

b. R2and R4each independently represents Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or an optionally substituted group selected from C1-C4-alkyl, C1-C4alkyloxy, 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; where R2and R4each, independently and optionally substituted (R6)zwhere z is 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR”(CH )3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4OR”;

C. R3is independently Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or an optionally substituted group selected from C1-C4of alkyl, C1-C4alkyloxy, where R3independently and optionally substituted (R6)zwhere z is 0 or 1, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -(CH 2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4OR”;

d. each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2/sub> )3Or SIG' or-NR'(CH2)4Or SIG', where R5optionally substituted (R7)ywhere y is 0, 1, 2 or 3, and each of R7is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR”(CH2)4'OR”.

In other embodiments of the compounds of the formulaI-Band subsets described directly above, R1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-toluensulfonyl (Ts), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or triethylsilyl (TES).

In other embodiments of the compounds of the formulaI-Band subsets described directly above,R 2, R3and R4each represents hydrogen. In still other embodiments, one of R2, R3and R4represents hydrogen. In other embodiments two of R2, R3or R4represent hydrogen. In other embodiments, R2and R4both represent hydrogen, and R3represents halogen, CN, NO2or V-R'. In other embodiments, R2and R4both represent hydrogen, and R3represents halogen. In other embodiments, R2and R4both represent hydrogen, and R3is Cl.

In other embodiments of the compounds of the formulaI-Band subsets described directly above, R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 1, 2 or 3, and each of R6is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and long is Ino substituted and where each of the previous With the 1-C6the alkyl group is a linear, branched or cyclic, provided that R3is not phenyl.

In some examples of embodiments of the compounds of the formulaI-Inand subsets described directly above, x is 1, 2 or 3 and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', -NR'(CH2)N(R')2or-NR'(CH2)2N(R')2. In other embodiments x is 1, 2 or 3 and at least one of R5is-OR'. In other embodiments x is 1, 2 or 3 and at least one of R5is-NR'r COR', -NR'r COCH2R' or CONR”NR'r CO(CH2)2R'. According to other embodiments x is 1, 2 or 3 and at least one of R5represents optionally substituted C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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 other embodiments of the compounds of the formulaI-Inand subsets described directly by you is e, R5optionally substituted (R7)ywhere y is 1, 2 or 3 and each of R7is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

In other embodiments of the compounds of the formulaI-Inand subsets described directly above, x is 1, 2 or 3; at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring, have her 0-3 heteroatoms, selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic the heterocyclic ring. In some embodiments the ring selected from (a)to(o)above,

where y and R7have the meanings described in General and in subgroups above.

According to other embodiments x is 1 and compounds have the General formulaI-To-i:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, KIS is Orada or sulfur, where each R' is optionally substituted (R7)y. In some embodiments, R5represents-N(R')2. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments x is equal to 0 to 3, and compounds have the General formulaI-V-ii:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and each R5independently selected from halogen, optionally substituted C1-C6of alkyl, -SR', -CN, -COOH, -CO2R', -CON(R')2 , -N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5is N(R')2. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or represents 5-to 10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected is independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments x is equal to 1-4 and compounds have the General formulaI-To-iii:

where

R3is optionally substituted group selected from halogen, optionally substituted C1-C6of alkyl, CN, N(R')2, CO2R', NR'r COR', CON(R')2CH2N(R')2, OR', SR', CH2OR';

x is 1, 2 or 3; and at least one of R5selected from halogen, optionally substituted C1-C6aliphatic group, -SR', -CN, -COOH, -CO2R', -CON(R')2, -N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' is selected from hydrogen, C1-C6Alif the political group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each is hydrogen and x is equal to 0 to 3, and are provided compounds of General formulaI-B-iv:

where

R3is optionally substituted group selected from halogen, optionally substituted C1-6aliphatic group, CN, N(R')2, CO2R', NR'r COR', -CON(R')2CH2N(R')2, OR', SR', CH2OR';

R5selected from halogen, optionally substituted C1-C6aliphatic group, -SR', -CN, -COOH, -CO2R', -CON(R')2, -N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' is selected from hydrogen, C1-C6aliphatic group, optionally substituted (R7)yor is the ring, using the data from (i)-(xLvi) or (xLvii), described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each is hydrogen and x is 2, and are provided compounds of General formulaI-To-v:

where R3is optionally substituted group selected from halogen, optionally substituted C1-6aliphatic group, CN, N(R')2, CO2R', NR'r COR', -CON(R')2CH2N(R')2, OR', SR', CH2OR';

R5selected from halogen, optionally substituted C1-C6aliphatic group, -SR', -CN, -COOH, -CO2R', -CON(R')2, -N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' is selected from hydrogen, C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' is Saty together with the nitrogen atom, to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each represents hydrogen, and x is equal to 2, and are provided compounds of General formulaI-V-vi:

where

R3is optionally substituted group selected from halogen, optionally substituted C1-6aliphatic group, CN, N(R')2, CO2R', NR'r COR', -CON(R')2CH2N(R')2, OR', SR', CH2OR';

R5selected from halogen, optionally substituted C1-C6aliphatic group, -SR', -CN, -COOH, -CO2R', -CON(R')2, -N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' is selected from hydrogen, C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered anatilicheskaya or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

Some additional subgroup of compounds of the formulaIinclude

compounds of the formulaI-E:

where R1, R2, R3, R4, R5and x each have the values described above.

In some embodiments of the compounds of the formulaI-E:

A. R1is:

i. T-R', where T represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-O-, -S-, -NR'-, -OCO-, -COO-, -SO2- or-CO - and R' represents hydrogen, C1-C4is alkyl or optionally substituted 5 - or 6-membered aryl or heteroaryl group, or

ii. -Si(R')3where R' represents hydrogen, C1-C4is alkyl or optionally substituted 5 - or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently from nitrogen, oxygen, or sulfur;

b. R2, R3and R4each independently represents hydrogen, R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r C(O)OR', -NR'r COCH2R', -NR'r CO(CH2)2R', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH )3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3N(R')2or-O(CH2)4N(R')2; where R2, R3and R4each optionally substituted (R6)zwhere z is equal to 0-5, and R6is =O, =NR, =S, halogen, -CN, -NO2or Z-R”, where Z represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR”-, -S-, -O-, -CS-, -CO2, -OCO-,

-CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-,

-CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-, -SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a optionally substituted 3-12 member is th rich, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen, or sulfur;

C. each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR'(CH2)4(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2)3Or SIG' or-NR'(CH2)4Or SIG', where R5optionally substituted (R7)ywhere y is 0-5, and R7is =O, =NR, =S, halogen, -CN, NO2or W-R', where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by a group NR”-, -S-,

-O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR”-, -NR”CO-, -NR”CO2-, -SO2NR”-, -NR”SO2-, -CNR”NR”-, -NR”CONR”-, -OCONR”-, -NR”NR”-, -NR”SO2NR”-, -SO-,

-SO2-, -PO-, -PO2- or-POR”-, and each R” is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R” taken together with the atom(s)to which they are attached, form a 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.

In other embodiments of the compounds of the formulaI-E:

A. R1represents hydrogen, C1-C4-alkyl, -COR', -SO2R' or-Si(R')3;

b. R2and R4each independently represents Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO 2NH2, -SO2N(Me)2or an optionally substituted group selected from C1-C4-alkyl, C1-C4alkyloxy, 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; where R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 0, 1, 2 or 3, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR”(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2) 3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4OR”;

C. R3is independently Cl, Br, F, -CN, -COOH, -COOMe, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2Och3, -CONH2, -COOCH3, -OH, -CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or an optionally substituted group selected from C1-C4of alkyl, C1-C4alkyloxy, where R3independently and optionally substituted (R6)zwhere z is 0 or 1, and each of R6is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR”(CH2)3N(R')2, -CONR”(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(H 2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR'(CH2)4OR”;

d. each of R5is independently hydrogen, R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR(CH2)4(R')2, -O(CH2)2Or SIG', -O(CH2)3Or SIG', -O(CH2)4Or SIG', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2Or SIG', -NR'(CH2)3Or SIG' or-NR'(CH2)4Or SIG', where R5optionally substituted (R7)ywhere y is 0, 1, 2 or 3, and each of R7is independently hydrogen, R',- CH2R”, halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR”, -CH2OR”, -SR”, -CH2SR”, -COOR”, -NR”COR”, -NR”COOR”, -CON(R')2, -SO2N(R')2, -CONR”(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR”(CH2)4N(R')2 , -O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR”CH(CH2OH)R”, -NR”CH(CH2CH2OH)R”, -NR”(CH2)R”, -NR”(CH2)2R”, -NR”(CH2)3R”, -NR”(CH2)4R”, -NR”(CH2)N(R')2, -NR”(CH2)2N(R')2, -NR”(CH2)3N(R')2, -NR”(CH2)4N(R')2, -NR”(CH2)OR”, -NR”(CH2)2OR”, -NR”(CH2)3OR” or-NR”(CH2)4'OR”.

In other embodiments of the compounds of the formulaI-Eand subsets described directly above, R1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-toluensulfonyl (Ts), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or triethylsilyl (TES).

In other embodiments of the compounds of the formulaI-Eand subsets described directly above, R2, R3and R4each represents hydrogen. In other embodiments, one of R2, R3or R4represents hydrogen. In other embodiments two of R2, R3or R4represent hydrogen. In other embodiments, R2and R4both represent hydrogen, and R3represents halogen, CN, NO2or V-R'. In other embodiments, R2and R4both represent hydrogen, and R3not only is no halogen. In other embodiments, R2and R4both represent hydrogen, and R3is Cl.

In other embodiments of the compounds of the formulaI-Eand subsets described directly above, R2, R3and R4each, independently and optionally substituted (R6)zwhere z is 1, 2 or 3, and each of R6is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), -CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

In some examples of embodiments of the compounds of the formulaI-Eand subsets described directly above, x is 1, 2 or 3 and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', -NR'(CH2)N(R')2Il is-NR'(CH 2)2N(R')2. In other embodiments x is 1, 2 or 3 and at least one of R5is-OR'. In other embodiments x is 1, 2 or 3 and at least one of R5is-NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'. According to other embodiments x is 1, 2 or 3 and at least one of R5represents optionally substituted C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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 other embodiments of the compounds of the formulaI-Eand subsets described directly above, R5optionally substituted (R7)ywhere y is 1, 2 or 3 and each of R7is independently F, Cl, Br, CN, OH, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), -CH2About(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2, -CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzo is l, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

In other embodiments of the compounds of the formulaI-Eand subsets described directly above, x is 1, 2 or 3; at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic is some ring, having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above,

where y and R7have the meanings described in General and in subgroups above.

According to other embodiments x is 1 and compounds have General formula I-E-i:

where R1, R2, R3and R4have the meanings described in General and in subgroups above and herein, and R5represents-N(R')2, -NR'r CH(CH2OH)', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)y. In some embodiments, R5represents-N(R')2. In some embodiments R' is hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen, Il is sulfur, where the ring is optionally substituted by 1-3 R7. In other embodiments R' is hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each represents hydrogen, and provided compounds of General formulaI-E-ii:

where

R3is optionally substituted group selected from halogen, optionally substituted C1-6of alkyl, CN, N(R')2, CO2R', NR'r COR', -CON(R')2CH2N(R')2, OR', SR', CH2OR';

x is 1, 2 or 3; and at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR2(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor performance is made by the ring, selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each is hydrogen and x is equal to 0 to 3, and are provided compounds of General formulaI-F-iii:

where

R3is optionally substituted group selected from halogen, optionally substituted C1-6of alkyl, CN, N(R')2, CO2R', NR'r COR', -CON(R')2CH2N(R')2, OR', SR', CH2OR';

R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form optionally substituted by the second 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

According to other embodiments, R1, R2and R4each represents hydrogen, and x is equal to 1, and are provided compounds of General formulaI-E-iv:

where

R3is optionally substituted group selected from halogen, optionally substituted C1-6of alkyl, CN, N(R')2, CO2R', NR'r COR', -CON(R')2CH2N(R')2, OR', SR', CH2OR'; R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'r CH2(CH3)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group, optionally substituted (R7)yor is a ring selected from (i)-(xLvi) or (xLvii)described above. In other embodiments, R5represents-N(R')2and two R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In some embodiments the ring selected from (a)to(o)above.

Compounds of the formulaIconfirmed by the examples in table 2 (see end of description). The compounds of table 2 can the set also presents II-xwhere x is the number of the compounds listed in table 2.

4. Application forms compositions and introduction

Pharmaceutically acceptable composition

As described above, the present invention provides compounds that are inhibitors of protein kinases, and thus the present compounds are useful for treating diseases, disorders and conditions, including but not limited to them, a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease or bone disorders. In some embodiments of compounds useful for the treatment of immune responses, such as allergic reactions or hypersensitivity type I or asthma; autoimmune diseases, such as graft rejection, disease graft-versus-host, rheumatoid arthritis, lateral to the lateral amyotrophic sclerosis and multiple sclerosis; neurodegenerative disorders, such as familial or hereditary lateral to the lateral amyotrophic sclerosis (FALS); and solid and hematologic malignancies, such cyclename and lymphoma.

These compounds and pharmaceutical compositions comprising them, are useful for the treatment or prevention of many disorders, including but not limited to them, heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases and viral diseases. The compositions are also useful in methods of preventing cell death and hyperplasia, and, therefore, can be used for treatment or prevention of reperfusion/ischemia in stroke, heart attacks and hypoxia bodies. The compositions are also useful in the prevention caused by thrombin accumulation of platelets. The composition is particularly useful from disorders such as chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocyte leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, but without limitation, ovarian cancer, breast cancer and endometrial cancer), liver disease, including hepatic ischemia, heart disease, such as myocardial infarction and congestive heart failure, pathologic immune the state, including activation of T cells, and neurodegenerative disorders.

Accordingly, according to another aspect of the present invention provides pharmaceutically acceptable compositions, these compositions comprise any of the compounds described in the description, and optionally include a pharmaceutically acceptable carrier, adjuvant or excipient. In some embodiments these compositions optionally further include one or more additional therapeutic agents.

Obviously it is also clear that some of the compounds of the present invention can exist in free form for treatment, or when it corresponds, in the form of its pharmaceutically acceptable derivative. According to the present invention pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which, after administration to a patient in need this, is able to give, directly or indirectly, a compound as described in the description otherwise, or its metabolite or residue.

Used in the description, the term “pharmaceutically acceptable salt” refers to those salts which are, within the limits of sound medical judgment, suitable for use in contact with the tissue, the s of humans and lower animals without undue toxicity, irritation, allergic response and similar, and are commensurate with a reasonable ratio of benefit/risk. “Pharmaceutically acceptable salt” means any non-toxic salt or salt of ester compounds of the present invention, which after administration to the recipient is able to give, either directly or indirectly, a compound of this invention or inhibitore active metabolite or residue. Used in the description of the term “inhibitore active metabolite or residue” means that a metabolite or residue it is also an inhibitor of JAK-3, ROCK and Aurora.

Pharmaceutically acceptable salts are known in the art. For example, S.M. Berge et al. describe in detail pharmaceutically acceptable salt publishing inJ. Pharmaceutical Sciences, 1977,66, 1-19, included in this description by reference. Pharmaceutically acceptable salts of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic additive salts of acids are salts of an amino group formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, Perlina acid, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or milonov the I acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, camphorato, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, econsultancy, formiate, fumaric, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonic, lactobionate, lactate, laurato, laurilsulfate, malatoy, maleato, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, realnuu, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate salt and similar. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal, ammonium and N+(C1-4alkyl)4the salt. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds described in the description. This quaternization can the be water - or oil-soluble or dispersible products. Typical representatives of the alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium and similar. Additional pharmaceutically acceptable salts may include salts of non-toxic ammonium, cybertechnologies and amine cations 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 include a pharmaceutically acceptable carrier, adjuvant or excipient, which includes any and all solvents, diluents, or other liquid filling, dispersion or suspension AIDS, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents and similar, which are suitable for a particular desired dosage forms. In Remington's Pharmaceutical Sciences, Sixteentg Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formation of pharmaceutically acceptable compositions and known techniques for their manufacture. In the scope of the present invention assumes the use of any conventional carrier medium except when wearing the l is incompatible with the compounds of the invention therefore, it turns out that any undesirable biological effect or otherwise harmful interference with any other component(s) of the pharmaceutically acceptable composition. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum 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 preteenslut, sour centripetal, sour califora, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block 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 oil; sesame oil; olive oil; corn oil and soybean oil; glycols, t is 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 saline; ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate and, optionally, the composition may also be present coloring agents, releasing agents, covering agents, sweeteners, taste and flavouring agents, preservatives and antioxidants.

The use of compounds and pharmaceutically acceptable compositions

In another aspect is provided a method of treating or reducing the severity of proliferative disorders, heart disease, neurodegenerative diseases, mental diseases, autoimmune diseases, conditions associated with organ transplantation, inflamatory diseases, immunologically-mediated diseases, viral diseases or diseases of the bones, including the appointment of an effective amount of a compound or pharmaceutically acceptable composition comprising the compound, to a subject in need of it. In some embodiments of the present invention, the term “effective amount” of a compound or pharmaceutically acceptable composition means h is about the amount is effective to treat or reduce the severity of proliferative disorders, heart disease, neurodegenerative diseases, mental diseases, autoimmune diseases, conditions associated with organ transplantation, inflamatory diseases, immunologically-mediated diseases, viral diseases or diseases of the bone.

In other aspects the invention provides a method of treating or reducing the severity of many different disorders, including but not limited to them, heart disease, diabetes, Alzheimer's disease, immunodeficiency, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases and viral diseases. In other aspects, the invention encompasses methods of preventing cell death and hyperplasia and therefore can be used for treatment or prevention of reperfusion/ischemia in stroke, heart attacks and hypoxia bodies. According to other embodiments the invention provides methods of preventing induced by thrombin accumulation of platelets. The invention also provides methods of treating, reducing the severity or prevention of disorders such as chronic myelogenous leukemia (CML), acute myeloid leukem is I (AML), acute promyelocyte leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer (including, without limitation, ovarian cancer, breast cancer and endometrial cancer), liver disease, including hepatic ischemia, heart disease, such as myocardial infarction and congestive heart failure, pathologic immune conditions, including activation of T cells, and neurodegenerative disorders.

Compounds and compositions in accordance with the method of the present invention may be administered using any amount and any route of administration effective for treating or reducing the severity of proliferative disorders, cardiac disorders, neurodegenerative disorders, autoimmune disorders, conditions associated with organ transplantation, inflammatory disorder, an immunologically mediated disorder, a viral disease or bone disorders. The exact quantity required will vary from subject to subject, depending on the species, age and General condition of the subject, the severity of the infection, the particular agent, its method of administration and similar factors. Compounds of the invention preferably are formulated or are in the form of dosage units for ease of administration and uniformity of dosage. The expression “dosage form unit, and is used in the description, refers to a physically discrete unit of agent required to receive the patient. Obviously it is clear, however, that the total daily usage of the compounds and compositions of the present invention is determined by the attending physician taking into account the known judgments and opinions of physicians. The specific effective dose for any particular patient or organism will depend on many factors, including the nature of the disorder being treated and the severity of the disorder; activity of the specific applied compounds; specifically applied 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 specifically applied composition; the duration of the treatment; drugs used in combination or simultaneously with specifically used by the connection, and similar factors well known in medicine. The term “patient”used in the description means an animal, preferably a mammal and most preferably a human.

Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, nutrizionale, intrawaginalno, administered intraperitoneally, by topical (as, for example, in the form of powders, ointments or drops), beech is real or cheek, in the form of an oral or nasal spray, or similar, depending on the severity of the exposed treatment of infection. In some embodiments of the compounds of the invention can be administered orally or parenterally at dosages from about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to 25 mg/kg body weight of the subject per day, one or more times per day to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in this field, 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, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, glycols and sorbitane esters of fatty acids, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agent is, emulsifying and suspendresume agents, sweeteners, flavoring and aromatic agents.

Injectable preparations, for example sterile injectable aqueous or oily suspensions may be formulated in accordance with known techniques using suitable dispersing or wetting agents and suspendida agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Among the acceptable fillers and solvents that can be used include water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition to the above, as a solvent or suspendida environment common apply sterile fixed oils. For this purpose, can be applied to any mixed fixed oils, including synthetic mono - or diglycerides. In addition, in the manufacture of injectable drugs used fatty acids such as oleic acid.

Injectable forms of the compositions can be sterilized, for example, by filtration through inhibiting bacteria filters, or by incorporating sterilizing agents in the form of sterile solid to the position, which can dissolve or dispergirujutsja in sterile water or other sterile injectable medium prior to use.

In order 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 by using a liquid suspension of crystalline or amorphous material with poor water solubility. The degree of absorption of connection depends then on its degree of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the input parenteral form of connection is achieved by dissolution or suspension of the compounds in the oil filler. Injectable forms of stored for storage, is manufactured by forming microencapsule matrix compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compounds and polymers and character specifically applied polymer can adjust the rate of release of connection. Examples of other biodegradable polymers include poly(complex orthoevra) and poly(anhydrides). Stored injectable forms are obtained by trapping compounds liposomes or micromoles is s, which are compatible with body tissues.

Compositions for rectal or vaginal injection are preferably suppositories, which can be prepared by mixing the compounds of the invention with suitable not cause irritation with excipients 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 for oral administration include capsules, tablets, pills, powders or pills. 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 extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and the Arabian gum, (c) humectants, such as glycerol, d) dezinfeciruyuhimi agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) is derivagem dissolving agents, 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 compounds, preventing clay, and i) lubricants or promote flowability agents 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 include buferiruemoi agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and similar. Solid dosage forms of tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as enterococci coatings and other coatings well known in the preparation of pharmaceutical forms. They may not necessarily contain agents that make the material opaque, and may also be of a composition that they release only the active ingredient(s), or preferentially, in a certain part of the intestinal tract, optionally, the slow way. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as polyethylene glycols of high molecular weight and similar.

Active compounds may also be presented in microencapsulating form with one or more excipients mentioned above. Solid dosage forms of tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as enterococci cover, cover, regulating the release, and other coatings well known in the manufacture of finished pharmaceutical forms. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include, as is customary in normal practice, additional substances other than inert diluents, for example tabletiruemye lubricating agents and other tabletiruemye AIDS such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills dosage forms may also include buferiruemoi agents. They can optional is about to contain agents making the opaque material, and may also be of a composition that they release only the active ingredient(s), or preferentially, in a certain part of the intestinal tract, optionally, the slow way. Examples of embedding compositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal injection of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants drugs or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, if it may be required. The scope of the present invention are also covered ophthalmic form of ear drops and eye drops. In addition to described the present invention also provides the use of transdermal patches, which have the additional advantage of providing a controlled or controlled delivery of compounds to the body. Such dosage forms can be manufactured by dissolving or dispersing the compound in an appropriate environment. To increase the passage of compounds through the skin can also be used amplifiers absorption. The speed can be adjusted, or by providing member the us, regulating speed, or dispersing the compound in a polymer matrix or gel.

As described in General above, the compounds of the invention are useful as inhibitors of protein kinases. According to one embodiment of the compounds and compositions of the invention are inhibitors of one or more JAK-3, ROCK and Aurora isoforms, and thus, without wishing to be bound by any particular theory, it should be noted that the compounds and compositions are particularly useful for treating or reducing the severity of the disease, condition or disorder, when in the disease, condition or disorder involved the activation of JAK-3, ROCK or Aurora. When any particular disease, condition or disorder implicated in the activation of JAK-3, ROCK or Aurora, the disease, condition, or disorder may also be called “JAK-3-mediated disease“, “ROCK-mediated disease“, “Aurora-mediated disease or symptom of the disease. Accordingly, according to another aspect of the present invention provides a method of treating or reducing the severity of the disease, condition or disorder, when the disease is implicated in the activation of one or more JAK-3, ROCK or Aurora isoforms.

The potency of the compound used in this invention as an inhibitor of JAK-3, ROCK or Aurora, can be analyzed in vitro, i vivo or in cell lines. The in vitro tests include tests which help determine the inhibition or activity, phosphorylation or activity of Atraz activated JAK-3, ROCK or Aurora. Alternate in vitro assays to determine quantitatively the ability of the inhibitor to bind JAK-3, ROCK or Aurora. The binding of the inhibitor can be measured by radiolabelling the inhibitor prior to binding, isolating the complex of the inhibitor/JAK-3 inhibitor/ROCK or inhibitor/Aurora and quantification of the associated RFID tags. Alternative binding of the inhibitor can be determined by conducting a competitive experiment, in which JAK-3, ROCK or Aurora associated with famous radio new inhibitors are incubated.

The term “inhibits measurable”used in the description refers to a measurable change in the activity of JAK-3, ROCK or Aurora between the design including the specified composition and JAK-3, ROCK or Aurora kinase and an equivalent sample comprising JAK-3, ROCK or Aurora kinase in the absence of a specified composition.

The term “JAK-mediated disease“, as used in the description, means any disease or other detrimental condition, which is known, that plays the role of a kinase of the JAK family. Such a condition includes, without limitation, immune responses, such as allergic reactions or hypersensitivity type I, asthma, AU is omanye disease, such as graft rejection, disease graft-versus-host, rheumatoid arthritis, lateral to the lateral amyotrophic sclerosis and multiple sclerosis, neurodegenerative disorders, such as family lateral to the lateral amyotrophic sclerosis (FALS), as well as solid and hematological malignant diseases such as leukemia and lymphoma.

The term “ROCK-mediated condition“ or “disease”, as used in the description, means any disease or other detrimental condition, which is known that it plays the role of a ROCK. The term “ROCK-mediated condition“ or “disease”, as used in the description, also means those diseases or conditions that are alleviated or mitigated by treatment with ROCK inhibitor. Such conditions include, without limitation, hypertension, breast toad, cerebrovascular insufficiency, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, atherosclerosis, spasm (spasm of cerebral vessels and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disease, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced damage and endothelial dysfunction.

The term “Aurora-mediated condition“ or “dis is evanie”, used in the description, means any disease or other detrimental condition, which is known that it plays the role of Aurora. The term “Aurora-mediated condition“ or “disease”, as used in the description, also means those diseases or conditions that are alleviated or mitigated through treatment Aurora a inhibitor. Such conditions include, without limitation, immune responses, such as allergic reactions or hypersensitivity type I, asthma, autoimmune diseases such as transplant rejection, disease graft-versus-host, rheumatoid arthritis, lateral to the lateral amyotrophic sclerosis and diffuse sclerosis, neurodegenerative disorders, such as family lateral to the lateral amyotrophic sclerosis (FALS), as well as solid and hematological malignant diseases such as leukemia and lymphoma.

Obviously, it is also clear that the compounds and pharmaceutically acceptable compositions of the present invention can be used in joint therapy, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or after administration of one or more other desired therapeutics or medical procedures. When a particular combination of therapies (therapeutic agents or procedures is) for use in Raman mode is taken into account compatibility of the desired therapeutics and/or procedures and achieve the desired therapeutic effect. Obviously it is also clear that the applied therapies can achieve the desired effect in respect of the same disease (e.g., the compounds of the invention can be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (for example, to restrain any harmful effects). Used in the description of the additional therapeutic agents, which typically are administered to treat or prevent a specific disease or condition, known as “relevant subjected to treatment of the disease or condition”.

Examples of agents that may be combined inhibitors of this invention include, without limitation funds from Alzheimer's disease such as Aricept® and Excelon®; funds from 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; funds from asthma such as albuterol and Singulair®; agents for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazin; immunomodulatory and IMM is nosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazin; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsive agents, blockers of ion channels, riluzole, and protivovarikoznye agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for treating blood disorders such as corticosteroids, antileykemichesky 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 is not more than the amount that is usually introduced to the composition that include therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent described in the present description, the compositions is in the range from about 50% to 100% of the amount normally present in a composition comprising the agent as edinstvennoj therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions based on them can also be included in compositions for coating implantable medical devices or devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention in accordance with another aspect encompasses a composition for coating an implantable device that includes in its composition a compound of the present invention, described in General above and in classes and subclasses disclosed in the description, and a carrier suitable for coating of specified implanted device. According to another aspect of the present invention provides an implantable device, the coating composition comprising the compound of the present invention described above and in classes and subclasses in the present description, and a carrier suitable for coating of specified implanted device.

Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the blood vessels after injury). However, patients using stents or other implantable devices, run the risk of clots or platelet activation. Data adverse effects can be prevented or soften the pre-coating device pharmaceutically acceptable composition, including the kinase inhibitor. Suitable coatings and the General method of manufacture of coated implantable devices are disclosed in U.S. patents 6099562, 5886026 and 5304121. Coatings are typically biocompatible polymeric materials, such as hydrogenii polymer polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. These coatings can optionally additionally be covered with a suitable top coating Versiliana, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart to the composition characteristics of the controlled release.

Another aspect of the invention relates to a method for inhibiting the activity of JAK-3, ROCK or Aurora in a biological sample or in a patient, which comprises administration to the patient, or contacting the specified biological sample with a compound of formula I or a composition comprising the specified connection. The term “biological sample”, as used in the description, include, without limitation, cell cultures or extracts; biological material obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

Inhibition of the activity of JAK-3, ROCK or Aurora kinase in a biological sample is useful for a variety of purposes, kotoreishvili specialists in this field. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological samples and biological tests.

EXAMPLES

Although certain exemplary embodiments are described in detail below, it is clear that additional compounds of General formula I can be obtained in accordance with the standard methods described in the description, using the appropriate starting materials by methods generally available to the experts in this field of technology.

Scheme 1

3-Bromo-1H-pyrrolo[2,3-b]pyridine (2)

Azaindole1(4 g of 0.025 mol) in 100 ml of chloroform was cooled to 0°C. was added dropwise a solution of bromine in 20 ml of chloroform, the mixture was stirred at 0°C for 1 hour. The obtained suspension was diluted to 0,5N HCl, and the aqueous layer was podslushivaet with 0,5N NaOH, and the solid was filtered off, yielding 4 g (82%) of the crude product2,which was used directly for the next stage.

3-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (3)

A solution of 3 g (0.015 mol) of the product2in 20 ml of anhydrous THF was cooled to -78°C. and dropwise added a solution of n-BuLi 2.5 M in hexane (6,7 ml, 0,167 mol). After 15 minutes of stirring was added dropwise a solution of tosylchloramide in 5 ml of THF. Cooling Benaudalla, and the reaction mixture stirred at room temperature for 1 hour. The mixture was extracted by a simple ether, and the organic phase was washed with saline, dried with magnesium sulfate and concentrated in vacuo, giving a white solid which was passed through a layer of silica (70% EtOAc; 30% hexane), giving the 4.65 g (84%) of product3.

1H NMR CDCl3a 8.4 (c, 1H). of 8.1 (d, 2H), and 7.8 (s, 2H), 7,2 (m, 3H), 2,3 (s, 3H).

3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (4)

The product3(850 mg, 0,0024 mol) was dissolved in 20 ml of DME, and added pinacolborane (921 mg, 0,0036 mol), Pd2Cl2(dppf)2(197 mg, 0.24 mmol) and Kaas (713 mg, 0,00726 mol)and the mixture stirred and heated under reflux at 90°C for 18 hours. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc/80% hexane), giving 900 mg (99%) of the desired product4.

3-(2-Methylsulfonylamino-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (5)

The complex mixture broowaha ether4(900 mg, 0,0023 mol), 4-chloro-2-dimethylpyrimidine (341 mg, 0,0029 mol), Pd(Ph3P)4(260 mg, 0.23 mmol) and 2 M sodium carbonate (3.4 ml, 0,0068 mol) in 20 ml of DE was heated under reflux in nitrogen atmosphere for 18 hours. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexane)to give 460 mg (51%) of the desired product5.

1H NMR CDCl3of 8.8 (d, 1H), 8,7 (m, 2H), and 8.4 (s, 1H)and 8.1 (d, 2H), 7,2 (m, 4H), and 2.6 (s, 3H), 2,3 (s, 3H).

3-(2-Methanesulfonamido-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (6)

The pyrimidine5(460 mg, 0,0012 mol) was dissolved in 20 ml of a mixture of methanol-water (1:1)was then added Oxon (2.14 g, 0,0035 mol)and the reaction mixture was heated under reflux for 18 hours. The methanol was removed in vacuum and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexane), giving 160 mg (32%) of the desired product6.

LCMS ES+= 428,9.

Benzyl-[4-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine (7)

A solution of the product6(20 mg, 0,047 mmol) and benzylamine (0,007 ml, 0.061 mmol) in 1 ml of ethanol was heated in a sealed tube at 80°C for 18 hours. The solvent was evaporated, and the crude product was purified using preparative thin-layer chromatography (TLC) (50% EtOAc/50% hexane)to give 20 mg of product, which which was filmed protection using 2 ml of 3N NaOH in methanol for 4 hours. Was added 2 ml of 3N HCl, and the mixture was evaporated to dryness. HPLC (high performance liquid chromatography or LC high pressure) with reversed phase (20-70% MeCN-water with 0.1% TFA (20 ml/min) gave 10 mg (75%) of the product7.

1H NMR DMSO-D6of 8.7 (s, 1H), and 8.4 (s, 1H), of 8.25 (d, 1H)and 8.1 (d, 1H), and 7.4 (m, 2H), 7,25 (m, 3H), 7,2 (s, 1H), 7,15 (DD, 1H), and 7.1 (s, 1H), and 4.8 (s, 2H). LCMS ES+= 302,0.

3-(6-Chloropyrimidine-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (8)

The solution boronate4(0.11 g, 0.276 mmol), 4,6-dichloropyrimidine (0,049 g, 0,331 mmol), catalyst Pd(PPh3)4and excess potassium carbonate in DMF was heated in a microwave oven at 160°C for 5 minutes, resulting in a transformation into a product according to TLC (20% EtOAc:hexane). The reaction mixture was distributed between EtOAc/N2Oh, were extracted, atarivalis in vacuo and purified using silica column (eluent: 5% EtOAc:hexane), giving the product8(0.035 g) as a white solid with a yield of 33%.

1-{4-[6-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-4-yl]-[1,4]diazepan-1-yl}Etalon (9)

A solution of the product8(0.035 g, 0,091 mmol), N-acetylhomocysteine (0.025 g, 0,181 mmol), excess potassium carbonate in DMF was heated at 80°C, resulting in a color change after 5 minutes. After 15 minutes the analysis LC/MS and TLC showed conversion into toilsomely product. To the reaction mixture were added 1 ml of 6N NaOH and 1 ml of the of ethanol, this will result in the immediate removal of toiley groups according to LC/MS (M+1=337). The reaction mixture was distributed between EtOAc/N2O and was extracted. The crude product was purified using preparative HPLC, giving the product9(0,022 g) as a clear oil with a yield of 73%.

NMR: MeOD 2,0 users(2H), 2,1 s(3H), 3.6 m(2H), 3,8-4,3 users(6H), 7,1 d(1H), 7.3 m(1H), 8.2(1H), 8,35 m(2H), 8,65 d(1H). LC/MS(M+1)=337

Benzyl-(2-chloropyrimidine-4-yl)amine (10)

To a solution of 2,4-dichloropyrimidine (0.15 g, 1.0 mmol), benzylamine (0,109 ml, 1.0 mmol) in THF was added (0,526 ml, 3.0 mmol) DIPEA and the reaction mixture was heated at the boiling point under reflux for 2 hours, resulting in the formation of a 4:1 mixture of regioisomers (desirable vs. undesirable) using TLC (thin layer chromatography) (5% methanol:methylene chloride). The reaction mixture was atarivalis in vacuo and purified using silica column (eluent: 2% methanol:methylene chloride), yielding 0.12 g (0,548 mmol) of the desired product10with the release of 54%.

LC/MS (M+1)=220

Benzyl-(6-chloropyrimidine-4-yl)amine (12)

Benzylamine (0,697 ml, 6,76 mmol) was added to 4,6-dichloropyrimidine (1.0 g, 6,76 mmol), causing a violent reaction and color change. The reaction mixture was slowly diluted with methylene chloride, resulting in a white precipitate fell out. Was added 1 ml of triethylamine, and TLC showed conversion to product is (5% Meon:methylene chloride). The reaction mixture was placed directly onto silica and purified (eluent:2% Meon:methylene chloride), giving 1,17 g (5,32 mmol) of the product12in the form of a yellow wax with the release of 79%.

Benzyl-[2-(1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-4-yl]amine (11)

Solution4(0.36 g, 0.09 mmol),10(0,028 g to 0.108 mmol), 2.0m Na2CO3(to 0.108 ml, 0,271 mmol) and catalyst PdCl2(PPh3)2in 1 ml of DMSO was heated in a microwave oven at 160°C for 5 minutes, resulting in a transformation into toilsomely product according to LC/MS (M+1)=456. To the reaction mixture was added NaOtBu (0,026 g, 0,271 mmol)and the mixture was heated in a microwave oven for 5 minutes at 160°C, resulting in a complete transformation in the product11. The reaction mixture was filtered and purified using preparative HPLC, giving 0,0032 g11in the form of a white solid with a yield of 11%.

NMR: MeOD 4,95 users(2H), 6.6(1H), 7.2 m(1H), 7.3 to 7.5 mm(5H), 8.0(1H), 8.3-d(1H), and 8.4(1H), 8,55 d(1H). LC/MS(M+1)= 302

The final product13was formed as described for11giving 0,012 g (0,039 mmol)13in the form of a white solid.

NMR: MeOD 4,8(2H), 7,05(1H), 7,2-7,6 m(6H), and 8.2(1H), 8.4 m(2H), 8,55(1H). LC/MS(M+1)=302

Scheme 2. The synthesis of analogs of 5-N-azaindolizines and pyridine

3-(2-Chloropyridin-4-yl)-1-(toluene-4-sulfonyl)-(1H-pyrrolo[2,3-b]pyridine (14)

A mixture of azaindole3/b> (80 mg, 0.23 mmol), 2-chloropyridin-4-Bronevoy acid (41 mg, 0.27 mmol), Pd(Ph3P)4(20 mg, 0.11 mmol) and 2M sodium carbonate (0,34 ml of 0.68 mmol) in 2 ml DME was heated in a microwave oven at 160°C in nitrogen atmosphere for 15 minutes. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine, then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexane), yielding 60 mg (68%) of the desired product14.

1H NMR CDCl3to 8.6 (d, 2H), 8,1 (m, 4H), 7,25 (m, 5H), and 2.5 (s, 3H).

2-Chloropyridin could be replaced, for example, benzylamino in the reaction under the influence of microwaves at 250°C for 30 minutes followed by removal of protection, by providing the connection15.

1-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)alanon (16)

7-Azaindole13(2.16 g, to 0.011 mol) was dissolved in 75 ml of dry DCM. To the solution was added aluminum trichloride (4,36 g, 0,0327 mol) and the reaction mixture is stirred for 1 hour at room temperature. To the mixture was added dropwise acetylchloride (1,16 ml, 0,0164 mol) and the mixture stirred at room temperature for 18 hours. Was added 20 ml of methanol, and the reaction continued for 1 hour. The mixture was concentrated in vacuum and suspendibility in water-EtOAc. The organic phase was extracted EtOAc and dried, after giving conc the simulation in vacuum 2.37 g (91%) of compound 14.

1H NMR CDCl39,5 (users, 1H), and 8.8 (s, 1H), 8,5 (s, 1H), and 7.9 (s, 1H), and 2.4 (s, 3H).

1-(5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-3-dimethylaminopropane (17)

To a suspension of NaH (263 mg, 0,0104 mol) in dry THF at 0°C was slowly added to a compound16(2.37 g, 0.01 mol) in THF. All were mixed at 0°C for 15 minutes, then was added p-toluensulfonate of 2.27 g, 0.012 mol) in THF, and the reaction mixture stirred for 18 hours at room temperature.The reaction was slaked with water and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo, giving 3,37 g of the solid residue, which was used directly in the next stage. The above intermediate compound was mixed with DMF-DMA (5.7 ml, 0,0428 mol) and was heated at 100°C for 22 hours. Was concentrated in vacuo and subjected to flash chromatography (60% EtOAc/40% hexane), giving 3,37 g (76% of the17) of the desired product15.

1H NMR CDCl3of 8.8 (s, 1H), and 8.3 (s, 1H)and 8.1 (s, 1H), with 8.05 (d, 2H), and 7.8 (d, 1H), 7,2 (s, 2H), 5,7 (d, 1H), 3,0 (users, 6H), 2,2 (s, 3H).

6-(5-Bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-1H-pyrimidine-2-tion (18)

To a freshly prepared solution of sodium (175 mg, 0,0076 mol) in ethanol (18 ml) was sequentially added compound17(1.0 g, 0,0022 mol) and thiourea (187 mg, 0,0025 mol). The mixture was heated to boiling point with bratim refrigerator for 4 hours. The solvent was removed and the residue was dissolved in 8 ml of water. The solution was kind of balanced out 1N HCl and was extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo, yielding 570 mg (75%) of technically pure product18.

1H NMR CDCl312,2 (s, 1H), and 8.6 (s, 1H), and 8.3 (s, 1H), and 8.2 (s, 1H), and 7.6 (d, 1H), and 5.8 (d, 1H).

5-Bromo-3-(2-methylsulfonylamino-4-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (19)

Suspension18(565 mg, 0,0018 mol), sodium acetate (526 mg, to 0.0039 mol), methyliodide (0,126 ml, 0,0020 mol) in 15 ml of ethanol-THF (9:1) was heated to boiling point under reflux for 2 hours. Was cooled to room temperature and filtered. Chromatography (70% EtOAc-30% hexane) gave 48 mg (9%) intermediate compounds thiomethyl. Totalrevenue gave 49 mg (70%) of the desired compound19.

1H NMR CDCl3of 8.8 (d, 1H), 8,5 (m, 2H), 8,35 (s, 1H)and 8.1 (d, 2H), 7,25 (m, 3H), and 2.7 (s, 3H), 2,3 (s, 3H).

Benzyl-[4-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)pyrimidine-2-yl]amine (20)

This compound can be obtained from the product19using oxidation Oksana and substitution benzylamine following scheme 1.

Scheme 3. The synthesis of analogs

5-substituted-azaindolizines and pyridine

5-Bromo-1-(tert-butyldimethylsilyl)-1H-pyrrolo[2,3-b]pyridine (19)

To a suspension of NaH (200 mg, 0,0078 mol) in 15 m of the dry DMF at 0°C was added azaindole 13(1,36 g to 0.007 mol) in 5 ml of DMF. All were mixed at 0°C for 10 minutes and was added TBDMSCl in 3 ml of DMF, and the resulting mixture stirred overnight. The mixture was taken into EtOAc and washed with water and brine. The organic layer was dried and concentrated in vacuo to an oil which was used directly for the next stage without additional purification.

1H NMR CDCl3of 8.3 (d, 1H), 7,9 (d, 1H), 7,2 (d, 1H), 6,4 (d, 1H), 0,85 (C, (H), 0,5 (s, 6H).

1-(tert-Butyldimethylsilyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (20)

To a solution of the product19(1.77 g, 0,0057 mol), 3-diarylpyrimidine (1.0 g, 0,0068 mol) in 80 ml of DME under nitrogen atmosphere was added PdCl2(Ph3P)2(320 mg, 0,455 mmol) and 2M aqueous sodium carbonate (8.5 ml of 0.017 mol). The reaction mixture was heated under reflux for 3 hours. Was cooled to room temperature and was diluted with ethyl acetate and washed with saline. The organic layer was dried and concentrated to an oil, which was subjected to flash chromatography (30% EtOAc-70% hexane), giving 1 g (57%) of the desired substance20.

1H NMR CDCl3the 8.9 (s, 1H), and 8.5 (d, 1H), and 8.4 (d, 1H), 8.0 a (d, 1H), 7,9 (d, 1H), 7.5 (d, 1H), 7,2 (d, 1H), 6,5 (d, 1H), of 0.85 (s, 9H), 0.55 and (s, 6H).

3-Bromo-1-(tert-butyldimethylsilyl)-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (21)

Bromide solution (0,166 ml, 0,0032 mol) in 1 ml of CCl dropwise added to a mixed solution20(1.0 g, 0,0032 mol) and pyridine (0,314 ml, to 0.0039 mol) in dry CHCl3(30 ml) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour and then was kind of balanced out 10 ml of a mixture of sodium bicarbonate-sodium thiosulfate (1:1). The organic layer was separated and further extracted with dichloromethane (3×10 ml), the combined organic substances were dried and concentrated in vacuum. The residue was subjected to flash chromatography (30% EtOAc-70% hexane)to give 0.97 g (78%) of the desired material21.

1H NMR CDCl3the 8.9 (s, 1H), 8,55 (d, 1H), and 8.4 (d, 1H), 8.0 a (d, 1H), 7,9 (d, 1H), and 7.4 (DD, 1H), 7,2 (s, 1H), and 0.9 (s, 9H), 0,5 (s, 6H).

5-Pyridin-3-yl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (22)

Connection21you can decelerate, for example, 10% HCl and tiliroside, for example, NaH and n-toluensulfonate. Connection22can be obtained using the same method as for compound4in the scheme 1.

3-(2-methanesulfonyl-pyrimidine-4-yl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (24)

Connection24can be obtained using the same method as for compound6in the scheme 1.

3-(6-chloropyrimidine-4-yl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (25)

Connection25can be obtained using the receiving of the same way, as for the connection8in the scheme 1.

3-(2-chloropyrimidine-4-yl)-5-pyridin-3-yl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (26)

Connection26can be obtained using the same method as for compound14in diagram 2.

Scheme 4

2-Methoxy-4-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]benzonitrile (29)

In the test tube was placed baronova acid28(35.4 mg, 200 µmol), toilsomely azaindole3(65,5 mg, 194 μmol) sodium carbonate (61,8 mg, 583 mmol) and tetrakis(triphenylphosphine)palladium(0) (8,3 mg, 7.2 μmol). Thereto, water was added (323 mg) and etilenglikolevye ether (848 mg)and the mixture was desoxyribonuclease. The test tube was germetizirovany and was heated up to 160°C for 10 minutes with stirring with a magnetic stirrer, using microwave radiation. The crude product was extracted with ethyl acetate and water. The organic layers were washed with saline, dried over sodium sulfate, filtered and concentrated, yielding the crude product (83 mg). The crude product was purified using flash chromatography and was elyuirovaniya gradient from 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7N ammonia in methanol, giving29(42 mg, 54%) and30(7.7 mg, 15%).

2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridine-3-yl]benzonitrile (30

Toilsomely group was removed from the product29by heating under reflux in dioxane (5 ml) with 1N sodium hydroxide (200 μl, 2 EQ.) over 4.5 hours. The reaction mixture was concentrated and extracted with ethyl acetate and saturated aqueous sodium bicarbonate. Organic substances were washed with saline, dried over sodium sulfate, filtered and concentrated, giving the product30(30 mg, 100%).

1H NMR CD3CN 10,00 (s, 1H), 8,32 (m, 2H), 7,83 (s, 1H), 7,65 (d, 1H), 7,40 (m, 2H), 7,20 (DD, 1H), was 4.02 (s, 3H), LC/MS(M+1)=250

2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridine-3-yl)benzamide (31)

Nitrile30(10 mg, 40 μmol) was dissolved in dimethyl sulfoxide (0.5 ml). To the mixture was added potassium carbonate (20 mg) and 30% hydrogen peroxide solution in water (100 μl). The reaction mixture was heated to approximately 60°C for 15 minutes. The reaction mixture was concentrated to dryness and were pulverized in water. The resulting precipitate was filtered and dried in vacuum overnight, giving the product31(10 mg, 93%).

1H NMR DMSO-d6 11,99 (s, 1H), 8,32 (d, 1H), 8,24 (m, 1H), 8,01 (m, 1H), 7,88 (d, 1H), to 7.59 (s, 1H), 7,40 (s, 1H), 7,37 (m, 2H), 7,15 (DD, 1H), 4.00 points (s, 3H), LC/MS(M+1)=268.

Scheme 5

Boranova acid with32Vfor32F(500 µl) were placed in test tubes with azaindole3(87 mg, 250 μmol). To each tube was added Carbo is at sodium (53 mg, 500 μmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 13 µmol). Water was added (1 ml) and etilenglikolevye ether (2 ml) and the tubes were desoxyribose and backed up. The tube was heated to 140°C under the influence of microwaves for 10 minutes. The reaction mixture was cooled to 0°C and was extinguished 2N solution of hydrochloric acid in water (1 ml). The reaction mixture was extracted with ethyl acetate. Organic substances were washed with saline, dried over sodium sulfate, filtered and concentrated. The products were subjected to purification on silica (gradient 50% ethyl acetate/hexane to 100% ethyl acetate), giving connection with33Bfor33F.

Connection with33Bfor33Fwas dissolved in methanol (20 ml) and was treated 2N sodium hydroxide in water (1 ml) at room temperature over night. The reaction mixture was kind of balanced out 2N solution of hydrochloric acid (1 ml) and concentrated to dryness. The products were purified using chromatography on silica gel (gradient 50% ethyl acetate/hexane to 100% ethyl acetate) or masses aimed chromatography with reversed phase C18 (15% acetonitrile/water with 0,09% triperoxonane acid up to 35% acetonitrile/water with 0,09% triperoxonane acid for 15 minutes), giving the products34C-34F.

3-(3-Benzyloxyphenyl)-1H-pyrrolo[2,3-b]pyridine (34B)

1H NMR DMSO-d61,95 (s, 1H), 8,29 (m, 1H), to 8.20 (d, 1H), 7,89 (s, 1H), 7,49 (d, 2H), 7,41 (t, 2H), 7,34 (m, 2H), 7,29 (m, 2H), 7,13 (DD, 1H), 6.90 to (m, 1H), 5,20 (s, 2H). LC/MS(M+1)=301.

3-(4-Benzyloxyphenyl)-1H-pyrrolo[2,3-b]pyridine (34C)

1H NMR DMSO-d611,84 (s, 1H), 8,28 (m, 2H), 7,76 (s, 1H), to 7.61 (d, 2H), of 7.48 (d, 2H), 7,39 (t, 2H), 7,32 (m, 1H), 7,15 (DD, 1H), to 7.09 (d, 2H), 5,13 (s, 2H), LC/MS(M+1)=301.

3-(3,4-Acid)-1H-pyrrolo[2,3-b]pyridine (34D)

1H NMR DMSO-d611,90 (s, 1H), 8,31 (d, 1H), 8,28 (d, 1H), 7,80 (s, 1H), 7,21 (m, 2H), 7,19 (DD, 1H), 7,02 (d, 1H), 3,86 (s, 3H), of 3.78 (s, 3H). LC/MS(M+1)=255.

3-(3,4,5-Trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (E)

1H NMR DMSO-d611,85 (s, 1H), 8,29 (d, 1H), 8,27 (d, 1H), 7,83 (s, 1H), 7,15 (d, 1H), 6,92 (s, 2H), 3,86 (s, 6H), of 3.69 (s, 3H). LC/MS(M+1)=285.

2-Methoxy-4-(1H-pyrrolo[2,3-b]pyridine-3-yl)phenol (34F)

1H NMR DMSO-d6/D2O 8,25-8,30 (m, 2H), 7,74 (s, 1H), 7,20 (m, 1H), 7,17 (DD, 1H), 7,10 (DD, 1H), 6,86 (d, 1H), 3,88 (s, 3H). LC/MS(M+1)=241.

Scheme 6

2-Methoxy-5-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]benzaldehyde (36)

In the test tube was placed complex brunatny ether35(131 mg, 500 μmol) and compound3(175 mg, 500 μmol) sodium carbonate (114 mg, of 1.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (22 mg, 19 μmol). Thereto was added water (0.9 g) and etilenglikolevye ether (2.1 g), and the mixture was desoxyribonuclease. The test tube was backed up and was heated to 110°C over night under stirring MAGN is based mixer. The crude product was extracted with ethyl acetate and water. The organic layers were washed with saline, dried over sodium sulfate, filtered and concentrated, yielding the crude product. The crude product was purified using flash chromatography and was elyuirovaniya gradient from 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7N ammonia in methanol, giving the product36(98 mg, 48%).

2-Methoxy-5-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]benzonitrile (37)

Aldehyde36(98 mg, 241 μmol) was dissolved in tetrahydrofuran (5 ml). Thereto was added 30% aqueous ammonium hydroxide solution (3 ml) and iodine (79 mg, 313 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and was extracted by a simple ether and ethyl acetate. Organic matter was filtered aqueous sodium sulfite (50 mg) in water (10 ml). Organic substances were washed with saline, dried over sodium sulfate, filtered and concentrated, giving37(95,8 mg, 98%).

2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridine-3-yl)benzonitrile (38)

Nitrile37(95,8 mg, 237 μmol) was dissolved in dioxane (5 ml) and was treated 2N sodium hydroxide in water (250 μl, 500 Microm). The reaction mixture was germetizirovany and heated up to the boiling point with reverse what holodilniki within 2 hours. The reaction mixture was concentrated to dryness and extracted with ethyl acetate and water. Organic substances were washed with saline, dried over sodium sulfate, filtered and concentrated, yielding the crude product (72,3 mg). The crude product was purified using flash chromatography and was elyuirovaniya gradient from 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7N ammonia in methanol, giving the product38(26,7 mg, 45%).

2-Methoxy-5-(1H-pyrrolo[2,3-b]pyridine-3-yl)benzamide (39)

Detailirohke nitrile38(26,7 mg, 107 μmol) was dissolved in dimethyl sulfoxide (2,49 g). Thereto were added potassium carbonate (32.7 mg, 237 μmol) and 30% hydrogen peroxide solution in water (85.5 mg) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with water and the resulting precipitate was rinsed with water, acetonitrile and simple ether, giving the final product39(to 25.3 mg, 88%).

1H NMR DMSO-d6up 11,86 (s, 1H), 8,28 (m, 1H), 8,19 (d, 1H), 8,11 (m, 1H), 7,81 (m, 2H), of 7.70 (s, 1H), 7,55 (s, 1H), 7,21 (d, 1H), 7,16 (m, 1H), 3,91 (s, 3H). LC/MS(M+1)=268

4-Bromo-2-methoxybenzonitrile

In a 1-liter round bottom flask 53,94 g (270 mmol) of 4-bromo-2-perbenzoate was dissolved in 500 ml of THF. Was added sodium methoxide (21,99 g, 407 mmol) and the mixture was heated to the boiling point of the mod is s ' fridge until until TLC (thin layer chromatography) showed complete consumption of starting material. The mixture is poured into 1N HCl and the THF was evaporated in vacuum. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and was filtered through silicagel tube. The tube was lirowaus CH2Cl2and the filtrate was evaporated in vacuo, giving 45,56 g (80%) of product as a white solid.

1H NMR (500 MHz, CDCl3) δ 7,42 (d, 1H), 7,17 (DD, 1H), 7,14 (d, 1H), 3,95 (s, 3H).

4-Cyano-3-methoxyphenylalanine acid (28)

3-necked 1-liter round-bottom flask was supplied to the top with a stirrer and a line for supplying nitrogen. The flask was loaded 45,56 g (215 mmol) of 4-bromo-2-methoxybenzonitrile, 64 ml (277 mmol) of triisopropylsilane and 500 ml of THF. The solution was cooled to -78°C. in a bath with a mixture of dry ice/acetone. Via an additional funnel was added dropwise n-utility (2.5 M, 110 ml, 275 mmol). The mixture was mixed for 30 minutes and was added 2N HCl. The mixture was mixed for one hour and poured into water. The mixture was extracted Et2O. the Organic solution was back extracted 1N Paon. The aqueous layer was filtered Et2O and pagkilala concentrated HCl. The mixture was extracted Et2O. the Organic extract was dried (MgSO4) and was evaporated in vacuo, giving 20,77 g (55%) of product as white is on solid.

1H NMR (500 MHz, d6-DMSO) δ to 7.68 (d, 1H), to 7.59 (s, 1H), 7,47 (d, 1H), 3,95 (s, 3H).

Scheme 7

Scheme 8

5-Chloro-3-yodellin-2-ylamine (40)

Iodine (16.28 per g, 64 mmol) was added to a mixture of 1-amino-5-chloropyridine (8,25 g, 64 mmol) and silver sulfate (20 g, 64 mmol) in 400 ml of ethanol and the mixture is stirred at room temperature for 20 hours. The mixture was filtered through celite, and the solvent was removed in vacuum. The residue was dissolved in DCM (600 ml) and washed with 5% aqueous NaOH (500 ml), water and brine. The organic layer was dried and concentrated in vacuo to a solid residue, which was subjected to flash chromatography (20% EtOAc-80% hexane), giving 9.8 g (60%) of compound40.

1H NMR (500 MHz, CDCl3) to 7.9 (s, 1H), and 7.7 (s, 1H), 5,0 (users, 2H).

5-Chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine (41)

A mixture of compound40(9.5 g, of 37.3 mmol) was dissolved in 320 ml of DMF and was added triethylsilane (20 ml, 112 mmol), Pd2Cl2(dppf)2(1.52 g, 1.9 mmol), lithium chloride (1,58 g of 37.3 mmol) and 2M Na2CO3(7.9 ml, 74,7 ml)and the mixture stirred and heated under reflux at 90°C for 15 hours under nitrogen atmosphere. All were diluted mixture (1:1) ethyl acetate-simple ether and the organic phase was washed with water and brine, then dried (Na 2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc-80% hexane), giving 4,37 g (44%) of the desired product41.

1H NMR (500 MHz, CDCl3) 9,4 (users, 1H), and 8.2 (s, 1H), and 7.9 (s, 1H), and 6.6 (s, 1H), and 0.9 (t, 9H), 0.75 in (square, 6H).

5-Chloro-1H-pyrrolo[2,3-b]pyridine (42)

Connection41(4,37 g, 0,0164 mol) was dissolved in THF. Added molecular sieve (10 g 3A) followed by addition of TBAF (32,75 ml, 0,0328). The reaction mixture was stirred at room temperature for 5 hours. It was diluted with ethyl acetate and was washed several times with water, brine, and the organic layer was dried and concentrated in vacuo to an oil, which was subjected to flash chromatography (30% EtOAc-70% hexane), giving 02,3 g (90%) of the desired material42.

1H NMR DMSO-d611,8 (users, 1H), and 8.2 (s, 1H)and 8.1 (s, 1H), and 7.5 (s, 1H), 6,5 (s, 1H).

1-(tert-Butyldimethylsilyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (43)

In a sealed tube equipped with a septum, nitrogen atmosphere was added42(600 mg, 0,00396 mol) and 20 ml of dry THF, and the solution was cooled to 0°C. in Portions was added NaH (110 mg, 0,00435 mol) and after 15 min stirring at 0°C was added TBSCl (656 mg, 0,00435 mol). The septum was replaced with a screw tube, and the tube was heated at 80°C for 3 hours. The mixture was cooled and was kind of balanced out by a solution of chloride of ammo the Oia and was extracted with hexane. The organic phase was dried and concentrated in vacuo to an oil, which was subjected to filtration through a short plug (10% EtOAc-90% hexane), giving 871 mg (82%) of compound43.

1H NMR (500 MHz, CDCl3) to 8.2 (s, 1H), and 7.8 (s, 1H), 7,25 (s, 1H), 6,4 (s, 1H), and 0.9 (s, 9H), 0.6 a (s, 6H).

Connection43can broniruutsja on the C-3 as described previously in scheme 3 for the connection21.

Connection19can literotica, for example, tert-BuLi and extinguished DMF, giving 5-formylindole44. Connection19can also be processed carbon monoxide and methanol in the presence of a palladium catalyst, for example Pd(Ph3P)4giving 5-carbomethoxyamino44.Functional group undergoes vzaimoprevrascheny in acid, primary, secondary and tertiary amides such as product45,using standard transformations. Connection44can homologations using, for example, the Wittig reaction in the connection is the same as49.

Connection19can zenitovtsa, for example, KCN in hot DMF in the presence of a catalyst, such as copper or palladium, giving 5-cyanoethyl46.

Amination of compounds19for example, an amine in the presence of a palladium catalyst, can give 5-aminirovanie azaindole, such as48.

Connection19can allroutes or heteroaromatic the use, for example, a combination of Suzuki or Stille for connection similar to the connection47.

According to another aspect of this feature other synthetic schemes and the syntheses of compounds:

Scheme 9

An example of a

5-Chloro-3-yodellin-2-ylamine (1):In a round bottom flask, equipped with air refrigerator, loaded 5-chloropyridin-2-ylamine (26 g, 0.2 mol), acetic acid (78 ml) and water (18 ml). This procedure was followed by adding dropwise sulfuric acid (2.6 ml)in portions, adding periodistas acid (9.5 g, 0.04 mol)and iodine (20 g, 0.08 mol). The reaction mixture was vigorously stirred at 80°C for 6 hours and then was left to cool to room temperature.

The reaction mixture was poured on ice (~700 g). The pH value of the suspension was brought to 8-9 5M aqueous NaOH solution. The brown solid was filtered off and solubilizers in EtOAc (1.2 l). The organic layer was washed with a saturated aqueous solution of Na2S2O3, 1M NaOH and brine. The organic layer was dried over MgSO4and concentrated. The residue was precrystallization from cyclohexane, yielding organic solid (42 g, 80%).

1H NMR (CDCl3): of 4.8 to 5.1 (2H, users), and 7.9 (1H, s), and 8.0 (1H, s).

5-Chloro-3-(trimethylsilylethynyl)pyridin-2-ylamine (2):In a 250 ml round bottom flask, under nitrogen atmosphere, is loaded 5-chloro-3-yodellin-2-ylamine(1)(42 g, 165 mmol), THF (100 ml), copper iodide (315 mg, of 1.65 mmol) and PdCl2(PPh3)2(1,15 g of 1.65 mmol). Was added triethylamine (70 ml, 0.5 mol) and trimethylsilylacetamide (30 ml, 0.21 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 0°C and was added diethyl ether. The suspension was filtered through celite and thoroughly washed with diethyl ether. The filtrate was concentrated and was pre-absorbed on silica gel and purified via column chromatography using as eluent pentane/DCM to 10% - 100%, giving not quite white solid (36 g, 100%).

1H NMR (CDCl3): 0,3 (9H, s), a 5.0 to 5.1 (2H, users), and 7.6 (1H, s), and 7.9 (1H, s), MS (ES+): 225, 227.

5-Chloro-1H-pyrrolo[2,3-b]pyridine (3):A solution of tert-butoxide potassium (36 g, 320 mmol) in N-organic (70 ml) under nitrogen atmosphere was heated to 80°C. Through the addition funnel was added dropwise a solution of 5-chloro-3-(trimethylsilylethynyl)pyridine-2-ylamine(2)(36 g, 160 mmol) in NMP (200 ml). The reaction mixture was stirred at 80°C for an additional fifty minutes. The reaction mixture was left to cool to room is temperature. To the reaction mixture was added brine (500 ml) and the mixture was extracted with diethyl ether (5×200 ml). The combined organic layers were washed with saline, dried over magnesium sulfate and concentrated in vacuum. The residue was purified using column chromatography using as eluent pentane/EtOAc 0 to 40% and further recrystallization from cyclohexane, yielding specified in the title compound (10 g, 41%).

1H NMR CDCl3of 6.5 (1H, s), and 7.4 (1H, s), and 8.0 (1H, s), and 8.2 (1H, s), of 10.4 to 10.6 (1H, users), MS (ES+) 153.

3-Bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (4):A solution of bromine (3.5 ml) in chloroform (40 ml) was added dropwise to a cooled with ice to a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine(3)(10 mg, 65 mm) in chloroform (260 ml). The reaction mixture is stirred for 60 minutes at 0°C. the Reaction mixture was then hydrolethalus water, and the pH value of the solution was brought to 10. The resulting solid was removed by filtration, and the aqueous phase was extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo, giving specified in the title compound (10.5 g, 69%).

1H NMR (DMSO-d6) and 7.8 (1H, s), and 7.9 (1H, s), and 8.3 (1H, s).

3-Bromo-5-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (5):(4)(10.5 g, 45 mmol) in dimethylformamide (70 ml) under nitrogen atmosphere. Thirty minutes to the reaction mixture was added taillored (8.7 g, 46 mmol)and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture hydrolethalus water (~150 ml), and the brown solid was obtained by filtration and drying under vacuum, giving specified in the title compound (14.8 g, 85%).

1H NMR CDCl32,4 (3H, s), 7.3 to 7.4 (2H, d), 7,8-7,9 (2H, 2C), of 8.1 to 8.2 (2H, d), and 8.4 (1H, s); MS(ES+) 387.

5-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl-1H-[2,3-b]pyridine (6):In a 500-ml round bottom flask under nitrogen atmosphere was loaded with 3-bromo-5-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine(5)(6,9 g, 18 mmol), babinkostova (6,9 g, 27 mmol, PdCl2(dppf)2(1.5 g, 1.8 mmol), potassium acetate (5.3 g, 54 mmol) and dimethoxyethane (100 ml). The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with saline. The organic phase was dried over magnesium sulfate and concentrated in vacuum. The residue was purified using column chromatography using as eluent pentane/EtOAc 0% to 20% and then were pulverized with n is ntana, giving is mentioned in the title compound (4 g, 50%).

1H NMR (CDCl3) to 1.4 (9H, s), 2,4 (3H, s), 7,2 (2H, d), 8,00-with 8.05 (2H, d), 8,10 (2H, s), and 8.3 (1H, s). MS(ES+) 433.

(6-Bromopyridin-2-yl)-(4-Chlorobenzyl)amine (7):In a test tube for microwave processing load 4-chlorobenzylamino (700 mg; 5 mmol; 5 EQ.) and 2,6-dibromopyridine (238 mg, 1 mmol). The reaction mixture was stirred in the microwave at 150°C three times for 10 minutes (200W max). The reaction mixture was diluted with diethyl ether (50 ml)were washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and saline. The organic phase was dried over magnesium sulfate and after filtration was concentrated in vacuo, giving in the form of oil specified in the title compound (300 g, 100% yield). LC/MS: 299[M+H]

(4-Chlorbenzyl)-[6-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)pyridine-2-yl]amine (8):In a test tube for microwave processing load 6-bromopyridin-2-yl)-(4-Chlorobenzyl)amine (300 mg, 1 mmol), 5-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl-1H-[2,3-b]pyridine(7)(215 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol), 2M sodium hydroxide solution (0.75 ml) and dimethoxyethane (5 ml). The suspension was degirolami nitrogen. The reaction mixture was stirred in the microwave at 130°C for 10 minutes 200W maximum). Then it was diluted with ethyl acetate (60 ml)were washed twice with saline, dried over magnesium sulfate and after filtration was concentrated in vacuum. The compound was purified using flash chromatography (eluent: petroleum ether/ethyl acetate 60/40)to give 50 mg tosylamide the connection specified in the header. The residue was taken in a mixture of methanol and tetrahydrofuran (1/3 ml). 1M sodium hydroxide solution (1 ml) was added to the reaction mixture which is then stirred at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo, and the residue was pulverized with methanol. The suspension was filtered, giving specified in the title compound (35 mg, 10%).

1H NMR (DMSO-d6): 4,60-4,70 (2H, m), 6,35-6,40 (1H, d), 7,05-7,10 (1H, d), 7,20-of 7.25 (1H, t), 7,35-7,45 (4H, m), 8,15-to 8.20 (2H, m), 8,55 at 8.60 (1H, s), and 12.5 (1H, s). LC/MS: 369 [M+H], 367 [M-N].

Table 3 (see below) displays the data for some illustrated examples of the compounds. The numbers of the compounds correspond to the numbers of the compounds shown in table 1. The sign "-" indicates that the measurement was not conducted.

Table 4 (see below) displays the data for certain exemplary compounds. The numbers of the compounds correspond to the numbers of the compounds shown in table 2. A space indicates that the measurement was not conducted.

B) biological Data is the test:

Example 1: analysis of the inhibition of JAK3

Compounds were screened for their ability to inhibit JAK3 using standard radioactive enzyme analysis. of 1.5 µl/well of the original solution of DMSO containing serial dilution of the compounds of the present invention (concentration ranging from 667 μm to 46 nm)were placed on 96-well polycarbonate plate. On the plate was also added at 50 μl per well of kinase buffer (100 mm HEPES (pH 7.4), 10 mm MgCl2, 25 mm NaCl, 1 mm DTT and 0.01% bovine serum albumin (BSA)containing 2 μm poly(Glu)4Tyr and 10 μm ATP (adenosine triphosphate). To initiate the reaction was added to 50 μl of kinase buffer containing 2 nm JAK3 enzyme. The final concentration of ATP was 5 μm [γ-33P] ATP (200 MX33P ATP/mmol ATP (Perkin Elmer, Cambridge, MA). After 20 minutes at room temperature (25°C.) the reaction was stopped by adding 50 μl of 20% trichloroacetic acid (TCA)/0.4 mm ATP in each well. Then all the contents from each well was transferred to a 96-well glass fiber filter plate using Cladosporium TomTek. After washing was added 60 μl of scintillation fluid was determined by the inclusion of33R using a Perkin Elmer TopCount (total score). After removal of the values of background values for all points dannydanny operated in accordance with the use of the software Prism to obtain the K i(app). Inhibition of JAK2 was measured, as described above, except that the final concentration of poly(Glu)4Tyr was 15 μm and the final concentration of ATP was 12 μm.

Example 2: analysis of the inhibition of ROCK

Compounds were screened for their ability to inhibit the activity of ROCK I (AA 6-553) using the standard system of related enzymes (Fox et al. (1998)Protein Sci.7, 2249). The reaction was carried out in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT and 1.5% DMSO. The final concentration of substrate in the analysis was 45 μm ATP (Sigma Chemicals, St Louis, MO) and 200 μm peptide (American Peptide, Sunnyvale, CA). Reactions were carried out at 30°C and 45 nm ROCK I. Final concentration of the components of the system related enzymes was 2.5 mm phosphoenolpyruvate, 350 mm NADF, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase.

Some compounds were screened for their ability to inhibit ROCK using standard radioactive enzyme analysis. The research was carried out in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT and 1.5% DMSO. The final concentration of substrate in the analysis was 13 μm [γ-33P] ATP (25 MX33P ATP/mmol ATP, (Perkin Elmer, Cambridge, MA/Sigma Chemicals, St Louis, MO) and 27 μm myelin basic protein (MBP). The final concentration of the enzyme in the analysis was ROCK nm. The research was carried out at room temperature. of 1.5 µl/well of the original solution of DMSO containing serial dilution of the compounds of the present invention (concentration ranging from 10 μm to 2.6 nm)were placed on 96-well plate. On the plate was added 50 μl of solution 1 (100 mm HEPES (pH 7.5), 10 mm MgCl2, 26 mm [γ-33P] ATP). The reaction was initiated by adding 50 μl of solution 2 (100 mm HEPES (pH 7.5), 10 mm MgCl2, 4 mm DTT, 54 mm MBP and 10 nm ROCK). After 2 hours the reaction was extinguished 50 μl of 30% trichloroacetic acid (TCA, Fisher)containing 9 mm ATP. Carried out the transfer of 140 μl of the quenched reaction mixture on a glass fiber filter plate (Corning. Cat. No. 3511) followed by rinsing 3 times with 5% TCA. Was added 50 μl of scintillation fluid Optima Gold (Perkin Elmer) and the tablets were subjected to calculation of total expense (Perkin Elmer). After subtracting the background values for all points on the graph, the data were processed using the software Prism to obtain the Ki(app).

Example 3: analysis of the inhibition of Aurora

Compounds were screened for their ability to inhibit the activity of full-Aurora-A by using a standard system of related enzymes (Fox et al.Protein Sci., 7, 2249 S. (1998)). Reactions were carried out in a solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 300 μm NADH, 1 mm DTT and 3% DMSO Final concentration of substrate in the analysis was 200 μm ATP (Sigma Chemicals, St Louis, MO) and 800 μm peptide (LRRASLG, American Peptide, Sunnyvale, CA). Reactions were carried out at 30°C and 35 nm Aurora-A. Final concentration of the components of the system related enzymes was 2.5 mm phosphoenolpyruvate, 200 μm NADF, 60 μg/ml pyruvate kinase, and 20 μg/ml lactate dehydrogenase.

Was made of the original buffer solution for analysis, containing all of the reagents listed above, with the exception of the Asia-Pacific and the test compound of interest. The original buffer solution for analysis (60 μl) were incubated in 96-well-plate with 2 μl of the test compound of interest at final concentrations spanning 0,002 - 30 μm at 30°C for 10 minutes. Usually conducted in a 12-cyclic titration by making serial dilutions (from 1 mm source connection) DMSO tested compounds in the child tablets. The reaction was initiated by adding 5 μl of ATP (final concentration 200 μm). The rate of reaction was obtained with the use of a spectrophotometer to read the tablets molecular devices Spectramax (Sunnyvale, CA) for 10 minutes at 30°C. the Ki Values were determined from the data rate as a function of the concentration of inhibitor using a computerized nonlinear regression (Prism 3.0, Graphpad Software, San Diego, CA). The activity of Aurora-C was skanirovali similarly using Aurora-C protein. Active is here Aurora In skanirovali using radioactive analysis of such as described in examples 1 and 2, but using the Aurora-a protein.

Table 5 (see below) displays the data (Ki) inhibition of enzymes for some exemplary compounds. The numbers of the compounds correspond to the numbers of the compounds shown in table 1.

Table 6 (see below) displays the data (Ki) inhibition of enzymes for some exemplary compounds. The numbers of the compounds correspond to the numbers of the compounds shown in table 2.

In Table 5 and 6, “A” represents the Kiless than 0.5 μm, “B” represents the Kibetween 0.5 and 5.0 μm, and “C” represents the Kigreater than 5.0 µm for the specified enzyme. If you define more than one value of Kiindicates the average value of Ki. If not specified, then Kiwas not determined. For RCK the term “enzyme” indicates that was used in the analysis of the bound enzyme; the term33P” indicates that was used radioactive analysis.

1. The compound of formula (IB)

or its pharmaceutically acceptable salt,
where R1represents hydrogen, alkyl or trialkylsilyl;
R2and R4represent hydrogen;
R3represents halogen, CN, NO2or V-R';
x is 1, 2 or 3;
each of R5is independently halogen, CN, NO2or U-R', where at least one R5is other than H;
V and U each independently represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units of the chain are not battelino and independently replaced by-NR'-, -S-, -O-, -CO2-, -OCO-, -CO-, -CONR'-,
-NR'r CO-, -NR'r CO2-, -SO2NR'-, -NR'r SO2-, -NR'r CONR'-, -OCONR'-, -NR'r SO2NR'- or-SO2-; and
each R' is independently hydrogen or optionally substituted group selected from C1-C6aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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; or two R' taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur,
provided that
(a) if R3is N, then R1is not trialkylsilyl; and
C) if R1is N, then R3is not phenyl or phenyl substituted O-phenyl or N(Me)2.

2. The compound according to claim 1, in which R1is trialkylsilyl.

3. The compound according to claim 1, in which R1represents hydrogen, C1-C4-alkyl or trialkylsilyl.

1represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or triethylsilyl (TES).

5. The compound according to claim 1, in which R3represents hydrogen, R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', or-NR'r CO(CH2)2R, CON(R')2, -SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH2)3N(R')2, CONR'(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR', O(CH2)2N(R')2, -O(CH2)3N(R')2or-O(CH2)4N(R')2.

6. The compound according to claim 1, in which R3represents Cl, Br, F, -CN,
-COOH, -Sooma, -NH2, -N(CH3)2, -N(Et)2, -N(iPr)2, -O(CH2)2OCH3, -CONH2-SOON3-HE,
-CH2OH, -NHCOCH3, -SO2NH2, -SO2N(Me)2or an optionally substituted group selected from C1-C4-alkyl, C1-C4alkyloxy, 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 is neither, having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

7. The compound according to claim 1, in which
a) R3represents hydrogen;
b) R3is optionally substituted group selected from 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;
c) R3represents an optionally substituted 5 - or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
d) R3is optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, teinila, furil, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl or oxadiazolyl.

8. The compound according to claim 1, in which R3optionally substituted (R6)zwhere z is equal to 0-5, and R6is =O, =NR, =S, halogen, -CN, -NO2or Z-R", where Z represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two stands the new links do not necessarily and independently replaced by a group-NR"-, -S-,
-O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR"-, -NR"CO-, -NR"CO2-, -SO2NR"-,
-NR"SO2-, -CONR"NR"-, -NR"CONR"-, -OCONR"-, -NR"NR"-, -NR"SO2NR"-, -SO-,
-SO2-, -PO-, -PO2- or-POR"-, and each R" is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R" taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur.

9. The connection of claim 8 in which z is 0, 1, 2 or 3 and each of R6is independently hydrogen, R',- CH2R", halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR",
-CH2OR", -SR", -CH2SR", -COOR", -NR"COR", -NR"COOR",
-CON(R')2, -SO2N(R')2, -CONR"(CH2)2N(R')2, CONR"(CH2)3N(R')2, -CONR"(CH2)4N(R')2,
-O(CH2)2OR', O(CH 2)3OR', O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2, -NR"CH(CH2OH)R", -NR"CH(CH2CH2OH)R", -NR"(CH2)R", -NR"(CH2)2R", -NR"(CH2)3R", -NR"(CH2)4R", -NR"(CH2)N(R')2, NR"(CH2)2N(R')2,
-NR"(CH2)3N(R')2, -NR"(CH2)4N(R')2, -NR"(CH2)OR", -NR"(CH2)2OR", -NR"(CH2)2OR" or-NR'(CH2)4'OR".

10. The connection of claim 8 in which z is 1, 2 or 3 and each of R6is independently F, Cl, Br, CN, HE, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), CH2O(C1-C6alkyl), -CO1-C6alkyl), COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2,
-CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the preceding phenyl, benzyl and C1-C6the alkyl groups is independently and optionally substituted, and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

11. The compound according to claim 1, in which each of R5is independently hydrogen, R', -CH2R', halogen, C, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR',
-SR', -CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2,
-SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR(CH2)3N(R')2, -CONR'(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2,
-NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R',
-NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -NR'(CH2)3N(R')2,
-NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2OR', -NR'(CH2)3OR', or-NR'(CH2)4OR'.

12. The compound according to claim 1, in which at least one of R5represents-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', NR'(CH2)N(R')2or-NR'(CH2)2N(R')2.

13. The compound according to claim 1, in which at least one of R5is-OR'.

14. The compound according to claim 1, in which at least one of R5is-NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'.

15. The compound according to claim 1, in which at least one of R5represents optionally substituted C1-C6aliphatic group, 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms selected independently 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.

16. The compound according to claim 1, in which x is 1 or 2 and each R5is independently halogen, R', CN, -CH2CN, -(CH2)2CN, NO2, -CH2NO2, -(CH2)2NO2,
-CON(R')2, -CH2CON(R')2, -(CH2)2CON(R')2, COOR', -CH2COOR', -(CH2)2COOR',
-SO2N(R')2, -CH2SO2N(R')2, -(CH2)2SO2N(R')2, NR'r SO2R', -CH2NR'r SO2R', -(CH2)2NR'r SO2R', NR'r CON(R')2, -CH2NR'r CON(R')2, -(CH2)2NR'r CON(R')2, -NR'r SO2N(R')2,
-CH2NR'r SO2N(R')2, -(CH2)2NR'r SO2N(R')2, -COCOR', -CH2COCOR', -(CH2)2COCOR', -N(R')2, -CH2N(R')2, -(CH2)2N(R')2, -OR', -CH2OR', -(CH2)2OR', -NR'r COR', -NR'r COCH2R',
-NR'r CO(CH2)2R', -CH2NR'r COR', or -(CH2)2NR'R COR'.

17. The connection clause 16, in which R5represents CN, -CH2-CN, -(CH2)2CN,
-NO2-CH 2NO2, -(CH2)2NO2, OR', -CH2OR', -CON(R')2, -SO2N(R')2, -N(R')2or R'.

18. The connection clause 16, in which each of R5is independently hydrogen, halogen, CN, -CH2CN, -(CH2)2CN, NO2, -CH2NO2, -(CH2)2NO2, -CONH2, -CON(C1-C4alkyl), -SO2NH2, -SO2N(C1-C4alkyl), NH2, -N(C1-C4alkyl), -OH, -O(C1-C4alkyl),
-CH2OH, -CH2O(C1-C4alkyl) or optionally substituted 5-or 6-membered unsaturated ring in which 0 to 3 ring carbon atom optionally replaced by oxygen, sulfur or nitrogen.

19. The compound according to claim 1, in which R5optionally substituted (R7)ywhere equal 0-5 and R7is =O, =NR, -S, halogen, -CN, NO2or W-R", where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR"-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR"-, -NR"CO-, -NR"CO2-, -SO2NR"-,
-NR"SO2-, -CONR"NR"-, -NR"CONR"-, -OCONR"-, -NR"NR"-, -NR"SO2NR"-, -SO-,
-SO2-, -PO-, -PO2- or-POR"-, and each R" is independently hydrogen or optionally substituted C1-C6aliphatic group, a 3-8-membered saturated, partially n is saturated, 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; or two R" taken together with the atom(s)to which they are attached, form a 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.

20. The connection according to claim 19, in which 0, 1, 2 or 3 and each of R7is independently hydrogen, R',- CH2R", halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR",
-CH2OR", -SR", -CH2SR", -COOR", -NR"COR", -NR"COOR", -CON(R')2,
-SO2N(R')2, -CONR"(CH2)2N(R')2, CONR"(CH2)3N(R')2, -CONR"(CH2)4N(R')2,
-O(CH2)2OR',- O(CH2)3OR',- O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2,
-O(CH2)4N(R')2, -NR"CH(CH2OH)R", -NR"CH(CH2CH2OH)R", -NR"(CH2)R", -NR"(CH2)2R", -NR"(CH2)3R", -NR"(CH2)4R", -NR"(CH2)N(R')2, -NR"(CH2)2N(R')2,
-NR"(CH2)3N(R')2, -NR"(CH2)4N(R')2, -NR"(CH 2)OR", -NR"(CH2)2OR", -NR"(CH2)3OR" or-NR"(CH2)4'OR".

21. The connection according to claim 19, in which 1, 2 or 3 and each of R7is independently F, Cl, Br, CN, HE, NH2, -CH2OH,1-C6alkyl, -O(C1-C6alkyl), -CH2O(C1-C6alkyl), -CO1-C6alkyl), -COO(C1-C6alkyl), -NHSO2(C1-C6alkyl), -SO2NH2,
-CONH2, -CON(C1-C6alkyl), -SO2(C1-C6alkyl), -SO2phenyl, phenyl, benzyl, -N(C1-C6alkyl)2or-S(C1-C6alkyl), where each of the foregoing phenyl, benzyl, and C1-C6the alkyl groups is independently and optionally substituted(Oh) and where each of the previous With the1-C6the alkyl group is a linear, branched or cyclic.

22. The compound according to claim 1, in which at least one of R5is
-N(R')2, -NR'r CH(CH2OH)R', -NR'r CH(CH2CH2OH)R', -NR'(CH2)R', -NR'(CH2)2R', NR'(CH2)N(R')2, -NR'(CH2)2N(R')2, -OR', -NR'r COR', -NR'r COCH2R' or-NR'r CO(CH2)2R'; and R' represents a C1-C6aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms, selected independently from and the PTA, 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; or two of R' taken together with the atom (s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where each of R' is optionally substituted (R7)ywhere equal 0-5 and R' is =O, =NR, =S, halogen, -CN, -NO2or W-R", where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR"-, -S-, -O-, -CS-, -CO2, -OCO-, -CO-, -COCO-, -CONR"-, -NR"CO-, -NR"CO2-, -SO2NR"-,
-NR"SO2-, -CONR"NR"-, -NR"CONR"-, -OCONR"-, -NR"NR"-, -NR"SO2NR"-, -SO-,
-SO2-, -PO-, -PO2- or-POR"-, and each R" is independently hydrogen or optionally substituted C1-C6aliphatic 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 floor is awn unsaturated bicyclic ring system, having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two R" taken together with the atom(s)to which they are attached, form a 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.

23. Connection p.22, in which R' represents hydrogen, C1-C6alkyl, optionally substituted by 1-3 R7or a 5-10 membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms, selected independently from nitrogen, oxygen or sulfur, where the ring is optionally substituted by 1-3 R7.

24. Connection p.22, in which R' represents hydrogen, C1-C4alkyl, optionally substituted by 1-3 R7or is a ring selected from












where equal 0-5 and R7is =O, =NR, =S, halogen, -CN, -NO2or W-R", where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR"-, -S-, -O-,-CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR"-, -NR"CO-,
-NR"CO2-, -SO2NR"-, -NR"SO2-, -CONR"NR"-, -NR"CONR"-, -OCONR"-, -NR"NR"-,
-NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2- or-POR"-, and each R" is independently bodoro is or optionally substituted C 1-C6aliphatic 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; or two R" taken together with the atom(s)to which they are attached, form a 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.

25. The compound according to claim 1, in which R5represents-N(R')2and two of R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring, in some embodiments the ring selected from




where equal 0-5 and R7is =O, =NR, =S, halogen, -CN, -NO2or W-R", where W represents a bond or optionally substituted C1-C6alkylidenes a circuit in which up to two methylene units optionally and independently replaced by-NR"-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR"-, -NR"CO-, -NR"CO2-, -SO2NR"-, -NR"SO2-, -CONR"NR"-, -NR"CONR"-, -OCONR"-, -NR"NR"-,
-NR"SO2NR"-, -SO-, -SO2-, -PO-, -PO2- or-POR"-, and each R" is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R" taken together with the atom(s)to which they are attached, form a 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.

26. The compound according to claim 1, which is a

27. The compound according to claim 1, in which R1represents hydrogen, C1-C4alkyl or trialkylsilyl.

28. Connection item 27, in which R1represents hydrogen.

29. The compound according to claim 1, in which R3selected from H, Cl, Br, F, -CN, -COOH,
-Sooma, -NH2, -N(R')2, -NO2, -OR', -CON(R')2, -COOR', -OH, -SR',
-C(R')2OR', -N(R')COR', -N(R')C(O)OR', -SO2NH2, -SO2N(R')2or an optionally substituted group selected from C1-C4aliphatic group1-C4alkyloxy or-C≡C1-C4aliphatic group.

30. The connection clause 29, in which R3selected from H, Cl, -Br, -CN, -COOH,
-Sooma, -CONHR', -CON(Me)2, -CH2OH, NO2, -NH2or optionally substituted C1-C4aliphatic group.

31. Connection item 30, in which R3selected from Cl, -Br, -CN, or optionally substituted C1-C4aliphatic group.

32. Connection item 30, in which R3is Cl.

33. The compound according to claim 1, in which R3selected from Cl, -Br, -CN, or optionally substituted C1-C4aliphatic group.

34. Connection item 30, in which R3is H, OR', NR'r C(O)R', NR'r C(O)OR', CON(R')2or Sooma.

35. Connection item 30, in which R3is OR', NR'r C(O)R', or NR'r C(O)OR'.

36. The compound according to claim 1, in which R3selected from H, OR', NR'r C(O)R', NR'r C(O)OR',CON(R') 2or Sooma.

37. The compound according to claim 1, in which each of R5independently selected from R', -CH2R', halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR',
-CH2SR', -COOR', -NR'r COR', -NR'r COR8R', -NR'r COOR', -CON(R')2, -SO2N(R')2,
-CONR'R8N(R')2, -OR8'OR', OR8N(R')2, -NR'r CH(R9)R', -NR'r CH(R9)C(O)OR', -N(R')R8R', N(R')R8N(R')2, -N(R')R8OR', -NR'r CH(R9)R', -NR'r CH2C(O)N(R')2or-NR'r CH(R9)C(O)N(R')2where R8represents optionally substituted C1-C4alkyl, and R9represents optionally substituted C1-C6aliphatic group.

38. The connection clause 37, in which each of R5independently selected from R', -CH2R', halogen, -CN, -NO2, -N(R')2, -CH2N(R')2, -OR', -CH2OR', -SR',
-CH2SR', -COOR', -NR'r COR', -NR'r COCH2R', -NR'r CO(CH2)2R', -NR'r COOR', -CON(R')2,
-SO2N(R')2, -CONR'(CH2)2N(R')2, -CONR'(CH2)3N(R')2, -CONR'(CH2)4N(R')2,
-O(CH2)2OR', -O(CH2)3Or SIG', -O(CH2)4OR', -O(CH2)2N(R')2, -O(CH2)3N(R')2,
-O(CH2)4N(R')2, -NR'r CH(CH2OR9)R', -NR'r CH(CH2CH2OR9)R', -NR'r CH(CH3)R', NR'r CH(CF3)R', -NR'r CH(CH3)C(O)OR', -NR'r CH(CF3)C(O)OR', -NR'(CH2)R',
-NR'(CH2)2 R', -NR'(CH2)3R', -NR'(CH2)4R', -NR'(CH2)N(R')2, -NR'(CH2)2N(R')2,
-NR'(CH2)3N(R')2, -NR'(CH2)4N(R')2, -NR'(CH2)OR', -NR'(CH2)2OR', -NR'(CH2)3OR',
-NR'(CH2)4OR', -NR'r CH(CH2CH3)R', -NR'r CH2C(O)N(R')2, -NR'r CH(CH3)C(O)N(R')2, NR'r CH(CF3)C(O)N(R')2, -NR'r CH(CH2CH3)C(O)N(R')2,
-NR'r CH(CH(CH3)2)C(O)N(R')2, -NR'r CH(C(CH3)3)C(O)N(R')2, NR'r CH(CH2CH(CH3)2)C(O)N(R')2, -NR'r CH(CH2OR9)C(O)N(R')2or NR'r CH(CH2CH2N(Me)2)C(O)N(R')2.

39. The connection clause 37, in which at least one of R5selected from-NR'r CH(CH2OH)R', -NR'r CH(CH2OMe)R', -NR'r CH(CH2OEt)R', NR'r CH(CH2OCF3)R', -NR'r CH(CH2CH2OH)R', -NR'r CH(CH2CH2OMe)R',
-NR'r CH(CH2CH2OEt)R', -NR'r CH(CH2CH2OCF3)R', -NR'r CH(CH3)C(O)OR',
-NR'r CH(CF3)C(O)OR', -NR'r CH(CH3)C(O)N(R')2, -NR'r CH(CF3)C(O)N(R')2,
-NR'r CH(CH2CH3)C(O)N(R')2, -NR'r CH(CH2OH)C(O)N(R')2, -NR'r CH(CH2OMe)C(O)N(R')2, -NR'r CH(CH2OEt)C(O)N(R')2or-NR'r CH(CH2OCF3)C(O)N(R')2where R' represents optionally substituted C1-C4aliphatic group.

40. The connection clause 37, in which at least one of R5selected from NHCH2C(O)other', -NHCH(CH3)C(O)other', -NHCH(THE N 2CH3)C(O)other',
-NHCH(CH(CH3)2)C(O)other', -NHCH(CH3)3)C(O)other', -NHCH(CH2CH(CH3)2)C(O)other', -NHCH(CH2OH)C(O)other', -NHCH(CH2OMe)C(O)other' or-NHCH(CH2CH2N(Me)2)C(O)other', where R' represents optionally substituted C1-C4aliphatic group.

41. The connection clause 37, in which at least one of R5independently selected from-other', -NH(CH2)R', -NH(CH2)2R', -NHCH(CH3)R', -NHCH2C(O)other',
-NHCH(CH3)C(O)other', -NHCH(CH2CH3)C(O)other', -NHCH(CH(CH3)2)C(O)other',
-NHCH(C(CH3)3)C(O)other', -NHCH(CH2CH(CH3)2)C(O)other', -NHCH(CH2OH)C(O)other', -NHCH(CH2OMe)C(O)other' or-NHCH(CH2CH2N(Me)2)C(O)other', where R' is optionally substituted phenyl.

42. The connection clause 37, in which at least one of R5is-NHCH(CH3)R', where R' is optionally substituted phenyl.

43. The connection clause 37, in which at least one of R5represents H, a halogen, CH3, CF3, COOH, Sooma or or', where R' represents a C1-C4aliphatic group.

44. The connection clause 37, in which x is 2 or 3 and at least one of R5is F.

45. The connection clause 37, in which R1is hydrogen and R5selected from-other', -NH(CH2)R', -NH(CH2)2R', -NHCH(CH3)R', -NHCH2(O)other',
-NHCH(CH3)C(O)other', -NHCH(CH2CH3)C(O)other', -NHCH(CH(CH3)2)C(O)other',
-NHCH(C(CH3)3)C(O)other', -NHCH(CH2CH(CH3)2)C(O)other', -NHCH(CH2OH)C(O)other', NHCH(CH2OMe)C(O)other' or-NHCH(CH2CH2N(Me)2)C(O)other', where R' is optionally substituted phenyl.

46. The connection clause 37, in which R1is hydrogen and R5selected from-NR'r CH(CH2OH)R', -NR'r CH(CH2OMe)R', -NR'r CH(CH2OEt)R', -NR'r CH(CH2OCF3)R', -NR'r CH(CH2CH2OH)R', -NR'r CH(CH2CH2OMe)R', NR'r CH(CH2CH2OEt)R', -NR'r CH(CH2CH2OCF3)R', -NR'r CH(CH3)C(O)OR', -NR'r CH(CF3)C(O)OR', -NR'r CH(CH3)C(O)N(R')2, -NR'r CH(CF3)C(O)N(R')2,
-NR'r CH(CH2CH3)C(O)N(R')2, -NR'r CH(CH2OH)C(O)N(R')2, -NR'r CH(CH2OMe)C(O)N(R')2, -NR'r CH(CH2OEt)C(O)N(R')2or NR'r CH(CH2OCF3)C(O)N(R')2where R' represents optionally substituted C1-C4aliphatic group.

47. The compound according to claim 1, in which R' represents hydrogen, C1-C6aliphatic group, optionally substituted (R7)yor R' represents a ring selected from












or two of R' taken together with the nitrogen atom to which they are attached, form a optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring, selected from




where y is 0, 1, 2 or 3 and each of R7is independently hydrogen, R",
-CH2R", halogen, CN, NO2, -N(R')2, -CH2N(R')2, -OR", -CH2OR", -SR",
-CH2SR", -COOR", -NR"COR", -NR"COOR", -CON(R')2, -SO2N(R')2, -CONR"(CH2)2N(R')2, -CONR”(CH2)3N(R')2, -CONR"(CH2)4N(R')2, -O(CH2)2OR', O(CH2)3OR', O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2,
-NR"CH(CH2OH)R", -NR"CH(CH2CH2OH)R", -NR"(CH2)R", -NR"(CH2)2R",
-NR"(CH2)3R", -NR"(CH2)4R", -NR"(CH2)N(R')2, -NR"(CH2)2N(R')2, -NR"(CH2)3N(R')2, -NR"(CH2)4N(R')2, -NR"(CH2)OR", -NR"(CH2)2OR", -NR"(CH2)3OR"or-NR"(CH2)4OR", and each R" is independently hydrogen or optionally substituted C1-C6aliphatic group, a 3-8-membered of NASA the military, 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; or two R" taken together with the atom(s)to which they are attached, form a 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.

48. The compound according to claim 1, in which x is 2 or 3 and at least two of R5on adjacent ring members are R' and in which the two R5taken together with the atoms to which they are attached, form a 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.

49. Connection p, which has the formula I-B-vii or I-B-viii:

where y is 0, 1, 2 or 3 and each of R7is independently hydrogen, R",
-CH2R", halogen, CN, NO3, -N(R')2, -CH2 N(R')2, -OR", -CH2OR", -SR",
-CH2SR", -COOR", -NR"COR", -NR"COOR", -CON(R')2, -SO2N(R')2, -CONR"(CH2)2N(R')2, -CONR"(CH2)3N(R')2, -CONR"(CH2)4N(R')2, -O(CH2)2OR',- O(CH2)3'OR",
-O(CH2)4OR',- O(CH2)2N(R')2, -O(CH2)3N(R')2, -O(CH2)4N(R')2,
-NR"CH(CH2OH)R", -NR"CH(CH2CH2OH)R", -NR"(CH2)R", -NR"(CH2)2R",
-NR"(CH2)3R", -NR"(CH2)4R", -NR"(CH2)N(R')2, -NR"(CH2)2N(R')2,
-NR"(CH2)3N(R')2, -NR"(CH2)4N(R')2, -NR"(CH2)OR", -NR"(CH2)2OR", -NR"(CH2)3OR"or-NR"(CH2)4OR", and each R" is independently hydrogen or optionally substituted C1-C6aliphatic 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; or two R" taken together with the atom(s)to which they are attached, form a optionally substituted 3-12-membered saturated, partially unsaturated or fully the capacity of the unsaturated monocyclic or bicyclic ring, having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

50. The compound according to claim 1, selected from compounds represented below:

The structural formulaconnection
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51. Pharmaceutical composition having inhibitory action against JAK-3, ROCK or Aurora kinase, comprising the compound according to any one of claims 1, 26 or 50, and a pharmaceutically acceptable carrier, adjuvant or excipient.

52. A method of inhibiting the activity of JAK-3, ROCK or Aurora kinase in a biological sample or in a patient, comprising contacting the specified biological sample or a specific patient with
a) a composition according to § 51 or
b) the compound according to claim 1.

53. A method of treating, preventing, or mitigating the severity of a disease or disorder selected from immune responses, such as allergic reactions or hypersensitivity reactions type I is whether asthma; autoimmune diseases, such as graft rejection, disease graft-versus-host, rheumatoid arthritis, lateral to the lateral amyotrophic sclerosis or multiple sclerosis; neurodegenerative disorders; or solid malignant tumors and hematologic malignancies, including placing a patient in need this song in § 49 or compounds according to claim 1.

54. The method according to item 53, wherein the disease is an autoimmune disease and is graft rejection, disease graft-versus-host, rheumatoid arthritis, lateral to the lateral amyotrophic sclerosis or multiple sclerosis.

55. The method according to item 53, wherein the disease is hypertension, angina pectoris, cerebrovascular insufficiency, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, atherosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, damage caused by ischemia/reperfusion, or endothelial dysfunction.

56. A method of treating, preventing or reducing the severity of the disease or disorder selected from the heart the disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders, osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases, viral diseases, hypertrophy, reperfusion/ischemia in stroke, heart attacks, hypoxia bodies caused by thrombin accumulation of platelets, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, hepatic ischemia, myocardial infarction, congestive heart failure, pathologic immune conditions, including activation of T cells, and neurodegenerative disorders, comprising the administration to a patient in need this song in § 51 or compounds according to claim 1.

57. The method according to p, characterized in that said cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or cancer of the colon, breast, lung, kidney, ovary, endometrium, pancreas, renal cancer (kidney cancer), cancer of the Central nervous system, cervical cancer, prostate cancer or cancer of the gastrointestinal tract, CML, AML, APL, acute linfocitos leukemia (ALL), mastocytosis or gastro-Ki is echnol stromal tumor (GIST).



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: new compounds have formula (I) , where values of radicals R1 - R10 are as given in paragraph 1 of the formula of invention; n equals 2 or 3, --- denotes absence of substitution or a single bond; and denotes a single bond or a double bond, or to salts thereof. The invention also relates to a method of producing compounds of formula (Ic), to a NK2 receptor antagonist, to a pharmaceutical agent, to a method of antagonising the NK2 receptor, to a method of preventing or treating functional gastrointestinal diseases, as well as to use of compounds given in paragraph 1.

EFFECT: obtaining new biologically active compounds with antagonistic effect on the NK2 receptor.

31 cl, 331 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of photoactivation of a photocatalyst by irradiating a composition containing the said catalyst. The method of using a photolatent catalyst (a) in which a composition containing said catalyst is irradiated before subsequent treatment is characterised by that, the photolatent catalyst is: (a1) a compound selected from a group consisting of a photolatent acid, an aromatic iodonium salt or oxime-based photolatent acid; (a2) a photolatent base compound. Also described is a substrate on which a coating made from the composition is deposited in accordance with the above described method. Also described is a method of using photolatent catalyst (a), in which a composition containing said catalyst is irradiated before subsequent treatment, characterised by that subsequent treatment is preparation of foam material and the composition contains polyol and isocyanate components and photolatent base (a2) as photolatent catalyst.

EFFECT: provision for solidification of the system.

13 cl, 10 tbl, 16 ex

FIELD: pharmacology.

SUBSTANCE: present invention refers to compounds of formula (I) , to its N-oxides, salts, stereoisomer forms where n is equal 1, 2 or 3; R1 means cyano group; X means bivalent radical NR2 or O; R2 means hydrogen or C1-10alkyl, each Q1 independently stands for direct coupling, -CH2- or -CH2-CH2-; each R4 independently means hydrogen or C1-4alkyl; each R5a, R5b, R5c independently means hydrogen, C1-4alkyl or arylC1-4alkyl; each R5e, R5f independently means hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f together can form bivalent alkandiyl radical of formula -CH2-CH2- or -CH2-CH2-CH2-; R11 means aryl, arylC1-4alkyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, pyridyl; -a1=a2-a3=a4- means a bivalent radical of formula -CH=CH-CH=CH- (c-1); where one or two hydrogen atoms in (c-1) are substituted by radical C1-6alkyl, C1-4alkoxy, halogen, hydroxy group, (R5g)(R5h)N-(C1-4alkandiyl)-O-trifluoromethyl, cyano group, radical -COOR4, (R5a)(R5b)N-sulphonyl, pyrrolidinyl-sulphonyl, piperidinyl sulphonyl, radical N(R5a)(R5b), radical (a-1), (a-7), morpholinyl, (R5g)(R5h)N-(C1-4alkandiyl)-N(R5c)-, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, C1-6alkylsulphonylamino, (R5a)(R5b)N-C1-4alkyl; R20 means hydrogen, spiro (C2-4alkylenedioxy), spiro (diC1-4alkyoxy) or -NR5gR5h; each R5g or R5h independently means either hydrogen, or C1-4alkyl, or R5g and R5h together with nitrogen atom whereto attached form pyrrolidinyl, piperidinyl or morpholinyl; R3 means nitro group, cyano group, amino group, halogen, hydroxy group or C1-4alkoxy; aryl means phenyl optionally substituted with one or more substitutes chosen from the group consisting of C1-6alkyl, C1-4alkoxy, halogen, hydroxy, amino and trifluoromethyl. Besides it relates to the pharmaceutical composition with antiviral activity, and method for making said compounds.

EFFECT: there are prepared and described new compounds with antiviral activity.

9 cl, 15 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a dynamic nuclear polarisation method of a compound which contains one or more carboxyl groups, distinguished by that, the radical of formula (I) , where M is one equivalent cation of an alkali metal; and R1, which are identical or different, each represents a C1-C6-alkyl group with a straight or branched chain or a -(CH2)n-X-R2 group, where n equals 1, 2 or 3; X is O; and R2 is a C1-C4alkyl group with a straight or branched chain, which are used a paramagnetic agent in the said dynamic nuclear polarisation process. The invention also relates to new radicals, to their use as paramagnetic agents.

EFFECT: obtaining new radicals of formula (I), which are used as paramagnetic agents in dynamic nuclear polarisation processes.

17 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a liquid composition which contains hyperpolarised 13C-pyruvate, involving: a) formation of a liquid mixture containing a radical of formula (I) , where M is hydrogen or one equivalent cation; and R1, which are identical or different, each represents hydroxylated and/or alkoxolated C1-C4-hydrocarbon group with a straight or branched chain, 13C-pyroracemic acid and/or 13C-pyruvate, and freezing this mixture; b) increasing polarisation of 13C nuclei of pyroracemic acid and/or pyruvate in this mixture through dynamic nuclear polarisation c) addition of a physiologically transferable buffer, which provides for pH in the range from 7 to 8, and a base to the frozen mixture for its dissolution and for converting 13C-pyroracemic acid to 13C-pyruvate, obtaining a liquid composition or, when at stage (a) only 13C-pyruvate is used, addition of a buffer to the frozen mixture for its dissolution, obtaining a liquid composition; and d) possible removal of the radical and/or its reaction products from the liquid composition. The invention also relates to use of such a composition and to a radical of formula (I).

EFFECT: obtaining a composition for use as MP of a visualising agent.

22 cl, 2 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with formula I: , where D is O; E is CH2 or O; n equals 1 or 2, and R1 is chosen from hydrogen, halogen or substituted or unsubstituted 5- or 6-member aromatic or heteroaromatic ring with 0, 1 or 2 nitrogen atoms, 0 or 1 oxygen atom, or is chosen from substituted or unsubstituted 8-, 9- or 10-member condensed heteroaromatic ring system with 0 or 1 nitrogen atom, 0 or 1 oxygen atom, where the said aromatic or heteroaromatic rings or ring systems, when they are substituted, have substitutes which are chosen from -C1-C6alkyl, -C3-C6cycloalkyl, -C1-C6alkoxy, halogen, -CF3, -S(O)mR2, where m equals 0, 1 or 2, -NR2R3, -NR2C(O)R3 or -C(O)NR2R3; R2 and R3 are in each case independently chosen from hydrogen, -C1-C4alkyl, -C3-C6cycloalkyl, aryl; or its stereoisomers, enantiomers or pharmaceutically acceptable salts; under the condition that the given compound is not 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-1-one. The invention also relates to compounds with formulae II or III, to a pharmaceutical composition, as well as to use of compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds with activity towards alpha 7 nicotinic acetylcholine receptors (α7 nAChRs).

8 cl, 72 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of formula I in the form of the salt or zwitter-ion, wherein R1 and R3 are independently phenyl, C3-C8 cycloalkyl or thienyl group, R2 is haloid or hydroxyl group; R4 is C1-C8 alkyl substituted with -NR5-CO-R6 or -CO-NR9R10; R5 is hydrogen ; R6 is C1-C8alkyl or C1-C8 alkoxy, each of them is optionally substituted with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R6 is 5-10-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur; R9 is hydrogen or C1-C8alkyl; R10 is C1-C8alkyl, optionally substituted with cyano group, C1-C8 alkoxy group or with 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur, or R10 is 5-9-membered heterocyclic group containing at least one ring heteroatom selected from nitrogen, oxygen and sulphur. The invention refers also to the pharmaceutic composition, to the application of compound of any of claims 1-5 as well as to the preparation method of compound of formula I of claim 1.

EFFECT: preparation of the new biologically active compounds taking the effect of muscarin receptor M3.

9 cl, 247 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula: I, where R1 is selected from hydrogen or methoxy; R2 is selected from a group consisting of hydroxy, lower alkoxy, provided that R2 does not denoe methoxy when R1 denotes methoxy, lower alkoxy, mono- or di-substituted with a hydroxy group, benzyloxy, amino, alkylamino, dialkylamino, cyano group, unsubstituted phenyl or tetrazolyl, -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen, lower alkyl or tetrazolyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, -O-(CH2)n-COOR10, where n equals 1 or 2 and R10 denotes hydrogen or lower alkyl, -O-(CH2)p-NH-C(O)-OR11, where p equals 1 or 2,and where R11 denotes lower alkyl, -O-SO2-R12, where R12 denotes lower alkyl, -NR13R14, where R13 denotes hydrogen or lower alkyl, and R14 denotes lower alkyl or benzyl, and -NH-CO-(CH2)q-R15, where q equals 1 or 2, and where R5 denotes tetrazolyl; R3 is selected from a group consisting of hydrogen, hydroxy, lower alkoxy, lower alkoxy which is mono- or di-substituted with a hydroxy group, alkoxy or unsubstituted phenyl, and -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen or lower alkyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, which can be substituted with lower alkyl; R4 is or , where R5 is selected from lower alkyl; or R5 can also denote hydrogen when selected from a group consisting of -(CH2)m-C(O)-NR8R9, -O-(CH2)p-NH-C(O)-OR11, -O-SO2-R12, -NR13R14, -NH-CO-(CH2)q-R15 and lower alkoxy which is mono- or di-substituted with a group selected from hydroxy, benzyloxy, amino or cyano; R6 is selected from a group consisting of hydrogen and lower alkyl; R7 is selected from a group consisting of lower alkyl and lower halogenalkyl; and to pharmaceutically acceptable salts of said compounds. The invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having DPP-IV enzyme inhibiting activity.

22 cl, 50 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which exhibits inhibitory effect on the FAAH enzyme having formula I , where n denotes an integer from 1 to 6; A denotes a group X; where when n equals an integer from 2 to 6, groups A are identical or different; X denotes C1-2-alkylene; R1 denotes a hydrogen atom; R2 denotes a hydrogen atom or a group selected from the following groups: phenyl, phenyloxy; R3 denotes either 2,2,2-trifluoroethyl or phenyl, if necessary substituted with one or more halogen atoms or C1-3-alkyl, C1-3-alkoxy, trifluoromethyl; provided that: the formula 1 compound is not 2,2,2-trifluoroethyl benzylcarbamate, when R3 denotes 2,2,2-trifluoroethyl and group -[A]n- denotes a -CH2- group, when R3 denotes phenyl, if necessary substituted, and group -[A]n-denotes a -CH2-, -CH2CH2-,-CH2CH2CH2- group, then R2 is not a hydrogen atom and is in form of a base, an addition salt with a pharmaceutically acceptable acid, as well as to a method for synthesis of the formula I compound and a pharmaceutical composition having inhibitory effect on FAAH, containing at least one formula I compound.

EFFECT: improved method.

5 cl, 6 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to novel pyrrolo[3,2-b]pyridine derivatives of formula I , where values of radicals R1-R5 are given in the description. The invention also covers pharmaceutically acceptable salts of these compounds, methods of producing these compounds and pharmaceutical compositions containing these compounds. Pyrrolo[3,2-b]pyridine derivatives and their pharmaceutically acceptable salts can provide proton pump reversible inhibitory effect.

EFFECT: obtaining novel pharmaceutically acceptable salts which can provide proton pump reversible inhibitory effect.

5 cl, 2 tbl, 289 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds having anxiolytic and antidepressant activity, which are derivatives of the formula 1 (a-b), or formula 2 (a-b) at that compounds of formula 2 (a-b) are intermediate products in synthesis of compounds of the formula , where R-Cl is a compound 1a or R'=COOC2H5 - compound 1b, , where R=COOC2H5 and R'=C1 - compound 2a; R=R-COOC2H5 - compound 2b.

EFFECT: obtaining new biologically active compounds that differ from analogues as intended in low toxicity and lack of side effects.

5 cl, 3 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have CDK1 and/or CDK2 kinase inhibiting activity. In formula R1 is selected from hydrogen, hydroxy-lower alkyl, C3-C6 cycloalkyl and R2-(X)n; X is selected from lower alkylene, hydroxy-lower alkylene, lower cycloalkylene or lower alkanoyloxy-lower alkylene; R2 is and is selected from phenyl and a 5- or 6-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of sulphur and nitrogen; R5 and R6 are independently selected from a group consisting of hydrogen, lower alkyl, halogen and lower alkoxy; and n equals 0 or 1.

EFFECT: design of a pharmaceutical composition for treating and preventing diseases whose condition can be improved by inhibiting CDK1 and/or CDK2 kinase, containing an effective amount of formula I compounds.

47 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel acylsulfonamide peri-substituted condensed bicyclic compounds of general formula (I), values of radicals are given in invention formula. Also described is pharmaceutical composition based on formula (I) compound.

EFFECT: compounds can be used for inhibition of prostaglandin E2 binding with receptor EP3.

30 cl, 371 ex, 4 tbl

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