ME01934B - Pyrazole derivatives as protein kinase modulators - Google Patents

Description

Description

This invention relates to pyrazole-containing aryl- and heteroaryl-alkylamine compounds that inhibit or modulate the activity of protein kinase B (PKB) and protein kinase A (PKA), then to the use of these compounds in the treatment or prevention of biolesions or conditions mediated through PKB and PKA, as well as new compounds that have inhibitory or modulatory activity towards PKB and PKA. Pharmaceutical compositions containing these compounds and new chemical intermediates are also provided.

Osnova pronalaska

Protein kinases form a large family of structurally related enzymes that are responsible for controlling a wide range of signal transduction processes within the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book I and II, Academic Press, San Diego, CA) . Kinases can be divided into families according to the substrate they phosphorylate (eg, protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (eg, Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407- 414 (1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell, 73:585-596 (1993); Garcia-Bustos, et al., EMBO J. , 13:2352-2361 (1994)).

Protein kinases can be characterized according to their regulatory mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. A single protein kinase can be regulated through more than one mechanism.

Kinases regulate many different cellular processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, and other signal transduction processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a number of different extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The respective protein kinase in signal transduction pathways functions by activating or inactivating (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signal transduction resulting from improper control of protein phosphorylation is involved in

a number of diseases, including, for example, inflammation, cancer, allergy/asthma, immune system diseases and conditions, central nervous system diseases and conditions, and angiogenesis.

Apoptosis or programmed cell death is an important physiological process that removes cells that are no longer needed by the body. This process is important in early embryonic development and development by allowing the non-necrotic controlled breakdown, removal and renewal of cellular components. Cell removal by apoptosis is also important in maintaining the chromosome and genome integrity of growing cell populations. There are several known checkpoints in the cell growth cycle where DNA damage and genome integrity are carefully monitored. The response to the detection of anomalies at these checkpoints is to stop the growth of such cells and initiate the repair process. If the damage or anomaly cannot be repaired, then the damaged cell begins apoptosis in order to prevent the defects and errors from multiplying. Cancer cells always contain numerous mutations, errors or rearrangements in their chromosomal DNA. It is widely believed that this occurs in part because most tumors are deficient in one or more of the processes responsible for initiating apoptotic processes. Normal control mechanisms fail to kill cancer cells and the chromosomal or DNA coding errors continue to multiply. Consequently, restoration of these proapoptotic signals or suppression of dysregulated survival signals represent attractive means for cancer treatment.

It has long been known that a signaling pathway that includes the enzymes phosphatidylinositol 3-kinase (PI3K), PDK1, and PKB, among others, mediates increased resistance to apoptosis or survival responses in many cells. There is a significant amount of data indicating that this pathway is an important survival pathway used by many growth factors to suppress apoptosis. The PI3K enzyme is activated by a number of growth and survival factors, e.g. EGF, PDGF and through the formation of polyphosphatidylinositol, initiates the activation of downstream signaling events including the activity of the kinases PDK1 and protein kinase B (PKB) which is also known as Akt. This is particularly true in host tissues, e.g. vascular endothelial cells as well as neoplasias. PKB is a ser/thr kinase protein consisting of a kinase domain together with an N-terminal PH domain and a C-terminal regulatory domain. The PKB enzyme itself is phosphorylated at Thr 308 by PDK1 and at Ser 473 by an as yet unidentified kinase. Full activation requires phosphorylation at both sites, while the linkage between PIP3 and the PH domain is required to bind the enzyme to the cytoplasmic side of the lipid membrane, ensuring optimal access to substrates.

Activated PKB then phosphorylates the substrate scope thereby contributing to the overall pro-survival response. Although we cannot be sure that we understand all the factors responsible for

mediating the PKB-dependent pro-survival response, some important activities are believed to be - phosphorylation and inactivation of the pro-apoptotic factor BAD and caspase 9, phosphorylation of "forkhead" transcription factors e.g. FKHR, which leads to their expulsion from the nucleus, and activation of Nf kappa B pathways of signal transduction through phosphorylation of downstream kinases in the cascade.

In addition to the anti-apoptotic and pro-survival activities of the PKB signaling pathway, this enzyme also plays an important role in stimulating cell proliferation. This activity is again likely to be mediated through several activities, some of which are believed to be phosphorylation and inactivation of the cyclin-dependent kinase inhibitor p21Cipl/WAFl, and phosphorylation and activation of mTOR, a kinase that controls several aspects of cell growth.

The polyphosphatidylinositol dephosphorylating and inactivating phosphatase PTEN is a key tumor suppressor protein that normally functions by regulating the PI3K/PKB survival pathway. The importance of the PI3K/PKB pathway in tumorigenesis can be determined from the observation that PTEN is one of the most common target sites of mutation in human tumors, with mutations in this phosphatase found in -50% or more of melanomas (Guldberg et al 1997, Cancer Research 57, 3660-3663) and advanced prostate cancer (Cairns et al 1997 Cancer Research 57, 4997). These and other observations suggest that a wide variety of tumor types are dependent on enhanced PKB activity for growth and survival and would respond therapeutically to appropriate PKB inhibitors.

There are 3 closely related PKB isoforms called alpha, beta, and gamma, which genetic studies suggest have distinct but overlapping functions. Evidence suggests that they may all independently play a role in cancer. For example, PKB beta has been found to be overexpressed or activated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al 1995, Int. J. Cancer 64, 280-285; Cheng et al 1996, PNAS 93, 3636-3641 ; Yuan et al 2000, Oncogene 19, 2324 - 2330), PKB alpha is amplified in human gastric, prostate and breast cancers (Staal 1987, PNAS 84, 5034 - 5037; Sun et al 2001, Am. J. Pathol. 159, 431-437) and increased PKB gamma activity has been reported in steroid-independent breast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274, 21528 - 21532).

The PKB pathway also functions in the growth and survival of normal tissues and can be regulated during normal physiology to control cellular and tissue function. Thus, disorders associated with unwanted proliferation and survival of normal cells and tissues may also benefit therapeutically from PKB inhibitor treatment. Examples of such disorders are immune cell disorders associated with prolonged expansion and survival of a cell population that leads to a prolonged or regulated immune response. For example, the response of T and B lymphocytes to cognate antigens or growth factors such as interleukin-2 activates the PI3K/PKB pathway and is responsible for maintaining the survival of lymphocyte-specific clones.

antigen during an immune response. Under conditions in which lymphocytes and other immune cells respond to inappropriate self or foreign antigens, or in which their abnormalities lead to prolonged activation, the PKB pathway contributes to an important survival signal preventing the normal mechanisms by which the immune response terminates via apoptosis of the activated cell population . There is a significant amount of evidence that indicates the expansion of lymphocyte populations that respond to their own antigens in autoimmune conditions such as multiple sclerosis and arthritis. Expansion of lymphocyte populations that respond inappropriately to foreign antigens is a feature of another group of conditions such as allergic responses and asthma. In summary, inhibition of PKB could provide a useful treatment for immune disorders.

Other examples of inappropriate expansion, growth, proliferation, hyperplasia, and survival of normal cells in which PKB may play a role include, but are not limited to, atherosclerosis, cardiac myopathy, and glomerulonephritis.

In addition to its role in cell growth and survival, the PKB pathway functions in the control of glucose metabolism via insulin. Available evidence from mice deficient in the alpha and beta isoforms of PKB suggests that this activity is mediated through the beta isoform. As a consequence, modulators of PKB activity may also find application in diseases in which there is dysfunction of glucose metabolism and energy storage such as diabetes, metabolic disease and obesity.

Cyclic AMP-dependent protein kinase (PKA) is a serine/threonine protein kinase that phosphorylates a wide range of substrates and is involved in the regulation of many cellular processes including cell growth, cell differentiation, ion channel permeability, gene transcription, and synaptic neurotransmitter release. In its inactive form, the PKA holoenzyme is a tetramer containing two regulatory subunits and two catalytic subunits.

PKA acts as a link between signal transduction events mediated by G proteins and the cellular processes they regulate. Binding of a hormone ligand such as glucagon to the transmembrane receptor activates the receptor-coupled G protein (GTP-binding and hydrolyzing protein). Upon activation, the alpha subunit of the G protein cleaves, binds to, and activates adenylate cyclase, which then converts ATP to cyclic AMP (cAMP). The cAMP thus produced then binds to the regulatory subunit of PKA, leading to the separation of the associated catalytic subunits. Catalytic subunits of PKA, which are inactive when associated with regulatory subunits, become active after separation and participate in the phosphorylation of other regulatory proteins.

For example, the catalytic subunit of PKA phosphorylates the kinase - phosphorylase kinase, which is involved in the phosphorylation of phosphorylase, the enzyme responsible for breaking down glycogen to make

released glucose. PKA is also involved in the regulation of glucose levels through the phosphorylation and deactivation of glycogen synthase. Thus, modulators of PKA activity (modulators that can increase or decrease PKA activity) may be useful in the treatment or management of diseases in which there is dysfunction of glucose metabolism and energy storage such as diabetes, metabolic disease and obesity.

PKA was also found to be an acute inhibitor of T cell activation. Anndahl et al. investigated the possible role of type I PKA in HlV-induced T cell dysfunction on the basis that T cells from HlV-infected patients have increased levels of cAMP and are sensitive to inhibition by cAMP analogs compared to normal T cells. From their studies, they concluded that increased activation of PKA type I may contribute to progressive T cell dysfunction in HIV infection and that PKA type I may therefore be a potential target site for immunomodulatory therapy. -Aandahl, E. M, Aukrust, P., Skalhegg, B. S., Miiller, F., Fraland, S. S., Hansson, V., Tasken, K. Protein kinase A type I antagonist restores immune responses of T cells from HlV-infected patients. FASEB J. 12, 855-862 (1998).

It is also understood that mutations in the regulatory subunit of PKA can lead to hyperactivation in endocrine tissue.

Due to the diversity and importance of PKA as a messenger in cellular regulation, abnormal cAMP responses can lead to a number of different human diseases such as abnormal cell growth and proliferation (Stratakis, C.A.; Cho-Chung, Y.S.; Protein Kinase A and human diseases. Trends Endrocri. Metab. 2002, 13, 50-52). Overexpression of PKA has been reported in a number of different human cancer cells including those obtained from patients with ovarian, breast and colon cancer. Inhibition of PKA would therefore represent an approach for cancer treatment (Li, Q.; Zhu, G-D.; Current Topics in Medicinal Chemistry, 2002, 2, 939-971).

Za prikaz uloge PKA u humanim bolestima, videti na primer, Protein Kinase A and Human Disease, Edited by Constantine A. Stratakis, Annals of the New York Academv of Sciences, Volume 968, 2002, ISBN 1-57331-412-9.

Several classes of compounds have been described that have inhibitory activity against PKA and PKB.

For example, a class of isoquinolinyl-sulfonamido-diamines having inhibitory activity against PKB is described in WO 01/91754 (Yissum).

VVOO/07996 (Chiron) describes substituted pyrazoles that have estrogen prescription agonist activity. These compounds are described as useful in the treatment or prevention of, inter alia, estrogen receptor mediated breast cancer. No inhibitory activity against PKB has been described.

WO 00/31063 (Searle) discloses substituted pyrazole compounds as inhibitors of p38 kinase.

WO 01/32653 (Cephalon) describes a class of pyrazolone kinase inhibitors. WO 03/059884 (X-Ceptor Therapeutics) describes N-substituted pyridine compounds as nuclear receptor modulators.

WO 03/068230 (Pharmacia) describes substituted pyridones as p38 MAP kinase modulators.

WO 00/66562 (Dr Reddy's Research Foundation) describes a class of 1-phenyl-substituted pyrazoles for use as anti-inflammatory agents. The 1-phenyl group is substituted with a sulfur-containing substituent such as a sulfonamide or sulfonyl group.

Summary of the invention

The invention provides compounds that have protein kinase B (PKB) and protein kinase A (PKA) inhibitory or modulating activity, and which are expected to be useful in the prevention or treatment of diseases or conditions mediated through PKB or PKA.

In a first aspect, the invention provides a compound of formula (I):

ili jejunu so, solvate, tautomer or N-oxide;

wherein, A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R and NR R and a maximum chain length of 4 atoms extending between E and NR R , whereby one of the carbon atoms in the linker group can optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may bear one or more substituents selected from oxo, fluorine or hydroxy, with the proviso that the hydroxy group when present is not on the carbon atom a relative to the NR2R3 group and with the proviso that the oxo group when is present located on the carbon atom a in relation to the NR2R3 group;

E is a monocyclic, bicyclic carbocyclic or heterocyclic group;

R 1 is an aryl or heteroaryl group;

R2 and R3 are independently selected from the group consisting of hydrogen, Cm hydrocarbyl and Cm acyl, wherein the hydrocarbyl and acyl groups are optionally substituted with one or more substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy;

or R and R together with the nitrogen atom to which they are attached form a cyclic group selected from an imidazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N;

or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing another heteroatom as a ring member selected from O and N;

or NR R and the carbon atom of the linker group A to which it is attached together form a cyano group;

R4 is selected from the group consisting of hydrogen, halogen, C1.5 saturated hydrocarbyl, C1.5 saturated hydrocarbyloxy, cyano and CF3; and

R 5 is selected from the group consisting of hydrogen, halogen, C 1.5 saturated hydrocarbyl, C 1.5 saturated hydrocarbyloxy, cyano, CONH 2 , CONHR 9 , CF 3 , NH 2 , NHCOR 9 or NHCONHR 9 ;

R9 is the group R9a or (CH2)R9a, wherein R9a is a monocyclic or bicyclic group which can be carbocyclic or heterocyclic;

carbocyclic group or heterocyclic group R a is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino; a Ra-Rbu group wherein Ra is a bond, O, CO, X'C(X2), C(X2)X\ X1C(X2)X1, S, SO, SO2, NRC, SO2NRC or NRCSO2; and Rb is selected from the group consisting of hydrogen, heterocyclic groups having from 3 to 12 ring members, and Ci« a hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro , carboxy, amino, mono- or di-Ci^ hydrocarbylamino, carbocyclic or heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C\s hydrocarbyl group may be optionally replaced by O, S, SO , SO2, NRC, X'C(X2), C(X2)X' or X'C(X2)X';

R c is selected from the group consisting of hydrogen and C 1-4 hydrocarbyl; and

X1 is O, S or NRC and X2 is =O, =S or =NRC.

The invention also provides a compound of formula (Ia):

ili jejunu so, solvate, tautomer or N-oxide;

wherein, A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3 , whereby one of the carbon atoms in the linker group can optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluoro, and hydroxy, with the proviso that the hydroxy group, when present, is not located on the a carbon atom relative to the NR 2 R 3 group, and with the proviso that the oxo group, when present, is located on the carbon atom a in relation to the NR R group;

E is a monocyclic, bicyclic carbocyclic or heterocyclic group;

R 1 is an aryl or heteroaryl group;

R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1-4 hydrocarbyl and Q 1-4 acyl;

or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N;

or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing another heteroatom as a ring member selected from O and N;

or NR2R3 and the carbon atom of the linker group A to which it is attached together form a cyano group;

R4 is selected from the group consisting of hydrogen, halogen, C1-5 saturated hydrocarbyl, cyano and

CF3;i

R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano, CONH 2 , CONHR 9 , CF 3 , NH 2 , NHCOR 9 or NHCONHR 9 ;

R 9 is phenyl or benzyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino; group Ra-Rb in which, Ra is a bond, O, CO,

X1C(X2), C(X2)X', X1C(X2)X1, S, SO, SO2) NRC, SO2NRC or NRCSO2; and Rb is selected from the group consisting of hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy , amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having 3 to 12 ring members and wherein one or more carbon atoms of the d-g hydrocarbyl group can optionally be replaced by O, S, SO, SO2, NRC , XJC(X2), C(X2)XI or XiC(X2)XI;

Rc is selected from the group consisting of hydrogen and C1-4 hydrocarbyl; and

X1 is O, S or NRC and X2 is =O, =S or =NRC.

Also given are compounds of the general formula (lb):

ili their salts, solvates, tautomers or N-oxides;

wherein, A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3 , whereby one of the carbon atoms in the linker group can optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A can optionally carry one or more substituents selected from fluorine and hydroxy, with the proviso that the hydroxy group is not located on the a carbon atom relative to the NR2R3 group;

E is a monocyclic, bicyclic carbocyclic or heterocyclic group;

R 1 is an aryl or heteroaryl group;

R and R are independently selected from the group consisting of hydrogen, C1-4 hydrocarbyl and Q1-4 acyl;

or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N;

or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms of the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing another heteroatom as a ring member selected from O and N;

or NR R and the carbon atom of the linker group A to which it is attached together form a cyano group;

R 4 is selected from the group consisting of hydrogen, halogen, C 1.5 saturated hydrocarbyl, cyano and CF 3 ;

R 5 is selected from the group consisting of hydrogen, halogen, C 1.5 saturated hydrocarbyl, cyano, CONH 2 , CF 3 , NH 2 , NHCOR 9 or NHCONHR 9 ;

R is phenyl or benzyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino; a Ra-Rb group wherein, Ra is a bond, O, CO, X1C(X2), C(X2)X', X1C(X2)X1, S, SO, SO2, NRC, SO2NR° or NRCSO2; and Rb is selected from the group consisting of hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-Ci-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group can optionally be replaced by O, S , SO, SO2, NRC, x'C(X2), C(X2)X' or X1C(X2)X1;

Rc is selected from the group consisting of hydrogen and C1-4 hydrocarbyl; and

X1 is O, S or NRC and X2 is =O, =S or -NRC.

The invention further provides:

* A compound per se of formula (II), (III), (IV), (V) or any other subgroup or variant of formula (I) as defined herein.

* A compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any other subgroup thereof as defined herein for use in the prevention or treatment of a disease or condition mediated through protein kinase B.

* Use of a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups as defined herein for the manufacture of a medicament for the prevention or treatment of a disease mediated by via protein kinase B.

* A method for the prevention or treatment of a disease or condition mediated by protein kinase B, wherein the method includes application to a subject in need thereof

compounds of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any subgroup thereof as defined herein.

* A method for treating a disease or condition comprising or originating from abnormal cell proliferation or abnormally arrested cell death in a mammal, wherein said method comprises administering to the mammal a compound of formula (I), (Ia), (lb), (II), (III) , (IV), (V) or any subgroup thereof as defined herein in an amount effective to inhibit protein kinase B activity.

* A method for inhibiting protein kinase B, wherein said method comprises bringing the kinase into contact with a compound that inhibits the kinase of formula (I), (Ia), (lb), (II), (III), (IV), (V) or by which subgroup thereof as defined here.

* A method for modulating cellular processes (eg cell division) by inhibiting protein kinase B activity using a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups as defined herein.

* A compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any subgroup or variant thereof as defined herein for use in the prevention or treatment of a disease or condition mediated via protein kinase A.

* Use of a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups or variants as defined herein for the production of a drug for the prevention or treatment of a disease or state mediated by protein kinase A.

* A method for the prevention or treatment of a disease or condition mediated through protein kinase A, wherein said method comprises application to a subject in need of the compounds of formula (I), (Ia), (lb), (II), (III), ( IV), (V) or any of its subgroups or variants as defined herein.

* A method for treating a disease or condition comprising or originating from abnormal cell growth or abnormally arrested cell death in a mammal, wherein the method comprises administering to the mammal a compound of formula (I), (Ia), (lb), (II), (III) , (IV), (V) or any subgroup or variant thereof as defined herein in an amount effective in inhibiting protein kinase A activity.

* A process for inhibiting protein kinase A, wherein the process comprises contacting the kinase with a compound that inhibits the kinase of formula (I), (Ia), (lb), (II), (III), (IV), (V) or by any of its subgroups or variants as defined here.

* A method for modulating cellular processes (eg cell division) by inhibiting protein kinase A activity using a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups or variants as defined herein.

* Use of a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups or variants as defined herein for the production of a drug for the prevention or treatment of a disease or a condition resulting from abnormal cell growth or abnormally arrested cell death.

* A method for the treatment of a disease or condition comprising or originating from an abnormal mast cell in a mammal, wherein the method comprises administering to the mammal a compound of formula (I), (Ia), (lb), (II), (III), (IV) , (V) or any subgroup thereof as defined herein in an amount effective in inhibiting abnormal cell growth or abnormally arrested cell death.

* A method for alleviating or reducing the incidence of a disease or condition comprising abnormal cell growth or abnormally arrested cell death in a mammal, said method comprising administering to the mammal a compound of formula (I), (Ia), (lb), (II) , (III), (IV), (V) or any subgroup thereof as defined herein in an amount effective in inhibiting abnormal cell growth.

* A pharmaceutical composition containing a novel compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any subgroup thereof as defined herein and a pharmaceutically acceptable carrier.

* A compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any subgroup thereof as defined herein for use in medicine.

* Use of a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any subgroup thereof as defined herein for the manufacture of a medicament for the prevention or treatment of any disease or conditions listed here.

* A method for the treatment or prevention of any disease or condition set forth herein, wherein said method comprises administering to a patient (e.g., a patient in need thereof) a compound (e.g., a therapeutically effective amount) of formula (I), (Ia) , (lb), (II), (III), (IV), (V) or any subgroup thereof as defined herein.

* A method for alleviating or reducing the incidence of a disease or condition listed herein, wherein the method comprises administering to a patient (e.g., a patient in need thereof) a compound (e.g., a therapeutically effective amount) of formula (I), (Ia), ( lb), (II), (III), (IV), (V) or any subgroup thereof as defined herein.

* A method for the diagnosis and treatment of a protein kinase B-mediated disease or condition, the method comprising (i) screening a patient to determine whether the disease or condition from which the patient suffers or may suffer is one that would be amenable to treatment with a compound that has activity against protein kinase B; and (ii) in the case where it is indicated that the disease or condition to which the patient is thus susceptible, then administration to the patient of compounds of formula (I), (Ia), (lb), (II), (III), (IV) ), (V) or any of its subgroups as defined herein.

* Use of a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups as defined herein for the manufacture of a medicament for the treatment or prevention of a disease in a patient who has been observed and has been determined to be suffering from, or at risk of developing, a disease or condition that would be amenable to treatment with a compound that has activity against protein kinase B.

* A method for the diagnosis and treatment of a disease or condition mediated through protein kinase A, the method comprising (i) screening a patient to determine whether the disease or condition from which the patient suffers or may suffer is one that would be amenable to treatment with a compound that has activity against protein kinase A; and (ii) in the case where it is indicated that the disease or condition is the disease or condition to which the patient is thus susceptible, then administration to the patient of compounds of formula (I), (Ia), (lb), (II), (III) ), (IV), (V) or any of its subgroups as defined herein.

* Use of a compound of formula (I), (Ia), (lb), (II), (III), (IV), (V) or any of its subgroups or variants as defined herein for the production of a drug for the treatment or prevention of a disease or conditions in a patient who has been observed and has been determined to suffer from, or to be at risk of developing, a disease or condition that would be amenable to treatment with a compound that has anti-protein kinase A activity.

General preferences and definitions

The following general preferences and definitions shall apply to each of Groups A, E and R1 through R5 and R9 and any sub-definition, subgroup or variant thereof, unless the context indicates otherwise.

Any mention of Formula (I) herein shall be deemed to include formulas (Ia), (lb), (II), (III), (IV), (V) and any other subgroup of compounds within formula (I). unless the context requires otherwise.

Reference to "carbocyclic" and "heterocyclic" groups as used herein shall include, unless the context indicates otherwise, both aromatic and non-aromatic ring systems. In general, such groups may be monocyclic or bicyclic and may contain, for example, 3 to 12 ring members, typically 5 to 10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, usually 3

up to 7, and preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and usually 9 or 10 ring members.

Carbocyclic or heterocyclic groups can be aryl or heteroaryl groups having from 5 to 12 ring members, usually from 5 to 10 ring members. The term "aryl" as used herein refers to a carbocyclic group having aromatic character and the term "heteroaryl" is used herein to refer to a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl" include polycyclic (eg, bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group can be attached via an aromatic ring, or via a non-aromatic ring. Aryl or heteroaryl groups may be monocyclic or bicyclic groups and may be unsubstituted or substituted with one or more substituents, for example one or more R 10 groups as defined herein.

The term non-aromatic group includes unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "unsaturated" and "partially saturated" refer to rings in which the ring structure(s) contain atoms that share more than a monovalent bond, i.e. ring contains at least one multiple bond e.g. C=C, C=C or N=C bond. The term "fully saturated" refers to rings in which there are no multiple bonds between atoms in the ring. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and typically from five to ten ring members. A heteroaryl group can be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed by fused five- and six-membered rings or two fused six-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, usually up to 2, eg one heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in heteroaryl rings can be basic, as in the case of imidazole or pyridine, or mostly non-basic as in the case of nitrogen in indole or pyrrole. In general, the number of base nitrogen atoms present in the heteroaryl group, including any amino ring substituents, will be less than five.

Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole, and tetrazole groups.

Examples of six-membered heteroaryl groups include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

A bicyclic heteroaryl group can be, for example, a group selected from:

a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring;

d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring;

f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 heteroatoms in the ring;

g) oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

1) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring;

m) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

n) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

o) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and

p) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

Examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (eg, adenine, guanine), indazole, benzodioxole and pyrazolopyridine groups.

Examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chromane, thiochromane, chromene, isochromene, chromane, isochromane, benzodioxane, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline , phthalazine, naphthyridine and pteridine groups.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran, 2,3-dihydrobenzo[l,4]dioxin, benzo[l,3]dioxole, 4,5, 6,7-tetrahydrobenzofuran, indoline and indane groups.

Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl groups.

Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, typically 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, and typically have from 1 to 5 heteroatoms as ring members (typically 1, 2, 3 or 4 heteroatoms as ring members), usually selected from nitrogen, oxygen and sulfur.

Heterocyclic groups may include, for example, cyclic ether groups (e.g., as in tetrahydrofuran and dioxane), cyclic thioether groups (e.g., as in tetrahydrothiophene and dithiane), cyclic amino groups (e.g., as in pyrrolidine), cyclic sulfones (e.g. .as in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides, and combinations thereof (eg, thiomorpholine). Other examples of non-aromatic heterocyclic groups include cyclic amide groups (eg, as in pyrrolidone) and cyclic ester groups (eg, as in butyrolactone).

Examples of monocyclic non-aromatic heterocyclic groups include 5-, 6- and 7-membered monocyclic heterocyclic groups. Specific examples include morpholine, thiomorpholine and its S-oxide and S,S-dioxide (especially thiomorpholine), piperidine (eg 1-piperidinyl, 2-piperidinyl 3-piperidinyl and 4-piperidinyl), N-alkyl piperidine such as N -methyl piperidine, piperidone, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran (2H-pyran or

4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazol, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydropyranyl), imidazolin, imidazolidinone, oxazolin, thiazolin, 2-pyrazolin, pyrazolidine, piperazone, piperazine and N-alkyl piperazin kao što su N-metil piperazin, N-etil piperazin i N-isopropylpiperazin.

One subgroup of monocyclic non-aromatic heterocyclic groups includes morpholine, piperidine (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), piperidone, pyrrolidine (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine , piperazone, piperazine and N-alkyl piperazine such as N-methyl piperazine. In general, preferred non-aromatic heterocyclic groups include piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkyl piperazine. A further specific example of a non-aromatic heterocyclic group, which also forms part of the aforementioned group of preferred non-aromatic heterocyclic groups, is azetidine.

Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.

Each of the definitions of carbocyclic and heterocyclic groups in this specification may optionally exclude any one or any combination of two or more of the following groups:

* substituted or unsubstituted pyridone rings;

* substituted or unsubstituted pyrolo[1,2-a]pyrimid-4-one;

* substituted or unsubstituted pyrazolones.

Where carbocyclic and heterocyclic groups are mentioned, the carbocyclic or heterocyclic ring may, unless the context otherwise dictates, be unsubstituted or substituted with one or more substituent groups R10 selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-Ci^ hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein, Ra is a bond, O, CO, X*C(X2), C(X2)X', X1C(X2)X1, S, SO, SO2, NRC, SO2NRC or NRCSO2; and Rb is selected from the group consisting of hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups which

have from 3 to 12 members in the ring and one or more carbon atoms of the Ci.8 hydrocarbyl group can be optionally replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X! or X1C(X2)X1;

Rc is selected from the group consisting of hydrogen and Cm hydrocarbyl; and

X1 is O, S or NRC and X2 is O, =S or =NRC.

In the case where the substituting group R10 contains or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted with one or more additional substituting groups R10. In one subgroup of compounds of formula (I), such additional substituting groups R 10 may comprise carbocyclic or heterocyclic groups, which are typically not further substituted. In the following subgroup of compounds of formula (I), the specified additional substituents do not include carbocyclic or heterocyclic groups, but are otherwise selected from the groups mentioned in the preceding text in the definition for R10.

The substituents R 10 may be chosen to contain no more than 20 non-hydrogen atoms, for example no more than 15 non-hydrogen atoms, e.g. not more than 12, or 10, or 9, or 8, or 7, or 6, or 5 non-hydrogen atoms.

In the case where carbocyclic and heterocyclic groups have a pair of substituents on adjacent ring atoms, the two substituents may be bonded to form a cyclic group. For example, an intended pair of substituents on adjacent ring carbon atoms may be attached via one or more heteroatoms and optionally substituted alkylene groups to form a fused oxa-, dioxa-, aza-, diaza-, or oxa-aza-cycloalkyl group. Examples of such bonded substituent groups include:

Examples of halogen substituents include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferred.

In the definition of compounds of formula (I) from the preceding text and as used hereinafter, the term "hydrocarbyl" is a generic term that includes aliphatic, alicyclic and aromatic groups having an all-carbon backbone, unless otherwise specified.

indicated. In certain cases, as defined herein, one or more carbon atoms making up the carbon backbone may be replaced by an indicated atom or group of atoms. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl, and aralkynyl groups. Such groups may be unsubstituted or, where indicated, may be substituted with one or more substituents as defined herein. The examples and preferences set forth below apply to each of the hydrocarbyl substituent groups or hydrocarbyl-containing substituent groups described in the various definitions of substituents for compounds of formula (I) unless the context dictates otherwise.

In general, for example, hydrocarbyl groups can have up to eight carbon atoms, unless the context dictates otherwise. Within the subgroup of hydrocarbyl groups having 1 to 8 carbon atoms, particular examples are C1-6 hydrocarbyl groups, such as C1-4 hydrocarbyl groups (eg, C1-3 hydrocarbyl groups or C1-2 hydrocarbyl groups), examples of which are any single value or a combination of values selected from C1, C2, C3, C4, C5, C6, C7 and C8 hydrocarbyl groups.

The term "alkyl" covers both straight chain and branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-butyl, 3-methyl butyl and n-hexyl and their derivatives. isomers. Within the subgroup of alkyl groups having 1 to 8 carbon atoms, particular examples are C1-6 alkyl groups, such as C1-4 alkyl groups (eg, C1-3 alkyl groups or C1-2 alkyl groups).

Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the subgroup of cycloalkyl groups, a cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being C3-6 cycloalkyl groups.

Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, and hexenyl. Within the sub-group of alkenyl groups, an alkenyl group will have 2 to 8 carbon atoms, particular examples being C2-6 alkenyl groups, such as C2-4 alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl. Within the subgroup of cycloalkenyl groups, cycloalkenyl groups have from 3 to 8 carbon atoms, and particular examples are C3-6 cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the subgroup of alkynyl groups having 2 to 8 carbon atoms, particular examples are C2-6 alkynyl groups, such as C2-4 alkynyl groups.

Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl, naphthyl, indane and indene groups.

Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups.

When present, and where indicated, the hydrocarbyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C1-4 hydrocarbylamino , and monocyclic, bicyclic carbocyclic and heterocyclic groups having from 3 to 12 (typically 3 to 10 and usually 5 to 10) ring members. Preferred substituents include halogen such as fluorine. Thus, for example, a substituted hydrocarbyl group may be a partially fluorinated or perfluorinated group such as difluoromethyl or trifluoromethyl. In one embodiment, preferred substituents include monocyclic carbocyclic and heterocyclic groups having 3-7 ring members.

Where indicated, one or more carbon atoms of the hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X1 or X1C(X2)X1 (or a subgroup thereof), in wherein, X1 and X2 are as defined herein, with the proviso that at least one carbon atom of the hydrocarbyl group remains. For example, 1, 2, 3 or 4 carbon atoms of the hydrocarbyl group may be replaced by one of the aforementioned atoms or groups, and the replacing atoms or groups may be the same or different. In general, the number of linear carbon atoms or backbone carbon atoms that are replaced will correspond to the number of linear backbone atoms or atoms in the group that replaces them. Examples of groups in which one or more carbon atoms of the hydrocarbyl group have been replaced by a substituent atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X' C(X2) or C(X2)X1), sulfones and sulfoxides (C replaced by SO or SO2), amine (C replaced by NRC). Additional examples include ureas, carbonates, and carbamates (C-C-C replaced by X1C(X2)X1).

In the case where the amino group has two hydrocarbyl substituents, they can, together with the nitrogen atom to which they are attached, and optionally with another heteroatom such as nitrogen, sulfur or oxygen, bond to form a ring structure of 4 to 7 members in the ring.

The definition of "Ra-Rb" as used herein, either in relation to substituents present on a carbocyclic or heterocyclic group, or in relation to other substituents present elsewhere on compounds of formula (I), includes, inter alia, compounds in which Ra is selected from the group consisting of the bond, O, CO, OC(O), SC(O), NRCC(O), OC(S), SC(S),

NRCC(S), OC(NRC), SC(NRC), NRCC(NRC), C(O)O, C(O)S, C(O)NRC, C(S)O, C(S)S, C(S)NRC, C(NRC)O, C(NRC)S, C(NRC)NRC, OC(O)O, SC(O)O, NRCC(O)O, OC(S)O, SC( S)O, NRCC(S)O, OC(NRC)O, SC(NRC)O, NRCC(NRC)O, OC(O)S, SC(O)S, NRCC(O)S, OC(S) S, SC(S)S, NRCC(S)S, OC(NRC)S, SC(NRC)S, NRCC(NRC)S, OC(O)NRC, SC(O)NRC, NRCC(O)NRC, OC(S)NRC, SC(S)NRC, NRCC(S)NRC, OC(NRC)NRC, SC(NRC)NRC, NRCC(NRC)NRC, S, SO, SO2, NRC, SO2NRC i NRCSO2 u kojima je Rc kao što je defmisano u prethodnom textu.

The group Rb may be hydrogen or may be a group selected from carbocyclic and heterocyclic groups having from 3 to 12 ring members (typically 3 to 10 and usually from 5 to 10), and a Ci.8 hydrocarbyl group optionally substituted such as defined in the previous text. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are as indicated above.

When Ra is O and Rb is a C1-8 hydrocarbyl group, Ra and Rb together form a hydrocarbyloxy group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy such as alkoxy (e.g., C1-6 alkoxy, usually C1-6 alkoxy such as ethoxy and methoxy, especially methoxy), cycloalkoxy (e.g., C3-4 cycloalkyloxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkylalkoxy (e.g. C3.6 cycloalkyl-C1-2 alkoxy such as cyclopropylmethoxy).

Hydrocarbyloxy groups may be substituted with various substituents as defined herein. For example, alkoxy groups can be substituted with halogen (eg, as in difluoromethoxy and trifluoromethoxy), hydroxy (eg, as in hydroxyethoxy), C1-2 alkoxy (eg, as in methoxyethoxy), hydroxy-C1-2 alkyl (as in hydroxyethoxyethoxy ) or a cyclic group (eg a cycloalkyl group or a non-aromatic heterocyclic group as defined above). Examples of alkoxy groups bearing a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, Ct-4-alkyl-piperazines, C3-7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran. and the alkoxy group is a C 1-4 alkoxy group, typically a C 1-3 alkoxy group such as methoxy, ethoxy or n-propoxy.

Alkoxy groups can be substituted with, for example, a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and their N-substituted derivatives such as N-benzyl, N-C14 acyl and N-C1.4 alkoxycarbonyl. Specific examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.

When Ra is a bond and Rb is a C1-8 hydrocarbyl group, examples of the hydrocarbyl groups Ra-Rb are as defined above. Hydrocarbyl groups can be saturated groups such as

cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl. Hydrocarbyl (eg, alkyl) groups may be substituted with various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted with one or more halogen atoms such as fluorine and chlorine (particular examples include bromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethyl and perfluoroalkyl groups such as trifluoromethyl), or hydroxy (e.g. . is methoxy - as in methoxyethyl), and cyclic groups such as cycloalkyl groups, aryl groups, heteroaryl groups and non-aromatic heterocyclic groups as defined above).

Particular examples of alkyl groups substituted with a cyclic group are those in which the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C14-alkyl-piperazines, C3-7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is A C 1 -C 3 alkyl group, typically a C 1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted with a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and their N-substituted forms as defined herein.

Particular examples of alkyl groups substituted with aryl groups and heteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.

When Ra equals SO2NRC, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb wherein Ra is SO2NRC include aminosulfonyl, C1-4 alkylaminosulfonyl and di-C1-4 alkylaminosulfonyl groups, and sulfonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as is N-methyl piperazine.

Examples of Ra-Rb groups in which Ra is SO2 include alkylsulfonyl, heteroarylsulfonyl and arylsulfonyl groups, especially monocyclic aryl and heteroarylsulfonyl groups. Particular examples include methylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When Ra equals NRC, Rb can be, for example, hydrogen or optionally substituted C1. 8 hydrocarbyl group, or carbocyclic or heterocyclic group. Examples of Ra-Rb wherein Ra is NRC include amino, Cm alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C1-4 alkylamino (e.g., dimethylamino and diethylamino), and cycloalkylamino (e.g., cyclopropylamino , cyclopentyl amino and cyclohexylamino).

Special variants and preferences for A. E. R1 to R5 and R9 Group "A"

In formula (I), A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3. Within these restrictions, groups E and R1 can each be attached anywhere on group A.

The term "maximum chain length" as used herein refers to the number of atoms lying directly between the two groups in question, and disregards any branching in the chain or any hydrogen atoms that may be present. For example, in structure A shown below:

the chain length between R1 and NR2R3 is 3 atoms, while the chain length between E and NR2R3 is equal to 2 atoms. In general, it is currently preferred that the linker group has a maximum chain length of 3 atoms (eg 1 or 2 atoms).

In one embodiment, the linker group has a chain length of 1 atom extending between R1 and

NR2R3.

In another embodiment, the linker group has a chain length of 2 atoms extending in between

R1 i NR2R3.

In another embodiment, the linker group has a chain length of 3 atoms extending between R1 and NR2R3.

Preferably, the linker group has a maximum chain length of 3 atoms extending between E and NR2R3.

In one particularly preferred group of compounds, the linker group has a chain length of 2 or 3 atoms extending between R and NR R and a chain length of 2 or 3 atoms extending between E and NR 2 R 3 .

One of the carbon atoms in the linker group can be optionally replaced by an oxygen or nitrogen atom.

When present, the nitrogen atom may be attached directly to the E group.

In one embodiment, the carbon atom to which the R group is attached is replaced by an oxygen atom.

In another embodiment, R 1 and E are attached to the same carbon atom of the linker group, and the carbon atom in the chain extending between E and NR R is replaced by an oxygen atom.

When a nitrogen atom or oxygen atom is present, preferably the nitrogen atom or oxygen atom and the NR 2 R 3 group are separated by at least two intervening carbon atoms.

In one particular group of compounds within formula (I), the linker atom attached directly to group E is a carbon atom and the linker group A has a skeleton that is all carbon.

The carbon atoms of the linker group A can optionally carry one or more substituents selected from the group consisting of oxo, fluorine and hydroxy, with the condition that the hydroxy group is not located on the carbon atom a in relation to the NR2R3 group, and also with the condition that the oxo group is located on the carbon atom a in relation to the NR2R3 group. Typically, the hydroxy group, if present, is in the P position relative to the NR2R3 group. In general, no more than one hydroxy group will be present. In the case where fluorine is present, it may be present as a single fluorine substituent or may be present in a difluoromethylene or trifluoromethyl group, for example. In one embodiment, the fluorine atom is located at the (3) position relative to the NR2R3 group.

It will be understood that when an oxo group is present on the carbon atom adjacent to the NR2R3 group, the compound of formula (I) will be an amide.

In one embodiment of the invention, no fluorine atom is present in the linker group A.

In the next variant of the invention, no hydroxy groups are present in the linker group A.

In another embodiment, no oxo group is present in the linker group A.

In one group of compounds of formula (I) neither hydroxy groups nor fluorine atoms are present in the linker group A, e.g. the linker group A is unsubstituted.

Preferably, when the carbon atom in the linker group A is replaced by a nitrogen atom, the A group carries no more than one hydroxy substituent and more preferably carries no hydroxy substituents.

When there is a chain of four atoms in length between E and NR2R3, it is preferred that the linker group A contains no nitrogen atoms and more preferably has a skeleton that is all carbon.

In order to modify the compound for metabolic degradation in vivo, the linker group A can have a branched configuration on the carbon atom that is attached to the NR2R3 group. For example, the carbon atom attached to the NR2R3 group may be attached to a pair of gem-dimethyl groups.

In one particular group of compounds of formula (I), the R'-A-NR2R3 portion of the compound is represented by the formula R^G)k-(CH2)m-W-Ob-(CH2)n-(CR6R7)p-NR2R3 wherein, G is NH, NMe or O; W is attached to group E and selected from (CH2)j-CR20, (CH2)j-N and (NH)jCH; b is 0 or 1,

j is 0 or 1, k is 0 or l, m is O or l, n is O, 1, 2 or 3 and p is 0 or 1; the sum of b and k is 0 or 1; the sum of j, k, m, n and p does not exceed 4; R 6 and R 7 are the same or different and are selected from methyl and ethyl, or CR 6 R 7 forms a cyclopropyl group; and R 20 is selected from the group consisting of hydrogen, methyl, hydroxy and fluorine;

In the following subgroup of compounds of formula (I), the R1-A-NR2R3 portion of the compound is represented by the formula R1-(G)k-(CH2)m-X-(CH2)n-(CR6R7)p-NR2R3 wherein, G is NH, NMe or O; X is attached to group E and is selected from (CH2)j-CH, (CH2)j-N and (NH)j-CH; j is 0 or 1, kje is 0 or 1, m is

0 or 1, n is 0, 1, 2 or 3 and p is 0 or 1, and the sum of j, k, m, n and p does not exceed 4; and R 6 and R 7 are the same or different and are selected from methyl and ethyl, or CR 6 R 7 forms a cyclopropyl group.

A special group of CR6R7 is C(CH3)2. Preferably X is (CH2)j-CH.

Particular configurations where the R'-A-NR2R3 part of the compound is represented by the formula R1-(G)k-(CH2)m-X-(CH2)n-(CR6R7)P-NR2R3 are those in which:

* k is 0, m is 0 or 1, n is 0, 1, 2 or 3 and p is 0. where l,m is 0, n is 0, 1, 2 or 3 and 0.

* X is (CH2)j-CH, k is 1, m is 0, n is 0, 1 or 2 and p is 1.

* X is (CH2)rCH, G is O, k is 1, mje is 0, n is 0, 1, 2 or 3 and p is 0.

Particular configurations in which the R1-A-NR2R3 portion of the compound is represented by the formula R1-(G)k-(CH2)m-W-Ob-(CH2)n-(CR6R7)p-NR2R3 are those in which:

* k is 0, mje 0, W is (CH2)rCR20, j is 0, R20 is hydrogen, b is 1, nje is 2 and p is 0.

* k is 0, mje is 0, W is (CH2)rCR20, j is 0, R20 is hydroxy, b is 0, nje is 1 and p is 0.

* k is 0, mje 0, W is (CH2)j-CR20, j is 0, R20 is methyl, bje is 0, nje is 1 and p is 0.

* k is 0, m is 0, W is (CH2)j-CR20, j is 0, R20 is fluorine, b is 0, n is 1 and p is 0.

In one preferred configuration, the R*-A-NR2R3 moiety of the compound is represented by the formula R1-X-(CH2)n-NR2R3 wherein, X is attached to the group E and it is the group CH, and it 2.

Particular examples of linker group A, together with their attachment points for groups R1, E

and NR R , are shown in Table 1 below.

Table 1

Currently preferred groups include A1, A2, A3, A6, A10, A1, A22 and A23. One particular set of groups comprises Al, A2, A3, Al 0 and Al 1. The next particular set of groups comprises A2 and Al 1. The next particular set of groups comprises A6, A22 and A23. The next set of groups includes Al, A2 and A3.

In group A2, an asterisk indicates a chiral center. Compounds having an R configuration at this chiral center represent a preferred subgroup of compounds according to the invention.

R1

The group R 1 is an aryl or heteroaryl group and may be selected from the list of such groups set forth in the section entitled General Preferences and Definitions.

R 1 can be monocyclic and bicyclic and, in one preferred embodiment, is monocyclic. Particular examples of monocyclic aryl and heteroaryl groups are six-membered aryl and heteroaryl groups containing up to 2 nitrogens as ring members, and five-membered heteroaryl groups containing up to 3 heteroatoms as ring members selected from O, S and N.

Examples of such groups include phenyl, naphthyl, thienyl, furane, pyrimidine and pyridine, with phenyl being currently preferred.

The group R1 may be unsubstituted or substituted with up to 5 substituents, and examples of substituents are those listed in the group R10 above.

Particular substituents include hydroxy; C1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; CONH2; nitro; C1-4 hydrocarbyloxy and C1-4 hydrocarbyl, each of which is optionally substituted with C1-2 alkoxy, carboxy or hydroxy; C1-4 acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; five- and six-membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S; phenyl; phenyl-C 1 -alkyl; phenyl-C1-4 alkoxy; heteroaryl-C1-4 alkyl; heteroaryl-C1-4 alkoxy and phenoxy, wherein each of heteroaryl, heteroaryloxy, phenyl, phenyl-C1-4 alkyl, phenyl-C1-4 alkoxy, heteroaryl-C1-4 alkyl, heteroaryl-C1-4 alkoxy and phenoxy is a group optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-2 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, CONH2, C1-2 hydrocarbyloxy and C1-2 hydrocarbyl, each of which is optionally substituted with methoxy or hydroxy.

Preferred substituents include hydroxy; C1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; C1-4 hydrocarbyloxy and C1-4 hydrocarbyl, each of which is optionally substituted with C1-2 alkoxy or hydroxy; C1-4 acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; five- and six-membered heteroaryl groups containing one or two heteroatoms selected from N, O and S, wherein the heteroaryl groups are optionally substituted with one or more C1-4 alkyl substituents; phenyl; pyridyl; and phenoxy, wherein each of the phenyl, pyridyl and phenoxy groups is optionally substituted with 1, 2 or 3 substituents selected from C1-2 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, C1-2 hydrocarbyloxy and C1-2

hydrocarbyl, each of which is optionally substituted with methoxy or hydroxy.

In one subgroup of compounds, the substituents for R 1 are selected from the group consisting of hydroxy; C1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; C1-4 hydrocarbyloxy and C1-4 hydrocarbyl, each of which is optionally substituted with C1-2 alkoxy or hydroxy.

Although up to 5 substituents may be present, typically there are 0, 1, 2, 3 or 4 substituents, preferably 0, 1, 2 or 3, and more preferably 0, 1 or 2.

In one embodiment, the group R is unsubstituted or substituted with up to 5 substituents selected from the group consisting of hydroxy; C1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; C1-4 hydrocarbyloxy and C1-4 hydrocarbyl, each of which is optionally substituted with C1-2 alkoxy or hydroxy.

In another embodiment, the group R1 may have one or two substituents selected from the group consisting of hydroxy, fluoro, chloro, cyano, phenyloxy, pyrazinyloxy, benzyloxy, methyl and methoxy.

In another embodiment, the group R1 may have one or two substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl and methoxy.

When R 1 is a phenyl group, particular examples of combinations of substituents include mono-chlorophenyl and dichlorophenyl.

Additional examples of combinations of substituents include those wherein R 1 is hydroxyphenyl, fluorochlorophenyl, cyanophenyl, methoxyphenyl, methoxy-chlorophenyl, fluorophenyl, difluorophenyl, phenoxyphenyl, pyrazinyloxyphenyl or benzyloxyphenyl.

When R 1 is a six-membered aryl or heteroaryl group, the substituent may conveniently be present in the para position on the six-membered ring. In the case where the substituent is present in the para position, it is preferably larger than the fluorine atom.

R2 and R3

In one group of compounds of formula (I), R and R3 are independently selected from the group consisting of hydrogen, C1-4 hydrocarbyl and C1-4 acyl, wherein the hydrocarbyl and acyl groups are optionally substituted with one or more substituents selected from consisting of fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy.

When the hydrocarbyl group is substituted with a hydroxy, amino, methylamino, dimethylamino or methoxy group, there are typically at least two carbon atoms between the substituent and the nitrogen atom of the NR 2 R 3 group. Particular examples of substituted hydrocarbyl groups are hydroxyethyl and hydroxypropyl.

In the next group of compounds according to the invention, R 2 and R 3 are independently selected from the group consisting of hydrogen, C 1-4 hydrocarbyl and C 1-4 acyl.

Typically, the hydrocarbyl group, whether substituted or unsubstituted, is an alkyl group, usually a C 1 , C 2 or C 3 alkyl group, and preferably a methyl group. In a particular subset of compounds, R 2 and R 3 are independently selected from hydrogen and methyl and thus NR 2 R 3 can be an amino, methylamino or dimethylamino group. In a particular embodiment, NR2R3 can be an amino group. In another particular embodiment, NR 2 R 3 may be a methylamino group.

In an alternative embodiment, the C1-4 hydrocarbyl group can be a cyclopropyl, cyclopropylmethyl or cyclobutyl group.

In the next group of compounds, R2 and R3 together with the nitrogen atom to which they are attached form a cyclic group selected from the imidazole group and saturated monocyclic

heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N.

In the next group of compounds, R and R together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N.

A saturated monocyclic heterocyclic group may be unsubstituted or substituted with one or more substituents R 10 as defined above in the General Preferences and Definitions section. Typically, however, all substituents on the heterocyclic group will be relatively small substituents such as C1-4 hydrocarbyl (eg, methyl, ethyl, n-propyl, /-propyl, cyclopropyl, n-butyl, sec-butyl, and tert-butyl), fluorine, chlorine, hydroxy, amino, methylamino, ethylamino and dimethylamino. Particular substituents are methyl groups.

The saturated monocyclic ring may be an azacycloalkyl group such as an azetidine, pyrrolidine, piperidine or azepane ring, and such rings are typically unsubstituted. Alternatively, the saturated monocyclic ring may contain an additional heteroatom selected from O and N, and examples of such groups include morpholine and piperazine. Where an additional N atom is present in the ring, it may form part of an NH group or an N-C1-4 alkyl group such as an N-methyl, N-ethyl, N-propyl or N-isopropyl group.

Where NR2R3 forms an imidazole group, the imidazole group may be unsubstituted or substituted, for example with one or more relatively small substituents such as C1-4 hydrocarbyl (eg methyl, ethyl, propyl, cyclopropyl and butyl), fluoro, chloro, hydroxy , amino, methylamino, ethylamino and dimethylamino. Particular substituents are methyl groups.

In the next group of compounds, one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N.

Examples of such compounds include compounds in which NR 2 R 3 and A form a unit of the formula:

wherein each t and u are 0, 1, 2 or 3, provided that the sum of t and u is within the range of 2 to 4. Additional examples of such compounds include compounds wherein NR 2 R 3 and A form a cyclic group of the formula:

in which v and w are each 0, 1, 2, or 3, provided that the sum of v and w is within the range of 2 to 5. Particular examples of cyclic compounds are those in which v and w are both equal to 2.

Additional examples of such compounds include compounds in which NR 2 R 3 and A form a cyclic group of the formula:

in which x and w are each 0, 1, 2, or 3, provided that the sum of x and w is in the range 2 to 4. Particular examples of cyclic units are those in which x is 2 and w is 1.

R4

In formula (I), R is selected from the group consisting of hydrogen, halogen, C1-5 saturated hydrocarbyl, C1-5 saturated hydrocarbyloxy, cyano and CF3.

Typically, R 4 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano and CF 3 . Preferred values for R4 include hydrogen and methyl. In a particular embodiment, R 4 is hydrogen.

R5

In formula (I), R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, C 1-5 saturated hydrocarbyloxy, cyano, CONH 2 , CONHR 9 , CF 3 , NH 2 , NHCOR 9 and NHCONHRR 9 ; NHCONHR9 wherein, R9 is the group R9a or (CH2)R9a, wherein R9a is an optionally substituted monocyclic or bicyclic group which may be carbocyclic or heterocyclic.

Examples of carbocyclic and heterocyclic groups are listed in the General Preferences and Definitions section.

Typically, carbocyclic and heterocyclic groups are monocyclic.

Preferably, the carbocyclic and heterocyclic groups are aromatic.

Particular examples of the group R9 are optionally substituted phenyl or benzyl.

Preferably, R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano, CONH 2 , CONHR 9 , CF 3 , NH 2 , NHCOR 9 and NHCONHR 9 wherein R 9 is optionally substituted phenyl or benzyl.

More preferably, R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano, CF 3 , NH 2 , NHCOR 9 and NHCONHR 9 wherein R 9 is optionally substituted phenyl or benzyl.

The group R9 is typically unsubstituted phenyl or benzyl, or phenyl or benzyl substituted with 1, 2 or 3 substituents selected from the group consisting of halogen; hydroxy; trifluoromethyl; cyano; carboxy; C1-4 alkoxycarbonyl; C1-4 acyloxy; amino; mono- or di-C 1-4 alkylamino; C1-4 alkyl optionally substituted with halogen, hydroxy or C1-2 alkoxy; C1-4 Alkoxy optionally substituted with halogen, hydroxy or C1-2 Alkoxy; phenyl, five- and six-membered heteroaryl groups containing up to 3 heteroatoms selected from O, N and S; and saturated carbocyclic and heterocyclic groups containing up to 2 heteroatoms selected from O, S and N.

Particular examples of the group R5 include hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, cyano, CF3, NH2, NHCOR9b and NHCONHR9b wherein, R9b is phenyl or benzyl optionally substituted with hydroxy, C1-4 acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, C1-4 hydrocarbyloxy (eg, alkoxy) and C1-4 hydrocarbyl (eg, alkyl) optionally substituted with C1-2 alkoxy or hydroxy.

Preferred examples of R5 include hydrogen, methyl and cyano. Preferably, R 5 is hydrogen or methyl.

Group "E"

In formula (I), E is a monocyclic, bicyclic carbocyclic or heterocyclic group and may be selected from the groups listed above in the General Preferences and Definitions section.

Preferred groups E are monocyclic and bicyclic aryl and heteroaryl groups and, in particular, groups containing a six-membered aromatic or heteroaromatic ring such as a phenyl, pyridine, pyrazine, pyridazine or pyrimidine ring, especially a phenyl, pyridine, pyrazine or pyrimidine ring, and preferably a pyridine or phenyl ring.

Examples of bicyclic groups include benzo-fused and pyrido-fused groups in which both the A group and the pyrazole ring are attached to a benzo or pyrido group.

In one embodiment, E is a monocyclic group.

Particular examples of monocyclic groups include monocyclic aryl and heteroaryl groups such as phenyl, thiophene, furan, pyrimidine, pyrazine and pyridine, with phenyl being currently preferred.

One subgroup of monocyclic aryl and heteroaryl groups includes phenyl, thiophene, furan, pyrimidine, and pyridine.

Examples of non-aromatic monocyclic groups include cycloalkanes such as cyclohexane and cyclopentane, and nitrogen-containing rings such as piperazine and piperazone.

Preferably, the A group and the pyrazole ring are not attached to adjacent ring members of the E group. For example, the pyrazole group may be attached to the E group in a meta or para relative orientation. Examples of such groups E include 1,4-phenylene, 1,3-phenylene, 2,5-pyridylene and 2,4-pyridylene, 1,4-piperazinyl and 1,4-piperazonyl. Additional examples include 1,3-disubstituted five-membered rings.

Groups E may be unsubstituted or may have up to 4 substituents R 8 which may be selected from the group R 10 as defined above. More typically, however, the R 8 substituents are selected from the group consisting of hydroxy; oxo (when E is non-aromatic); halogen (eg chlorine and bromine); trifluoromethyl; cyano; C1-4 hydrocarbyloxy optionally substituted with C1-2 alkoxy or hydroxy; and C1-4 hydrocarbyl optionally substituted with C1-2 alkoxy or hydroxy.

Preferably, it has 0-3 substituents, more preferably 0-2 substituents, for example 0 or 1 substituent. In one embodiment, group E is unsubstituted.

E can be different from the following:

* substituted pyridone group;

* substituted thiazole group;

* substituted or unsubstituted pyrazole or pyrazolone group;

* substituted or unsubstituted bicyclic fused pyrazole group;

* a phenyl ring fused to a thiophene ring or a six-membered heteroaryl ring containing nitrogen fused to a thiophene ring;

* substituted or unsubstituted piperazine group;

Group E can be an aryl or heteroaryl group having five or six members and containing up to three heteroatoms selected from O, N and S, group E is represented by the formula:

wherein, * denotes the point of attachment to the pyrazole group, and "a" denotes the attachment of the A group;

rjeO, 1 or 2;

Uje selected from N and CR12a; and

V is selected from N and CR12b; wherein R12a and R12b are the same or different and each is hydrogen or a substituent containing up to ten atoms selected from C, N, O, F, Cl and S provided that the total number of non-hydrogen atoms present in R12a and R12b together does not exceed ten;

or R12a and R12b together with the carbon atoms to which they are attached form an unsubstituted five- or six-membered saturated or unsaturated ring containing up to two heteroatoms selected from O and N;i

R10 is as defined above.

In one preferred group of compounds, E is a group:

wherein, * denotes the point of attachment to the pyrazole group, and "a" denotes the attachment of the A group;

P, Q and T are the same or different and are selected from N, CH and NCR10, with the proviso that group A is attached to a carbon atom; and U, V and R10 are as defined above.

Examples of R12a and R12b include hydrogen and substituent groups R10 as defined above having no more than ten non-hydrogen atoms. Particular examples of R12a and R12b include methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, chloro, methoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethyl, cyano, amino, methylamino, dimethylamino, CONH2, CO2Et, CO2H, acetamido, azetidinyl, pyrrolidino, piperidine, piperazino, morpholino, methylsulfonyl, aminosulfonyl, mesylamino, and trifluoroacetamido.

Preferably, when U is CR12a and/or V is CR12b, the atoms or groups in R12a and R12b which are directly attached to the carbon atoms of the ring members are selected from H, O (e.g. as in methoxy), NH (e.g. as in amino and methylamino) and CH2 (eg as in methyl and ethyl).

Specific examples of linker group E, together with their attachment points to group A (a) and the pyrazole ring ( ) are shown in Table 2 below.

Table 2:

In the table, the substituting group R13 is selected from the group consisting of methyl, chlorine, fluorine and trifluoromethyl.

The following optional exceptions may apply to the definition of E in any of formulas (I), (Ia), (lb), (II), (III), (IV) and (V) and any of their subgroups or sub- definition as defined here:

• E can be different from a phenyl group that has a sulfur atom attached to the vapor position relative to the pyrazole group.

• E can be different from a substituted or unsubstituted benzimidazole, benzoxazole or benzthiazole group.

One subgroup of compounds of formula (I) has the general formula (II):

wherein, group A is attached to the meta or para position of the benzene ring, q is 0-4; R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein in connection with formula (I) and its subgroups, examples and preferences; and R 8 is a substituting group as defined above. In formula (II), q is preferably 0, 1 or 2, more preferably 0 or 1 and most preferably 0. Preferably, the group A is attached to. para position of the benzene ring.

Within formula (II), a particular subgroup of compounds according to the invention is represented by formula (III):

wherein, A' is a residue of group A and R1 through R5 are as defined herein.

Within formula (III), one preferred group of compounds is represented by formula (IV):

wherein z is 0, 1 or 2, R 20 is selected from the group consisting of hydrogen, methyl, hydroxy and fluoro and R 1 through R 5 are as defined herein, with the proviso that when z is 0, R 20 is other than hydroxy .

The following group of compounds within formula (III) is represented by formula (V):

wherein, R1 and R3 through R5 are as defined herein.

In formula (V), R 3 is preferably selected from hydrogen and C 1-4 hydrocarbyl, for example C 1-4 alkyl such as methyl, ethyl and isopropyl. More preferably, R 3 is hydrogen.

In each of formulas (II) to (V), R 1 is an optionally substituted phenyl group as defined herein.

In a further subgroup of compounds of the invention, A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, wherein one of the carbon atoms in the linker group can be optionally replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from fluorine and hydroxy, with

the condition that the hydroxy group, when present, is not located on the carbon atom a in relation to the NR R group; and

R is selected from the group consisting of hydrogen, C1-4 saturated hydrocarbyl, cyano, CONH2, CF3, NH2, NHCOR9 and NHCONHR9.

For the avoidance of doubt, it is to be understood that each general and specific preference, variant and example of group R can be combined with each general and specific preference, variant and example of group R2 and/or R3 and/or R and/or R5 and/ or R9, and that all such combinations are covered by this application.

The various functional groups and substituents that make up the compounds of formula (I) are typically chosen so that the molecular weight of the compound of formula (I) does not exceed 1000. Typically, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.

Particular compounds of the invention are illustrated in the examples below and are selected from the following:

2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;

3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile;

2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine;

2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;

2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine;

3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine;

3-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;

{3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;

{3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;

{3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;

3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;

3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;

3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;

4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-(4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-(4-chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine;

dimethyl-{3-(4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine;

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(R);

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(S);

4-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-morpholine;

4-{4-[ 1 -(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1 H -pyrazole;

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine;

dimethyl-{2-phenyl-2-[4-( 1 H -pyrazol-4-yl)-phenyl]-ethyl}-amine;

{2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;

{2,2-bis-[4-(1H-pyrazol-4-yl)-fenil]-ethyl}-methyl-amine;

2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(R);

2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(S);

2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;

1-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine;

1. {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperidine;

4-{4-[2-azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole;

1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;

2-(4-chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;

N-methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)phenyl]-ethyl}-methyl-amine;

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine;

4-{4-[ 1 -(4-chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1 H -pyrazole;

methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;

{2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;

methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;

methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;

2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine;

4-{4-[1-(4-chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1 H -pyrazole;

4-{4-[3-azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1 H -pyrazole;

methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine;

dimethyl-(4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)phenyl]-propyl}-phenyl)-amine;

{3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;

4-{4-[4-(4-chloro-fenil)-piperidin-4-yl]-fenil}-1H-pyrazole-3-carbonitrile;

3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;

1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;

1-methyl-4-{fenil-[4-(1H-pyrazol-4-yl)-fenil]-metil}-[1,4]diazepan;

{3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;

methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine;

4-{4-[ 1 -(4-chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1 H -pyrazole;

4-[4-(3-imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1Hpyrazole;

4-{4-[4-(1H-pyrazol-4-yl)-fenil]-piperidin-4-yl}-phenol;

1 - {(4-chloro-phenyl)-[4-( 1 H -pyrazol-4-yl)-phenyl]-methyl}-piperazine;

{2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;

{2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;

4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-[4-(3-methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide;

2-(4-{2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide;

{2-(3-chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;

3- {2-(4-chloro-fenil)-2-[4-(1H-pyrazol-4-yl)-fenil]-ethylamino}-propan-1-ol;

2-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol;

3- {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;2-{2-(4-chloro- phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl )-phenyl]-ethyl}-cyclopropylmethylamine; methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine;

4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;3-(4-methoxy-phenyl)-3-[4-(1H-pyrazole) -4-yl)-phenyl]-propylamine; 4-(4-chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidin; 2-(4- chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine;(4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin- 4-yl}-phenoxy)-sirćetna kiselina;

Methyl ester (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid;

4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile;

{2-(4-chlorophenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;

1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;

2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;

4-(3,4-dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-(4-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzoic acid;

4-[4-(1H-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4']bipyridinyl;

3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;

2-methylamino-1-(4-nitro-phenyl)-1-[4-(14H-pyrazol-4-yl)-phenyl]-ethanol;

2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;

2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;

3-(3,4-dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine;

2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)phenyl]-ethylamine;

4-(2-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;

1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine;

2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;

{2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;

4-{4-[2-azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole;

3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)phenyl]-propylamine;

{3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)phenyl]-propyl}-methyl-amine;

1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; i

C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)phenyl]-methylamine;

i nijhoh soli, solvata, tautomerima i N-oxide.

In one variant, compound formula (I) is selected from the group consisting of: {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl- amine(R); 4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine; i 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine.

An additional subgroup of compounds of formula (I) consists of the following: 4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R isomer); and their salts, solvates, tautomers and N-oxides.

Salts, solvates, tautomers, isomers, N-oxides, esters. prolekovi i isotopi

In this part, as in all other parts of this application, unless the context indicates otherwise, the reference to formula (I) includes the reference to formulas (Ia), (lb), (II), (III), (IV) and (V) and all their other subgroups, preerences and examples as defined here.

Unless otherwise indicated, recitation of a particular compound also includes its ionic forms, salts, solvates, and protected forms, for example, as discussed below.

Many compounds of formula (I) may exist in the form of salts, for example acid addition salts or, in certain cases, salts of organic and inorganic bases such as carboxylate, sulphonate and phosphate salts. All such salts are within the scope of this invention, and the recitation of compounds of formula (I) includes salt forms of the compounds. As in the previous parts of this application, all references to formula (I) should also be understood as references to formula (II) and its subgroups, unless the context dictates otherwise.

Salt forms can be selected and prepared according to procedures described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover , 388 pages, August 2002. For example, acid addition salts can be prepared by dissolving the free base in an organic solvent in which the given salt form is insoluble or sparingly soluble and then adding the required acid to the appropriate solvent so that the salt precipitates out of solution.

Acid addition salts can be formed with a wide range of different acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (eg, L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butyric. . hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (eg D-glucuronic), glutamic {eg L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrogen bromide, hydrogen chloride, hydrogen iodide, isethionic, lactic (eg (+)-L-lactic and (6)-DL-lactic), lactobionic, maleic, malic, (- )-L-malic, malonic, (6)-DL-almond, methanesulfonic, naphthalenesulfonic (eg naphthalene-2-sulfonic), naphthalene-1,5-disulfonic, 1 -hydroxy-2-naphthalenecarbonic, nicotinic, nitrogenous, oleic , orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,

succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, toluenesulfonic (eg p-toluenesulfonic), undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

One particular group of acid addition salts includes salts formed with hydrochloric, hydroiodic, phosphoric, nitrogenous, sulfuric, citric, lactic, amber, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, valerian, acetic, propionic, butyric, malonic, glucuronic and lactobionic acids.

The next group of acid addition salts includes salts formed from acetic, adipic, ascorbic, aspartic, citric, DL-lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, methanesulfonic, sebacic, stearic, amber and tartaric acids.

The compounds of the invention can exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed. In stronger acids, the base nitrogen from pyrazole, as well as the nitrogen atom in the NR2R3 group, can participate in salt formation. For example, where the acid has a pKa of less than about 3 (eg, an acid such as hydrochloric acid, sulfuric acid, or trifluoroacetic acid), the compounds of the invention will typically form salts with 2 molar equivalents of the acid.

If the compound is anionic, or has a functional group that can be anionic (eg, -COOH can be -COO-), then a salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth metal cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (ie, NH4+) and substituted ammonium ions (eg, NH3R+, NHzR+, NHR3+, NR4+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

In the case where the compounds of formula (I) contain an amine functional group, they can form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I).

Compounds of formula (I) containing an amine functional group can also form N-oxides. Reference herein to compounds of formula (I) containing an amine functional group also includes N-oxide.

In the case where the compound contains several amine functional groups, one or more of the nitrogen atoms may be oxidized to form an N-oxide. Particular examples of N-oxides are tertiary amine N-oxides or the nitrogen atom of a nitrogen-containing heterocycle.

N-Oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (eg peroxycarboxylic acid), see for example Advanced Organic Chemistrv, by Jerry March, 4th Edition, Wiley Interscience, pages. In particular, N-oxides can be made by a procedure given by L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as is dichloromethane.

Compounds of formula (I) can exist in a number of different geometric isomeric and tautomeric forms and the listing of compounds of formula (I) includes all such forms. For the avoidance of doubt, where a compound may exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by formula (I).

For example, in the compounds of formula (I), the pyrazole group can have either of the following two tautomeric forms A and B.

For simplicity, the general formula (I) illustrates Form A, but this formula should be understood to include both Form A and Form B.

In the case where compounds of formula (I) contain one or more chiral centers, and may exist in the form of two or more optical isomers, the listing of compounds of formula (I) includes all their optical isomeric forms (eg enantiomers and diastereomers), either as individual

optical isomers, or mixtures of two or more optical isomers, unless the context requires otherwise.

For example, group A may include one or more chiral centers. Thus, when E and R1 are simultaneously attached to the same carbon atom on the linker group A, said carbon atom is typically chiral and therefore the compound of formula (I) will exist as a pair of enantiomers (or more than one pair of enantiomers in the case where more than of one chiral center present in the compound).

Optical isomers may be characterized and identified by their optical activity (ie as + and - isomers) or may be characterized by their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistrv by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966,5,385-415.

Optical isomers can be separated using a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to those skilled in the art.

As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluloyl-L-tartaric acid, (+)- mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, by separating the diastereoisomers by preferential crystallization, and then dissociating the salt to give the single enantiomer of the free base.

In the case where compounds of formula (I) exist as two or more optically isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, under certain conditions, it may be desirable to use only one pair of enantiomers, or only one of a larger number of diastereomers, as a therapeutic agent. Accordingly, the invention provides compositions comprising a compound of formula (I) having one or more chiral centers, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90 % or 95%) of the compound of formula (I) present as a single optical isomer (eg enantiomer or diastereoisomer). In one general embodiment, 99% or more (eg, substantially all) of the total amount of the compound of formula (I) may be present as a single optical isomer (eg, enantiomer or diastereoisomer).

Esters such as carboxylic acid esters and acyloxy esters of compounds of formula (I) bearing a carboxylic acid group or a hydroxy group are also encompassed by formula (I). In one variant of the invention, formula (I) includes within its scope esters of compounds of formula (I) which

carry a carboxylic acid group or a hydroxyl group. In the following variant according to the invention, formula (I) within its scope does not include esters of compounds of formula (I) that carry a carboxylic acid group or a hydroxyl group. Examples of esters are compounds containing the group -C(=O)OR, where R is an ester substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably C1-7, alkyl group. Particular examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse esterification) groups are represented by -OC(=O)R, where R is an acyloxy substituent, for example, a C1-7 alkyl group, a C3-20 heterocyclyl group, or a C5-20 aryl group, preferably C1 -7 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph and -OC(=O)CH2Ph.

Formula (1) also includes all polymorphic forms of the compound, solvates (eg hydrates), complexes (eg inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compound, and prodrugs of the compound. "Prodrugs" mean, for example, any compound that is converted in vivo into a biologically active compound of formula (I).

For example, some prodrugs are esters of the active compound (eg, a physiologically acceptable metabolically unstable ester). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters may be formed by esterifying, for example, any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by followed by deprotection if necessary.

Examples of such metabolically unstable esters include those of the formula -C(=O)OR, wherein R is:

C1-7 alkyl (eg, -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C1-7 aminoalkyl (e.g., aminoethyl; 2-(N,N-methylamino)ethyl; 2-(4-morpholino)ethyl); i

acyloxy-C1-7alkyl (eg, acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-rnethoxy-1-methyl)ethylcarbonyloxyethyl; 1-(benzoyloxy)ethyl;

isopropoxycarbonyloxymethyl; 1-isopropoxycarbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1 -cyclohexyloxy-

carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)-carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)-carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to produce the active compound, or a compound that, after an additional chemical reaction, produces the active compound (for example,

as in antigen-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) and Uganda-directed enzyme prodrug therapy (LIDEPT). For example, the prodrug may be a sugar derivative or other glycosidic conjugate, or may be an amino acid ester derivative.

Procedures for the preparation of compounds of formula (I)

In this part, as in all other parts of this application, unless the context dictates otherwise, the reference to formula (I) includes the reference to formulas (Ia), (lb), (II), (III), (IV) and (V) and all their subgroups, preferences and examples as defined here.

Compounds of formula (I) can be prepared by reacting a compound of formula (X) with a compound of formula (XI) or its N-protected derivative:

wherein, A, E and R1 to R5 are as defined above, one of the groups X and Y is a chlorine, bromine or iodine or trifluoromethanesulfonate (triflate) group, and the other of the groups X and Y is an organoboron residue, on example organoboric acid ester or organoboric acid.

The reaction can be carried out under typical Suzuki coupling conditions in the presence of a palladium catalyst such as bis(tri-t-butylphosine)palladium and a base (eg, a carbonate such as potassium carbonate). The reaction can be carried out in an aqueous solvent system, for example an aqueous ethanol solution, and the reaction mixture is typically subjected to heating, for example a temperature above 100°C.

An illustrative synthetic route involving a Suzuki coupling step is shown in Scheme 1. The starting material for the synthetic route shown in Scheme 1 is a halo-substituted aryl- or heteroarylmethyl nitrile (XII) in which X is a chlorine, bromine or iodine atom or a triflate group. The nitrile (XII) is condensed with the aldehyde R'CHO in the presence of an alkali such as sodium or potassium hydroxide in an aqueous solvent system such as aqueous ethanol. The reaction can be carried out at room temperature.

The obtained substituted acrylonitrile derivative (XIII) was then treated with a reducing agent that will selectively reduce the double bond of the alkene without reducing the nitrile group. A borohydride such as sodium borohydride can be used for this purpose to obtain

substituted acetonitrile derivative (XIV). The reduction reaction is typically carried out in a solvent such as ethanol and usually with heating, for example to a temperature of up to about 65°C.

The reduced nitrile (XIV) is then coupled with the organoboronic acid pyrazole ester (XV) under the Suzuki coupling conditions described above to give a compound of formula (I) wherein A-NR2R3 is a substituted acetonitrile group.

The substituted acetonitrile compound (XVI) can then be reduced to the corresponding amine (XVII) by treatment with a suitable reducing agent such as Raney nickel and ammonia in ethanol.

The synthetic route shown in Scheme 1 provides amino compounds of formula (I) in which the aryl or heteroaryl group E is attached to the P-position of group A relative to the amino group. In order to obtain amino compounds of the formula (I) in which R1 is attached to the p-position in relation to the amino group, the functional groups on the two starting materials in the condensation step can be returned to the initial state so that the compound of the formula X-E-CHO, in wherein X is bromine, chlorine, iodine or a triflate group, condenses with a compound of the formula r'-CH2-CN to give a substituted acrylonitrile derivative which is then reduced to the corresponding acetonitrile derivative before coupling with an organoboric acid pyrazole ester (XV) and reduction cyano group to amino group.

Compounds of formula (I) in which R1 is attached to the a-position relative to the amino group can be prepared by a series of reactions shown in Scheme 2.

In Scheme 2, the starting material is a halo-substituted aryl- or heteroarylmethyl Grignard reagent (XVIII, X = bromine or chlorine) which is reacted with a nitrile R1-CN in a dry ether such as diethyl ether to give an intermediate imine (not shown) which is reduced to give the amine (XIX) using a reducing agent such as lithium aluminum hydride. The amine (XIX) can be reacted with the organoboron ester (XV) under the Suzuki coupling conditions described above to give the amine (XX).

Compounds of formula (I) can also be prepared from the substituted nitrile compound (XXI):

wherein, PG is a protecting group such as a tetrahydropyranyl group. The nitrile (XXI) can be condensed with an aldehyde of the formula R1-(CH2)r-CH0, in which r is 0 or 1, and the resulting substituted acrylonitrile is then reduced to the corresponding substituted nitrile under

conditions that are analogous to those specified in Scheme 1 in the previous text. The PG protecting group can then be removed using a suitable procedure. The nitrile compound can then be reduced to the corresponding amine using a suitable reducing agent as described above.

The nitrile compound (XXI) can also be reacted with a Grignard reagent of the formula R1-(CH2)r-MgBr under standard Grignard reaction conditions, followed by deprotection to give the amino compound of the invention having the structure shown in the formula ( XXII).

In the preparative procedures mentioned above, coupling of aryl or heteroaryl group E to pyrazole was achieved by reaction of halo-pyrazole, halo-aryl or heteroaryl compounds with organoboric acid ester or organoboric acid in the presence of palladium catalyst and base. Many boronates suitable for use in the preparation of the compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Ina, of San Diego, USA. In the case where boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the work presented by N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457. Thus, boronates can be prepared by reacting the appropriate bromo compound with an alkyl lithium such as butyl lithium and then reacting with a boronic acid ester. The resulting organoboric acid ester derivative can, if desired, be hydrolyzed to give the corresponding organoboric acid.

Compounds of formula (I) in which group A contains a nitrogen atom attached to group E can be prepared by well-known synthetic procedures from compounds of formula (XXIII) or their protected form. Compounds of formula (XXIII) can be obtained by the Suzuki coupling reaction of a compound of formula (XV) (see Scheme 1) with a compound of formula Br-E-NH2 such as 4-bromoaniline.

Compounds of formula (I) in which R 1 and E are attached to the same carbon atom can be prepared as shown in Scheme 3.

In Scheme 3, an aldehyde compound (XXIV) in which X is bromo, chlorine, iodine or a triflate group was condensed with ethyl cyanoacetate in the presence of base to give the cyanoacrylate ester

intermediate (XXV). The condensation is typically carried out in the presence of a base, preferably a non-hydroxide such as piperidine, by heating under Dean Stark conditions.

The cyanoacrylate intermediate (XXV) is then reacted with a Grignard reagent R'MgBr suitable to introduce the R1 group via Michael addition to the carbon-carbon double bond of the acrylate group. The Grignard reaction can be carried out in a polar non-protic solvent such as tetrahydrofuran at a low temperature, for example at about 0°C. The product of the Grignard reaction is the cyanopropionic acid ester (XXVI) which undergoes hydrolysis and decarboxylation to give the propionic acid derivative (XXVII). The hydrolysis and decarboxylation steps can be achieved by heating in an acidic medium, for example a mixture of sulfuric acid and acetic acid.

Propionic acid derivative (XXVII) was converted into amide (XXVIII) by reaction with amine HNR2R3 under conditions suitable for amide bond formation. The coupling reaction between the propionic acid derivative (XXVII) and the amine HNR2R3 is preferably carried out in the presence of a reagent of the type commonly used in the formation of peptide bonds. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc. 1955, 77 1067), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (designated herein as EDC or EDAC) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based coupling agents such as β-(7-azabenzotriazol-1-yl)-N,N,N',N '-tetramethyluronium hexafluorophosphate (HATU) and phosphonium-based coupling agents such as 1-benzotriazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). Carbodiimide-based coupling agents are advantageously used in combination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J. Amer. Chem. Soc, 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt) (Konig et al. , Chem. Ber., 103, 708, 2024-2034). Preferred coupling reagents include EDC (EDAC) and DCC in combination with BOAt or HOBt.

The coupling reaction is typically carried out in a non-aqueous, non-protic solvent such as acetonitrile, dioxane, dimethylsulfoxide, dichloromethane, dimethylformamide or N-methylpyrrolidine, in an aqueous solvent optionally together with one or more water-miscible co-solvents. . The reaction can be carried out at room temperature or, in the case where the reactants are less reactive (for example in the case of electron-deficient anilines with groups such as sulfamide) at a suitably elevated temperature. The reaction can be carried out in the presence of a non-interfering base, for example a tertiary amine such as triethylamine or N,N-diisopropylethylamine.

In the case where the amine is HNR 2 R 3 ammonia, the amide coupling reaction can be performed using 1,1'-carbonyldiimidazole (CDI) to activate the carboxylic acid prior to addition of ammonia.

As an alternative, a reactive carboxylic acid derivative can be used, e.g. anhydride or acid chloride. Reaction with a reactive derivative such as an anhydride is typically accomplished by mixing the amine and anhydride at room temperature in the presence of a base such as pyridine.

Amide (XXVIII) can be converted to a compound of formula (XXX) (corresponding to a compound of formula (I) in which A has an oxo substituent next to the NR R group) by reaction with boronate (XV) under Suzuki coupling conditions as described above. The amide (XXX) can then be reduced using a hydride reductant such as lithium aluminum hydride in the presence of aluminum chloride to give an amine of formula (XXXI) (corresponding to a compound of formula (I) wherein, A is CH-CH2-CH2- ). The reduction reaction is typically carried out in an ethereal solvent, for example diethyl ether, with heating to the reflux temperature of the solvent.

Before the amide (XXVIII) reacts with the boronate (XV), the amide can instead be reduced with lithium aluminum hydride/aluminum chloride, for example in an ether solvent at ambient temperature, to give the amine (XXIX) which is then reacted with the boronate (XV) under the Suzuki coupling conditions described above to give the amine (XXX).

In order to obtain the homologue of the amine (XXIX) containing one less methylene group, the carboxylic acid (XXVII) can be converted to the azide by standard procedures and subjected to a Curtius rearrangement in the presence of an alcohol such as benzyl alcohol to give the carbamate (see Advanced Organic Chemistrv, 4th edition, by Jerry March, John Wiley & sons, 1992, pages 1091-1092). The benzylcarbamate can function as a protecting group for the amine during the later Suzuki coupling step, and the benzyloxycarbonyl group in the carbamate group can then be removed by standard procedures after the coupling step. Alternatively, the benzylcarbamate group can be treated with a hydride reducing agent such as lithium aluminum hydride to give a compound in which NR2R3 is a methylamino group instead of an amino group.

Intermediate compounds of the formula (X) in which the group X is a chlorine, bromine or iodine atom and A is a CH-CH2- group can be prepared by reductive amination of an aldehyde compound of the formula (XXXII):

with an amine of the formula HNR R under standard reductive amination conditions, for example in the presence of sodium cyanoborohydride in an alcoholic solvent such as methanol or ethanol.

The aldehyde compound (XXXII) can be obtained by oxidation of the corresponding alcohol (XXXIII) using, for example, Doss-Martin periodinane (see Dess, D.B.; Martin, J.C. J. Org. Soc, 1983, 48, 4155 and Organic Syntheses, Vol. 77, 41 ).

Compounds of formula (I) in which A, N and R 2 together form a cyclic group may be formed by Suzuki coupling of a boronate compound of formula (XV) with a cyclic intermediate of formula (XXXIV) or an N-protected derivative thereof.

Cyclic intermediates of formula (XXXIV), wherein R 1 is an aryl group such as an optionally substituted phenyl group, can be formed by Friedel Crafts alkylation of an aryl compound R'-H with a compound of formula (XXXV):

Alkylation is typically carried out in the presence of a Lewis acid such as aluminum chloride at reduced temperature. at a temperature lower than 5°C.

The Friedel Crafts reaction has been found to be generally applicable for the preparation of a range of intermediates of formula (X). Therefore, in a general procedure for the preparation of a compound of formula (X), a compound of formula (LXX):

reacts with a compound of the formula R.'-H under Friedel Crafts alkylation conditions, for example in the presence of an aluminum halide (e.g. AlCl 3 ).

In the following procedure for the preparation of compounds of formula (I) in which the group NR2R3 is attached to the CH2 group of group A, the aldehyde of formula (XXXVI) can be coupled with an amine of formula HNR2R3 under conditions of reductive amination as described above. In formulas (XXXVI) and (XXXVII), A' is the remainder of group A - ie. groups A' and CH2 together form group A. The aldehyde (XXXVII) can be formed by oxidation of the corresponding alcohol using, for example, Dess-Martin periodinane.

A Friedel Crafts alkylation procedure of the type described above for the synthesis of intermediates of formula (XXXIV) can also be used to prepare intermediates of formula (X) wherein X is bromine. An example of such a procedure is shown in Scheme 4.

The starting material for the synthetic route shown in Scheme 4 is an epoxide (XXXVIII) which can be obtained commercially or can be prepared by procedures well known to those skilled in the art, for example by reacting aldehyde Br-E-CHO with trimethylsulfonium iodide. The epoxide (XXXVIII) is reacted with the amine HNR2R3 under conditions suitable for the ring-opening reaction with the epoxide to give the compound of formula (XXXIX). The ring-opening reaction can be carried out in a polar solvent such as ethanol at room temperature or optionally with gentle heating, and typically with a large excess of amine.

The amine (XXXIX) is then reacted with an aryl compound R!H, typically a phenyl compound, capable of participating in a Friedel Crafts alkylation (see for example Advanced Organic Chemistry, by Jerry March, pages 534-542). Thus, an amine of formula (XXXIX) is typically reacted with an aryl compound R H in the presence of an aluminum chloride catalyst at or around room temperature. In the case where the aryl compound R1H is a liquid, e.g. as in the case of methoxybenzenes (eg, anisole) or halobenzenes such as chlorobenzene, the aryl compound may serve as the solvent. Otherwise, a less reactive solvent such as nitrobenzene can be used. Friedel Crafts alkylation of compound R*H with amine (XXXIX) gives a compound of formula (XL) corresponding to a compound of formula (X) wherein X is bromine and A is CHCH 2 .

The hydroxy intermediate (XXXIX) in Scheme 4 can also be used to prepare compounds of formula (X) in which the carbon atom of the hydrocarbon linker group A adjacent to the R1 group is replaced by an oxygen atom. In this way, the compound of formula (XXXIX), or its N-protected derivative (in which R2 or R3 is hydrogen) can be reacted with a phenolic compound of formula R'-OH under conditions of Mitsunobu alkylation, e.g. in the presence of diethyl azodicarboxylate and triphenylphosphine. The reaction is typically carried out in a polar non-protic solvent such as tetrahydrofuran at a moderate temperature such as ambient temperature.

An additional application of the hydroxy-intermediate (XXXIX) is for the preparation of the corresponding fluoro-compound. In this way, the hydroxy group can be replaced by fluorine by reaction with a pyridine:hydrogen fluoride complex (Olah's reagent). The fluorinated intermediate can then be subjected to a Suzuki coupling reaction to give the compound of formula (I) with a fluorinated hydrocarbon group A. The fluorinated compound of formula (I) could alternatively be prepared by first coupling the hydroxy intermediate (XXXIX), or its protected form, with pyrazole with organoboric acid or boronate under Suzuki reaction conditions and then replacing the hydroxy group of the obtained compound of formula (I) with fluorine using a pyridine: hydrogen fluoride complex.

Compounds of formula (I) in which, the group:

is a group:

in which, A" is a hydrocarbon residue of group A, can be prepared by a series of reactions shown in Scheme 5.

As shown in Scheme 5, the aldehyde (XXIV) reacts with the Grignard reagent R'MgBr under standard Grignard reaction conditions to give the secondary alcohol (XLI). The secondary alcohol can then be reacted with a compound of formula (XLII) in which, R2'

and R3' represent groups R2 and R3 or an amine-protecting group, A" is a residue of group A, and X' represents a hydroxy group or a leaving group.

The amine protecting group may be, for example, a phthalolyl group in which case NR 2 R 3 is a phthalimido group.

When X' is a hydroxy group, the reaction between compounds (XLI) and (XLII) may take the form of a condensation reaction catalyzed by toluene sulfonic acid. Alternatively, when X' is a leaving group such as halogen, the alcohol (XLI) may first be treated with a strong base such as sodium hydride to form the alcoholate which is then reacted with compound (XLII).

The resulting compound of formula (XLIII) is then subjected to a Suzuki coupling reaction with a pyrazole boronate reagent (XV) under typical Suzuki coupling conditions of the type described above to give a compound of formula (XLIV). The protecting group can then be removed from the amine protected group NR2 ́R3 ́ to give a compound of formula (I).

A compound of formula (I) in which, the group:

is a group:

in which, A" is a hydrocarbon residue of group A, can be prepared by a series of reactions shown in Scheme 6.

The starting material in Scheme 6 is a chloroacyl compound (XLV) which can be prepared using literature procedures (eg, the procedure described in J. Med. Chem., 2004, 47, 3924-3926) or procedures analogous thereto. Compound (XLV) is converted to the secondary alcohol (XLVI) by reduction with a hydride reducing agent such as sodium borohydride in a polar solvent such as water/tetrahydrofuran.

The secondary alcohol (XLVI) can then be reacted with a phenolic compound of the formula R'-OH under Mitsunobu alkylation conditions, e.g. in the presence of diethyl azodicarboxylate and triphenylphosphine, as described above, to give the aryl ether compound (XLVII).

The chlorine atom in the aryl ester compound (XLVII) was then replaced by reaction with the amine HNR2R3 to give the compound of formula (XLVIII). A nucleophilic substitution reaction can be performed by heating an amine with an aryl ether in a polar solvent such as an alcohol at

elevated temperature, for example approximately 100°C. Heating can conveniently be done using a microwave heater. The resulting amine (XLVIII) can then be subjected to a Suzuki coupling procedure with a boronate of formula (XV) as described above to give compound (XLIX).

In a variation of the reaction sequence shown in Scheme 6, the secondary alcohol (XLVI) can undergo a nucleophilic substitution reaction with the amine HNR2R3 prior to the introduction of the R1 group via the Mitsunobu ether formation reaction.

Another route to compounds of formula (I) in which E and R 1 are attached to the same carbon atom in group A is illustrated in Scheme 7.

In Scheme 7, N-protected pyrazolyl organoboronic acid (L) reacts under Suzuki coupling conditions with the cyano compound X-E-CN where X is typically a halogen such as bromine or chlorine. The protecting group of PG at position I of the pyrazole ring can be, for example, a triphenylmethyl (trityl) group. Organoboric acid (L) can be prepared using the procedure described in EP 1382603 or procedures analogous to it.

The resulting nitrile (LI) can then be reacted with the Grignard reagent R1-MgBr to introduce the R1 group and form the ketone (LII). The ketone (LII) is converted to the enamine (LIV) by reaction with diphenylphosphinoylmethylamine (LIII) in the presence of a strong base such as alkyl lithium, especially butyl lithium.

The enamine (LIV) is then hydrogenated over a palladium-on-charcoal catalyst to reduce the enamine double bond and remove the 1-phenethyl group. In the case where the PG protecting group is a trityl group, hydrogenation also removes the trityl group, thereby producing a compound of formula (LV).

Alternatively, the enamine (LIV) can be reduced with a hydride reducing agent under the conditions described in Tetrahedron: Asymmetry 14 (2003) 1309-1316 and subjected to chiral separation. Removal of the 2-phenethyl protecting group and the PG protecting group then gives the optically active form of the compound of formula (LV).

Intermediates of formula (X) in which A and R 2 are linked to form a ring containing an oxygen atom can be prepared by the general procedure illustrated in Scheme 8.

In Scheme 8, the ketone (LVI) reacts with trimethylsulfonium iodide to form the epoxide (LVH). The reaction is typically carried out in the presence of a hydride base such as sodium hydride in a polar solvent such as dimethylsulfoxide.

The epoxide (LVII) is subjected to a ring-opening reaction with ethanolamine in the presence of a non-interfering base such as triethylamine in a polar solvent such as an alcohol (eg, isopropanol), usually with gentle heating (eg, to about 50°C). The resulting secondary alcohol is then cyclized to form the morpholine ring by treatment with concentrated sulfuric acid in a solvent such as ethanolic dichloromethane.

The morpholine intermediate (LIX) can then be reacted with the boronate (XV) under Suzuki coupling conditions to give a compound of formula (LX), which corresponds to a compound of formula (I) in which A-NR2R3 forms the morpholine group.

Instead of reacting the epoxide (LVII) with ethanolamine, it can instead react with mono- or dialkylamines providing a route to compounds containing the group:

Compounds in which R2 and R3 are both hydrogen can be prepared by reacting the epoxide (LVII) with potassium phthalimide in a polar solvent such as DMSO. During the Suzuki coupling step, the phthalimide group can undergo partial hydrolysis to give the corresponding phthalic acid semiamide which can be cleaved using hydrazine to give the amino group NH2. Alternatively, the phthalic acid semiamide can be recycled to the phthalimide using a standard amide forming reagent and the phthaloyl group is then removed using hydrazine to give the amine.

An additional synthetic route to compounds of formula (I) in which A and NR 2 R 3 are combined to form a cyclic group is illustrated in Scheme 9.

In Scheme 9, the starting material (LXI) is typically a di-aryl/heteroaryl methane in which one or both aryl/heteroaryl groups are capable of stabilizing or facilitating the formation of an anion formed on the methylene group between E and R1. For example, R 1 can advantageously be a pyridine group. Initial

material (LXI) is reacted with N-protected bis-2-chloroethylamine (LXII) in the presence of a strong non-interfering base such as sodium hexamethyldisilazide in a polar solvent such as tetrahydrofuran at reduced temperature (eg, about 0°C) to give obtained the N-protected cyclic intermediate (LXIII). The protecting group can be any standard amine protecting group such as a Boe group. After cyclization, intermediate (LXIII) is coupled with boronate of formula (XV) under Suzuki coupling conditions and then deprotected to give compound of formula (I).

Compounds of formula (I) in which, the group:

is a group:

wherein, "Alk" is a lower alkyl group such as methyl or ethyl, may be formed by the synthetic route illustrated in Scheme 10.

In Scheme 10, the carboxylic acid of formula (LXIV) was esterified by treatment with methanol in the presence of an acidic catalyst such as hydrochloric acid. The ester (LXV) is then reacted with a strong base such as lithium diisopropylamide (LDA) and an alkyl iodide such as methyl iodide at reduced temperature (eg between 0°C and -78°C). The garnet ester (LXVI) was then hydrolyzed outward to the acid (LXVII) and coupled with the amine HNR2R3 under standard amide formation conditions of the type described above. The amide (LXVIII) can then be reduced to the amine (LXIX) using lithium aluminum hydride, and the amine (LXIX) is then reacted with a pyrazole boronate or an organoboronic acid, under Suzuki coupling conditions to give a compound of formula (I).

Once formed, many compounds of formula (I) can be converted to other compounds of formula (I) by standard functional group interconversions. For example, compounds of formula (I) in which NR 2 R 3 formed part of the nitrile group can be reduced to the corresponding amine. Compounds in which, NR2R3 is an NH2 group can be translated into

the corresponding alkylamine by reductive alkylation, or to a cyclic group. Compounds in which R1 contains a halogen atom such as chlorine or bromine can be used to introduce an aryl or heteroaryl substituent into the R1 group by a Suzuki coupling reaction. Additional examples of mutual conversions of one compound of formula (I) into another compound of formula (I) can be found in the examples below. Additional examples of functional group interconversions, reagents, and conditions for performing such conversions can be found in, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York, Fiesers' Reagents for Organic Synthesis, Volumes 1 -17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2) and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8) .

In many of the reactions previously described, it may be necessary to protect one or more groups to prevent the reaction from occurring at an undesirable site on the molecule. Examples of protecting groups, and procedures for protection and deprotection of functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

The hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), for example, as: t-butyl ether; benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether, trimethylsilyl or t-butyldimethylsilyl ether; or acetyl ester (-OC(=O)CH3, -OAc). An aldehyde or ketone group can be protected, for example, as an acetal (R-CH(OR)2) or a ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (> C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group can easily be regenerated by hydrolysis using a large excess of water in the presence of acid. The amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: methyl amide (-NHCO-CHj); benzyloxy amide (-NHCOOCH2C6H5, -NH-Cbz); as t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxy amide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as 9-fluorenylmethoxy amide (-NH-Fmoc), as 6-nitroveratrilox amide (-NH-Nvoc), as 2 -trimethylsilylethyloxy amide (-NH-Teoc), as 2,2,2-trichloroethyloxy amide (-NH-Troc), as allyloxy amide (-NH-Alloc), or as 2-(phenylsulfonyl)ethyloxy amide (-NH-Psec ). Other amine protecting groups, such as cyclic amines and heterocyclic N-H groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups and benzyl groups such as a para-methoxybenzyl (PMB) group. The carboxylic acid group may be protected as an ester, for example, as: C1-7 alkyl ester (eg, methyl ester; t-butyl ester); C1-7 haloalkyl ester (eg, C1-7 trihaloalkyl ester); triC1-7 alkylsilyl-C1-7 alkyl ester; or C5-20 aryl-C1-7 alkyl ester (eg, benzyl ester; nitrobenzyl ester); or as an amide, for example,

as methyl amide. The thiol group can be protected, for example, as a thioether (-SR), for example, as: benzyl thioether, acetamidomethyl ether (-S-CH2NHC(=O)CH3).

1(H) position of the pyrazole group by the compounds of formula (I) or their precursors can be protected by different groups, whereby the protecting group is chosen according to the nature of the reaction conditions to which the group is exposed. Examples of pyrazole N-H protecting groups include tetrahydropyranyl, benzyl and 4-methoxybenzyl groups.

Many of the chemical intermediates described above are novel and such novel intermediates form an additional aspect of the invention.

Pharmaceutical formulations

While it is possible for the active compound to be administered individually, it is preferred that it be in a pharmaceutical composition (e.g. formulation) containing at least one active compound according to the invention together with one or more pharmaceutically acceptable carriers, adjuvants, inert fillers, diluents, fillers, buffers, stanylizers, preservatives, lubricants or other materials that are well known to experts in the given wafer technique and optionally other therapeutic or prophylactic means.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods for the preparation of pharmaceutical compositions comprising mixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, inert fillers, buffers, adjuvants, stabilizers, or other materials, as described herein.

The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for administration in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation , allergic response or other problem or complication, proportionate to the reasonable benefit/risk ratio. Any carrier, inert filler, etc. it must also be "acceptable" in the sense that it is compatible with the other ingredients of the formulation.

Accordingly, in a further aspect, the invention provides compounds of formula (I) and subgroups thereof as defined herein in the form of pharmaceutical compositions.

The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal or transdermal administration. In the case where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous

administration or for direct administration to a target organ or tissue by injection, infusion or other means of administration.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient concerned; and aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents. Formulations may be present in single-dose or multi-dose containers, e.g., hermetically sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid vehicle, e.g., water for injection, immediately prior to administration. .

Unprepared solutions and suspensions for injections can be prepared from sterile powders, granules and tablets.

In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. application, for example by injection or infusion.

In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or plasters, and buccal plasters.

Pharmaceutical compositions containing compounds of formula (I) may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

Thus, tablet compositions may contain a unit dose of the active compound together with an inert diluent or carrier such as sugar or sugar alcohol, e.g. lactose, sucrose, sorbitol or mannitol; and/or a non-sugar-derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or a derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (eg, cross-linked swellable polymers such as cross-linked carboxymethylcellulose), lubricants (eg, stearates), preservatives (eg, , parabens), antioxidants (eg BHT), buffering agents (eg phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such inert fillers are well known and need not be discussed in detail here.

Capsule formulations can be hard gelatin or soft gelatin and can contain the active component in solid, semi-solid or liquid form. Gelatinous capsules can be formed from animal gelatin or its equivalents of synthetic or vegetable origin.

Solid dosage forms (eg, tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, for example a protective film coating (eg, wax or varnish) or a release control coating. The coating (eg, a Eudragit™ type polymer) can be designed to release the active component to the desired site within the gastrointestinal tract. In this way, the coating can be chosen to break down under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum or duodenum.

Instead of a coating, or in addition to a coating, the drug may be in a solid matrix containing a release control agent, for example a release delay agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or slow-release coating may be in the form of erodible polymers (eg, maleic anhydride polymer) that are generally continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound may be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other sustained release or sustained release formulations may be prepared according to procedures well known to those skilled in the art.

Compositions for topical application include ointments, creams, sprays, patches, gels, liquid drops, and inserts (eg, intraocular inserts). Such compositions may be formulated according to known procedures.

Compositions for parenteral administration are typically in the form of sterile aqueous or oily solutions or fine suspensions, or may be in the form of a finely divided sterile powder for preparation with sterile water for injection.

Examples of formulations for rectal or intra-vaginal administration include uterine pads and suppositories which may be, for example, formed from a molded gooey or waxy material containing the active compound.

Compositions for inhalation administration may be in the form of inhalation powder compositions or liquid or powder sprays, and may be administered in standard form using a powder inhalation device or an aerosol nebulizer. Such devices are

well known. For administration by inhalation, powder formulations typically contain the active compound together with an inert solid powder diluent such as lactose.

The compounds of the invention will generally be in unit dosage form and, as such, will typically contain sufficient compound to provide the desired level of biological activity. For example, a formulation intended for oral administration may contain from 1 nanogram to 2 milligrams, for example 0.1 milligram to 2 grams of active ingredient, usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams, or 0.1 milligrams to 2 milligrams.

The active compound will be administered to a patient in need thereof (for example, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Inhibitory activity against protein kinase

The activity of the compounds according to the invention as inhibitors of protein kinase A and protein kinase B can be measured using the tests mentioned in the examples below and the level of activity exhibited by the given compound can be defined according to the IC50 value. Preferred compounds according to the present invention are compounds that have an IC50 value of less than 1 mM, preferably less than 0.1 mM, against protein kinase B.

Therapeutic applications

Prevention or progression of proliferative disorders

Compounds of formula (I) are inhibitors of protein kinase A and protein kinase B. As such, they are expected to be useful in providing agents for growth prevention or induction of apoptosis of neoplasia. Accordingly, it is anticipated that the compounds will prove useful in the treatment or prevention of proliferative disorders such as cancers. In particular, tumors with deletions or inactivating mutations in PTEN or loss of PTEN expression or rearrangement in the (T-cell lymphocyte) TCL-1 gene may be particularly sensitive to PKB inhibitors. Tumors that have other abnormalities that lead to an upregulated PKB signaling pathway may also be particularly sensitive to PKB inhibitors. Examples of such abnormalities include, but are not limited to, overexpression of one or more PI3K subunits, overexpression of one or more PKB isoforms, or mutations in PI3K, PDK1, or PKB that lead to an increase in the basal activity of the enzyme in question, or a consequent downregulation or overexpression or mutational activation of a growth factor receptor such as a growth factor selected from the following

family: epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor 1 (IGF-1R), and vascular endothelial factor receptor of growth (VEGFR).

It is also envisaged that the compounds of the invention will be useful in the treatment of other conditions resulting from disorders in proliferation or survival such as viral infections, and neurodegenerative diseases, for example. PKB plays an important role in maintaining the survival of immune cells during the immune response and therefore PKB inhibitors could be particularly useful in immune disorders including autoimmune conditions.

Therefore, PKB inhibitors could be useful in the treatment of diseases in which there is a disorder of proliferation, apoptosis or differentiation.

PKB inhibitors may also be useful in diseases resulting from insulin resistance and insensitivity, and glucose, energy and fat storage disorders such as metabolic disease and obesity.

Examples of cancers that could be inhibited include, but are not limited to, cancers, for example, bladder, breast, colon (eg, colorectal cancers such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung, for example adenocarcinoma, small cell lung cancer and non-small cell lung cancer, esophagus, gall bladder, ovary, pancreas e.g. cancer of the exocrine pancreas, stomach, cervix, endometrium, thyroid, prostate or skin, eg squamous cell carcinoma; a hematopoietic tumor of the lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of the myeloid lineage, for example acute and chronic myelogenous leukemia, myelodysplastic syndrome, or promyclocytic leukemia; thyroid follicular cancer; tumor of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoactantoma; thioridic follicular cancer; or Kaposi's sarcoma.

Thus, in the pharmaceutical compositions, applications or methods of the present invention for the treatment of a disease or condition comprising abnormal cellular growth, wherein the disease or condition comprising abnormal cellular growth is in one embodiment cancer.

Specific cancer subgroups include breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell carcinoma, and non-small cell lung cancer.

An additional subgroup of cancers includes breast cancer, ovarian cancer, prostate cancer, endometrial cancer, and glioma.

It is also possible that some protein kinase B inhibitors can be used in combination with other anticancer agents. For example, it may be useful to combine an inhibitor that induces apoptosis with another agent that acts through a different mechanism to regulate cell growth, thereby creating two of the hallmarks of cancer development. Examples of such combinations are listed below.

Immune disorders

Immune disorders for which PKA and PKB inhibitors may be useful include, but are not limited to, autoimmune conditions and chronic inflammatory diseases, for example, systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus, eczema and hypersensitivity reactions, asthma, COPD, rhinitis, and upper respiratory tract disease.

Other therapeutic applications

PKB has a role in apoptosis, proliferation, differentiation and therefore PKB inhibitors could also be useful in the treatment of the following diseases besides cancer and those related to immune dysfunction; viral infections, for example herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HlV, HPV, HCV and HCMV; prevention of the development of AIDS in persons infected with HlV; cardiovascular diseases, for example cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, myocardial infarction associated with ischemic injuries, stroke and reperfusion injury, degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease.

Treatment procedures

The compounds of formula (I) are expected to be useful in the prevention or treatment of a number of diseases or conditions mediated through protein kinase A and/or protein kinase B. Examples of such diseases and conditions are set forth above.

Compounds of formula (I) are generally administered to a subject in whom there is a need for such administration, for example a human or animal patient, preferably a human.

The compounds will typically be administered in amounts that are therapeutically or prophylactically useful and are generally non-toxic. However, in certain situations (for example in the case of life-threatening diseases), the benefits of administering a compound of formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer the compound in amounts associated with by the degree of toxicity.

The compounds may be administered over a long period of time to maintain beneficial therapeutic effects or may be administered only for a short period. Alternatively, they can be applied in a pulsating manner.

A typical daily dose of the compound may be in the range of 100 picograms to 100 milligrams per kilogram of body weight, typically 10 nanograms to 10 milligrams per kilogram of body weight, more typically 1 microgram to 10 milligrams, although higher or lower doses may be administered where appropriate. . Finally, the amount of compound administered will be proportional to the nature of the disease or physiological condition being treated and will be determined by the physician.

The compounds of formula (I) may be administered as a single therapeutic agent or may be administered in combination therapy with one or more other compounds for the treatment of a particular disease, for example a neoplastic disease such as cancer as defined above. Examples of other therapeutic agents or treatments that may be co-administered (either simultaneously or at different time intervals) with the compounds of formula (I) include, but are not limited to:

* Inhibitore topoizomeraze I

* Antimetabolite

* Agents that target tubulin

* DNA binding agent and topoisomerase II inhibitors

* Alkylating agents

* Monoclonal antibodies

* Anti-hormone

* Inhibitors of signal transmission

* Proteazome inhibitor

* DNK methyl transferase

* Cytokines and retinoids

* Radiotherapy.

In the event that protein kinase A inhibitors or protein kinase B inhibitors are combined with other therapies, two or more treatments may be given in individually variable dosage regimens and via different routes of administration.

In the case where the compound of formula (I) is administered in combination therapy with one or more therapeutic agents, the compounds may be administered simultaneously or sequentially. When administered consecutively, they may be administered at close intervals (for example, over a period of 5-10 minutes) or at longer intervals (for example, 1, 2, 3, 4 or more hours apart, or even separated by longer periods where necessary), where the exact dosage regimen is proportional to the properties of the therapeutic agent(s).

The compounds of the invention can also be administered together with non-chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diet,

For use in combination therapy with another chemotherapeutic agent, a compound of formula (I) and one, two, three, four or more other therapeutic agents may, for example, be formulated together in a dosage form containing two, three, four or more therapeutic agents . Alternatively, the individual therapeutic agents may be formulated separately and presented together in kit form, optionally with instructions for their administration.

A person skilled in the art would, by virtue of his or her general knowledge, know the dosage regimens and combination therapy to use.

Procedures for diagnosis

Prior to administration of a compound of formula (I), the patient may be observed to determine whether the disease or condition from which the patient suffers or may suffer is one that would be amenable to treatment with a compound having activity against protein kinase A and/or protein kinase B.

For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, from which the patient suffers or may suffer, is one characterized by a genetic abnormality or abnormal expression of a protein that leads to upregulation PKA and/or PKB or to sensitization of the pathway to normal PKA and/or PKB activity, or to upregulation of signal transduction components downstream of PKA and/or PKB such as, in the case of PKB, P13K, GF receptors and PDK 1 & 2 .

Alternatively, a biological sample taken from the patient can be analyzed for the loss of a negative regulator or suppressor of the PKB pathway such as PTEN. In the context presented, the term "loss" includes deletion of a gene encoding a regulator or suppressor, excision of a gene (at

example by mutation), truncation of the transcribed product of a gene, or inactivation of a transcribed product (eg via point mutation) or inhibition by the product of another gene.

The term constitutive upregulation includes increased expression or overexpression, including gene amplification (ie, multiple copies of a gene) and increased expression via a transcriptional effect, and hyperactivity and activation, including activation via mutations. In this way, the patient can be subjected to a diagnostic test for the detection of a marker characteristic for the subsequent reregulation of PKA and/or PKB. The term diagnosis includes screening. A marker includes genetic markers including, for example, measuring DNA composition to identify PKA and/or PKB mutations. The term marker also encompasses markers that are characteristic of up-regulation of PKA and/or PKB, including enzyme activity, enzyme levels, enzyme state (eg, phosphorylated or not), and mRNA levels of the aforementioned proteins.

The foregoing diagnostic tests and screenings are typically performed on a biological sample selected from the group consisting of tumor biopsy samples, blood samples (isolation and enrichment of removed tumor cells), stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, or urine.

Identification of a person carrying a mutation in PKA and/or PKB or a rearrangement of TCL-1 or loss of PTEN expression may mean that the patient will be particularly suitable for treatment with a PKA and/or PKB inhibitor. Tumors can preferably be tested for the presence of PKA and/or PKB variants before treatment. The screening procedure will typically involve direct sequencing, oligonucleotide microarray analysis, or a mutant-specific antibody.

Procedures for the identification and analysis of mutations and associated protein regulation are known to those skilled in the art. Screening procedures may include, but are not limited to, standard procedures such as reverse-transcriptase-polymerase chain reaction (RT-PCR) or in-situ hybridization.

In RT-PCR screening, the level of mRNA in the tumor is assessed by making a cDNA copy of the mRNA followed by PCR amplification of the cDNA.

PCR amplification procedures, primer selection, and amplification conditions are known to those skilled in the art. Nucleic acid manipulations and PCR are performed by standard procedures, as described for example in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et al., eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001, 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor

Laboratory Press. Alternatively, a commercially available RT-PCR kit can be used (for example Roche Molecular Biochemicals), or the methodology as outlined in US Patents 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864 and 6,218,529 and is incorporated herein.

An example of an in-situ hybridization technique for assessing mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer, 1987 Meth. Enzvmol., 152: 649).

In general, in situ hybridization includes the following main steps: (1) fixation of the tissue to be analyzed; (2) prehybridization treatment of the sample to increase the accessibility of the target nucleic acid, and to reduce nonspecific binding; (3) hybridization of a mixture of nucleic acids to a nucleic acid in a biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments that did not bind during hybridization, and (5) detection of hybridized nucleic acid fragments. Probes used in such applications are typically labeled with, for example, radioactive isotopes or fluorescent reporters. Preferred probes are long enough, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization to the target nucleic acid(s) under appropriate conditions. Standard procedures for performing FISH are described in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Ine and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

Alternatively, protein products expressed from mRNA can be analyzed by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art. technique for the detection of specific proteins. Detection procedures would include the use of site-specific antibodies. It will be clear to a person skilled in the art that all such well-known techniques for the detection of upregulation of PKB, or the detection of PKB variants would be applicable in the presented case.

Therefore, all these techniques could also be used to identify tumors particularly suitable for treatment with PKA and/or PKB inhibitors.

For example, as noted above, PKB beta has been found to be upregulated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al 1995, Int. J. Cancer 64,280-285; Cheng et al 1996, PNAS 93 , 3636-3641; Yuan et al 2000, Oncogene 19,

2324 - 2330). Therefore, it is predicted that PKB inhibitors, and especially PKB beta inhibitors, can be used for the treatment of ovarian and pancreatic cancer.

PKB alpha is amplified in human gastric, prostate and breast cancer (Staal 1987, PNAS 84, 5034-5037; Sun et al 2001, Am. J. Pathol. 159, 431-437). Therefore, it is envisaged that PKB inhibitors, and particularly PKB alpha inhibitors, can be used for the treatment of human gastric, prostate and breast cancer.

Increased PKB gamma activity has been reported in steroid-independent breast and prostate cell lines (Nakatani et al 1999, J. Biol. Chem. 274, 21528 - 21532). Therefore, it is predicted that PKB inhibitors, and especially PKB gamma inhibitors, can be used for steroid-independent treatment of breast and prostate cancer.

EXPERIMENTAL DEO

The invention will now be illustrated, but not limited; by reference to the specific variants described in the following procedures and examples.

Starting materials for each of the procedures described below are commercially available, unless otherwise noted.

In the examples, the prepared compounds were characterized by liquid chromatography, mass spectroscopy and *H nuclear magnetic resonance spectroscopy using the system and operating conditions listed below.

Proton Magnetic Resonance (*H NMR) spectra were recorded on a Bruker AV400 instrument operating at 400.13MHz, in Me-^-OD at 27°C, unless otherwise noted, and were recorded as follows: chemical shift 67ppm (proton number , diversity where s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad). The residual protic solvent MeOH (8h = 3.31 ppm) was used as an internal standard.

For mass spectra, where chlorine is present, the mass given for the compound is for 35C1.

In each example, where the compounds are isolated or formed as a free base, they may be converted into a salt form such as an acetic acid or hydrochloric acid salt. Conversely, where the compounds are isolated or formed as a salt, the salt may be converted to the appropriate free base using procedures well known to those skilled in the art, and then optionally converted to another salt.

A number of liquid chromatography systems were used and are described below.

platform system

HPLC sistem: Waters 2795

Mass spectrometric detector: Micromass Platform LC

PDA detector: Waters 2996 PDA

Acidic analytical conditions 1:

Eluent A: H2O (0.1% formic acid)

Eluent B: CH3CN (0.1% formic acid)

Gradient: 5-95% eluent B over 3.5 minutes

Flow: 1.5 ml/min

Kolona: Phenomenex Svnergi 4mMax-RP 80A, 50x4.6mm

Acid analytical conditions 2:

Eluent A: H2O (0.1% formic acid)

Eluent B: CH3CN (0.1% formic acid)

Gradient: 5-95% eluent B over 3.5 minutes

Flow: 0.8 ml/min

Column: Phenomenex Svnergi 4mMax-RP 80A, 50x2.Mother

Acid analytical conditions 3:

Eluent A: H2O (0.1% formic acid)

Eluent B: CH3CN (0.1% formic acid)

Gradient: 5-95% eluent B for 15 minutes

Flow: 0.4 ml/min

Column: Phenomenex Svnergi 4mMax-RP 80A, 50x2.Mother

Basic analytical conditions 1:

Eluent A: H2O (10 mM NH4HCO3 pufer podešen do pH=9.5 sa NH4OH)

Eluent B: CH3CN

Gradient: 05-95% eluent B during 3.5 minutes

Flow: 1.5 ml/min

Kolona: Waters XTerra MS Cl8 5mm 4.6x50mm

Basic analytical conditions 2:

Eluent A: H2O (10 mM NH4HCO3 pufer podešen do pH=9.5 sa NH4OH)

EluentB:CH3CN

Gradient: 05-95% eluent B during 3.5 minutes

Flow: 0.8 ml/min

Kolona: Thermo Hypersil-Keystone BetaBasic-18 5mm, 50x2.1 mm

Basic analytical conditions 3:

Eluent A: H2O (10 mM NH4HCO3 pufer podešen do pH=9.5 sa NH4OH)

Eluent B:CH3CN.

Gradient: 05-95% eluent B during 3.5 minutes

Flow: 0.8 ml/min

Column: Phenomenex Luna Cl8(2) 5mm, 50x2.Mother

Basic analytical conditions 4;

Eluent A: H2O (10 mM NHCO3 buffer adjusted to pH=9.2 with NH4OH)

Eluent B: CH3CN

Gradient: 05-95% eluent B for 15 minutes

Flow: 0.8 ml/min

Column: Phenomenex Luna Cl8(2) 5mm, 150x2.Mother

Polar analytical conditions:

Eluent A: H2O (0.1% formic acid)

Eluent B: CH3CN (0.1% formic acid)

Gradient: 00-50% eluent B for 3 minutes

Flow: 1.5 ml/min

Kolona: Phenomenex Svnergi 4m Hydro 80A, 50x4.6mm

MS conditions:

Capillary voltage: 3.5 kV or 3.6 kV

Tap voltage: 30 V

Source temperature: 120 °C

Scanning range: 165-700 amu

Ionization mode: electrospray negative, positive or positive & negative

FractionLynx sistem

System: Waters FractionLynx (dual analytical/prep.)

HPLC pumpa: Waters 2525

Injector-Autosampler: Waters 2767

Mass spectrometric detector: Waters-Micromass ZQ

PDA detector: Waters 2996 PDA

Acidic analytical input vi:

Eluent A: H2O (0.1% formic acid)

Eluent B: CH3CN (0.1% formic acid)

Gradient: 5-95% eluent B for 5 minutes

Flow: 2.0 ml/min

Kolona: Phenomenex Svnergi 4mMax-RP 80A, 50x4.6mm

Polar analytical conditions:

Eluent A: H2O (0.1% formic acid)

Eluent B: CH3CN (0.1% formic acid)

Gradient: 00-50% eluent B for 5 minutes

Flow: 2.0 ml/min

Kolona: Phenomenex Svnergi 4mMax-RP 80A, 50x4.6mm

MS parameters for acidic and polar analytical conditions:

Capillary voltage: 3.5 kV

Voltage on the cone: 25 V

Source temperature: 120 °C

Scanning range: 125-800 amu

Ionization mode: electrospray positive or electrospray positive & negative

Chiral analytical conditions: Eluent: MeOH + 0.1 % NH4/TFA Flow: 1.2 ml/min Total time: 16.00 min Inj. volume: lOmL Sample concentration: 2 mg/ml

Column: Astec, Chirobiotic V; 250x4.6mm Mass spectrometer is off.

Agilent system

HPLC system: Agilent 1100 series Mass spectrometry detector: Agilent LC/MSD VL Multiple wavelength detector: Agilent 1100 seriesMWD Software: HP Chemstation

Chiral analytical input vi:

Eluent: MeOH+0.2%NH4/AcOH at room temperature

Flow: 2.0 ml/min

Total time: 8.5 min

Inj. volume: 20 uL

Sample concentration: 2 mg/ml

Kolona: Astec, Chirobiotic V; 250x4.6 mm

Hiralni preparatory conditions 1:

Eluent: MeOH+ 0.1% NH4/TFA at room temperature

Flow: 6.0 ml/min

Total time: 10 min

Inj. volume: 100 uL

Sample concentration: 20 mg/ml

Kolona: Astec, Chirobiotic V; 250x10 mm

Hiralni preparatory conditions 2:

Eluent: MeOH + 0.2% NH4/AeOH at room temperature

Flow: 20.0 ml/min

Total time: 19 min

Inj. volume: 950 uL

Sample concentration: 25 mg/ml

Colona: Astec, Chirobiotic V2; 250 x 21.2 mm

MS entered vi (analytical procedure only):

Capillary voltage: 3000 V

Fragmentor: 150

Profit: 1.00

Gas for drying: 12.0 L/min

T gas for drying: 350°C

Nebulizer pressure: 35 (psig)

Scanning range: 125-800 amu

Ionization mode: electrospray positive

In the examples below, the following key was used to identify the LCMS conditions used:

PS-A Platform Svstem - acid analytical conditions 1

PS-A2 Platform Svstem - acid analytical conditions 2

PS-A3 Platform Svstem - acid analytical conditions 3

PS-B Platform Svstem - basic analytical conditions 1

PS-B2 Platform Svstem - basic analytical conditions 2

PS-B3 Platform Svstem - basic analytical conditions 3

PS-B4 Platform System - basic analytical conditions 4

PS-P Platform Svstem - polar analytical conditions

FL-A FractionLynx Svstem - acidic analytical conditions

FL-P FractionLynx Svstem - polar analytical conditions

FL-C FractionLynx Svstem - chiral analytical conditions

AG-CA Agilent Svstem - chiral analytical conditions

AG-CP1 Agilent Svstem - hiralni preparativni usoli 1

AG-CP2 Agilent Svstem - hiralni preparativni uslovi 2

PRIMER 1 2-Phenyl-2-[4-flH-pyrazol-4-yn-phenyl-ethylamine

To a suspension of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride (134 mg, 0.5 mmol, 1.0 equiv.) (Array PPA-Q02-1) in toluene (0.8 ml) was added bis(tri-t-butylphosphine)palladium (0) (3 mg, 1 mol%) (Strem) and the mixture was purged with nitrogen. A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (107 mg, 0.55 mmol, 1.1 equiv) (Aldrich 52,505-7) in ethanol (0.8 ml) and then potassium carbonate (415 mg, 3.0 mmol, 6 equiv.) in water (2.5 ml). The mixture was purged with nitrogen and hermetically sealed. The reaction mixture was heated in a CEM Explorer™ microwave to 135°C for 15 minutes using a 50 watt power supply. The solvents were removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (SiCh), eluting with a mixture of dichloromethane (90 mL): methanol (18 mL): acetic acid (3 mL): H 2 O (2 mL) to give the title compound 14 mg (9 %); LCMS (PS-A) R, 1.79 min; mlz [M+H]+ 264.

FIRST 2

3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl1-propionitrile 2A. 2-(3-Bromo-phenyl)-3-phenyl-propionitrile

A solution of 40% KOH (2.83 g in 5.0 ml H2O) in ethanol (13 ml) was added to a solution of benzaldehyde (2.85 ml, 28.05 mmol) and 3-bromophenylacetonitrile (5 g, 25.50 mmol) in ethanol (9 ml). The reaction mixture was then stirred at room temperature for 2 h and the precipitate was collected by suction filtration and washed with cold ethanol (6.68 g, 92%). Raw product (3.45 g, 12.14

mmol) was then dissolved in ethanol (35 ml) and heated to 65 °C. Sodium borohydride (459 mg, 12.14 mmol) was added in portions and the reaction mixture was maintained at this temperature for another 2 hours. After cooling, water (10 ml) was added and the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the desired product (1.80 g, 52%), which was used without purification.

2B. 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-promonitrile

2-(3-Bromo-phenyl)-3-phenyl-propionitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure that was listed in Example 1 to give the title compound. (LC/MS: (PS-A) Rt 2.98 [M+M]+ 274).

PRIMER 3 2-r4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl1-2-phenyl-ethylamine

By following the procedure from Example 1, but using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Boron Molecular D03-BM152 ) instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the title compound was obtained. (LC/MS: (PS-A)Rt1.79[M+H]+292.

PRIMER 4 2-(4-chloro-phenin-2-[4-(lH-pyrazol-4-yn-phenyl]-ethylamine)

By following the procedure from Example 1, but using 2,2-bis-(4-chloro-phenyl)-ethylamine instead of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride*, the title compound was obtained. (LC/MS: (PS-A) Rt 1.99 [M+H]+ 298).

*This starting material can be made using the procedure described in J. Amer. Chem. Soc, 1983, 105, 3183-3188.

FIRST 5

2-r3-(3,5-Dimetil-lH-pirazol-4-il)-fenill-l-fenil-etilamin 5A. 2-(3-Bromo-fenil)-l-fenil-etilamin

Benzonitrile (500 mg, 4,849 mmol) was added dropwise to a solution of 3-bromobenzylmagnesium bromide (0.275 M solution in diethyl ether, 21.1 ml, 5,818 mmol) under a nitrogen atmosphere at room temperature. The reaction mixture was then heated to reflux over a period of 2 hours, then allowed to cool. Lithium aluminum hydride (1.0 M in THF, 4.85 mL, 4.849 mmol) was then carefully added and the reaction mixture was allowed to reflux for another 16 h. After cooling, the reaction was carefully quenched and water (5 mL) was added dropwise and then partitioned between water (20 mL) and ethyl acetate (100 mL). The organic layer was separated, dried (MgSCO4), filtered and concentrated. Purification by ion exchange chromatography afforded the desired compound (420 mg, 31%).

5B.2-[3-(3,5-Dimethyl-1H-pyrazol-4-yn-phenyl]-1-phenyl-ethylamine

The product or 5B was reacted with 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole following the procedure outlined in Example 1 to give the title compound. (LC/MS: (PS-B) Rt 2.54 [M+H]+ 292).

FIRST 6

3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl-propylamine

To a solution of the product from Example 2 (70 mg, 0.256 mmol, 1.0 equiv.) in ethanol (25 ml) was added concentrated ammonia (0.5 ml) and Raney nickel (approximately 0.5 ml aqueous suspension) and the reaction mixture was subjected to an atmosphere of hydrogen for 17 hours. The mixture was filtered through celite and the resulting liquid was concentrated under reduced pressure to give the title compound which was purified by preparative liquid chromatography. (LC/MS: (PS-A) Rt 1.89 [M+H]+278.

FIRST 7

3-Phenyl-2-["4-(1H-pyrazol-4-yn-phenyl]-propylamine 7A. 2-(4-Bromo-phenyl*)-3-phenyl-propionitrile

Following the procedure described in Example 2A, but replacing 4-bromophenylacetonitrile with 3-bromophenylacetonitrile, the title compound was obtained which was used in the next step without further purification.

7B. 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propiotryl

By following the procedure described in Example 1, but substituting 2-(4-Bromo-phenyl)-3-phenyl-propionitrile for 2-(4-chlorophenyl)-2-phenylethylamine, the title compound was obtained.

7C. 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

The nitrile product of Example 7B was reduced using the conditions described in Example 6 to give the title compound. (LC/MS: (PS-B) Rt 3.03 [M+H]+ 278.

FIRST 8

{3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-fenil1propyl}-methyl-amine 8A. Ethyl estar 3-(4-bromo-fenil)-2-cyano-akrilne kisite (J. Med. Chem., 1983, 26, 935-947)

To 4-bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 ml, 17.84 mmol) in toluene was added piperidine (27 ml) and the reaction mixture was refluxed for 1 h with Dean-Stark

separator. The solvent was removed under reduced pressure, the residue was triturated with hot ethyl acetate, filtered to give the desired product as a yellow solid (4.03 g, 89% yield). LC/MS: (PS-A2) Rt 3.44.

8B. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethyl ester

A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (1.5 g, 5.36 mmol) in dry toluene (12 ml) was added dropwise to 4-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran, 6.96 ml , 6.96 mmol) at 0°C. The reaction mixture was heated to 85°C for 3 hours, poured onto ice, acidified to 1N HCl and extracted with ethyl acetate. The organic layer was separated, dried (MgSCU), filtered and concentrated, the crude product was purified by flash chromatography on silica gel eluting with petroleum ether to ethyl acetate/petroleum (5:95) to give the desired product (1.91 g, 91 % yield.) LC/MS: (PS-A2) Rt 3.78 [M+H]-391.93.

8C. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid

A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethyl ester (1.91, 4.87 mmol), acetic acid (10 ml), concentrated sulfuric acid (5 ml) and water (5 ml) was refluxed for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum (1:1) to give the desired product (0.82 g, 50% yield ).LC/MS: (PS-A2) R, 3.39 [M+H]- 338.86.

8P. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide

A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid (0.25 g, 0.74 mmol) and 1-hydroxybenzotriazole (0.12 g, 0.88 mmol) in dichloromethane (3 ml) was stirred for 15 minutes before adding methylamine (40% solution in water, 0.11 ml, 1.47 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88 mmol). The reaction mixture was stirred for 16 h, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium bicarbonate, brine, dried (MgSO 4 ), filtered and concentrated to give the title compound which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 353.95.

8E. [3-(4-Bromo-phenyl)-3-(4-chloro-phenyl-propyl]-methyl-amine

Under nitrogen atmosphere, crude 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide cooled to 0°C, lithium aluminum hydride (0.075 g, 1.97 mmol) and diethyl ether (3 ml). With cooling, aluminum chloride (0.23 g, 1.69 mmol) was dissolved in diethyl ether (2 mL) and added. The reaction mixture was stirred for 16 hours, quenched by adding water, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSC>4), filtered and concentrated, the crude product was purified by chromatography on a Phenomenex_Strata SCX column eluting with methanol and then with 2N ammonia in methanol to give the desired product (0.254 g, 62% yield for two steps 1D and 1E in total). LC/MS: (PS-B3) R, 3.20 [M+Hf 339.85.

8F. {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yn-phenyl-propyl-methyl-amine)

[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazole following the procedure outlined in Example 1 to give the title compound. LC/MS: (PS-B3) R, 2.63 [M+H] + 326.00. 1H NMR (Me-d3-OD) δ 2.37-2.47 (2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (1H, t), 7.25-7.34 (6H, m), 7.54 (2H, d), 7.92 (2H, s), 8.51 (IH, no s - due to formic acid).

FIRST 9

{3-(3,4-Difluoro-phenin-3-[4-(1H-pyrazol-4-yl)-phenyl1propy}-methyl-amine 9A. 3-(4-Bromo-phenyl)-3-(3, 4-difluoro-phenyl)-N-methyl-propionamide

Following the procedure described in Example 8A to Example 8C, but substituting 4-chlorophenylmagnesium bromide for 3,4-difluorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) R, 3.12 [M+H] + 355.84.

9B.3-(3,4-Difluoro-phenyl)-N-methyl-3-r4-(1H-pyrazol-4-yl)-phenin-propionamide

3-(4-Bromo-phenyl)-3-(3,4-difluoro-phenyl)-N-methyl-propionamide reacted with 4-(4,4,5,5-tetamethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-A2) Rt 2.55 [M+H]+ 341.93.

9C. (3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl-propyl)-methyl-amine

Lithium aluminum hydride was added to a suspension of 3-(3,4-Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide in diethyl ether, followed by a soln. of aluminum chloride in diethyl ether at 0°C, under a nitrogen atmosphere. Toluene was added and the reaction mixture was heated to 70°C for 18 hours. After cooling, the reaction was quenched by adding water, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated to give the desired compound. LC/MS: (PS-A2) Rt 2.15 [M+H]+ 328.06. 1H NMR (Me-^-OD) δ 2.19-2.29 (2H, m), 2.35 (3H, s), 2.51 (2H, t), 4.00 (1H, t), 7.06-7.24 (3H, m), 7.27 (2H, d), 7.52 (2H, d), 7.92 (2H, s).

PRIMER 10 (3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl-propyl}-methyl-amine

Following the procedure described in Example 8, but replacing 4-chlorophenylmagnesium bromide with 3-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-B3) R, 2.67 [M+H] + 326.00. !H NMR (Me-d3-OD) δ 2.43-2.50 (2H, m), 2.68 (3H, s), 2.94 (2H, m), 4.13 (IH, t), 7.24 (IH, m), 7.27- 7.36 (3H, m), 7.41 (2H, d), 7.66 (2H, d), 8.50 (2H, s).

PRIMER 11 3-(4-chloro-phenyl)-3-r4-(1H-pyrazol-4-yn-phenyl1-propionamide)

Following the procedure described in Example 9A and 9B, but substituting 4-chlorophenylmagnesium bromide for 3,4-difluorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) R, 2.54 [M+H]+ 326. [H NMR (Me-d3-OD) δ 2.95 (2H, d), 4.53 (1H, t), 7.27 (6H, m ), 7.50 (2H, d), 7.91 (2H, s).

FIRST 12

3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine 12A. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)propionamide

A solution of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid* (0.25 g, 0.74 mmol) and 1'-carbonyldiimidazole (0.24 g, 1.47 mmol) in dichloromethane was stirred for 45 minutes before addition of ammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reaction mixture was stirred for 2 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum (1:4) to afford the title compound (0.091 g, 36% yield ).LC/MS: (PS-A2) Rt 3.08 [M+H]+ 339.93.

*This starting material can be made using the procedure described in Example 8A through 8C.

12B. 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine

Following the procedure described in Example 8E, but substituting 3-(4-bromo-phenyl)-3-(4-chlorophenyl)-3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionamide -N-methyl-propionamide, the title compound was obtained. LC/MS: (PS-B2) Rt 3.88 [M+H]+ 359.87.

12C. 3-(4-chloro-phenyl N3-r4-(1H-pyrazol-4-yl)-phenyl1-propylamine

3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- with lH-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-B3) R, 2.54 [M+H]+ 312.04. !H NMR (Me-d3-OD) δ 2.39 (2H, m), 2.84 (2H, t), 4.06 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.91 ( 2H, s).

FIRST 13

3-(3,4-Dichloro-fenil)-3-[4-(1H-pyrazol-4-yl)-fenill-propylamin

Following the procedure described in Example 12, but substituting 4-chlorophenylmagnesium bromide for 3,4-dichlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) R, 2.17 [M+H] + 345.95. *H NMR (Me-cf3-OD) δ 2.39 (2H, m), 2.84 (2H, t), 4.07 (1H, t), 7.24-7.31 (4H, m), 7.45-7.49 (2H, m), 7.56 (2H, d), 7.93 (2H, s).

FIRST 14

4-(4-chloro-phenyl)-4-r4-(1H-pyrazol-4-yn-phenyl]-piperidine

14A. 4-(4-Bromo-phenylN4-(4-chloro-phenylNpiperidine).

A suspension of 4-(4-Bromo-phenyl)-piperidin-4-ol (4.02 g, 15.7 mmol) in chlorobenzene (30 mL) was added dropwise to a suspension of aluminum chloride (7.32 g, 54.9 mmol) in chlorobenzene (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 2 hours, quenched by adding ice, then methyl t-butyl ether was added. After stirring for 1 hour, the precipitate was collected by filtration, washed with water, methyl t-butyl ether and water to give the title compound (5.59 g, 92% yield). LC/MS: (PS-B3) R, 3.57 [M+H] + 350, 352.

14B. 4-(4-chloro-fenil)-4-[4-(1H-pyrazol-4-yl)-fenil]-piperidin

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- with lH-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-A3) R, 7.22 [M+H]+ 338.08. 1H NMR (Me-d3-OD) δ 2.64-2.74 (4H, m), 3.22-3.25 (4H, m), 7.33-7.45 (6H, m), 7.65 (2H, d), 8.37 (2H, s ).

PRIMER 15 4-(4-Methoxy-phenyl)-4-r4-(1H-pyrazol-4-yl)-phenin-piperidin

Following the procedure described in Example 14, but substituting anisole for chlorobenzene, the title compound was obtained. LC/MS: (PS-B3) Rt 2.42 [M+H]+ 334.00. !H NMR (Me-d3-OD) δ 2.69 (4H, m), 3.23 (4H, m), 3.76 (3H, s), 6.90 (2H, d), 7.28 (2H, d), 7.40 (2H, d), 7.65 (2H, d), 8.53 (2H, s).

FIRST 16

4-(4-chloro-phenylV 1 -methyl-4-[4-( 1 H-pyrazol-4-yl)-phenyl]-piperidin

16A. Ethyl ester 4-(4-Bromo-phenylV4-(4-chloro-phenin-piperidin-l-karbonske kiske)

To a stirred suspension of 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine* (0.28 g, 0.80 mmol) in dichloromethane (10 ml), was added triethylamine (0.45 ml, 3.2 mmol) and ethyl chloroformate (0.085 ml, 0.88 mmol). The reaction mixture was stirred for 3 hours, diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate and saline. The organic layer was separated, dried (MgSO 4 ), filtered and concentrated to give the title compound (0.29 g, 94% yield). LCMS: (PS-A2), R, 4.02 [M+H]+ 422, 424.

*This starting material can be made using the procedure described in Example 14A

16B. 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine

Under a nitrogen atmosphere, 4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid ethyl ester (0.28 g, 0.66 mmol) and lithium aluminum hydride (0.051 g) were suspended in tetrahydrofuran. (5 ml) and mixed for 2 hours. The reaction mixture was quenched by addition of water, the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and 2N NaOH. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to give the desired product (0.241 g, 99% yield). LC/MS: (PS-B3) Rt 3.78 [M+H]+ 363.95, 365.73.

16C. 4-(4-chloro-fenilV1-methyl-4-[4-(1H-pyrazol-4-yl)-fenil1-piperidin

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-1-methyl-piperidine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1H-pyrazole following the procedure outlined in Example 1 to give the title compound. LC/MS: (PS-B3) Rt, 2.90 [M+H]+ 352. *H NMR (Me-d3-OD) δ 2.41-2.53 (2H, m), 2.82 (3H, d), 2.97-3.12 (4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s), 7.34 (IH, m), 7.42 (IH, d), 7.49 (IH, d), 7.54 (IH, d), 7.61 (1H, d), 7.75 (1H, d), 8.52 (2H, d).

PRIMER 17 4-Phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl-piperidin

By following the procedure described in Example 1, but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for 4-(4-chloro-phenyl)-4-phenyl-piperidine, the title compound was obtained. LC/MS: (PS-A2) Rt 1.88 [M+H]+ 304. 1H NMR (Me-d3-OD) δ 2.65-2.71 (4H, m), 3.21 (4H, t), 7.18-7.22 (1H , m), 7.32-7.38 (6H, m), 7.55 (2H, d), 7.93 (2H, s).

FIRST 18

4-r4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl1-4-phenyl-piperidin

Following the procedure described in Example 1, but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole for 4-(4-chloro-phenyl)-4-phenyl-piperidine and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolane-2- 11)-1H-pyrazole, the title compound was obtained. LC/MS: (PS-A2) Rt 2.95 [M+H]+ 315. *H NMR (Mc-d3-OD) δ 2.22 (6H, s), 2.66-2.76 (4H, m), 3.16-3.28 ( 4H, m), 7.19-7.44 (9H, m).

PRIMER 19 Dimethyl-(3-r4-(1H-pyrazol-4-yn-phenyl-3-pyridin-2-yl-propyl)}-amine

By following the procedure described in Example 1, but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for brompheniramine maleate, the title compound was obtained. LC/MS: (PS-B2) Rt 2.29 [M+H]+ 307. 1H NMR (Me-d3-OD) δ 2.44-2.54 (1H, m), 2.59-2.70 (1H, m), 2.77 (6H , s), 2.93-3.01 (2H, m), 4.20 (1H, t), 7.25-7.28 (1H, m), 7.32-7.36 (3H, m), 7.54 (2H, d), 7.75 (IH, dt ), 7.94 (2H, no. s).

FIRST 20

{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl-ethyl)-dimethyl-amine 20A. 2,2-Bis-(4-chloro-phenylVN,N-dimethyl-acetamide

Bis-(4-chloro-phenyl)-acetic acid was reacted with dimethylamine following the procedure outlined in Example 8D to give the title compound. LC/MS: (PS-A2) Rt 3.40 [M+H]+309.95.

20B. r2,2-Bis-(4-chloro-phenyl)-ethyl-1-dimethylamine

Following the procedure described in Example 8E, but substituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide for 2,2-Bis-(4-chlorophenyl)-N ,N-dimethylacetamide, the title compound was obtained. LC/MS: (PS-B2) R, 3.75 [M+H] + 295.99.

20C. (2-(4-chloro-phenyl')-2-[4-(1H-pyrazol-4-yl)-phenyl-ethyl-dimethyl-amine

[2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-arnine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- with lH-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-B2) Rt 3.07 [M+H]+ 325.99. 1H NMR (Me-d3-OD) 6 2.5 (6H, s), 2.98 (2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H , with).

PRIMER21 (2-r4-chloro-phenin-2-r4-(1H-pyrazol-4-ylVphenyl-ethyl-methyl-amine

Following the procedure described in Example 20, but substituting methylamine for dimethylamine, the title compound was obtained. LC/MS: (PS-B2) Rt 2.83 [M+H]+ 312.07. 1H NMR (Me-d3-OD) δ 2.42 (3H, s), 3.20-3.23 (2H, dd), 4.18 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.92 (2H, no. s).

PR1MER 22 (2-f4-hlon)-phenin-2-r4-(1H-pyrazol-4-ylVphenyl-ethyl)-methyl-amine(R)

It was prepared using the same procedure as in Example 21, but the enantiomers were separated by chiral preparative HPLC using the AG-CP2 procedure. LCMS: (AG-CA) Rt 5.58 min, 97.4% enantiomeric excess. !H NMR (Me-d3-OD) δ 2.75 (3H, s), 3.78 (2H, d), 4.43 (1H, t), 7.39 (4H, s), 7.44 (2H, d), 7.69 (2H, d), 8.43 (2H, s).

PRIMER 23 (2-r4-chloro-phenin-2-r4-(1H-pyrazol-4-yn-phenyl-ethyl-methyl-amine (S)

It was prepared using the same procedure as in Example 21, but the enantiomers were separated by chiral preparative HPLC using the AG-CP2 procedure. LCMS: (AG-CA) Rt 4.51 min, 98.0% enantiomeric excess. 1H NMR (Me-d3-OD) 8 2.75 (3H, s), 3.79 (2H, d), 4.51 (1H, t), 7.37-7.43 (4H, m), 7.49 (2H, d), 7.73 (2H , d), 8.66 (2H, s).

FIRST 24

4-(2-(4-chloro-phenyl)-2-[4-( 1 H-pyrazol-4-yn-phenyl]-ethyl}-morpholine

Following the procedure described in Example 20, but substituting dimethylamine for morpholine, the title compound was obtained. LC/MS: (PS-B3) R, 3.07 [M+H]+ 368.05. 1H NMR (Me-d3-OD) δ 2.50 (4H, m), 2.97 (2H, m), 3.60 (4H, t), 4.26 (1H, t), 7.27 (6H, m). 7.49 (2H, d), 7.89 (2H, s).

FIRST 25

4-(4-r 1 -(4-chloro-phenin-2-pyrrolidin-1 -yl-ethyl-phenyl 1 -1 H-pyrazole

Following the procedure described in Example 20, but substituting dimethylamine for pyrrolidine, the title compound was obtained. LC/MS: (PS-A2) R, 2.06 [M+H]+ 354.01. !H NMR (Me-d3-OD) δ 1.85 (4H, m), 2.87 (4H, m), 3.47 (2H, d), 4.31 (IH, t), 7.30-7.37 (6H, m), 7.54 ( 2H, d), 7.92 (2H, s).

PRIMER 26 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl-ethyl-isopropyl-amine

Following the procedure described in Example 20, but substituting isopropylamine for dimethylamine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.10 [M+H]+ 340. *H NMR (Me-d3-OD) δ 1.31 (6H, d), 3.38-3.45 (IH, m), 3.65-3.74 ( 2H, m), 4.39 (1H, no t), 7.37 (6H, m), 7.59 (2H, d), 7.94 (2H, s).

FIRST 27

Dimethyl-(2-phenyl-2-r4-(1H-pyrazol-4-yl)-phenylt-ethyl-amine

Following the procedure described in Example 20, the title compound was obtained. LC/MS: (PS-B2) Rt 2.82 [M+H]+ 292.11. 1H NMR (Me-d3-OD) δ 2.25 (6H, s), 2.95-3.04 (2H, m), 4.20 (IH, t), 7.16 (IH, t), 7.26-7.33 (6H, m), 7.49 (2H, d), 7.89 (2H, s).

FIRST 28

(2,2-Bis-r4-(1H-pyrazol-4-yl)-phenyl-ethyl)-dimethyl-amine

Following the procedure described in Example 20, the title compound was obtained. LC/MS: (PS-B2) Rt 2.45 [M+H]+ 358.11. 'H NMR (Me-d3-OD) δ 2.69 (6H, s), 3.59 (2H, d), 4.43 (1H, t), 7.39 (4H, d), 7.57 (4H, d), 7.93 (4H, with).

PRIMER 29 {2,2-Bis-4-(1H-pyrazol-4-yl)-phenyl-ethyl}-methyl-amine

106

51546 B

Following the procedure described in Example 21, the title compound was obtained. LC/MS: (PS-B2) Rt 2.18 [M+H]+ 344.11. !H NMR (Me-^-OD) δ 2.65 (3H, s), 3.60 (2H, d), 4.34 (1H, t), 7.36 (4H, d), 7.59 (4H, d), 7.94 (4H, with).

PRIMER 30 2-(4-chloro-phenin-2-r4-(1H-pyrazol-4-ylVphenin-ethylamine(R)

It was prepared using the same procedure as in Example 4, but the enantiomers were separated by chiral preparative HPLC using the AG-CP1 procedure. LCMS: (FL-C) R, 10.97 min, 95.7% enantiomeric excess. *H NMR (Me-d3-OD) δ 3.65 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.16 (2H, s).

PRIMER 31 2-(4-chloro-phenylV2-r4-(1H-pyrazol-4-yl)-phenyl1-ethylamine(S)

Prepared using the same procedure as in Example 4, but the enantiomers were separated by chiral preparative HPLC using the AG-CP1 procedure. LCMS: (FL-C) Rt 9.63min, 100% enantiomeric excess. *H NMR (Me-d3-OD) δ 3.66 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.15 (2H, s).

PRIMER 32 2-(4-chloro-phenyl)-2-[4-riH-pyrazol-4-yl)-phenyl]-acetamide

Following the procedure described in Example 12A and then 12C, but substituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid for Bis-(4-chloro-phenyl)-acetic acid , the title compound was obtained. LC/MS: (PSA2) Rt 2.53 [M+H]+ 312. *H NMR (Me-d3-OD)

δ 4.99 (IH, s), 7.30-7.33 (6H, m), 7.55 (2H, d), 7.86-8.02 (2H, br s).

FIRST 33

l-(2-(4-chloro-phenin-2-[4-riH-pyrazol-4-yl)-phenyl]-ethyl-piperazin 37A. Bis-(4-chloro-pheniD-acetaldehyde

Dess-Martin periodinan (3.17 g, 7.49 mmol) was added to a solution of 2,2-Bis-(4-chloro-phenyl)-ethanol in dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 17h under nitrogen, 2N NaOH (15ml) was added and the organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound which was used in the next step without further purification. . LC/MS: (PS-B3) Rt, 3.62 [M+H]+ 262.91.

33B. tert-butil estar 4-r2,2-Bis-(4-chloro-fenil)-ethyl-piperazin-l-karbonske kiske

To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) in methanol under a nitrogen atmosphere, NBOC-piperazine (1.05 g, 5.61 mmol) was added, the reaction mixture was stirred for 1 hour before the addition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reaction mixture was stirred for 18 h, water (3 ml) was added and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was separated, dried (MgSCO4), filtered and concentrated. It was purified via flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (3:7) to afford the title compound (0.18 g, 11% yield for steps 30A and 30B combined). LC/MS: (PS- A2) Rt 2.66 [M-BOC+H]+ 335.02.

33C. 1 -r2.2-Bis-(4-hloro-fenil)-etill-piperazine

4-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-Butyl ester was treated with HCl in ethyl acetate (saturated, 5 mL) for 1 h, the solvent was removed under under reduced pressure to give the title compound as the HCl salt.

33D. 1 - (2-(4-chloro-phenin-2-[4-d H -pyrazol-4-yl)-phenyl]-ethyl}-piperazine

1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- l H-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-B3) Rt 2.63 [M+H]+ 326.00. 1H NMR (Me-d3-OD)

δ 3.55-3.68 (8H, m), 3.74 (IH, t), 4.10-4.17 (2H, m), 7.39 (2H, d), 7.48 (2H, d), 7.54 (2H, d), 7.70 (2H, d), 8.57 (2H, br s).

FIRST 34

1 - (2-(4-chloro-phenyl V 2-f4-( 1 H-m'razol-4-in-phenyl-ethyl I-piperidin

Following the procedure described in Examples 33A, 33B and 33D, but substituting piperidine for N-BOC-piperazine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 366.09. 1H NMR (Me-J3-OD) δ 1.44 (2H, m), 1.53 (4H, m), 2.39-2.57 (4H, m), 2.94-3.09 (2H, m), 4.26 (1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s).

FIRST 35

4-(4-r2-Azetidin-l-il-l-(4-hloro-fenin-etil1-fenill-lH-pirazol 35A. 2-(4-hloro-fenin-2-r4-nH-pirazol-4- il)-fenin-etanol

2,2-Bis-(4-chloro-phenyl)-ethanol was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure that was listed in Example 1 to give the title compound. LC/MS: (PS-A2) R, 2.72 [M+H]+ 299.00.

35B. (4-chloro-phenin-[4-(lH-pyrazol-4-yl)phenyl]-acetaldehyde

Following the procedure described in Example 33A, but substituting 2,2-Bis-(4-chloro-phenyl)-ethanol for 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl) )-phenyl]-ethanol, the title compound was obtained. LC/MS: (PS-B3) R, 2.97 [M+H]" 294.98.

35C.4-{4-[2-Azetidin-1-yl-1-(4-chloro-fenil)ethin]-fenil}-1H-pyrazole

Following the procedure described in Example 33B, but replacing bis-(4-chlorophenyl)-acetaldehyde and NBOC-piperazine with (4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-acetaldehyde and azetidine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.99 [M+H]+ 338.09. 1H NMR (Me-d3-OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71-3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m) , 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s).

FIRST 36

1-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenin-ethylamine

-N

Following the procedure described in Example 5, but substituting 3-bromobenzylmagnesium bromide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H -pyrazole with 4-bromobenzylmagnesium bromide and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the title compound was obtained. LC/MS: (PS-B2) Rt 2.44 [M+H]+ 264.04. 'H NMR (Me-d3-OD) δ 2.99 (2H, d), 4.13 (1H, t), 7.10 (2H, d), 7.20-7.38 (5H, m), 7.45 (2H, d), 7.91 ( 2H, s).

FIRST 37

[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-acetonitrile

37A. 4-Bromo-5-methyl-1-(tetrahydro-pyran-2-yn-3-trifluoromethyl-1H-pyrazole

To a solution of 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.4 g, 6.2 mmol, 1.0 equiv.) in chloroform (31 ml) was added sulfonic acid p-toluene monohydrate (118 mg, 0.62 mmol), 0.1 equiv.). The solution was cooled to 0°C and 3,4-dihydro-2H-pyran (0.85 ml, 9.3 mmol, 1.5 equiv.)

was added dropwise over 5 minutes. The mixture was allowed to warm to room temperature for 1 hour and the solvents were removed under reduced pressure. The crude mixture was purified by column chromatography (SiO2), eluting with 0-->25% EtOAc-petroleum through a linear gradient to give the title compound 1.4 g (59%), LCMS (PS-A) Rt 3.72 min [M +H]+314.

37B. (4-R5-Methyl-1-(tetrahydro-pyran-2-yn-3-trifluoromethyl-1H-pyrazol-4-yn-phenylacetonitrile

The product of Example 37A, 4-bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole, was reacted with 4-(cyanomethylphenyl)organoboronic acid (Combi-Blocks, San Diego , USA Cat No. 2444-001) under the conditions described in Example 1, to give the title compound.

37C. r4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl1-acetonitrile

U {4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl}-

To acetonitrile (Example 8B) (35 mg, 0.1 mmol, 1.0 equiv.) in ethyl acetate (1 mL) was added HCl in ethyl acetate (1 mL) and the mixture was stirred for 1 h. The solvents were removed under reduced pressure and the title compound was purified by column chromatography (SiC>2) eluting with linear

gradient (0->30% ethyl acetate-petroleum ether) 16 mg (60%); LCMS (PS-A) Rt 2.85 min [M+H]+ 266.

37D. Preparation of compounds of formula (I) from [4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl-phenyl-acetonitrile

(i) The product of Example 37B can be reacted with benzaldehyde under the conditions described in Example 2 to give 2-[4-(5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl- 1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrile which can be deprotected by removal of the 1-tetrahydropyranyl group under the conditions outlined in Example 37C to give 2-[4-(5-methyl-3-trifluoromethyl -1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrile.

2-[4-(5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrile or its 1-tetrahydropyranyl derivative can be reduced according to the procedure of Example 6 (and then where deprotection is necessary according to the procedure from Example 41C) to obtain 2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-3-phenyl-propylamine.

The product of Example 37B can also be reacted with benzyl magnesium bromide or phenyl magnesium bromide under the Grignard reaction conditions described in Example 5 to give (after deprotection using the procedure of Example 37C) 1-benzyl-2-[4-(5 -methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-ethylamine and 2-[4-(5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-1 - phenylethylamine, respectively.

FIRST 38

Construction of the pyrazole ring system

38A. Sinteza 4-(4-Bromo-fenil)-3-methyl-1H-pyrazola

To 4-bromophenylacetone (5.0 g, 23.5 mmol, 1.0 equiv) (Acros Organics 34216) was added N,N-dimethylformamide dimethyl acetal (11.3 ml, 84.6 mmol, 3.6 equiv) and the mixture was heated to 90°C for 6 hours. . The solvents were removed and the resulting gum was dissolved in ethanol (235 ml) with additional heating. Hydrazine hydrate (1.37 mL, 28.2 mmol, 1.2 equiv.) was added and the mixture was

heated to reflux for 15 hours. The solvents were removed under reduced pressure and the solid was triturated with dichloromethane to give the title compound, 2.24 g (40%); LCMS (PS-A) Rt 2.87 min [M+H]+ 238. Additional material could be isolated from the starting liquid.

38B. Conversion of 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole to compounds of formula (I)(i) 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole can be protected at position- 1 pyrazole ring by forming a tetrahydropyranyl (THP) derivative following the procedure outlined in Example 38A. The Grignard reagent can then be prepared from the bromo-phenyl group by treating the magnesium-protected derivative in an ether solvent in a standard manner (see J. March, Advanced Organic Chemistry, 4th Edition, 1992, John Wiley, New York, pages 622-625). A Grignard reagent can be reacted with nitrostyrene (nitrostyrene is prepared using a standard procedure such as that described in Organic Syntheses, Collective Volume 1, page 413) and the resulting nitroethyl compound is reduced to give 2-{4-[3-methyl -1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine. Removal

tetrahydropyranyl grupe primenom projeda iz Primera 8C daje 2-{4-[3-methyl-1H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine.

(ii) The bromo compound of Example 38A can be converted to compounds of formula (I) in which group A contains a nitrogen atom attached to group E. Introduction of the nitrogen-containing group can be achieved by reacting the compound of Example 38A with tert-butyl ester of [3-(4-chloro-phenylamino)-propyl]-methyl-carbamic acid under palladium-catalyzed amination conditions of the type described in Organic Letters, 2002, vol. 4, No. 17, pp 2885-2888, followed by removal of the t-butyloxycarbonyl protecting group using standard procedures.

PRIMERS 39 [3-(lH-Pyrazol-4-yl)-phenyl]-acetonitrile

By following the procedure stated in Example 1, but using 3-bromophenylacetonitrile instead of 2-(4-chlorophenyl)-2-phenylethylamine, the title compound was obtained. LCMS (PS-A) 2.35 min [M+H]+ 184.

3-(1H-Pyrazol-4-yl)-phenyl]-acetonitrile can be used as an intermediate in the preparation of compounds of formula (I), for example by an aldehyde condensation reaction as described in Example 2 or a Grignard reaction such as described in Example 5.

PRIMER 40 2-(4-chloro-phenylVN-methyl-2-r4-nH-pyrazol-4-yl')-phenin-acetamide

Following the procedure described in Example 12A and then 12C, but substituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid for Bis-(4-chloro-phenyl)-acetic acid and ammonia for methyl amine, the title compound was obtained. LC/MS (PS-A2); Rt 2.64 [M+H]+ 326. 'H NMR (Me-d3-OD) δ 2.79 (3H, s), 4.94, (IH, br s), 7.26-7.35 (6H, m), 7.55-7.57 ( 2H, m), 7.96 (2H, no s)

PRIMER 41 N-Methyl-2.2-bis-r4-nH-pyrazol-4-ylVphenyl-acetamide

Following the procedure described in Example 40, the title compound was obtained. LC/MS (PS-A2): Rt 2.19 [M+H]+ 358. 'H NMR (Me-d3-OD) δ 2.80 (3H, s), 4.95, (1H, br s), 7.32 (4H, d), 7.56 (4H, d), 7.98 (4H, no s)

FIRST 42

(2-(4-chloro-fenil)-2-[4-(1H-pyrazol-4-yl)-fenill-ethyl-metil-amin 42A. 1 -(4-Bromo-fenil)-2-metilamino-ethanol

A solution of 2-(4-bromophenyl)-oxirane (0.5 g, 2.51 mmol) in methylamine (6.6 ml, 33% by volume in ethanol, 25.12 mmol) was stirred at room temperature under a nitrogen atmosphere. After 18 hours the solvent was removed in vacuo and the residue was purified over flash silica eluting with dichloromethane:methanol:acetic acid:water (120:15:3:2) to give the desired compound as the acetic acid salt. Additional purification over a Phenomenex_Strata_SCX column eluting with methanol followed by 2N ammonia in methanol afforded the desired product.LC/MS: (PS-B3) Rt 2.52 [M+H]+ 230.

42B. [2-(4-Bromo-phenin-2-f4-chloro-phenylVetiH-methyl-amine

Aluminum chloride (278 mg, 2.087 mmol) was added portionwise to a stirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg, 0.696 mmol) in chlorobenzene (3 mL) and the reaction mixture was stirred at room temperature 17 hours. Water (2 ml) was added dropwise and the reaction mixture was then partitioned between dichloromethane (100 ml) and saturated NaHCO 3 (30 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified by chromatography on a Phenomenex_Strata_SCX column eluting with methanol followed by 2N ammonia in methanol to afford the desired product. LC/MS: (PS-B3) R, 3.58 [M+H] + 324.

42C. (2-(4-chloro-phenine-2-r4-αH-pyrazole-4-yne-phenine-ethyn-methyl-amine

A solution of [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-ethyl-amine (6.1 g, 13.716 mmol), 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g, 27.431 mmol) and K3PO4 (10.19 g, 48.00 mmol) in ethanol (7.5 ml), methanol (11.5 ml), toluene (7.5 ml) and of water (11.5 ml) was purged with nitrogen for 2 minutes. Bis(tri-t-butylphosphine)palladium(0) (175 mg, 2.5 mol%) was then added and the reaction mixture was purged with nitrogen for an additional 2 minutes. The mixture was then heated to 80°C under nitrogen for 17 hours. The solvents were removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (SiCl), eluting with dichloromethane:methanol:acetic acid:water (90:18:3:2) to afford the title compound (3.6 g); LCMS (PS-A2) Rt 2.08 min [M+H]+ 312.

PRIMER 43 (2-f4-chloro-phenylV2-r4-(1H-pyrazol-4-yn-phenyl-ethyl-ethyl-amine

Following the procedures described in Examples 42A to 42C, but substituting methylamine for ethylamine, the title compound was obtained. LC/MS: (PS-A2) R, 2.11 [M+H]+ 326. 1H NMR

(Me-d3-OD) δ 1.15 (3H, t), 2.83 (2H, q), 3.35-3.43 (2H, m), 4.25 (IH, t), 7.30-7.48 (6H, m), 7.57 (2H, d), 7.95 (2H, s).

FIRST 44

4- (4-r 1 -(4-chloro-phenylV2-imidazol-1-yl-ethyl-phenyl}-1H-pyrazole

Following the procedures described in Examples 42A to 42C, but substituting imidazole for methylamine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.73 [M+H]+ 349. 1H NMR (d6-DMSO) δ 4.60 (1H, t), 4.95 (2H, d), 7.32 (2H, d), 7.42 ( 4H, s), 7.53-7.60 (3H, m), 7.70 (IH, s), 8.05 (2H, s), 9.0 (IH, s).

FIRST 45

Methyl-(2-(4-phenoxy-phenin-2-4-(1H-pyrazol-4-yl)phenyl-ethyl-amine)

45A r2-(4-Bromo-phenyl)-2-(4-phenoxy-phenyl)-ethyn-methyl-amine

Following the procedure described in Example 42B, but substituting diphenyl ether for chlorobenzene and using nitrobenzene as solvent, the title compound was obtained. LC/MS: (PS-A2) Rt 2.54 [M+H]+ 382.

45B Methyl-(2-(4-phenoxy-phenin-2-r4-(1H-pyrazol-4-yn-phenyl]-ethyl)-amine

Following the procedure described in Example 42C, but substituting [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for [2-(4-Bromo-phenyl)- 2-(4-phenoxy-phenyl)-ethyl]-methyl-amine, the title compound was obtained. LC/MS: (PS-B3) Rt 3.04 [M+H]+ 370. *H NMR ((Me-d3-OD)

δ 2.75 (3H, s), 3.75 (2H, d), 4.38 (IH, t), 6.98 (4H, dd), 7.12 (IH, t), 7.33-7.40 (6H, m), 7.61 (2H, d), 7.95 (2H, s).

PR1MER 46

(2-(4-Methoxy-phenin-2-[4-(1H-pyrazol-4-yl)-phenylethyl-methyl-amine 46A. r2-(4-Bromo-phenylV2-(4-methoxy-phenyl)-ethyl) -methyl-amine

Following the procedure described in Example 42B, but substituting anisole for chlorobenzene, the title compound was obtained as a mixture of regioisomers (about 4:1) with the corresponding ortho-methoxy analogue. LC/MS: (PS-B3) R, 3.24 [M+H] + 320.

46B. [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine

BOC2O (941 mg, 4.309 mmol) was added to a solution of [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine (and its regioisomer) (1.38 g, 4.309 mmol ) in dichloromethane (10 ml). After stirring at room temperature for 16 h, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography eluting with ethyl acetate/petroleum (1:9) to afford the intermediate BOC protected compound as the desired single isomer (540 mg ).The product was then stirred in a saturated solution of HCl in diethyl ether (30 mL) for 3 days. Removal of the solvent under reduced pressure gave the title compound as the HCl salt. LC/MS: (PS-B3) Rt 3.21 [M+H] + 320.

46C. {2-(4-Methoxy-phenyl)-2-[4-qH-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

Following the procedure described in Example 42C, but substituting [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for [2-(4-Bromo-phenyl)- 2-(4-methoxy-phenyl)-ethyl]-methyl-amine, the title compound was obtained. LC/MS: (PS-B3) R, 2.52 [M+H]+ 308. 1H NMR (Me-d3-OD)

δ 2.75 (3H, s), 3.75 (2H, dd), 3.80 (3H, s), 4.38 (IH, t), 6.95 (2H, d), 7.32 (2H, d), 7.45 (2H, d), 7.70 (2H, d), 8.52 (2H, s).

FIRST 47

Methyl {2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine 47A. 4-T1-(4-Bromo-phenyl)-2-methylamino-ethyl-phenol

Boron tribromide (7.8 mL, 1.0 M in dichloromethane) was slowly added to a solution of [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine (500 mg, 1.56 mmol) in dichloromethane (8 ml) at 0°C, under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and then stirred for an additional hour. The mixture was poured onto ice and then diluted with dichloromethane and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated to give the desired product. LC/MS: (PS-B3) R, 2.76 [M+H]+ 306.

47B. tert-Butyl estar r2-(4-Bromo-fenilV2-(4-iidroxy-fenil)-etill-metil-karbaminske

acid

BOC2O (269 mg, 1.23 mmol) was added to a solution of 4-[1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol (360 mg, 1.18 mmol) in dichloromethane (20 mL). After stirring at room temperature for 16 h, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (S1O2), eluting with ethyl acetate/petroleum (1:4) to afford the compound. LC/MS: (FL-A) R, 3.55 [M+H] + 406.

47C (2-(4-Bromo-phenyl')-2-[4-(pyrazin-2-yloxy)-phenin-ethyl-methyl-amine

A solution of [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (125 mg, 0.31 mmol), 2-chloropyrazine (35.2 mg, 0.31 mmol ) and K2CO3 (213 mg, 1.54 mmol) in dimethylformamide (8 ml) was heated to 100°C for 17 hours. After cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was dried (MaSCO4), filtered and concentrated. The crude product was then treated with saturated HCl in diethyl ether (15 ml) and stirred at room temperature for 72 hours. The solvent was then removed under reduced pressure and the crude product was purified by chromatography on a Phenomenex_Strata_SCX column eluting with methanol followed by 2N ammonia in methanol to afford the desired product (82 mg). LC/MS: (PS-B3) Rt 3.17 [M+H]+ 384.

47DMethyl-(2-r4-pyrazin-2-yloxyVphenyl1-2-[4-nH-pyrazol-4-yl)-phenyl-ethyl)-amine

Following the procedure described in Example 42C, but substituting [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for {2-(4-Bromo-phenyl)- 2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl}-methyl-amine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.48 [M+H]+ 372. !H NMR (Me-<*3-OD) δ 2.80 (3H, s), 3.75-3.90 (2H, m), 4.50 ( IH, t), 7.23 (2H, d), 7.50 (4H, t), 7.75 (2H, d), 8.12 (IH, d), 8.33 (IH, d), 8.42 (2H, s), 8.48 (IH , with).

FIRST 48

Methyl-|2-phenoxy-2-f 4-( 1 H -pyrazol-4-ylV phenyl -ethyl) -amine

48A. tert-Butyl estar r2-(4-Bromo-pheniD-2-hydroxy-etin-metil-carbaminske kiske

BOC 2 O (1.90 g, 8.69 mmol) was added to a solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (2.00 g, 8.69 mmol) in dichloromethane (20 mL). After stirring at room temperature for 16 h, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum (1:4) to afford the desired product (2.1 g). LC/MS: (PS-B3) R, 3.16 [M+H]+ 330.

48B [2-(4-Bromo-phenyl)-2-phenoxy-ethyl-methyl-amine

Diethyl azodicarboxylate (358 ml, 2.27 mmol) was added dropwise to a solution of [2-(4-Bromo-phenyl)-2-hydroxy-ethyl]-methyl-carbamic acid tert-butyl ester (500 mg, 1.51 mmol), triphenylphosphine ( 596 mg, 2.27 mmol) and phenol (285 mg, 3.03 mmol) in tetrahydrofuran (10 ml) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:9) to give the intermediate BOC-protected compound, which was then stirred in a saturated solution of HCl in diethyl ether (20 ml) for 24 h. . Removal of the solvent under reduced pressure gave the title compound as the HCl salt. Further purification by chromatography on a Phenomenex_Strata_SCX column, eluting with methanol and then with 2N ammonia in methanol, afforded the desired product as the free base (94 mg). LC/MS: (PS-B3) Rt 4.04 [M+H]+ 406.

48C Methyl-{2-phenoxy-2-[4-( 1 H-pyrazol-4-yl)-phenyl]-phenyl}-amine

Following the procedure described in Example 42C, but substituting [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for [2-(4-Bromo-phenyl)- 2-phenoxy-ethyl]-methyl-amine, the title compound was obtained. LC/MS: (PS-B3) R, 2.73 [M-PhO+H]+ 200. 1H NMR (Me-d3-OD) δ 2.50 (3H, s), 2.90 (1H, dd), 3.15 (1H, dd), 5.40 (1H, dd), 6.85 (IH, t), 6.90 (2H, d), 7.18 (2H, t), 7.40 (2H, d), 7.55 (2H, d), 7.93 (2H, s ).

FIRST 49

2-((4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy:sil-ethylamine 49A. (4-Bromo-phenyl)-(4-chloro-phenyl)- methanol

4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether) was slowly added to a solution of 4-bromobenzaldehyde (2.0 g, 10.81 mmol) in tetrahydrofuran (25 ml) at 0°C under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 17 hours. Water (3 ml) was then added and the solvent was removed under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl solution. The organic layer was washed with saline, dried (MgSO4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum (1:9), to afford the title compound (2.30 g). LC/MS: (PS-B3) Rt 3.49 [M-H]+ 297.

49B. 2-{24(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxyl-ethyl|-isoindole-1,3-dione

A mixture of (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol (2-3 g, 7.73 mmol), N-(2-hydroxyethyl)phthalimide (1.4 g, 7.36 mmol) and para-toluenesulfonic acid monohydrate ( 560 mg, 2.94 mmol) in toluene (50 ml) was heated to reflux under Dean-Stark conditions for 17 hours. After cooling, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was then dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (S1O2), eluting with ethyl acetate/petroleum (1:4), to afford the title compound (1.95 g). LC/MS: (PS-B3) Rt 4.07 with no detectable mass ion.

49C. N-(2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl-methoxy}-ethyl)poluamid phtalne kiske

Following the procedure described in Example 42C, but substituting [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine for 2-{2-[(4-Bromo- phenyl)-(4-chloro-phenyl)-methoxy]-ethyl}-isoindole-1,3-dione, the title compound was obtained. LC/MS: (FS-A) Rt 2.85 [M-H]+ 474.

49D.2-((4-chloro-phenin-4-riH-pyrazol-4-yl)-phenyl-methoxy)-ethylamine

Hydrazine monohydrate (159 mL, 3.28 mmol) was added to a solution of N-(2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-polamide of phthalic acid (260 mg, 0.55 mmol) in methanol (6 ml) and the reaction mixture was stirred at 80°C for 16 hours. After cooling, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiCh), eluting with dichloromethane: methanol: acetic acid: water (90:18:3:2). Additional purification by chromatography on a Phenomenex Strata_SCX column, eluting with methanol followed by 2N ammonia in methanol, afforded the desired product as the free base (120 mg). LC/MS: (FL-A) Rt 2.07 [M-NH2CH2CH2O+H]+ 267. 'H NMR (Me-d3-

OD) δ 2.85 (2H, t), 3.55 (2H, t), 5.45 (IH, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95 (2H, s).

FIRST 50

4-(4-Fl-(4-chloro-fenil)-3-Dirolidin-1-yl-propyn-fenil|-1H-pyrazole

Following the procedure described in Example 8, but substituting methylamine for pyrrolidine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.25 [M+H]+ 366. 'H NMR (Me-d3-

OD) δ 1.83-1.95 (2H, m), 1.95-2.09 (2H, m), 2.4-2.5 (2H, m), 2.88-2.97 (2H, m), 3.02 (2H, dd), 3.52-3.61 ( 2H, m), 4.02 (1H, t), 7.25 (4H, q), 7.32 (2H, d), 7.55 (2H, d), 8.41 (2H, s).

PRIMER51

4-(4-r3-Azetidin-1-yl-1-(4-chloro-phenyl)-propyl-phenyl-1H-pyrazole

Following the procedure described in Example 8, but substituting methylamine for pyrrolidine, the title compound was obtained. LC/MS; (PS-A2) R, 2.18 [M+H]+ 352. 1H NMR (Me-d3-

OD) δ 2.12-2.25 (2H, m), 3.00 (2H, t), 3.85-3.98 (5H, m), 4.05-4.17 (2H, m), 7.18 (2H, d), 7.19 (4H, s), 7.45 (2H, d), 7.83 (2H, s).

PRIMER 52 Methyl-(3-naphthalen-2-yl-3-r4-(1H-pyrazol-4-yl)-phenyl1-propyl)-amine

Following the procedure described in Example 8, but substituting 2-naphthylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) Rt 2.26 [M+H]+ 342. *H NMR (Me-^-OD) 6 2.57-2.70 (2H, m), 2.70 (3H, s), 2.90-3.10 ( 2H, m), 4.32 (1H, t), 7.40-7.52 (5H, m), 7.70 (2H, m), 7.80-7.90 (4H, m), 8.70 (2H, s).

FIRST 53

Dimethyl-(4-(3-methylamino-1-F4-(1H-pyrazol-4-iD-phenyl-propyl)-pheniO-amine

Following the procedure described in Example 8, but substituting 4-(N,N-dimethyl)anilinemagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) R, 1.55 [M+H]+ 335. !H NMR (Me-d3-OD) δ 2.46-2.60 (2H, m), 2.69 (3H, s), 2.95 (2H , t), 3.27 (6H, s), 4.25 (1H, t), 7.45 (2H, d), 7.60-7.72 (6H, m), 8.50 (2H, s).

PRIMER 54 (3-(4-Fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl|-methyl-amine

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) Rt 2.05 [M+H]+ 310. IH NMR (Me-dj-OD) 8 2.40-2.55 (2H, d), 2.70 (3H, s), 2.90-3.0 (2H , m), 4.12 (1H, t), 7.05 (2H, t), 7.32-7.40 (4H, m), 7.63 (2H, d), 8.33 (2H, s).

PRIMER 55 4-{4-[4-(4-chloro-phenyl)piperidin-4-yl-phenyl]-1H-pyrazole-3-carbonitrile

Following the procedure from Example 1, but using 4-(4-chloro-phenyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] -piperidine instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-bromo-1H-pyrazole-3-carbonitrile instead of 2-(4- chlorophenyl)-2-phenylethylamine hydrochloride gave the title compound. LC/MS: (PS-A2) R, 2.22 [M+H]+ 363. 1H NMR (Me-d3-OD) δ 2.52-2.70 (4H, m), 3.10-3.20 (4H, m), 7.25 (4H, s), 7.37 (2H, d), 7.58 (2H, d), 8.02 (1H, s).

PRIMER 56 3-[4-Phenoxy-phenyl]-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 4-phenoxyphenylmagnesium bromide and methylamine for ammonia, the title compound was obtained. LC/MS: (PS-A2) R, 2.28 [M+Hf 370.34. 1H NMR (Me-J3-OD) δ 2.38-2.46 (2H, m), 2.85-2.92 (2H, t), 4.03-4.10 (1H, t), 6.94-7.0 (4H, d), 7.08-7.14 (IH, t), 7.30-739 (6H, m), 7.55-7.58 (2H, d), 7.90-7.97 (2H, br s), 8.54-8.60 (IH, br s).

FIRST 57

1 - {(4-chloro-phenyl)-[4-( 1 H-pyrazol-4-yl)-phenyl]-methyl}-piperizine

By following the procedure described in Example 1, but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for 1-(4,4'-dichloro-benzhydryl)-piperazine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.82 [M-H]+ 351.27. 'H NMR (Me-d3-OD) δ 3.0-3.25 (4H, m), 3.45-3.65 (4H, m), 5.05-5.25 (IH, br s), 7.40-7.50 (2H, d), 7.65- 7.83 (6H, m), 8.45 (2H, s).

PRIMER 58 1-Methyl-4-(phenyl-r4-(1H-pyrazol-4-in-phenyl-methyl-ri,41diazepan)

Following the procedure described in Example 1, but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride for 1-[p-chlorodiphenylmethyl]-4-methyl-1,4-diazacycloheptane dihydrochloride, the title compound was obtained. LC/MS: (PS-B3) Rt 2.85 [M+H]+ 347.18. 'H NMR (Me-d3-OD) δ 2.25-2.60 (2H, br m), 3.00 (3H, s), 3.40-4.18 (8H, br m), 5.78 (IH, s), 7.40-7.48 (IH , m), 7.49-7.55 (2H, t), 7.75-7.80 (2H, d), 7.82-7.98 (4H, m), 8.32 (2H, s).

FIRST 59

(3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-fenil]propiU-metil-amin 59A. 1 -(4-Bromo-fenil')-3-chloro- propan-1-ol (J. Med. Chem., 2004, 47, 3924-3926)

To a solution of l-(4-Bromo-phenyl)-3-chloro-propan-l-one (1 g, 4.04 mmol) in tetrahydrofuran (9 ml) and water (0.58 ml) was added sodium borohydride (0.16 g, 4.28 mmol ). The reaction mixture was stirred at room temperature for 2 hours, quenched by careful addition of water, and extracted with ethyl acetate. The organic layers were separated, dried (MgSO 4 ), filtered and concentrated to give the title compound, which was used in the next step without further purification. LC/MS: (PS-A2) R, 3.07 [M+H]+ without ionization.

59B [3-(4-Bromo-phenyl)-3-f3-chloro-phenoxy)-propyl]-chloride

3-Chlorophenol was reacted with l-(4-Bromo-phenyl)-3-chloro-propan-l-ol following the procedure outlined in Example 48B to give the title compound, which was used in the next step without additional purification.

59C. r3-(4-Bromo-phenyl>3-(3-chloro-phenoxy)-propyne-methyl-amine

A solution of 3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloride in 33% methylamine in ethanol (4 ml) was heated in a CEM microwave at 100°C for 30 minutes using 50W power supply. The solvent was removed and the crude product was purified over a Phenomenex_Strata_SCX ion exchange column eluting with methanol and then with 2N ammonia in methanol. The product was purified by column chromatography (SiO2), eluting with dichloromethane to dichloromethane: methanol: acetic acid: water (90:18:3:2).

using SP4 biotag to give the title compound. LC/MS: (PS-B3) Rt 3.42 [M+H]+ 356.19.

59D. (3-(3-chloro-phenoxy)-3-[4-[H-pyrazol-4-yl]-phenyl]-propyl}-methyl-amine

[3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)-1H-pyrazole following the procedure outlined in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.80 [M+H]+ 342.26. [H NMR (Me-d3-OD) δ 2.19-2.30 (IH, m), 2.30-2.45 (IH, m), 2.72 (3H, s), 3.10-3.28 (2H, m), 5.40-5.47 (IH , m), 6.80-6.88 (1H, d), 6.88-6.94 (IH, d), 6.96 (IH, s), 7.15-7.20 (IH, t), 7.38-7.45 (2H, d), 7.57-7.65 (2H, d), 7.98 (2H, s).

FIRST 60

Methyl-(2-fenil-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl-ethyl|-amine 60A. 6-(3-Methyl-1-trityl-1H-pyrazol- 4-yl)-nicotinonitrile

Into a solution of 6-chloro-nicotinonitrile (0.2 g, 1.49 mmol) and 3-methyl-l-trityl-1H-pyrazole-4-organoboric acid* (0.5 g, 1.36 mmol) in ethylene glycol dimethyl ether (3 ml), sodium carbonate (0.36 g, 3.39 mmol) in water (1.5 mL) was added. The reaction mixture was degassed with nitrogen before the addition of tetrakis(triphenylphosphine)palladium(0) and then heated in a CEM microwave at 135°C for 30 minutes (50W power). The reaction was partitioned between water and ethyl acetate, aq

a portion was basified with 2N NaOH, the organic extracts were combined, dried (MgSC>4) and the solvent was removed. The crude product was suspended in a small volume of methanol, the white precipitate was filtered to give the title compound (0.32g, 53% yield). LC/MS: (PS-A2) Rt 4.52 [M+H]+ 427.26.

* This starting material can be made using the process described in EP1382603A1

60B. (4-chloro-fenil)-r6-(3-metil-l-tritil-1 H-pirazol-4-il)-piridin-3-in-metanon

To a solution of 6-(3-Methyl-1-trityl-1H-pyrazol-4-yl)-nicotinonitrile (0.5 g, 1.17 mmol) in dry tetrahydrofuran (4 ml) was added 4-chlorobenzenemagnesium bromide (1.52 ml), 1.52 mmol , IM in diethyl ether); the reaction mixture was stirred under nitrogen for 16 hours. The reaction was quenched to below pH 2 by addition of 2N HCl and stirred for 1 hour. It was then adjusted to pH 8 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO 4 ), the solvent was removed and the residue was purified by column chromatography (SiO 2 ), eluting with petroleum ether to ethyl acetate:petroleum (15:85) to afford the title compound (0.49 mg, 77% yield). LC/MS: (PS-A2) R, 4.45 [M+H] + 540.30, 542.28.

60C. (2-(4-chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl-vinyl-

methyl-(1-phenylethyl)amine

n-Butyllithium (0.47 ml, 0.76 mmol, 1.6M in hexanes) was added dropwise to a solution of (R) (Diphenyl-phosphinoylmethyl)-methyl-(l-phenyl-ethyl)-amine* (0.18 g, 0.51 mmol) in dry tetrahydrofuran (9 ml) at -15°C. After 15 minutes, a solution of (4-chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone (0.14 g, 0.25 mmol) was added. in tetrahydrofuran (0.9 ml) and the reaction mixture was stirred for an additional 30 minutes at -15°C before warming to room temperature for 1 hour. The reaction mixture was quenched with water, extracted with diethyl ether, the organic extracts were combined, dried (MgSO 4 ) and concentrated to give the title compound, which was used in the next step without further purification.

* This starting material can be made using the procedure described in Tetrahedron Asymmetry, 2003, 14, 1309-1316.

60D. Metil-(2-fenil-2-r6-(lH-Dirazol-4-il)-piridin-3-il1-etiU-amin

In a solution of {2-(4-chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(l -phenyl-ethyl)-amine in ethanol, palladium, 10 wt. % on activated carbon and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through celite and

the starting liquid was concentrated, the residue was purified by column chromatography eluting with dichloromethane:methanol:acetic acid:water (240:20:3:2) to dichloromethane:methanol:acetic acid:water (90:18:3:2) to give gave the title compound. LC/MS: (PS-A2) R, 1.59 [M+H] + 293.18. 1H NMR (Me-d3-OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (IH, t), 7.10-7.18 (IH, m), 7.25 (4H, m), 7.45 (IH, d), 7.67 (IH, dd), 7.80 (IH, s), 8.38 (IH, s).

EXAMPLE 61

4- {4-[ 1 -(4-chloro-phenyl)-3-imidazol-1-yl-propyl-phenyl}-1 H-pyrazole 61 A. 1 -(4-Bromo-phenyl)-3-imidazol- 1-yl-propan-1-ol

A solution of l-(4-Bromo-phenyl)-3-chloro-propan-l-ol* (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated to 100°C 18 hours, then partitioned between water and ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, concentrated and purified by column chromatography (SiO2), eluting with methanol:dichloromethane (2:98) to methanol:dichloromethane (6:94) to afford the title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt 2.48 [M+H]+ 281.14, 283.11.

*This starting material can be made using the procedure described in Example 43 A.

61B. 1 -r3-(4-Bromo-phenin-3-(4-chloro-phenyl')-propyl1-1H-imidazole

Chlorobenzene (5 mL) was reacted with l-(4-Bromo-phenyl)-3-imidazol-l-yl-propan-l-ol (0.41 mg, 1.46 mmol) following the procedure outlined in Example 42B to give title compound (0.37g, 67% yield). LC/MS: (PS-A2) Rt 2.40 [M+H]+ 375.16, 377.17.

61C. 4- (4-r 1 -(4-chloro-phenin-3-imidazol-1 -yl-propyl-phenyl I -1 H-pyrazole

1-[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-1H-imidazole reacted with 4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 363.28. *H NMR (Me-d3-OD) δ 2.55-2.70 (2H, m), 3.85-3.95 (IH, m), 3.95-4.10 (2H, m), 7.05 (IH, s), 7.10-7.60 (9H , m), 7.65 (IH, s), 7.90-8.00 (2H, d).

PRLMER 62

4-f 4-(3-Imidazol-1-yl-1-phenoxy-propiD-phenyl]-1H-pyrazole

62A. 1-|"3-(4-Bromo-phenyl)-3-phenoxy-propyl-1-1H-imidazole

Phenol was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol* following the procedure outlined in Example 48B to give the title compound. LC/MS: (PS-A2) Rt 2.30 [M+H]+ 357.26, 359.27.

*This starting material can be made using the procedure described in Example 47A.

62B. 4-[4-(3-Imidazol-1-yl-1-phenoxy-propyl)-phenyl1-1H-pyrazole

1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole by following the procedure outlined in Example 1 to give the title compound. LC/MS: (PS-A2) R, 2.05 [M+H] + 345.30. 1H NMR (Me-d3-OD) δ 2.30-2.55 (2H, m), 4.25-4.45 (2H, m), 5.10-5.15 (IH, m), 6.80-6.90 (3H, m), 7.10 (IH, s), 7.15-7.20 (2H, t), 7.25 (IH, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d), 7.85 (IH, s), 7.95 (2H, s) .

FIRST 63

4-{4-f4-(1H-Pyrazol-4-in-fenili-piperidin-4-yl}-phenol

Following the procedure described in Example 14, but substituting chlorobenzene for phenol and using nitrobenzene as solvent, the title compound was obtained. LC/MS: (PS-A3) Rt 5.07 [M+H]+ 320. 1H NMR (d6-DMSO) δ 7.97 (2H, s), 7.49 (2H, d), 7.25 (2H, d), 7.10 ( 2H, d), 6.68 (2H, d), 2.840 (4H, bs), 2.376 (4H, bs).

FIRST 64

1 - {(4-chloro-phenyl)-r4-(1H-pyrazol-4-iD-phenin-methyl I-piperazine

Following the procedure described in Example 57, the title compound was obtained. LCMS: (PS-A3) Rt 6.38 [M+H]+ 319. 1H NMR (Me-d3-OD) δ 8.53 (2H, s), 7.90 (2H, d), 7.83 (2H, d), 7.71 (2H, d), 7.40-7.30 (3H, m), 5.70 (1H, s), 3.68 (4H, bs), 3.51-3.48 (4H, m).

FIRST 65

(2-(4-Fluoro-phenyl')-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl-methyl-amine

65A. Benzil estar r2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl-carbamic acids

To a solution of 3-(4-fluorophenyl)-3-(4-bromophenyl)propionic acid* (1.0 g, 3.09 mmol) in acetone (4 ml) at 0°C was sequentially added triethylamine (561 ul, 4.02 mmol) in acetone (1.6 ml) and ethyl chloroformate (443 µl, 4.64 mmol) in acetone (1.6 ml). The reaction was allowed to warm to room temperature, stirred for 30 minutes before re-cooling to 0°C and sodium azide (402 mg, 6.18 mmol) in water (1.6 mL) was added. The resulting brown solution was stirred for 45 minutes before adding water (10 ml) and diethyl ether (10 ml). The aqueous layer was separated and further extracted with ethyl acetate (10 ml). The combined organic liquids were washed with saturated saline, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in anhydrous toluene (12 ml) before addition of benzyl alcohol (567 µl, 9.27 mmol) and heating to 80°C for 40 minutes. The reaction was allowed to cool to room temperature before adding ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL). The organic liquids were separated and washed with additional bicarbonate solution (50 ml), hydrochloric acid (2N, 100 ml) and saturated saline (50 ml) before drying (MgSO4) and concentrating in vacuo. The residue was purified by column chromatography (SiO2), eluting

with a gradient of ethyl acetate/petroleum (5:95) to (15:85) to give the title compound (594 mg, 45%). LC/MS: (PS-A2) Rt 3.18 without ionization.

* This starting material can be made using the procedure described in Examples 8A to 8C, substituting 4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide.

65B. Benzil estar (2-(4-Fluoro-fenilV2-r4-dH-pyrazol-4-in-fenill-etiU-carbaminske

acid

[2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzyl ester reacted with 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole following the procedure outlined in Example 1 to afford the title compound. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 416.

65C. (2-(4-Fluoro-phenyl)-2-r4-(1H-pyrazol-4-yn-phenyl-ethyl-methyl-amine)

Lithium aluminum hydride (5.3 mL, 5.30 mmol, 1M in tetrahydrofuran) was slowly added to {2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl benzyl ester }-carbamic acid (439 mg, 1.06 mmol) in tetrahydrofuran (5 ml) at 0°C under nitrogen. The reaction mixture was allowed to warm to room temperature, stirred for 51 h and quenched with water (5 ml), aqueous sodium hydroxide (2N, 5 ml) and ethyl acetate (10 ml). The aqueous layer was separated, extracted with ethyl acetate (2x20ml). The combined organic liquids were washed

saturated saline, then dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2), eluting with a gradient of dichloromethane:methanol:acetic acid:water (120:15:3:2) to (90:18:3:2) to give the title compound, which then translated into the hydrochloride salt (100 mg, 32%). LC/MS: (PS-A2) Rt 1.87 [M+Hf 296. 1H NMR (Me-d3-OD) δ 8.20 (2H, s), 7.57 (2H, d), 7.34-7.29 (4H, m) , 7.02 (2H, t), 4.32 (1H, t), 3.67 (2H, d), 2.65 (3H, s).

FIRST 66

(2-(3 -chloro-phenin-2-[4-( 1 H-pyrazol-4-yn-phenyll -ethyl}-methyl-amine

Following the procedure described in Example 65, but substituting 4-fluorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A3) Rt 4.92 [M+H]+ 312. 1H NMR (Me-d3-OD) δ 8.50 (2H, s), 7.63 (2H, d), 7.39 (2H, d), 7.34 (1H, s), 7.30-7.20 (3H, m), 4.40 (1H, t), 3.70 (2H, d), 2.65 (3H, s).

FIRST 67

4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine 67A. tert-Butyl estar 4-(4-Bromo-pheniQ-4-(4-hydroxy-phenyl)-piperidin-l-karbonske kiske

Following the procedure described in Example 47B, but substituting 4-[1-(4-Bromo-phenyl)-2-methylaminoethyl]-phenol for 4-[4-(4-Bromo-phenyl)-piperidin-4-yl] -phenol* the title compound was obtained. 1H NMR (dć-DMSO) δ 7.45 (2H, d), 7.25 (2H, d), 7.11 (2H, d), 6.68 (2H, d), 3.35-3.18 (4H, m), 2.31-2.20 ( 4H, m), 1.38 (9H, s).

* This starting material can be made using the procedure described in Example 63

67B. tert-Butyl estar 4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidin-l-karbonske kiske

A solution of 4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol), 2-bromoethyl methyl ether (200 µl) and potassium carbonate (64 mg, 0.46 mmol) in dimethylformamide (2 ml) was heated in a CEM Explorer™ microwave to 50°C for 30 minutes using a 50 watt power supply. The reaction was poured into sodium hydroxide (2N, 4 ml), stirred for 5 minutes and then extracted into ethyl acetate (2x30ml). The combined organic liquids were dried (MgSO4 ), concentrated and the residue purified by column chromatography (SiCl), eluting with a gradient of ethyl acetate/petroleum (25:75) to (50:50) to afford the title compound (82 mg). LCMS: (PS-A2) Rt 4.00 [M+H]+ 490.

67C.4-f4-f2-Methoxy-ethoxy)-phenyl1-4-[4-(1H-pyrazol-4-yl)-phenin-piperidin

N

Br

4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-Butyl ester reacted with 4-(4,4,5,5- tetramethyl,1,3,2-dioxaborolan-2-yl)1H-pyrazole by following the procedure stated in Example 1, replacing tetrakis triphenylphosphine palladium (0) as a catalyst, the title compound was obtained. LC/MS: (PS-A2) Rt 3.27 [M+H]+ 478.

67D. 4-r4-r2-Methoxy-ethoxy)-phenyl-4-r4-(1H-pyrazol-4-yn-phenyl-piperidin

fj-N

Trifluoroacetic acid (1 ml) was added to a solution of 4-[4-(2-Methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine (87 mg) in dichloromethane (1 ml). After 30 minutes at room temperature, the reaction is concentrated. The residue was dissolved in ethyl acetate and then extracted into hydrochloric acid (2N, 2x20ml). The combined aqueous fractions were washed with ethyl acetate and then basified (2N NaOH) before re-extraction in ethyl acetate (2x20ml). The combined organic liquids were washed with saturated saline, then dried (MgSO 4 ) and concentrated to give the title compound (66 mg). LCMS: (PS-A3) Rt 6.08 (M+H)+ 378. [H NMR (Me-^-OD) δ 7.92 (2H, s), 7.51 (2H, d), 7.31 (2H, d), 7.25 (2H, d), 6.89 (2H, d), 4.13 (2H, t), 3.73 (2H, t), 3.42 (3H, s), 2.94 (4H, bs), 2.44 (4H, bs).

FIRST 68

4-[4-(3-Methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl-1-piperidine 68A. tert-Butyl estar 4-(4-Bromo-fenilV4-[4-(3-methoxy-propoxy)-phenyl]-piperidin-l-karbonske kiske

Tosyl chloride (572 mg, 3.0 mmol) was added to a solution of 3-methoxypropanol (191 µL, 2.0 mmol) in pyridine (1 mL). It was stirred at room temperature for 5.5 hours, then diluted with ethyl acetate (20 ml) and washed with hydrochloric acid (2N, 3x1 Omi) and saturated saline (10 ml). The liquids were dried (MgSO 4 ) and concentrated to give a colorless oil (600 mg). This oil was dissolved in dimethylformamide (2 ml) and to this solution was added potassium carbonate (64 mg, 0.46 mmol) and 4-(4-Bromo-phenyl)-4-(4-hydroxy-phenyl)-piperidine tert-butyl ester. -1-carboxylic acid* (100 mg, 0.231 mmol). The resulting mixture was stirred at 100°C for 4 hours. When cooled, water (20 mL) was added and the mixture was extracted with ethyl acetate (3x1 mL). The combined organic liquids were washed with saline (10 ml) before drying (MgSO4) and concentration. The residue was purified by column chromatography (SiO 2 ), eluting with a gradient of 10-20% ethyl acetate/petroleum to afford the title compound as a colorless oil (131 mg). LCMS: R, 4.20 [M+H] + 504.

* This starting material can be made using the procedure described in Example 67A

68B. 4-r4-(("3-Methoxy-propoxy)-phenyl-4-r4-(1H-pyrazol-4-yl)-phenin-piperidin

By following the procedure described in Examples 67C and 67D, but substituting 4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester for 4-(4-Bromo-phenyl)-4-[4-(3-methoxy-propoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester, the title compound was obtained. LCMS: R, 6.65 [M+H]+ 392. 11 NMR (Me-J3-OD) δ 7.94 (2H, s), 7.57 (2H, d), 7.34 (2H, d), 7.27 (2H, d ), 6.91 (2H, d), 4.04 (2H, t), 3.56 (2H, t), 3.34-3.33 (5H, m), 3.24-3.22 (4H, m), 2.67-2.66 (4H, m)

PRIMER 69 3-(3,4-Dichloro-phenyl)-3-r4-(1H-pyrazol-4-yl)-phenin-propionamide

Following the procedure described in Example 9A and 9B, but substituting 3,4-difluorophenylmagnesium bromide for 3,4-dichlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A3) Rt 9.82 [M+H]+ 360.14, 362.12. 1H NMR ((Me-d3-OD)

δ 2.90-3.00 (2H, d), 4.50-4.60 (1H, t), 7.10-7.30 (3H, m), 7.40-7.45 (2H, d), 7.50-7.55 (2H, d), 7.85-8.05 (2H, br s).

PRIMER 70 2-(4-{2-Methylamino-1-r4-(1H-pyrazol-4-yl)-phenyl]-ethyl-phenoxy)-isonicotinamide

Following the procedure described in Example 47, but replacing 2-chloropyrazine with 2-chloro-4-cyanopyridine, the title compound was obtained. LC/MS: (PS-B3) Rt 2.27 [M+H]+ 414. 1H NMR (Me-d3-OD) δ 2.45 (3H, s), 3.55 (IH, dd), 3.65 (IH, dd), 4.25 (IH, t), 7.10 (2H, d), 7.30-7.38 (3H, m), 7.40 (2H, d), 7.48 (IH, d), 7.56 (2H, d), 7.95 (2H, s) , 8.22 (IH, d).

FIRST 71

(2-(4-chloro-phenoxy)-2-r4-flH-pyrazol-4-ylVphenin-ethyl}-methyl-amine

Following the procedure described in Example 48, but substituting 4-chlorophenol for phenol, the title compound was obtained. LC/MS: (PS-A3) R, 2.29 [M-ClPhO+H]+ 200. *H NMR (Me-d3-OD) δ 2.50 (3H, s), 2.86 (IH, dd), 3.10 (IH , dd), 5.35 (1H, dd), 6.89 (2H, d), 7.17 (2H, d), 7.40 (2H, d), 7.57 (2H, d), 7.93 (2H, s).

PRIMER 72 3-{2-(4-chloro-phenyl)-2-r4-(1H-pyrazol-4-yl)-phenyl1-ethylaninol-propan-1-ol

By following the procedure described in Example 20, but substituting dimethylamine for 3-aminopropan-1-ol, the title compound was obtained. LC/MS: (PS-A2) Rt 2.05 [M+H]+ 356. *H NMR (Me-di-OD) δ 1.87 (2H, quintet), 1.98 (AcOH, s), 3.23 (2H, t) , 3.68 (2H, t), 3.75 (2H, dd), 4.4 (1H, t), 7.36 (2H, d), 7.4 (4H, s), 7.62 (2H, d), 7.97 (2H, s).

PRIMER 73 2-(2-(4-chloro-phenyl)-2-r4-(1H-pyrazol-4-yl)-phenyl1-ethylaminol-ethanol

By following the procedure described in Example 20, but replacing dimethylamine with 2-aminoethan-1-ol, the title compound was obtained. LC/MS: (PS-A2) Rt 2.05 [M+H]+ 342. 1H NMR (Me-d3-OD) δ 1.98 (AcOH, s), 3.10 (2H, s), 3.69 (2H, dd), 3.78, (2H, t), 4.39 (1H, t), 7.36 (2H, d), 7.38 (4H, s), 7.61 (2H, d), 7.97 (2H, s).

PRIMER 74 (2-((4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethylamine)

By following the procedure described in Example 20, but substituting dimethylamine for cyclopropylmethylamine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 352. 'H NMR (Me-d3-OD) δ -0.4-0.3 (2H, m), 0.35-0.40 (2H, m), 0.78 -0.87 (IH, m), 2.42 (2H, d), 3.15-3.25 (2H, m), 4.11 (IH, t), 7.16-7.27 (6H, m), 7.45 (2H, d), 7.82, ( 2H, s).

PRIMER 75 Methyl-r2-r4-(1H-pyrazol-4-yn-phenin-2-(4-pyridin-3-yl-phenyl)-ethyn-amine

Following the procedure described in Example 1, but substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 3-(4,4,5, 5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and coupling to {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl] -ethyl}-methyl-amine*, the title compound was obtained. LC/MS: (PS-B3) Rt 2.42 [M+H]+ 355. 1H NMR (Me-d3-OD)

δ 1.94 (AcOH, s), 2.72 (3H, s), 3.73 (2H, d), 4.46 (IH, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d).

* This starting material can be made using the procedure described in Example 21.

FIRST 76

4- 13-Methylamino-1 -\4-( 1H-pyrazol-4-io-fenill-propyl}-phenol

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 4-anisylmagnesium bromide, the title compound can be obtained. LC/MS: (PS-A2) R, 1.82 [M+H]+ 308. 1H NMR (Me-d3-OD) δ 1.92 (AcOH, s), 2.34-2.43 (2H, m), 2.64 (3H, s), 2.86-2.92 (2H, m), 3.96 (1H, t), 6.75 (2H, d), 7.13 (2H, d), 7.29 (2H, d), 7.52 (2H, d), 7.93 (2H , d).

PRIMER 77 3-(4-Methoxy-phenin-3-r4-(1H-pyrazol-4-ylVphenyl-propylamine)

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 4-anisylmagnesium bromide and methylamine for ammonia (2M in methanol), the title compound was obtained. LC/MS: (PS-A2) Rt 1.82 [M+H]+ 308. 'H NMR (Me-d3-OD) δ 2.23-2.32 (2H, m), 2.74 (2H, dd), 3.65 (3H, s), 3.89 (IH, t), 6.77 (2H, d), 7.11 (2H, s), 7.17 (2H, d), 7.41 (2H, d), 7.71 (2H, s), 8.41 (HCO2H, no with).

FIRST 78

4-(4-hloro-phenO-4-|^-(3-methyl-lH-pyrazol-4-yl)-phenyl]-piperidine

78A.4-r4-chloro-phenyl)-4-r4-(3-methyl-1-trityl-1H-pyrazol-4-yn-phenyl-piperidine

4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine hydrochloride was reacted with 3-methyl-1-trityl-1H-pyrazole-4-organoboronic acid* following the procedure outlined in Example 1 , but using tetrakis(triphenylphosphine)palladium(0) as a catalyst to give the title compound. LC/MS: (PS-B3) R, 2.78 min [M+H]+ 594.

* This starting material can be made using the process described in EP 1382603

78B.4-r4-chloro-phenin-4-r4-f3-methyl-1H-pyrazol-4-yl)-phenyl-piperidin

A suspension of 4-(4-chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine (178 mg, 0.30 mmol) in 5N hydrochloric acid ( 5 mL), THF (5 mL) and methanol (5 mL) was stirred for 140 minutes. The organic solvents were removed in vacuo, then the resulting solution was diluted with 2N HCl and washed with water. The aqueous phase was basified by adding sodium hydroxide beads and then extracted with ethyl acetate. This organic extract was washed with saline, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) and dichloromethane. The product was further purified by preparative HPLC to give the title compound which was converted to its hydrochloride salt (84 mg, 80%); LCMS (PS-A3) R, 6.86 min [M+H]+ 352. 'H NMR (Me-d3-OD) δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H , m), 7.35-7.41 (4H, m), 7.47-7.54 (4H, m), 8.32 (2H, s).

FIRST 79

2-f4-chloro-phenin-2-r4-(1H-pyrazol-4-yl')-phenin-morpholin 79A. 2-(4-chloro-phenyl)-2-(4-iodo-phenylVoxirane).

Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placed under N 2 and then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g, 3.2 mmol) was added as a solid after 15 min, and then (4-chloro-phenyl)-(4-iodo-phenyl)-methanone was added after an additional 30 min. The mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate and washed with 1:2 water/saline, water and saline (x2).

The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (1.01 g, 97%), which was used without further purification. LCMS (PS-A2) Rt 4.07 min [M-H]~ 355.

79B. 1 -f4-chloro-phenyl>2-(2-hydroxy-ethylaminoV 1 -M-iodo-phenylD-ethanol

A solution of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane (0.60 g, 1.68 mmol), ethanolamine (0.5 mL, 8.3 mmol) and triethylamine (0.5 mL, 3.6 mmol) in isopropanol ( 5 mL) was maintained at 50°C for 72 hours and then concentrated in vacuo. The residue was poured into ethyl acetate and washed with a saturated solution of potassium carbonate/water (1:9). The aqueous phase was extracted a second time with ethyl acetate, then the combined extracts were washed with saline, dried (MgSO 4 ), filtered and concentrated to give the title compound (701 mg, quantitative); LCMS (PS-A2) Rt 2.29 min [M+H]+ 418, [M-H2O+H]+ 400.

79C. 2-(4-chloro-phenin-2-(4-iodo-phenylVmorpholine).

A solution of l-(4-chloro-phenyl)-2-(2-hydroxy-ethylamino)-l-(4-iodo-phenyl)-ethanol (701 mg, 1.68 mmol) in DCM (10 mL) was treated with concentrated H2SO4 (0.1 mL, 1.9 mmol). After 20 hours, a second portion of H2SO4 (1.0 mL, 19 mmol) was added and the mixture was stirred for another 2 hours. The mixture was diluted with ethyl acetate and washed with saturated potassium carbonate and saline, then dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2), eluting with 0.5% triethylamine in ethyl acetate to give the title compound (290 mg, 43%); LCMS (PS-A2) Rt 2.40 min [M+H]+ 400.

79D. 2-(4-chloro-phenin-2-f4-f 1 H-Dyrazol-4-yl)-phenin-morpholine

2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole by following the procedure outlined in Example 1 but using tetrakis(triphenylphosphine)palladium(0) as catalyst to give the title compound. LCMS (PS-A3) R, 6.88 min [M+H]+ 340. *H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, no.s).

FIRST 80

(4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-sirćetna kiselina i metil estar f4-(4-["4-(1H-Pirazol -4-in-phenyl]-piperidin-4-yl}-phenoxyVsirćetne kišite

80A. ethyl estar

Following the procedure described in Example 42B, but substituting ethyl phenoxyacetate for chlorobenzene and using nitrobenzene as the solvent, the title compound was obtained. LCMS (PS-A2) R, 2.37 min [M+H]+ 418.

80B. (4-{4-[4-(1H-Pirazol-4-yl)-phenyl]-piperidin-4-yl|-phenoxy)-sirćetna kiselina i metil estar (4- (4-F4-( 1 H-Pirazol -4-yl)-phenyl-1-piperidin-4-yl 1-phenoxy)-acetic acids

{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl ester reacted with 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole by following the procedure described in Example 1, but using tetrakis(triphenylphosphine)palladium(0) as catalyst and heating at 80°C for 30 minutes, to obtain a mixture of compounds from title. Workup The basic aqueous extract was neutralized with hydrochloric acid and extracted with ethyl acetate (x2), then these organic extracts were combined and washed with saline, dried (MgSO4), filtered and concentrated to give the crude product which was recrystallized from water to give gave (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid (12 mg, 5%); LCMS (PS-A3) Rt 5.33 min [M+H]+ 378. 1H NMR (DMSO-d6) δ 2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11 (2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, no.s).

The material not extracted into the base was converted by standing in methanol to a single compound, {4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid methyl ester. This compound was purified by preparative HPLC to give the title compound (18 mg, 7%); LCMS (PS-A3) Rt 6.13 min [M+H]+ 392. 1H NMR (Me-d3-OD) δ 2.34-2.45 (4H, m), 2.87 (4H, apparent t), 3.75 (3H, s) , 6.83 (2H, d), 7.21 (2H, d), 7.26 (2H, d), 7.47 (2H, d), 7.89 (2H, s).

EXAMPLE 81

4-(4-[4-( 1 H -Pirazol-4-yl)-fenil] -piperidin-4-yl} -benzonitrile 81 A. 4-(4-chloro-fenil)-4-(4-iodo- phenyl)-piperidine

Following the procedure described in Example 42B, but substituting iodobenzene for chlorobenzene, the title compound was obtained. LCMS (PS-A2) 2.68 min [M+H]+ 398.

81B. 4-F4-C4-chloro-phenyl)-piperidin-4-yn-benzonitrile

A mixture of 4-(4-chloro-phenyl)-4-(4-iodo-phenyl)-piperidine and copper (I) cyanide in DMF was heated to 140°C under nitrogen for 6 hours, then allowed to cool. The mixture was diluted with ethyl acetate, washed with a mixture conc. ammonia and saline (x5), dried (MgSO4), filtered and concentrated to give a residue which was partially purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 10%) and dichloromethane to give the title compound was obtained (46 mg, <16%). It was used in the next reaction without further purification. LCMS (PS-A2) Rt 2.39 min [M+H]+ 297.

81C.4-{4-[4-riH-Pyrazol-4-in-fenil]-piperidin-4-yl)-benzonitrile

4-[4-(4-chloro~phenyl)-piperidin-4-yl]-benzonitrile reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole by following the procedure outlined in Example 1, but using tetrakis(triphenylphosphin)palladium(0) as catalyst and heating at 100°C for 15 minutes, to give the title compound. LCMS (PS-A3) Rt 6.68 min [M+H]+ 329. *H NMR (Me-d3-OD) δ 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, no.s).

FIRST 82

(2-(4-chloro-phenylV2-[4-(1H-pyrazol-4-yl')-phenyl]-propyl}-methyl-amine 82A. metil estar Bis-(4-chloro-phenyl)-sirćetne kišite

Bis-(4-chloro-phenyl)-acetic acid (4.33 g, 15.4 mmol) was suspended in anhydrous methanol (20 mL) and concentrated hydrochloric acid (5 drops) was added. After 1 day, the reaction was quenched by adding saturated sodium bicarbonate solution, then the organic solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 50% saturated potassium carbonate solution. The organic phase was washed with saline, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with 10% ethyl acetate/petroleum, to give the title compound as a colorless oil ( 3.57 g, 78%); LCMS (PS-B3) R, 3.79 min, no ionization. 1H NMR (CDCl 3 ) δ 3.74 (3H, s), 4.96 (1H, s), 7.20-7.23 (4H, m), 7.28-7.32 (4H, m).

82B. 2,2-Bis-(4-chloro-phenyl)-propionic acid methyl ester

A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g, 4.0 mmol) in THF (20 ml) was cooled to -78°C under nitrogen. A solution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) was added over 5 min, then after an additional 20 min, iodomethane (0.63 mL, 10.1 mmol) was added. After 4 hours, the reaction was quenched by addition of saturated ammonium chloride solution and allowed to warm to room temperature, then concentrated in vacuo to remove organic solvents. The mixture was diluted with ethyl acetate/petroleum 1:4 and washed with sat. (1% to

2%), to give the title compound as a colorless oil (210 mg, 17%); LCMS (PS-B3) R, 4.01 min, no ionization. 1H NMR (CDCl 3 ) δ 1.88 (3H, s), 3.73 (3H, s), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).

82C. 2,2-Bis-(4-chloro-phenyl)-propionic acid

A solution of 2,2-bis-(4-chloro-phenyl)-propionic acid methyl ester (210 mg, 0.67 mmol) in THF/water/methanol (1:1:1, 18 mL) was stirred at room temperature for 5 days and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 2N hydrochloric acid, then the organic phase was washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (186 mg, 93%) as a yellow solid which was used without additional purification. LCMS (PS-B3) Rt 2.40 min [M-CO2H]" 249.

82D. 2,2-Bis-(4-chloro-phenyl)-N-methyl-propionamide

Following the procedure described in Example 8D, but substituting 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid for 2,2-bis-(4-chloro-phenyl)-propionic acid , the title compound was obtained. LCMS (PS-B3) R, 3.40 min [M+H]+ 308.

82E. [2.2-Bis-(4-chloro-fenil)-propyl]-methyl-amine

Following the procedure described in Example 8E, but substituting 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide for 2,2-Bis-(4-chlorophenyl)-N -methyl-propionamide, the title compound was obtained. LCMS (FLA) Rt 2.35 min [M+H]+ 294

82F. {2-(44-chloro-phenyl)-2[4-(1H-pyrazol-4-yl)-phenyl]-propyl|-methyl-amine

[2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- with lH-pyrazole following the procedure outlined in Example 1 to afford the title compound. LCMS (PS-A3) R, 6.94 min [M+H]+ 326. 1H NMR (Me-d3-OD) δ 1.86 (3H, s), 2.77 (3H, s), 3.89 (2H, s), 7.26-7.33 (4H, m), 7.37-7.40 (2H, m), 7.68 (2H, d), 8.35 (2H, s).

PRIMER 83 1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

Following the procedure described in Examples 79A, 79B and 79D, but substituting ethanolamine for methylamine, the title compound was obtained. LCMS (PS-A3) Rt 5.28 min [M+Hf 328, [M-H2O+H]+ 310. [H NMR (Me-d3-OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-7.31 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s).

FIRST 84

2- Amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

84A. 2-r2-(4-chloro-phenyl)-2-hydroxy-2-(4-iodo-phenin-ethyl-isoindole-L3-dione

A mixture of 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* (571 mg, 1.60 mmol) and potassium phthalimide (340 mg, 1.84 mmol) in THF (5 mL) and DMSO (2 mL) was heated at 100°C for 20 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate, washed with water and saline (x2), dried (MgSO4), filtered and concentrated to give the crude product which was purified by column chromatography (SiO2), eluting with an ethyl acetate/petroleum gradient. (2.5% to 100%), then 10% methanol/dichloromethane to give the title compound (273 mg, 34%); LCMS (PS-A2) Rt 3.22 min [M+H]+ 504.

* This starting material can be made using the procedure described in Example 79A

84B.N-{2-(4-chloro-phenin-2-hydroxy-2-r4-(1H-pyrazol-4-yn-phenyl-ethyl-polyamidphtalne)

acid

2-[2-(4-chloro-phenyl)-2-hydroxy-2,(4-iodo-phenyl)-ethyl]-isoindole-1,3-dione reacted with 4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-H-pyrazole by following the procedure outlined in Example 1, but using tetrakis(triphenylphosphine)palladium(0) as catalyst, to give the title compound. LCMS (PS-A2) Rt 2.62 min [M-H]" 460.

84C.2-Amino-1-(4-chloro-phenyl')-1-r4-1H-pyrazol-4-yn-phenyl-ethanol

Following the procedure described in Example 49D, but substituting phthalic acid N-(2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethyl)-semiamide for N-{2-(4-chloro-phenyl)-2-hydroxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-halfamide of phthalic acid, the title compound was obtained. LCMS (PS-A3) R, 6.29 min [M-H2O+H]+ 296. 1H NMR (Me-d3-OD) δ 3.29-3.38 (2H, m), 7.32 (2H, d), 7.41-7.46 (4H, m), 7.55 (2H, d), 7.94 (2H, s).

PRIMER 85 4-(3,4-Dichloro-phenyl-4-r4-(1H-pyrazol-4-yl)phenyl-piperidin

Following the procedure described in Example 14, but substituting 1,2-dichlorobenzene for chlorobenzene, the title compound was obtained. LCMS (PS-B4) Rt 7.20 min [M+H]+ 372. *H NMR (Me-d3-OD) δ 2.62-2.69 (2H, m), 2.73-2.81 (2H, m), 3.18-3.30 ( 4H, m), 7.34 (IH, dd), 7.46-7.52 (3H, m), 7.53 (IH, d), 7.72 (2H, d), 8.56 (2H, s).

PRIMER 86 4-(3-chloro-4-methoxy-phenyl-4-r4-(1H-pyrazol-4-yl)-phenyl1-piperidin

Following the procedure described in Example 14, but substituting 2-chloroanisole for chlorobenzene, the title compound was obtained. LCMS (PS-B4) R, 6.24 min [M+H]+ 368. *H NMR (Me-d3-OD) 8 2.62-2.75 (4H, m), 3.23 (4H, apparent t), 3.86 (3H, s), 7.06 (IH, d), 7.30 (IH, dd), 7.34 (IH, d), 7.45 (2H, d), 7.69 (2H, d), 8.57 (2H, s).

FIRST 87

4-(4-hloro-3-fluoro-fenin-4-[4-(lH-pyrazol-4-ylVfenill-piperidine 87A. terc-butyl estar 4-(4-hloro-3-fluoro-phenyl)-4- hydroxy-piperidine-l-carbonske kiseline

A solution of 4-chloro-3-fluorophenylmagnesium bromide (15 mL, 7.5 mmol, 0.5 M in THF), under nitrogen, was added to 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.02 g, 5.1 mmol). After 24 hours, saturated ammonium chloride solution was added and then the organic solvent was removed in vacuo. The mixture was extracted with ethyl acetate, then this extract was washed with saline, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiCh), eluting with a gradient of ethyl acetate/petroleum (0% to 20 %) to give the title compound (511 mg, 30%). 1H NMR (Me-^-OD) δ 1.48 (9H, s), 1.67 (2H, n.d), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99 (2H, n.d) , 7.27 (IH, dd), 7.38 (IH, dd), 7.42 (IH, t).

87B. 4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine

Following the procedure described in Example 42B, but substituting bromobenzene for chlorobenzene, the title compound was obtained. LCMS (PS-A2) Rt 2.43 min [M+H]+ 368.

87C.4-(4-hloro-3-fluoro-fenin-4-[4-(1H-pirazol-4-in-fenil]-piperidin

4-(4-Bromo-phenyl)-4-(4-chloro-3-fluoro-phenyl)-piperidine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole by following the procedure outlined in Example 1, but using tetrakis(triphenylphosphine)palladium(0) as catalyst, to give the title compound. LCMS (PS-A3) Rt 7.11 min [M+H]+ 356. 1H NMR (Me-d3-OD) δ 2.62-2.80 (4H, m), 3.18-3.30 (partial overlap with solvent, 4H, m) , 7.23 (IH, t), 7.34-7.39 (IH, m), 7.22 (IH, dd), 7.30 (1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H , s).

FIRST 88

4-{4-[4-(1H-Pirazol-4-ylVfenil]-piperidin-4-yl|-benzoeva kiselina

88A. tert-butyl ester 4-(4-carboxy-phenyD-4-(4-hloro-phenyD-piperidin-l-carbons

acid

Under nitrogen, a solution of 4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester* (888 mg, 1.97 mmol) in THF (5 mL) was cooled to -78°C. A solution of n-butyl lithium (1.5 mL, 1.6M in hexanes) was added dropwise and the mixture was maintained at this temperature for 25 minutes. Carbon dioxide gas (made from dry ice and dried by passing through a column of calcium chloride beads) was passed through the anion solution for 80 minutes and then the mixture was allowed to warm to room temperature. The solvents were removed in vacuo, then the residue was partitioned between 1N hydrochloric acid and diethyl ether. The organic phase was separated, dried (MgSO4), filtered and concentrated. The combined aqueous phases were further extracted with ethyl acetate, this extract was also dried (MgSO4), filtered, combined with the ether extract and concentrated to give tert-butyl ester 4-(4-carboxy-phenyl)-4-(4- chloro-phenyl)-piperidine-1-carboxylic acid (889 mg); LCMS (PS-A2) Rt 3.52 min [M-tBu+H]+ 360.

* This starting material can be made using the procedure described in Example 14A and then in Example 48A

88B. tert-butil estar 4-(4-Karboksi-fenil)-[4-(1H-pyrazol-4-yl)-fenil]-piperidin-1-karbonske kiske

4-(4-Carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-Butyl ester reacted with 4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-pyrazole following the procedure outlined in Example 1 to afford the title compound. LCMS (PS-A2) Rt 2.92 min [M+H]+ 448.

88C. 4-{4-[4-(1H-Pirazol-4-yl)-fenil]-piperidin-4-yl)-benzoeva kiselina

4-(4-Carboxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine-1-carboxylic acid tert-Butyl ester (26 mg, 0.06 mmol) was dissolved in dioxane ( 2 mL) and 1N hydrochloric acid (2 mL). After 24 h the mixture was concentrated in vacuo and triturated with diethyl ether to give the title compound as the dihydrochloride salt (22 mg, 90%); LCMS (PS-A3) Rt 5.22 min [M+H]+ 348. !H NMR (Me-d3-OD) δ 2.70-2.82 (4H, m), 3.26 (4H, apparent t), 7.46 (2H, d ), 7.51 (2H, m), 7.68 (2H, d), 8.00 (2H, d), 8.47 (2H, s).

FIRST 89

4-[4-(lH-Pirazol-4-in-phenyl]-1.2.3.4.5.6-hexahydror4.4'1bipyridinyl 89A. terc-butyl estar 4-(4-hloro-phenin-3.4.5.6-tetrahydro-2H -[4.4']bipyridinyl-l-carbonske kiseline

Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled on ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed by a solution of sodium hexamethyldisilazide (10 mL, 20 mmol, 2M in THF) over two minutes. The mixture was stirred at 0°C for 3.5 hours, then allowed to warm to room temperature and stirred for another 20 hours. Methanol was added and then the mixture was concentrated in vacuo. The residue was poured into ethyl acetate and washed with 1N hydrochloric acid (x3) and brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with a gradient of 2M methanolic ammonia in dichloromethane. (1% to 5%). Second purification by chromatography

on a column (S1O2), elution with 50% ethyl acetate/petroleum gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373.

* This starting material can be made using the procedure described in J. Chem. Soc, Perkin Trans 1, 2000, p3444-3450

89B. 4-[4-(lH-Pirazol-4-in-fenil]1.2.3A5.6-hexahidro-[4.4']bipiridinil

tert-Butyl ester 4-(4-chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-carboxylic acid reacted with 4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure outlined in Example 1, followed by treatment with 4M HCl in dioxane, to afford the title compound. LCMS (PS-B4) R, 4.28 min [M+H]+ 305. 1H NMR (Me-d3-OD) δ 2.76 (2H, no.t), 3.01 (2H, no.d), 3.24 (2H, no.t), 3.39 (2H, no.d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d), 8.37 (2H, s), 8.82 (2H, d).

PRIMER 90 3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 3-chlorophenylmagnesium bromide and methylamine for ammonia, the title compound was obtained. LCMS (PS-B3) Rt 2.60 min [M+H]+ 312. 1H NMR (Me-d3-OD) δ 2.44 (2H, apparent qd), 2.87 (2H, dd), 4.14 (IH, t), 7.24 (1H, dt), 7.27-7.33 (2H, m), 7.34 (1H, t), 7.42 (2H, d), 7.68 (2H, d), 8.58 (2H, s).

FIRST 91

2-Methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl1-ethanol

Following the procedure described in Example 83, but substituting (4-chlorophenyl)-(4-iodo-phenyl)-methanone for (4-Bromo-phenyl)-(4-nitro-phenyl)-methanone, the title compound was obtained . LCMS (PS-A) Rt 1.79 [M+H]+ 339. 1H NMR (Me-d3-OD) δ 8.27 (2H, d), 7.98 (2H, s), 7.80 (2H, d), 7.65 (2H , d), 7.52 (2H, d), 4.00 (2H, dd), 2.73 (3H, s) - CH(OH) signal assumed to be given under the water peak.

PRIMER 92 2-(3-chloro-4-methoxy-phenyl)-2-r4-(1H-pyrazol-4-yl)-phenyl-ethylamine

Following the procedure described in Example 87B and Example 42C, but replacing 1-(4-bromo-phenyl)-2-methylamino-ethanol with 2-amino-1-(4-bromo-phenyl)-ethanol and chlorobenzene with 2- with chloroanisole, the title compound was obtained. LCMS (PS-B3) Rt 2.55 [M+H]+ 328.20. 'H NMR (Me-d3-OD) δ 3.65-3.70 (2H, d), 3.90 (3H, s), 4.30-4.35 (IH, t), 7.05-7.10 (IH, d), 7.30-7.35 (IH , d), 7.40 (1H, s), 7.45-7.50 (2H, d), 7.70-7.75 (2H, d), 8.60 (2H, s).

PRIMER 93 2-f4-chloro-phenin-2-fluoro-2-r4-(1H-pyrazol-4-yl)-phenin-ethylamine

93A. 2.2-Bis-f4-chloro-phenylV2-fluoro-ethylarnine

2-Amino-1,1-bis-(4-chloro-phenyl)-ethanol (293 mg, 1.04 mmol) was dissolved in pyridine-HF (2 ml) with cooling. After 24 hours, the mixture was diluted in 1N sodium hydroxide solution and extracted with DCM (33). Each extract was dried (MgSC4) and filtered before combining and concentrating to give a residue which was purified by column chromatography (SiC2), eluting with 0.5% triethylamine in ethyl acetate to give the title compound (192 mg, 65%) ; LCMS (PS-B3) Rt 3.34 min [M-F]+ 266. 1H NMR (DMSO-d6) δ 3.41 (2H, d), 7.39-7.46 (8H, m).

93B.2-(4-hloro-fenin-2-fluoro-2-r4-(lH-pirazol-4-ilVfenill-etilamin)

2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole by following the procedure described in Example 1, with the difference that the heating was carried out at 100°C for 5 minutes using a power supply of 300W in a CEM microwave, to obtain the title compound. LCMS (PS-B4) Rt 6.69 min [M-F-]+ 296. 1H NMR (Me-d3-OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d).

PRIMER 94 3-(3,4-Dihloro-fenilV3-r6-nH-pirazol-4-il>piridin-3-iH-propilarnin

By following the procedure described in Example 60, but replacing 6-chloro-nicotinonitrile with 6-chloro-pyridine-3-carbaldehyde and replacing 3-methyl-l-trityl-lH-pyrazole-4-organoboric acid with l-trityl-lH -pyrazole-4-organoboronic acid, and then following the procedure described in Example 8, the title compound can be obtained.

PRIMER 95 2-(4-hloro-3-fluoro-femn-2-r4-(lH-pyrazol-4-in-phenyl-ethylamine

By following the procedure described in Example 87, but replacing 4-oxo-piperidine-1-carboxylic acid tert-butyl ester with (2-oxo-ethyl)-carbamic acid tert-butyl ester, the title compound can be obtained.

PRIMER 96 4-(2-chloro-3-fluoro-phenyl)-4-r4-(1H-pyrazol-4-yl)-phenyl-piperidin

Following the procedure described in Example 14, but replacing chlorobenzene with 1-chloro-2-fluorobenzene, the title compound can be obtained.

FIRST 97

1-{(3,4-Dichloro-phenin-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}piperazine 97A. (4-chloro-phenyl)-(3,4-dichloro-phenyl) -methanol

Commercially available chlorophenyl magnesium bromide and 3,4-dichlorobenzaldehyde can be reacted together according to the procedure described in J. Medicinal Chem., (2000), 43(21), 3878-3894 to give the title compound.

97B. 1.2-Dichloro-4-chloro-(4-chloro-phenyl)-methyl-benzene

The product of Example 97 A can be reacted with SO 2 Cl 2 according to the procedure described in Organic Letters, (2003), 5(8), 1167-1169 to give the title compound.

97C. 1-((3,4-Dichloro-phenin-4-(1H-pyrazol-4-yl)-phenyl-methyl-piperazine)

The title compound can be prepared from the compound of Example 97C using the procedure and conditions described in Zhongguo Yaowu Huaxue Zazhi (2002), 12(3),125-129.

PRIMER 98 2-(3.4-Dichloro-phenylV2-r4-(1H-pyrazol-4-yn-phenyl-ethylamine)

By following the procedure described in Example 42, in step 42B, but replacing the chlorobenzene with 1,2-dichloro-benzene, the title compound can be obtained.

FIRST 99

(2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine

Following the procedure described in Example 42, in step 42B, but substituting 2-chloroanisole for chlorobenzene, the title compound was obtained. LC/MS: (PS-A2) Rt 2.03 [M+H]+ 342. 1H NMR (Me-d3-OD) δ 2.45 (3H, s), 3.22 (2H, d), 3.85 (3H, s) , 4.15 (1H, t), 7.04 (1H, d), 7.33 (1H, d), 7.27-7.34 (3H, m), 7.55 (2H, d), 7.92 (2H, s).

FIRST 100

4-(4-r2-Azetidin-1-yl-1-(4-chloro-phenoxy)-phenyl-1H-pyrazole

Following the procedure described in Example 42A, but replacing methylamine with azetidine and following the procedure of Example 45, the title compound can be obtained.

PRIMER 101 3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine

By following the procedure described in Example 61, but replacing the imidazole with potassium phthalimide in Step 61A and replacing the chlorobenzene with 1-chloro-2-methoxy-benzene in Step 61B, and then removing the phthaloyl protecting group under the conditions outlined in Examples 84B and 84C, the title compound can be prepared.

PRIMER 102 {3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl-methyl-amine

Following the procedure described in Example 61, but replacing imidazole with methylamine in step 61A and replacing chlorobenzene with 1-chloro-2-methoxy-benzene in step 61B, the title compound can be obtained.

FIRST 103

l-[(3-hloro-4-methoxy-phenyl-(4-hloro-phenylVmethyl]-piperazine 103A. (3-hloro-4-methoxy-phenyl)-(4-hloro-phenyl')-methanol

The title compound can be prepared using the procedure of Example 97A, but replacing 3,4-dichlorobenzaldehyde with 3-chloro-4-methoxybenzaldehyde.

103B. 2-chloro-4-chloro-(4-chloro-phenyl)-methyl-1-methoxy-benzene

The hydroxy compound of Example 103 A can be converted to the title chloro compound by following the procedure of Example 97B.

103C. 1-r(3-chloro-4-methoxy-phenyl)-(4-chloro-phenyl)-methyl-piperazine

The title compound can be prepared from the product of Example 103B by following the procedure of Example 97C.

PRIMER 104 C-(4-chloro-phenin-C-r4-(1H-pyrazol-4-yl)-phenyl-methylamine

By following the procedure described in Example 1, but replacing 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride with C,C-bis-(4-chloro-phenyl)-methylamine, the title compound can be obtained.

FIRST 105

(2-(4-chloro-phenyl)-2-[4-(3-methyl-lH-pyrazol-4-yl)-phenin-ethyl}-methyl-amine

105A.2-(4-chloro-phenin-N-methyl-2-r4-f3-methyl-1-trityl-1H-pyrazol-4-yl')-phenin-acetamide

2,2-Bis-(4-chloro-phenyl)-N-methyl-acetamide was prepared by reacting a commercially available suitable carboxylic acid with methylamine using the procedure from Example

21a. The N-methyl-acetamide compound was converted to the title compound by the procedure described in Example 1. LCMS (PS-B3) Rt 4.21 min; mlz [M+H]+ 582.

105B. 2-(4-chloro-phenyl)-N-methyl-2-r4-(3-methyl-1H-pyrazol-4-ylVphenyl1-acetamide

The trityl-protected compound of Example 104A was deprotected using the procedure described in Example 60D to give the title compound. LCMS (PS-B3) Rt 2.41 min; mlz [M+H]+ 340. 1H NMR (methanol-d4) δ 2.40 (3H, s), 2.78 (3H, s), 4.95 (IH, s), 7.29-7.34 (6H, m), 7.41 (2H , d), 7.69 (IH, s).

105C. (2-(4-chloro-phenin-2-[4-(3-methyl-lH-pyrazol-4-yl)-phenyl-ethyl-methyl-amine

Following the procedure described in Example 20B, the title compound was obtained. LCMS (PS-B3) Rt 2.80 min; m/z [M+H]+ 326. 1H NMR (methanol-d4) δ 2.52 (3H, s), 2.75 (3H, s), 3.80 (2H, d), 4.46 (IH, t), 7.41 (4H , s), 7.49 (2H, d), 7.54 (2H, d), 8.24 (1H, s).

BIOLOGICAL ACTIVITY

FIRST 106

Measurement of inhibitory activity against PKA kinase (IC50)

Compounds of the invention can be tested for PK inhibitory activity using the PKA catalytic domain from Upstate Biotechnology (#14-440) and specific

a 9-residue PKA peptide (GRTGRRNSI), also from Upstate Biotechnology (#12-257), as a substrate. A final concentration of 1 nM enzyme was used as a buffer comprising 20 mM MOPS pH 7.2, 40 mM ATP/γ33P-ATP and 5 mM substrate. The compounds are added to a solution of dimethylsulfoxide (DMSO) to a final DMSO concentration of 2.5%. The reaction was allowed to proceed for 20 minutes before excess orthophosphoric acid was added to quench the activity. Unincorporated y33P-ATP was then separated from phosphorylated proteins on a Millipore MAPH filter plate. Plates were washed, scintillant was added and plates were then counted on a Packard Topcount.

% inhibition of PKA activity was calculated and graphed to determine the concentration of test compound required to inhibit 50% of PKB activity (IC50).

Compounds from Examples 1, 4, 43, 44, 45, 46, 47, 48, 49, 52, 54, 59, 63, 66, 67, 73, 78, 79, 81, 82, 83, 84, 85, 86 and 90 have IC50 values of less than 1 mM, with the compounds of Examples 5, 7 and 80 having IC50 values of less than 15 mM.

FIRST 107

Measurement of inhibitory activity against PKB kinase (IC50)

Inhibition of protein kinase B (PKB) activity by compounds can be determined generally as described by Andjelkovic et al. (Mol. Cell. Biol. 19, 5061-5072 (1999)), but using a fusion protein described as PKB-PIF and fully described by Yang et al. (Nature Structural Biology 9, 940-944 (2002)). The protein was purified and activated with PDK1 as described by Yang et al. Peptide AKTide-2T (H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OH) obtained from Calbiochem (# 123900) was used as a substrate. A final concentration of 0.6 nM enzyme was used in a buffer containing 20 mM MOPS pH 7.2, 30 mM ATP/γ33P-ATP and 25 mM substrate. The compounds are added to the DMSO solution to a final DMSO concentration of 2.5%. The reaction was allowed to proceed for 20 minutes before addition of excess orthophosphoric acid to quench activity. The reaction mixture is transferred to a phosphocellulose filter plate where the peptide binds and the unused ATP is washed away. After washing, the scintillant was added and the incorporated activity was measured by scintillation counting.

The % inhibition of PKB activity was calculated and graphed in order to determine the concentration of the test compound required to inhibit 50% of PKB activity (IC50).

Following the protocol described above, the IC50 values of the compounds of Examples 1, 4, 8-10, 12-17, 20-23, 25-31, 33-35, 43, 44, 46, 47, 49 were found to be -52, 54, 56, 57, 59, 61, 63, 65, 66, 69, 71-73, 76-79, 81-87, 90, 91, 94 and 104 less than 1 mM, while

each of the compounds of Examples 2, 3, 5, 6, 7, 11, 18, 19, 24, 32, 36, 45, 48, 53, 55, 58, 60, 64, 67, 68, 75, 80 and 89 has an IC50 value of less than 5 mM, and each of the compounds of Examples 40, 41, 62 and 70 has an IC50 value of less than 50 mM.

PHARMACEUTICAL FORMULATIONS

FIRST 108

(i) Tablet formulation

A tablet composition containing a compound of formula (I) was prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant and pressing to form a tablet in a known manner.

(ii) Capsule formulation

The capsule formulation was prepared by mixing 100 mg of the compound of formula (I) with 100 mg of lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injectable formulation I

A parenteral composition for administration by injection may be prepared by dissolving a compound of formula (I) (eg in salt form) in water containing 10% propylene glycol to obtain a concentration of active compound of 1.5% by weight. The solution is then sterilized by filtration, filled into ampoules and hermetically sealed.

(iv) Injectable formulation II

A parenteral composition for injection was prepared by dissolving the compound of formula (I) (e.g., in salt form) (2 mg/ml) and mannitol (50 mg/ml) in water, sterile filtering the solution, and filling it into a 1 ml vial or ampoule that was hermetically sealed. they close.

(iv) Subcutaneous injection formulation

A composition for subcutaneous administration was prepared by mixing a compound of formula (I) with pharmaceutical grade corn oil to obtain a concentration of 5 mg/ml. The composition is sterilized and filled into a suitable container.

Equivalence

The foregoing examples are presented to illustrate the invention and should not be construed as limiting the scope of the invention. It will be apparent that it is possible to make numerous modifications and changes to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and changes are determined to be covered by this application.

Claims (55)

1. Compound of formula (I): or its salt, solvate, tautomer or N-oxide; wherein, A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R and NR R and a maximum chain length of 4 atoms extending between E and NR R , whereby one of the carbon atoms in the linker group can be optionally replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxide, with the proviso that the hydroxy group when present is not located on the carbon atom a relative to the NR 2 R 3 group and with the proviso that the oxo group when present is on the carbon atom a in relation to the NR2R3 group; E is a monocyclic, bicyclic carbocyclic or heterocyclic group in which E is unsubstituted or has up to 4 substituents R8 selected from the group consisting of hydroxy, oxo (when E is non-aromatic), chlorine, bromine, trifluoromethyl, cyano, C1-4 hydrocarbyloxy and C1 -4 hydrocarbyl optionally substituted with C1-2 alkoxy or hydroxyl; R 1 is an aryl or heteroaryl group which is unsubstituted or carries one or more substituents selected from the group consisting of hydroxy; C1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; CONH2; nitro; C1-4 hydrocarbyloxy and C1-4 hydrocarbyl, each of which is optionally substituted with C1-2 alkoxy, carboxy or hydroxy; C1-4 acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; five- and six-membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S; phenyl; phenyl-C1-4 alkyl; phenyl-C1-4 alkoxy; heteroaryl-C1-4 alkyl; heteroaryl-C1-4 alkoxy and phenoxy, wherein each of heteroaryl, heteroaryloxy, phenyl, phenyl-C1-4 alkyl, phenyl-C1-4 alkoxy, heteroaryl-C1-4 alkyl, heteroaryl-C1-4 alkoxy and phenoxy is a group optionally substituted with 1, 2 or 3 substituents selected from the group consisting of C1-2 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, CONH2, C1-2 hydrocarbyloxy and C1-2 hydrocarbyl, each of which is optionally substituted with methoxy or hydroxyl; R2 and R3 are independently selected from the group consisting of hydrogen, C1-4 hydrocarbyl and C1-4 acyl, wherein the hydrocarbyl and acyl groups are optionally substituted with one or more substituents selected from the group consisting of fluorine, hydroxy, amino, methylamino , dimethylamino and methoxy; or R2 and R3 together with the nitrogen atom to which they are attached form a cyclic group selected from an imidazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N; or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing another heteroatom as a ring member selected from O and N; or NR2R3 and the carbon atom of the linker group A to which it is attached together form a cyano group; R 4 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, C 1-5 saturated hydrocarbyloxy, cyano and CF 3 ; and R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, C 1-5 saturated hydrocarbyloxy, cyano, CONH 2 , CONHR 9 , CF 3 , NH 2 , NHCOR 9 or NHCONHR 9 ; R9 is a group R9a or (CH2)R9a, wherein, R9a is a monocyclic or bicyclic group which may be carbocyclic or heterocyclic; the carbocyclic group or the heterocyclic group R9a is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino; a group Ra-Rb wherein, Ra is a bond, O, CO, X1C(X2), C(X2)X\ X'C(X2)X1, S, SO, SO2, NRC, SO2NRC or NRCSO2; and Rb is selected from the group consisting of hydrogen, heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S , SO, SO2, NRC, X'C(X2), C(X2)X' or x'C(X2)X'; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X1 is O, S or NRC and X2 is =O, =S or =NRC. 2. Compound according to claim 1 of formula (Ia): or its salt, solvate, tautomer or N-oxide; wherein, A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3 , whereby one of the carbon atoms in the linker group can be optionally replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluoro, and hydroxy, with the proviso that the hydroxy group, when present, is not located on the carbon atom a relative to the NR2R3 group, and with the proviso that the oxo group when present is on the carbon atom a in relation to the NR2R3 group; E is a monocyclic, bicyclic carbocyclic or heterocyclic group, wherein E is unsubstituted or has up to 4 substituents R8 as defined in claim 1; R 1 is an aryl or heteroaryl group which is unsubstituted or substituted as defined in claim 1; R and R are independently selected from the group consisting of hydrogen, C1-4 hydrocarbyl and CC1-4 acyl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom as a ring member selected from O and N; or one of R2 and R3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing another heteroatom as a ring member selected from O and N; or NR2R3 and the carbon atom of the linker group A to which it is attached together form a cyano group; R 4 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano and CF 3 ; and R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano, CONH 2 , CONHR 9 , CF 3 , NH 2 , NHCOR 9 or NHCONHR 9 ; R 9 is phenyl or benzyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4 hydrocarbylamino; a group Ra-Rb wherein, Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X', S, SO, SO2, NRC, SO2NRC or NRCSO2; and Rb is selected from hydrogen, heterocyclic groups having 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, halogen, cyano, nitro , carboxy, amino, mono- or di-Ci-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 members in the ring and wherein one or more carbon atoms of the Ci_8 hydrocarbyl group can optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X' or X1C(X2)X1; Rc is selected from hydrogen and C1-4 hydrocarbyl; and X1 is O, S or NRC and X2 is =O, =S or =NRC. 3. A compound according to claim 1 or 2, characterized in that A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, wherein the linker group has a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR 2 R 3 , wherein one of the carbon atoms in the linker group may be optionally replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from fluorine and hydroxy, with the proviso that the hydroxy group, when present, is not located on the carbon atom a relative to the NR2R3 group; and R 5 is selected from the group consisting of hydrogen, halogen, C 1-5 saturated hydrocarbyl, cyano, CONH 2 , CF 3 , NH 2 , NHCOR 9 and NHCONHR 9 . 4. A compound according to any one of claims 1 to 3, characterized in that the linker group A has a maximum chain length of 3 atoms extending between R1 and NR2R3. 5. The compound according to claim 4, characterized in that the linker group A has a maximum chain length of 2 atoms extending between R1 and NR2R3. 6. A compound according to any one of claims 1 to 5, characterized in that the linker group A has a maximum chain length of 3 atoms extending between E and NR 2 R 3 . 7. The compound according to claim 6, characterized in that the linker group A has a chain length of 2 or 3 atoms extending between R1 and NR2R3 and a chain length of 2 or 3 atoms extending between E and NR2R3. 8. The compound according to any of the previous patent claims, characterized in that the atom of the linker group which is attached directly to the group E is a carbon atom and the linker group Aima is a skeleton completely of carbon. 9. The compound according to any one of claims 1 to 7, characterized in that the R'-A-NR2R3 compound represented by the formula R1-(G)k-(CH2)m-W-Ob-(CH2)n-(CR6R7)p- NR 2 R 3 , wherein G is NH, NMe or O; W is attached to group E and selected from (CH2)j-CR20, (CH2)rN and (NH)j-CH;b is O or 1, j is 0 or 1, k is 0 or l,m is O or 1, n is 0, 1, 2 or 3 and p is 0 or 1; the sum of b and k is 0 or 1; the sum of j, k, m, n and p does not exceed 4; R 6 and R 7 are the same or different and are selected from methyl and ethyl, or CR 6 R 7 forms a cyclopropyl group; and R 20 is selected from the group consisting of hydrogen, methyl, hydroxy and fluorine. 10. The compound according to any one of claims 1 to 7, characterized in that the group R'-A-NR2R3 is represented by the formula R1-(G)k-(CH2)m-X-(CH2)n-(CR6R7)p-NR2R3, in which , G is NH, NMe or O; X is attached to group E and selected from (CH2)j-CH, (CH2)j-N and (NH)j-CH; j is 0 or 1, k is 0 or 1, m is 0 or 1, nj is 0, 1, 2 or 3 and p is 0 or 1, and the sum of j, k, m, n and p does not exceed 4; and R and R7 are the same or different and are selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group. 11. The compound according to claim 10, characterized in that (i) k is 0, m is 0 or 1, n is O, 1, 2 or 3 and p is O; or (ii) k is 0, m is 0 or l,n is 0, 1 or 2 and p is 1. 12. The compound according to claim 10, characterized in that (i) X is (CH2)j-CH, k is 1, m is 0, n is O, 1, 2 or 3 and p is O; or (ii) X is (CH2)jCH, k is 1, m is 0, n is 0, 1 or 2 and P is 1. 13. A compound according to claim 10 or 12, characterized in that (i) j is 0; or (ii) j is 1; or (iii) CR 6 R 7 is C(CH 3 ) 2 . 14. The compound according to claim 10, characterized in that the part R'-A-NR2R3 of the compound is represented by the formula R1-X-(CH2)n-NR2R3, in which, X is attached to the group E and it is the group CH, and n is 2. 15. A compound according to claim 1 or 2, characterized in that R1-A(E)-NR2R3 is selected from the groups Al to Al1 from the following text: 16. The compound according to any of the preceding claims, characterized in that E is a monocyclic group. 17. The compound according to any of the preceding claims, characterized in that E is an aryl or heteroaryl group, each of them being unsubstituted or substituted with 4 substituents R8 as defined in claim 1. 18. The compound according to claim 17, characterized in that optionally substituted phenyl, thiophene, fluorine, pyrimidine and pyridine groups are selected, each of them being unsubstituted or substituted with up to 4 substituents R8 as defined in claim 1. 19. The compound according to claim 18, characterized in that E is a phenyl group which is unsubstituted or substituted with up to 4 substituents R8 as defined in claim 1. 20. A compound according to any of the preceding patent claims, characterized in that the group A and the pyrazole group are attached to the group E in a meta or para relative orientation; ie And the ipyrazole group is not attached to the neighboring ring members of group E. 21. The compound according to claim 20, characterized in that E is selected from the group consisting of 1,4-phenylene, 1,3-phenylene, 2,5-pyridylene and 2,4-pyridylene, 1,4-piperazinyl and 1,4 -piperazonyl, each of them being unsubstituted or substituted with up to 4 substituents R8 as defined in claim 1. 22. The compound according to any of the preceding claims, characterized in that E has 0-3 substituents. 23. The compound according to claim 22, characterized in that E has 0-2 substituents. 24. The compound according to claim 23, characterized in that E has 0 or 1 substituent. 25. The compound according to patent claim 24, characterized in that it is Enes substituted. 26. The compound according to patent claim 19, characterized in that it has the formula (II): in which, the group A is attached to the meta or ipara position of the benzene ring and q is 0-4. 27. The compound according to claim 26, characterized in that q is 0, 1 or 2. 28. The compound according to claim 27, characterized in that q is 0 or 1. 29. The compound according to claim 28, characterized in that q is 0. 30. A compound according to claim 19, characterized in that it has the formula (III): wherein, A' is a residue of the group A and R 1 to R 5 are as defined in any of the preceding claims. 31. A compound according to claim 19, characterized in that it has the formula (IV): wherein, z is 0, 1 or 2, R 20 is selected from the group consisting of hydrogen, methyl, hydroxy and fluorine, with the proviso that when z is equal to 0, R 20 is different from hydroxy. 32. A compound according to claim 19, characterized in that it has the formula (V): ,3 in which, R 3 is selected from hydrogen and C 1-4 hydrocarbyl. 33. The compound according to claim 32, characterized in that R3 is hydrogen. 34. A compound according to any one of the preceding claims, characterized in that R1 is selected from the group consisting of phenyl, naphthyl, thienyl, furan, pyrimidine and pyridine, each of which is optionally substituted as defined in claim 1. 35. A compound according to claim 26, characterized in that R1 is phenyl. 36. A compound according to any of the preceding claims, characterized in that R1 is unsubstituted or substituted with up to 5 substituents selected from the group consisting of hydroxy, C1-4 acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, Cm hydrocarbyloxy and C1-4 hydrocarbyl optionally substituted with C1-2 alkoxy or hydroxy. 37. The compound according to patent claim 36, characterized in that the group R1 has one or two substituents selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl imethoxy. 38. The compound according to claim 37, characterized in that R1 is a mono-chlorophenyl or dichlorophenyl group. 39. A compound according to any one of the preceding claims, characterized in that R 4 is selected from hydrogen and methyl. 40. A compound according to any one of the preceding claims, characterized in that R 5 is selected from hydrogen, methyl and cyano. 41. The compound according to claim 40, characterized in that R5 is hydrogen or methyl. 42. A compound according to any one of the preceding claims, characterized in that R2 and R3 are independently selected from the group consisting of hydrogen, Cm hydrocarbyl and Cm acyl. 43. A compound according to claim 42, characterized in that R2 and R3 are independently selected from hydrogen and methyl. 44. A compound according to claim 43, characterized in that R2 and R3 are hydrogen at the same time. 45. The compound according to any of the preceding claims, characterized in that it has a molecular weight of less than 525. 46. Compound according to patent requirement 1 formula (I), indicated by the following compound: 2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile; 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine; 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine; 3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine; 3-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; {3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide; 3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(4-chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine; dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(R); {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine(S); 4-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-morpholine; 4. (4- [ 1 -(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1 H-pyrazole; {2-(4-chloro-phenyl)-2-[4 -(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine;dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine ; {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine; {2,2-bis-[4-(1H-pyrazol-4-yl) )-phenyl]-ethyl}-methyl-amine; 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(R); 2-(4- chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine(S);2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4- 1)-phenyl]-acetamide; 1-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperazine; 1-{2-( 4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-piperidine;4-{4-[2-azetidin-1-yl-1-(4-chloro -phenyl)-ethyl]-phenyl}-1H-pyrazole;1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;2-(4-chloro-phenyl)-N- methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide;N-methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;{2-(4-chloro-phenyl)-2-[ 4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine; 4-{4-[ 1 -(4-chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1 H -pyrazole; methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; {2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; 2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine; 4-{4-[1-(4-chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1 H -pyrazole; 4-{4-[3-azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1 H -pyrazole; methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine; {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitrile; 3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; 1-methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepan; {3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine; 4-{4-[ 1 -(4-chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1 H -pyrazole; 4-[4-(3-imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1 H -pyrazole; 4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol; 1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; (2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 4-[4-(2-methoxy-ethoxy)-phenyl ]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine;4-[4-(3-methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4- 1)-phenyl]-piperidine; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide; 2-(4-(2-methylamino- 1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide;{2-(3-chloro-phenoxy)-2-[4-(1H-pyrazol-4- yl)-phenyl]-ethyl}-methyl-amine;3-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1 -ol; 2-{2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol; 3-{2-(4-chloro-phenyl) )-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol;2-{2-(4-chloro-phenyl)-2-[4-(1H -pyrazol-4-yl)-phenyl]-ethylamino}-ethanol; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl- amine; methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine; 4-{3-methylamino-1 -[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl] -propylamine;4-(4-chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidin;2-(4-chloro-phenyl)-2-[ 4-(1H-pyrazol-4-yl)-phenyl]-morpholine; (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-sirćetna kiselina; 4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 4-(3,4-dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(4-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-[4.(1H-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4']bipyridinyl; 3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 2-methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 3-(3,4-dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine; 2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 4-(2-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; 2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 4-{4-[2-azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyrazole; 3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; {3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; ii C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine; and their salts, solvates, tautomers and N-oxides. 47. The compound according to claim 46, characterized in that it is 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or its salt, solvate, tautomer or N-oxide. 48. The compound according to any of the preceding patent claims, characterized in that it is in the form of a salt, solvate, ester or N-oxide. 49. Compound according to any one of claims 1 to 48 for use in medicine. 50. A compound according to any one of claims 1 to 48 for use in (a) preventing or treating a disease or condition mediated through protein kinase B; or (b) preventing or treating a protein kinase A-mediated disease or condition. 51. The compound according to any one of patent claims 1 to 48 for use in the prevention or treatment of a disease or condition selected from bladder, breast, colon, kidney, epidermal carcinoma, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach , cervix, endometrium, thyroid, prostate, or skin, hematopoietic tumor of the lymphoid lineage, hematopoietic tumor of the myeloid lineage, thyroid follicular cancer, tumor of mesenchymal origin, tumor of the central or preferred nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xerodermapigmentosum, keratoacanthoma, thyroid follicular cancer or Kaposi's sarcoma. 52. A compound according to any of claims 1 to 48 for use in the prevention or treatment of a disease or condition selected from breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell carcinoma, and small cell lung carcinoma. 53. Use of a compound according to any one of patent claims 1 to 48 for: (a) the production of a drug for the prevention or treatment of a disease or condition mediated by protein kinase B; or (b) the production of a drug for the prevention or treatment of a disease or condition mediated by protein kinase A; or (c) the production of a drug for the prevention or treatment of a disease or condition resulting from abnormal cell growth; (d) the production of medicine for the prevention or treatment of diseases in which there is a disorder of proliferation, apoptosis or differentiation. 54. A pharmaceutical composition containing a novel compound according to any one of claims 1 to 48 and a pharmaceutically acceptable carrier. 55. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 48, characterized in that it contains: (a) the reaction of a compound of formula (X) with a compound of formula (XI) or its N-protected derivative: in which, A , E and R to R are as defined in any of claims 1 to 48, one of X and Y is selected from chlorine, bromine, iodine and trifluoromethanesulfonate, and the other of X and Y is an organoboric acid ester or organoboric acid residue, in the presence of a palladium catalyst and a base; with HNR2R3 in the presence of a reducing agent; and optionally (c) converting one compound of formula (I) into another compound of formula (I). (b) reductive amination of compounds of formula (XXXVI):