PT1706385E - Pyrazole derivatives as protein kinase modulators - Google Patents

Description

ΡΕ1706385 1

DESCRIPTION " PYRAZOLE DERIVATIVES AS KINETIC PROTEIN MODULATORS "

This invention relates to pyrazole-containing aryl and heteroaryl alkylamine compounds which inhibit or modulate the activity of protein kinase B (PKB) and protein kinase A (PKA), the use of the compounds in the treatment or prophylaxis of disorders or diseases mediated by PKB and PKA and to novel compounds with PKB and PKA inhibitory or modulatory activity. Also provided are pharmaceutical compositions containing the compounds and novel chemical intermediates.

BACKGROUND OF THE INVENTION

Protein kinases constitute a large family of structurally related enzymes, which are responsible for the control of a wide variety 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 categorized by families by the substrates they phosphorylate (for example, protein tyrosine, protein serine / threonine, lipids, etc.). Sequence motifs which generally correspond to each of these kinase families have been identified (for example, Hanks, S. 2 ΡΕ1706385 K., Hunter, Τ., FASEB J., 9: 576-596 (1995); Knighton, et al., Cell, 73: 585-596 (1993), Garcia-et al., Science, 253: 407-414 (1991), Hiles et al., Cell, 70: 419-429 (1992) Bustos, et al., EMBO J., 13: 2352-2361 (1994)).

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

Kinases regulate many different cellular processes, including but not limited to proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by the addition of phosphate groups to the target proteins. These phosphorylation events act as molecular switches that turn on and off, which can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors etc.), cell cycle events, environmental or nutritional stresses etc. Suitable functions of the protein kinase in signaling pathways, for activating or inactivating (directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signaling, due to defective control of protein phosphorylation, has been implicated in various diseases, including, for example, inflammation, cancer, allergy / asthma, diseases and disorders of the immune system, diseases and disorders of the central nervous system and angiogenesis. Apoptosis or programmed cell death is an important physiological process that removes cells that are no longer needed by an organism. The process is important in early embryonic growth and development, allowing non-necrotic controlled disruption, removal, and recovery of cellular components. Removal of cells by apoptosis is also important in maintaining the chromosomal and genomic integrity of growing cell populations. There are several known checkpoints in the cell growth cycle where DNA damage and genomic integrity are carefully controlled. The response to detecting anomalies at such checkpoints is to halt the growth of such cells and initiate repair processes. If the damage or anomalies can not be repaired, then apoptosis is initiated by the injured cell in order to avoid propagation of failures and errors. Cancer cells often contain numerous mutations, errors or rearrangements in their chromosomal DNA. It is widely believed that this occurs in part because most tumors have a defect in one or more processes responsible for the initiation of the apoptotic process. Normal control mechanisms can not kill cancer cells and DNA or chromosomal coding errors continue to be propagated 4 ΡΕ1706385. Accordingly, restoration of these pro-apoptotic signals or suppression of deregulated survival signals is an attractive means of treating cancer. The signal transduction pathway containing the enzymes phosphatidylinositol 3-kinase (PI3K), PDK1 and PKB, among others, has long been known to mediate increased resistance to apoptosis or survival responses in many cells. There is a considerable 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, for example EGF, PDGF and through the generation of polyphosphatidylinositols, initiates the activation of downstream signaling events, including the activity of PDK1 and protein kinase B kinases ( PKB), also known as Akt. This also applies to host tissues, for example, in vascular endothelial cells, as well as in neoplasms. PKB is a Ser / thr kinase protein consisting of a kinase domain together with an N-terminal PH domain and C-terminal regulatory domain. The PKB enzyme itself is phosphorylated in Thr 308 by PDK1 and in Ser 473 by a hitherto unidentified kinase. Total activation requires phosphorylation at both sites, whereas the association between PIP3 and the PH domain is required for anchoring the enzyme on the cytoplasmic face of the lipid membrane, providing optimal access to substrates. 5 ΡΕ1706385 Activated PKB, in turn, phosphorylates a number of substrates contributing to the overall survival response. Although we can not be sure that we understand all the factors responsible for mediating the PKB-dependent survival response, it is believed that some important actions are the phosphorylation and inactivation of the pro-apoptotic factor BAD and caspase 9, the phosphorylation of the for example, FKHR, resulting in its exclusion from the nucleus and activation of the NfkappaB pathway by phosphorylation of the kinases upstream of the cascade.

In addition to the anti-apoptotic and pro-survival actions of the PKB pathway, the enzyme also plays an important role in promoting cell proliferation. This action is likely to be mediated through a number of actions, some of which are thought to be phosphorylation and inactivation of the cyclin-dependent kinase inhibitor p2iClpl / WAF1 and phosphorylation and activation of mTOR, a kinase that controls various aspects of cell growth. PTEN phosphatase, which dephosphorylates and inactivates polyphosphatidyl inositols, is a key tumor suppressor protein, which normally acts to regulate the PI3K / PKB survival pathway. The significance of the PI3K / PKB pathway in tumorigenesis can be judged by the observation that pten is one of the most common mutation targets in human tumors, mutations in this phosphatase having been found in -50% or 6 ΡΕ1706385 plus melanomas (Guldberg et al, 1997, Cancer Research 57, 3660-3663) and in advanced prostate cancers (Cairns et al., 1997, Cancer Research 57, 4997). These observations and others suggest that a wide range of tumor types depend on increased PKB activity for their growth and survival and would have a therapeutic response to suitable PKB inhibitors. There are 3 closely related isoforms of PKB called alpha, beta and gamma, which genetic studies suggest to have distinct but overlapping functions. Evidence suggests that all of them may play a role in cancer, independently. For example, beta PKB 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), that PKB alpha is amplified in gastric, prostate and human breast cancer (Staal 1987, PNAS 84, 5034-5037, Sun et al. 2001, Am. J. Pathol 159, 431-437) and increased gamma PKB activity was observed 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 the function of cells and tissues. Thus, disorders associated with proliferation and undesirable survival of cells and normal tissues and tissues may also have a therapeutic benefit from treatment with a PKB inhibitor. Examples of such disorders are disorders of immune cells associated with prolonged expansion and survival of the cell population, resulting in a prolonged or up-regulated immune response. For example, response to T and B lymphocytes for cognate antigens or growth factors such as interleukin-2 activates the PI3K / PKB pathway and is responsible for maintaining the survival of antigen-specific lymphocyte clones during the immune response. In conditions where lymphocytes and other immune cells respond to inappropriate or foreign inappropriate antigens, or in which other abnormalities result in prolonged activation, the PKB pathway contributes to an important survival signal, avoiding the normal mechanisms by which the immune response is terminated by apoptosis of the activated cell population. There is a considerable degree of evidence demonstrating the expansion of lymphocyte populations responding to their own antigens in autoimmune diseases such as multiple sclerosis and arthritis. The expansion of lymphocyte populations that respond inadequately to foreign antigens is an aspect of another set of diseases, such as allergic responses and asthma. Briefly, inhibition of PKB could provide a beneficial 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 the role in cell growth and survival, the PKB pathway functions in the control of glucose metabolism by insulin. Available evidence from mice with deficiencies in PKB alpha and beta isoforms suggests that this action is mediated by the beta isoform. As a consequence, modulators of PKB activity may also be useful in diseases in which glucose metabolism dysfunction and energy storage, such as diabetes, metabolic disease and obesity. Cyclic AMP-dependent protein kinase (PKA) is a serine / threonine protein kinase, which phosphorylates a wide range of substrates and is involved in the regulation of many cellular processes, including cell growth, cell differentiation, ion channel conductivity, gene transcription and synaptic release of neurotransmitters. In its inactive form, the PKA holoenzyme is a tetramer, comprising two regulatory subunits and two catalytic subunits. PKA acts as a link between the signal transduction events mediated by the G-protein and the cellular processes they regulate. Binding of a hormone ligand, such as glucagon, to a transmembrane receptor activates a receptor-coupled G-protein (hydrolyzing and GTP-binding protein). On activation, the alpha subunit of G protein dissociates and binds and activates the 9 ΡΕ1706385 adenylate cyclase, which, in turn, converts ATP to cyclic AMP (cAMP). The cAMP thus produced binds to the regulatory subunits of PKA, resulting in the dissociation of the associated catalytic subunits. Catalytic subunits of PKA, which are inactive when associated with regulatory subunits, become active in dissociation and take part 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 the breakdown of glycogen to release glucose. PKA is also involved in regulating glucose levels by phosphorylating and deactivating glycogen synthase. Thus, modulators of PKA activity (whose modulators may increase or decrease PKA activity) may be useful in the treatment or control of diseases in which glucose metabolism dysfunction and energy storage, such as diabetes, metabolic disease and obesity. PKA has also been established as an acute inhibitor of T cell activation. Anndahl et al. investigated the possible role of PKA type I in HIV-induced T cell dysfunction based on the fact that T cells from HIV-infected patients increased cAMP levels and are more sensitive to inhibition by cAMP analogs than T cells normal. Through their studies, they concluded that increased activation of PKA type I can contribute to the progressive dysfunction of T cells in HIV infection and that PKA type I may therefore be a potential target for immunomodulatory therapy. Aandahl, E. M., Aukrust, P., Skalhegg, B. S., Muller, F., Froland, S. S., Hansson, V., Taskén, K. Protein kinase A type I antagonist restores immune responses of T cells from HIV-infected patients. FASEB j. 12,855-862 (1998).

It has also been recognized that mutations in the PKA regulatory subunit may result in hyperactivation of the endocrine tissue.

Because of the diversity and importance of PKA as a messenger in regulating cells, abnormal responses of cAMP may result in a variety of human diseases, such as irregular cell growth and proliferation (Stratakis, C.A., Cho Chung, Y.S., Protein Kinase A and human

diseases Tends Endrocri. Metab. 2002, 13, 50-52). Overexpression of PKA was observed in a variety of human cancer cells, including those from ovarian, breast and colon cancer patients. Inhibition of PKA would therefore be an approach to treatment of cancer (Li, Q., Zhu, G-D, Current Topicals in Medicinal Chemistry, 2002, 2, 399-971).

For a review of the role of PKA in human disease, see, for example, Protein Kinase A and Human Disease / Edited by Constantine A. Stratakis, Annals of the New York Academy of Sciences, Volume 968, 2002, ISBN 1-57331-412 -9. 11 ΡΕ1706385

Several classes of compounds have been described as having inhibitory activity for PKA and PKB.

For example, a class of isoquinolinyl sulfo-namido diamines with PKB inhibitory activity is disclosed in WO 01/91754 (Yissum). WOO / 07996 (Chiron) discloses substituted pyrazoles with estrogen receptor agonist activity. The compounds are described as being useful in the treatment or prevention, inter alia, of estrogen receptor-mediated breast cancer. The inhibitory activity of PKB is not described. WO 00/31063 (Searle) discloses substituted pyrazole compounds as inhibitors of p38 kinase. WO 01/32653 (Cephalon) discloses a class of pyrazolone kinase inhibitors. WO 03/059884 (X-Ceptor Therapeutics) discloses N-substituted pyridine compounds as modulators of nuclear receptors. WO 03/068230 (Pharmacia) discloses substituted pyridones as modulators of p38 MAP kinase. WO 00/66562 (Dr Reddy's Research Foundation) discloses a class of 1-phenyl-substituted pyrazoles for use as anti-inflammatory agents. The 1-phenyl group is 12 ΡΕ1706385 substituted with a sulfur-containing substituent as a sulfonamide or sulfonyl group.

SUMMARY OF THE INVENTION The invention provides compounds which have protein kinase B (PKB) and protein A (PKA) inhibitory or modulating activity and are considered useful in preventing or treating PKB or PKA-mediated disorders or diseases.

In a first aspect, the invention provides a compound of Formula (I): R2

R1-A-N

or a salt, solvate, tautomer or N-oxide thereof; wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R1 and NR2 R3 and a maximum chain length of 4 atoms, extending is among E and NR 2 R 3, wherein one of the carbon atoms of the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally contain one or more substituents selected from oxo, fluoro and hydroxy, provided that the hydroxy group, when present, is not located on an α-carbon to the group NR 2 R 3 and provided that the oxo group, when present, is located on a carbon atom α with respect to the NR 2 R 3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R1 is an aryl or heteroaryl group; R2 and R3 are independently selected from hydrogen, C1 -C4 hydrocarbyl and C1 -C4 acyl, wherein the hydrocarbyl and acyl components are optionally substituted by one or more substituents selected from fluoro, 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second ring member of heteroatom 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second ring member heteroatom selected from O and N; or NR 2 R 3 and the carbon atom of the linker group A to which it is attached form a cyano group; R4 is selected from hydrogen, halogen, C1-C5 saturated hydrocarbyl, C1-C5 saturated hydrocarbyloxy, cyano and CF3; and 14ΡE1706385 R5 is selected from hydrogen, halogen, saturated C1-C5 hydrocarbyl, saturated C1-C5 hydrocarbyloxy, cyano, CONH2, CONHR9, CF3, NH2, NHCOR9 or NHCONHR9; R 9a is a group R 9a or (CH 2) R 9a, wherein R 9a is a monocyclic or bicyclic group, which may be carbocyclic or heterocyclic; the carbocyclic group or heterocyclic group R9a being optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1 -C6 hydrocarbylamino; a group Ra-Rb wherein Ra is a bond, O, CO, X1 X2), C (X2) X1, X1 C (X2) X1, S, SO, SO2, NRC, SO2 NRc or NRcS02; and Rb is selected from hydrogen, heterocyclic groups having 3 to 12 ring members and a C 1 -C 8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono or di-C 1 -C 4 hydrocarbylamino, carbocyclic and heterocyclic ring having 3 to 12 ring members and wherein one or more carbon atoms of the C 1 -C 8 hydrocarbyl group may optionally be replaced by O, S, SO, SO 2, NRC, X1C (X2), C (X2) X1 or X9C (X2) X1;

R c is selected from hydrogen and C 1 -C 4 hydrocarbyl; and X 1 is O, S or NRC and X 1 is = O, = S or = NRC. The invention also provides a compound of formula (la): ???????? R 1 ?????

or a salt, solvate, tautomer or N-oxide thereof; wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R1 and NR2 R3 and a maximum chain length of 4 atoms, R2 is selected from the group consisting of E and NR2 R3, wherein one of the carbon atoms in the linker group may be optionally substituted by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally contain one or more substituents selected from oxo, fluoro and hydroxy, provided that the hydroxy group, when present, is not located on a carbon atom α with respect to the group NR 2 R 3 and that the oxo group, when present, is located on a carbon atom α with respect to the group NR 2 R 3; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R1 is an aryl or heteroaryl group; R2 and R3 are independently selected from hydrogen, C1 -C4 hydrocarbyl and C1 -C4 acyl; or R 2 and R 3, together with the nitrogen atom to which they are attached, form a saturated heterocyclic monocyclic group having a 4-7 membered ring and optionally containing a second heteroatom 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second ring member heteroatom selected from O and N; or NR 2 R 3 and the carbon atom of the linker group A to which they are attached together form a cyano group; R4 is selected from hydrogen, halogen, C1-C5 saturated hydrocarbyl, cyano and CF3; and R5 is selected from hydrogen, halogen, C1-C5 saturated hydrocarbyl, cyano, CO2 NH2, CONHR9, CF3, NH2, NHCOR9 or NHCONHR9; R9 is phenyl or benzyl, each optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono or α-hydrocarbylamino; a group Ra-Rb, wherein Ra is a bond, O, CO, X4 C (X2), C (X2) X4, X4 C (X2) x1, S, SO, SO2, NRC, SO2 NRc or NRcS02; and Rb is selected from hydrogen, heterocyclic groups having 3 to 12 ring members and a C 1 -C 8 hydrocarbyl group optionally substituted by one or more substituents selected from the hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono - or di-C1 -C4 hydrocarbylamino, carbocyclic and heterocyclic rings having 3 to 12 ring members and wherein one or more C1-6 hydrocarbyl carbon atoms may optionally be substituted by O, S, SO, SO2, NRC , X 4 C (X 2), C (X 2) X 4 or X 1 C (X 2) X 1; 17 ΡΕ1706385

R c is selected from hydrogen and C 1 -C 4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or NRC. Also provided are compounds of General Formula (Ib): H2

R 1 -A-N

or salts, solvates, tautomers or N-oxides thereof; wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R1 and NR2 R3 and a maximum chain length of 4 carbon atoms extending is among E and NR 2 R 3, wherein one of the carbon atoms of the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally contain one or more substituents selected from fluoro and hydroxy, provided that the hydroxy group is not located on a carbon atom α with respect to the group NR 2 R 3; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R1 is an aryl or heteroaryl group; 18 and 170 are independently selected from hydrogen, C1 -C4 hydrocarbyl and C1 -C4 acyl; or R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic monocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second ring member heteroatom selected from O and N; or NR 2 R 3 and the carbon atom of the linker group A to which it is attached together form a cyano group; R4 is selected from hydrogen, halogen, C1-C5 saturated hydrocarbyl, cyano and CF3; and R5 is selected from hydrogen, halogen, C1-C5 saturated hydrocarbyl, cyano, CONH2, CF3, NH2, NHCOR9 or NHCONHR9; R9 is phenyl or benzyl, each optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono or di-C1 -C4 hydrocarbylamino; a group Ra-Rb, wherein Ra is a bond, O, CO, X4C (X2), C (X2) X4, X1C (X2) X1, S, SO, SO2, NRC, SO2NRc or NRcS02; and Rb is selected from hydrogen, 3- to 12-membered ring heterocyclic groups and a C1-6 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, 19β, 170, 385, mono- or di-C1 -C4 hydrocarbylamino, carbocyclic and heterocyclic ring having 3 to 12 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 (t X 2), 0 (Χ 2) Χχ OR X 1 C (X 2) X 1;

R c is selected from hydrogen and C 4 -C 4 hydrocarbyl; and x1 is 0, S or nrc and x2 is = O, = S or = nrc. The invention further provides: A compound by itself of Formula (II), (III), (IV), (V) or any other subgroup or embodiment of Formula (I) as defined herein. A compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein for use in the prophylaxis or treatment of a disorder or disease, mediated by protein kinase B. The use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof, defined herein for the manufacture of a medicament for the prophylaxis or treatment of a protein kinase B mediated disorder or disease. A method for the prophylaxis or treatment of a protein kinase B mediated disorder or disease, which method comprises administering to a patient (I), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein. A method for treating a disorder or disease, comprising or being caused by abnormal cell growth or abnormally disrupted cell death in a mammal, the method comprising administering to the mammal a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof, as defined herein, in an amount effective to inhibit the activity of protein kinase B. A method of inhibiting protein kinase B, a method comprising contacting the kinase with a kinase inhibitor compound of Formula (I), (la), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein. A method for modulating a cellular process (e.g., cell division) by inhibiting the activity of a protein kinase B by using a compound of Formula (I), (Ia), (Ib), (II), (III) , (IV), (V) or any subgroup thereof, as defined herein. The compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup or embodiment thereof, as defined herein, for use in prophylaxis or treatment of a protein kinase A mediated disorder or disease. The use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup or an embodiment thereof, as defined herein, for the manufacture of a medicament for the prophylaxis or treatment of a protein kinase A mediated disorder or disease. A method for the prophylaxis or treatment of a protein-mediated disorder or disease (I), (Ib), (II), (III), (IV), (V), or any subgroup or embodiment of this compound as defined herein. A method for treating a disorder or disease, comprising or arising from abnormal cell growth or abnormally disrupted cell death in a mammal, the method comprising administering to the mammal a compound of Formula (I), (la), (Ib), ( II), (III), (IV), (V) or any subgroup or embodiment thereof as defined herein, in an amount effective to inhibit the activity of protein kinase A. A method of inhibiting protein kinase A comprising contacting the kinase with a kinase inhibitor compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup or embodiment thereof as herein defined. A method for modulating a cellular process (e.g., Cell division) by inhibiting the activity of a protein kinase A, using a compound of Formula (I), (la), (Ib), (II), (III ), (IV), (V) or any subgroup or embodiment thereof as defined herein. The use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein, for the manufacture of a medicament for the prophylaxis or treatment of a disorder or disease resulting from abnormal cell growth or abnormally disrupted cell death. A method for treating a disorder or disease comprising or resulting from abnormal growth of cells in a mammal, a method comprising administering to the mammal a compound of Formula (I), (Ib), (II), (III ), (IV), (V) or any subgroup thereof as defined herein in an amount effective to inhibit abnormal cell growth or abnormally disrupted cell death. A method of alleviating or reducing the incidence of a disease or disorder comprising or resulting from abnormal cell growth or abnormally disrupted cell death in a mammal, which method comprises administering to the mammal a compound of Formula (I), (la), ( (IV), or any subgroup thereof, as defined herein, in an amount effective to inhibit abnormal cell growth. A pharmaceutical composition comprising a novel compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein and a pharmaceutically acceptable carrier. A compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein for use in medicine. The use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein, for the manufacture of a medicament for the prophylaxis or treatment of any of the diseases or disorders described herein.

A method for the treatment or prophylaxis of any of the disorders or diseases disclosed herein, a method comprising administering to a patient (e.g., a patient in need thereof) a compound (e.g., a therapeutically effective amount) of Formula (I) , (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein. A method of alleviating or reducing the incidence of a disorder or disorder described herein, a method comprising administering to a patient (e.g., a patient in need thereof) a compound (e.g., a therapeutically effective amount) of Formula (I), ( 1a), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein. A method for the diagnosis and treatment of a protein kinase B mediated disorder or disorder, which method comprises (i) evaluating a patient to determine whether the disorder or disease of which the patient is suffering or likely to suffer would be susceptible to treatment with a compound with activity against protein kinase B; and (ii) when it is indicated that the disorder or disease of which the patient suffers is amenable to treatment, thereafter administer to the patient a compound of Formula (I), (Ia), (Ib), (II), (III) , (IV), (V) or any subgroup thereof as defined herein. The use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup thereof as defined herein, for the manufacture of a medicament for the treatment or prophylaxis of a disorder or disease in a patient who has been assessed and who has been determined to be suffering or at risk of suffering from a disease or disorder that would be amenable to treatment with a compound having activity against protein kinase B. A method for the diagnosis and treatment of a protein kinase A mediated disorder or disease, which method comprises (i) evaluating a patient to determine whether a disease or disorder of which the patient is suffering or likely to suffer would be susceptible to treatment with a compound having activity against protein kinase A; and (ii) when it is indicated that the disease or disorder of which the patient suffers is amenable to treatment, thereafter administer to the patient a compound of Formula (I), (Ia), (Ib), (II), (III) , (IV), (V) or any subgroup of this or embodiment as defined herein. The use of a compound of Formula (I), (Ia), (Ib), (II), (III), (IV), (V) or any subgroup of this or embodiment, as defined herein, for manufacture of a medicament for the treatment or prophylaxis of a disorder or disease in a patient who has been assessed and determined to be suffering or at risk of suffering from a disease or disorder that would be amenable to treatment with a compound having activity against protein kinase THE.

Preferences and General Settings

The following general preferences and definitions will be applied to each of the components A, E and R1 to R5 and R9 and any sub-definition, subgroup or embodiment thereof, unless otherwise indicated in the context. 25 ΡΕ1706385

Any references to Formula (I) will also be construed as referring to Formulas (I), (Ia), (Ib), (II), (III), (IV), (V) and any other subgroup of compounds within of Formula (I) unless otherwise indicated in the context.

References to " carbocyclic " and " heterocyclic ", as used herein, unless otherwise indicated in the context, include 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, generally 5 to 10 ring members. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7 and 8 ring members, generally 3 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 generally 9 or 10 ring members.

The carbocyclic or heterocyclic groups may be aryl or heteroaryl groups having 5 to 12 ring members, generally 5 to 10 ring members. The term " aryl " as used herein refers to a carbocyclic group having an aromatic character and the term " heteroaryl " is used herein to denote a heterocyclic group having an aromatic character. The terms " aryl " and " heteroaryl " encompass polycyclic ring systems, wherein one or more rings are non-aromatic provided that at least one ring is aromatic. In such polycyclic systems, the group may be attached by the aromatic ring or a non-aromatic ring. The aryl or heteroaryl groups may be monocyclic or bicyclic groups and may be unsubstituted or substituted by one or more substituents, for example one or more R 10 groups as defined herein. The term non-aromatic group encompasses unsaturated ring systems with no 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 (s) atoms sharing more than one valence bond, i.e., the ring contains at least one multiple bond, e.g. a C = C, C C CC or N = C. The " fully saturated " refers to rings in which there are no multiple bonds between the ring atoms. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example, cyclopentenyl, cycloheptenyl and cyclooctenenyl.

Examples of heteroaryl groups are monocyclic and bicyclic groups, containing five to twelve ring members and generally five to ten ring members. The heteroaryl group may be, for example, a five-membered or six-membered monocyclic ring or a bicyclic structure formed of fused five- and six-membered rings or two fused six-membered rings. 27 ΡΕ1706385

Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring contains up to 3 heteroatoms, generally up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one nitrogen atom in the ring. The nitrogen atoms of the heteroaryl rings may be basic, as in the case of an imidazole or pyridine or essentially non-basic, as in the case of an indole or pyrrole nitrogen. In general, the number of nitrogen atoms present in the heteroaryl group, including any amino substituents on the ring, 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 may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms in the ring; (c) a pyridine ring fused to a 5 or 6 ring containing 1, 2 or 3 heteroatoms in the ring; 28 ΡΕ1706385 d) one ring members, containing 1, 2 e) one ring members, containing 1, 2 if) one ring members, containing 1, 2 'g) one ring members, containing 1, 2 h) one ring members, containing 1, 2 ii) a ring members, containing CM I-1 j) one ring members, containing 1, 2 ik) one ring members, containing 1, 2 i 1) one ring members, containing 1, 2 m) one ring members , containing 1 or 3 ring members containing 1 or 1 ring or 6 members containing one ring, one pyrrole ring fused to a ring of 5 or 6 heteroatoms in the ring; a pyrazole ring fused to a ring of 5 or 6 heteroatoms in the ring; an imidazole ring fused to a ring of 5 or 6 heteroatoms in the ring; an oxazole ring fused to a ring of 5 or 6 heteroatoms in the ring; an isoxazole ring fused to a ring of 5 or 6 heteroatoms in the ring; a thiazole ring fused to a 5- or 6-membered ring 1, 2 or 3 heteroatoms; a isothiazole ring fused to a ring of 5 or 6 heteroatoms in the ring; a thiophene ring fused to a ring of 5 or 6 heteroatoms in the ring; a furan ring fused to a ring of 5 or 6 heteroatoms in the ring; an oxazole ring fused to a ring of 5 or 6 ring heteroatoms; an isoxazole ring fused to a 5 or 6 ring ring 1, or 2 heteroatoms in the ring; a cyclohexyl ring fused to a 5: ring ring having 1, 2 or 3 ring heteroatoms; a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

Examples of benzofuran, benzothiophene, benzofuran, benzothiophene, benzimidazole, benzooxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzene, benzisoxazole, benzisoxazole, benzisoxazole, benzisoxazole, benzisoxazole, zofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, benzodioxole and pyrazolopyridine.

Examples of bicyclic heteroaryl groups containing two fused six-membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chromane, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, iridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinolinal, dihydrobenzothieno, dihydrobenzofuran, 2,3-dibenzo [1,4] dioxine, benzo [1,3] dioxol, 4,5,6,7-tetrahydrobenzofuran, indoline and indane.

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, generally 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, and typically have 1 to 5 members 30 ΡΕ1706385 in the ring of heteroatoms (generally 1, 2,3 or 4 heteroatom ring members), generally selected from nitrogen, oxygen and sulfur.

The heterocyclic groups may contain, for example, cyclic ether fractions (for example, as in tetrahydrofuran and dioxane), cyclic thioether components (for example as in tetrahydrothiophene and dithiane), cyclic amine components (for example, as in pyrrolidine), cyclic sulphones (e.g., as in sufolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides and combinations thereof (for example, thiomorpholine). Other examples of non-aromatic heterocyclic groups include cyclic amide components (for example, as in pyrrolidone) and cyclic ester components (for example, as in butyrolactone).

Examples of non-aromatic monocyclic heterocyclic groups include 5.6 and 7-membered monocyclic heterocyclic groups. A specific example includes morpholine, thiomorpholine and its S-oxide and S-dioxide (particularly thiomorpholine), piperidine (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-pipieridinyl), N-alkyl piperidines, 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, tetrahydrofuran, tetrahydrofuran, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydrofuran (for example 4-tetrahydropyranyl), imidazole, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine and N-alkyl piperazines such as N-methyl piperazine, N-ethyl piperazine and N-isopropylpyrazine.

A subgroup of non-aromatic monocyclic heterocyclic groups includes morpholine, piperidine (e.g., 1-piperidinyl, 2-piperidinyl 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (e.g., 1-pyrrolidinyl, 3-pyrrolidinyl and 3 pyrrolidinyl), pyrroloidone, pyran (2H-pyran or 4H-pyran), dihydrobiofene, dihydropyran, dihydrofuran, dihydrothiozole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., 4-tetrahydropyranyl ), imidazoline, imidazolidinone, oxazoline, thiaxoline, 2-pyrazoline, prazolidine, piperazone, piperazine and N-alkyl piperazines such as N-methyl piperazine. In general, preferred non-aromatic heterocyclic groups include piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkyl piperazines. Another specific example of a non-aromatic heterocyclic group, which is also part of the above 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. 32 ΡΕ1706385

Each of the definitions of carbocyclic and heterocyclic groups in this report may optionally exclude any or any combination of two or more of the following components: - substituted or unsubstituted pyridone rings; - pyrrolo [1,2-a] irimid-4-ones; substituted or unsubstituted pyrazolones.

Where reference is made in this disclosure to carbocyclic and heterocyclic groups, the carbocyclic or heterocyclic ring may, unless otherwise indicated in the context, be unsubstituted or substituted by one or more R10 substituent groups selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carbocyclic, amino, mono or di-C1 -C4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; 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 NRcS02; and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having 3 to 12 ring members and a C 1 -C 8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1 -C4 hydrocarbylamino, carbocyclic and heteroaryl groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may be optionally substituted by O, S, SO, SO2 (X2) X1, X1, X1, X1, X1, X1, X1, X1, X1; 33 ΡΕ1706385

R c is selected from hydrogen and C 1 -C 4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or = NRC.

Where the substituent group R 10 comprises or includes a carbocyclic or heterocyclic group, said carbocyclic or heterocyclic group may be unsubstituted or may itself be substituted by one or more additional R 10 substituent groups. In a subgroup of compounds of Formula (I), such additional substituent groups R 10 may include carbocyclic or heterocyclic groups, which are not themselves more typically substituted. In another subgroup of compounds of Formula (I), said additional substituents do not include carbocyclic or heterocyclic groups, but are, on the other hand, selected from the groups listed above in the definition of R 10.

The substituents R 10 may be selected such that they contain no more than 10 non-hydrogen atoms, for example not more than 15 non-hydrogen atoms, for example not more than 12 or 10 or 9 or 8 or 7 or 6 or 5 non-hydrogen atoms.

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

Examples of halogen substituents include fluoro, chloro, bromo and iodo. Fluorine or chlorine are particularly preferred.

In the definition of the above compounds of Formula (I) and as used below, the term " hydrocarbyl " is a generic term encompassing aliphatic, alicyclic and aromatic groups, having a full carbon backbone, unless otherwise noted. In certain cases, as defined herein, one or more of the carbon atoms comprising the carbon backbone may be replaced by a specified 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 provided, may be substituted by one or more substituents as defined herein. The examples and preferences expressed below apply to each of the hydrocarbyl substituent groups ΡΕ1706385 or hydrocarbyl containing substituent groups, referred to in the various definitions of substituents for the compounds of Formula (I), unless otherwise stated in the context.

In general terms, by way of example, the hydrocarbyl groups may have up to eight carbon atoms unless otherwise stated in the context. Within the subset of the hydrocarbyl groups having 1 to 8 carbon atoms, specific examples are C 1-6 hydrocarbyl groups, such as C 1 -C 4 hydrocarbyl groups (for example, C 1 -C 3 hydrocarbyl groups or C 1 -C 2 hydrocarbyl groups), specific examples being any individual value or combination of selected values of C1, C2, C3, C4, C5, C6, C7 and Ce hydrocarbyl groups. The term " alkyl " covers both straight and branched chain 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 the like. their isomers. Within the subset of alkyl groups having 1 to 8 carbon atoms, specific examples are C 1 -C 6 alkyl groups, such as C 1 -C 4 alkyl groups (for example, C 1 -C 3 alkyl groups or C 1 -C 2 alkyl groups).

Examples of cycloalkyl groups are the cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane derivatives. Within the subset of the cycloalkyl groups, the cycloalkyl group will have from 3 to 8 carbon atoms, specific examples being C 3 -C 6 cycloalkyl groups. 36 ΡΕ1706385

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 subset of the alkenyl groups, the alkenyl group will have 2 to 8 carbon atoms, specific examples being C 2 -C 6 alkenyl groups, such as C 2 -C 4 alkenyl groups.

Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclopentadienyl and cyclohexenyl. Within the subset of the cycloalkenyl groups, the cycloalkenyl groups have from 3 to 8 carbon atoms and specific examples are C 3 -C 6 cycloalkenyl groups.

Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the subset of alkynyl groups having 2 to 8 carbon atoms, specific examples are C 2 -C 6 alkynyl groups, such as C 2 -C 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 whenever referred to, a hydrocarbyl group may be optionally substituted by one or more substituents selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C1 -C4 hydrocarbylamino and monocyclic or carbocyclic and heterocyclic bicyclics having from 3 to 12 (typically 3 to 10 and generally 5 to 10) ring members. Preferred substituents include halogen, such as fluorine. Thus, for example, the substituted hydrocarbyl group may be a partially fluorinated or perfluorinated group, such as difluoromethyl or trifluoromethyl. In a preferred embodiment, the substituents include carbocyclic and heterocyclic monocyclic groups having 3-7 ring members.

Whenever referred to, one or more carbon atoms of a hydrocarbyl group may optionally be substituted by O, S, SO, SO2, NRc, X2 C (X2), C (X2) X2 or X1 C (X2) X1 (or a subgroup thereof ), wherein X 1 and X 2 are as hereinbefore defined, provided 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 substituted by one of the listed atoms or groups and the substituent atoms or groups may be the same or different. In general, the number of linear or substituted backbone atoms will correspond to the number of linear or backbone atoms in the group replacing them. Examples of 38 ΡΕ1706385 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 esters and thioethers (C substituted by O or S), amides, esters, thioamides and thioesters (substituted CC (C 1 -substituted C 1 -C 2 -alkyl), C 1 -cycloalkyl (X 2 -C 1 -C 2 -alkyl), C 1 -cycloalkyl, .

When an amino group has two hydrocarbyl substituents, they may, together with the nitrogen atom to which they are attached and optionally with another heteroatom, such as nitrogen, sulfur or oxygen, to form a ring structure of 4 to 7 members in the ring. The definition " Ra-Rb " as used herein with respect to substituents present on a carbo-cyclic or heterocyclic component, or with respect to other substituents present elsewhere in the compounds of Formula (I), includes among other compounds wherein Ra is selected from a bond, O, CO, OC (O), SC (O), NRcC (O), OC (S), SC (S), NRcC (S), OC (NRC), SC (NRc), C (S) 0, C (S) S, C (S) NRC, C (NRc) 0, C (NRc) S, C (O) NRc) NRc, 0C (0) 0, SC (0) 0, NRcC (0) 0, 0C (S) 0, SC (S) 0, NRcC (S) 0, NRcC (NRC) 0, 0 C (O) S, SC (O) S, NRcC (O) S, SC (NRc) S, NRcC (NRc) S, OC (O) NRC, NRCC (O) NRC, 0C (S) NRc, SC (S) NRc, NRcC (S) NRc, OC NRC) NRC, NRcC (NRCNRC), S, SO, SO2, NRC, SO2 NRc and NRcS02, wherein Rc is as defined hereinbefore. The component 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 C 1-6 hydrocarbyl group C8 alkyl, optionally substituted as defined herein. Examples of hydrocarbyl, carbocyclic and heterocyclic groups are given above.

When Ra is O and Rb is a C1-8 hydrocarbyl group, Ra and Rb together form a hydrocarbylloxy group. Preferred hydrocarbyloxy groups include saturated hydrocarboyloxy, such as alkoxy (e.g., C 1-6 alkoxy, more usually C 1-4 alkoxy, such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (e.g. C 3 -C 6 cycloalkoxy such as cyclopropyloxy, cyclobutyl and cyclohexyloxy) and cycloalkylalkoxy (for example, C3 -C6 cycloalkyl-C1 -C2 alkoxy, such as cyclopropylmethoxy).

The hydrocarbyloxy groups may be substituted by several substituents as defined herein. For example, the alkoxy groups may be substituted by halogen (for example as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g. as in hydroxyethoxy), C1 -C2 alkoxy (e.g. as in methoxyethoxy), hydroxy-C1 -C2 alkyl group (as in hydroxyethoxyethoxy) or a cyclic group (for example, a cycloalkyl group or non-aromatic heterocyclic group as defined herein). Examples of the alkoxy groups containing 40 ΡΕ1706385 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, C1 -C4 -alkyl-pierzines, C 1 -C 4 cycloalkyl piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C 1 -C 4 alkoxy group, more typically a C 1 -C 3 alkoxy group, such as methoxy, ethoxy or n-propoxy.

The alkoxy groups may be substituted, for example, by a monocyclic group, such as pyrrolidine, piperidine, morpholino and piperazine and their N-substituted derivatives, such as N-benzyl, N-C 1 -C 4 acyl and N-C 1 -C 4 alkoxycarbonyl. Specific examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.

When Ra is a bond and Rb is a C1-6 hydrocarbyl group, examples of hydrocarbyl groups Ra-Rb have already been defined herein. The hydrocarbyl groups Ra-Rb are as hereinbefore defined. The hydrocarbyl groups may be saturated groups, such as cycloalkyl and alkyl, and specific examples of such groups include methyl, ethyl and cyclopropyl. The hydrocarbyl (e.g., alkyl) groups may be substituted by various groups and atoms as defined herein. Exemplary alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (specific examples including bromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethyl and perfluoroalkyl groups such as trifluoromethyl), or hydroxy (for example, hydroxymethyl and hydroxy-ethyl), C1 -C8 acyloxy (e.g., acetoxymethyl and benzyloxymethyl), amino and mono and dialkylamino (e.g. aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and tert-butylaminomethyl ), alkoxy (e.g., C 1 -C 2 alkoxy such as methoxy or methoxyethyl) and cyclic groups such as cycloalkyl groups, aryl groups, heteroaryl groups and non-aromatic heterocyclic groups as defined hereinbefore).

Specific examples of alkyl groups substituted by a cyclic group are those in which the cyclic group is a saturated cyclic amine, such as morpholine, piperidine, pyrrolidine, piperazine, C1 -C4 -alkylpyrazinines, C3 -C7 -cycloalkylpiperazines , tetrahydropyran or tetrahydrofuran and the alkyl group is a C 1 -C 4 alkyl group, more typically a C 1 -C 3 alkyl group, such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted by a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazino-methyl and the N-substituted forms thereof, as defined herein.

Specific examples of alkyl groups substituted by aryl groups and heteroaryl groups include benzyl, phenethyl and pyridylmethyl groups.

When Ra is SO2 NRC, Rb may be, for example, hydrogen or an optionally substituted C1-8 hydrocarbyl group, or a carbocyclic or heterocyclic group. 42 ΡΕ1706385

Examples of Ra-Rb, wherein Ra is SO2 NRC, include aminosulfonyl, C1 -C4 -alkylaminosulfonyl and di-C1 -C4 -alkylaminosulfonyl groups, and sulfonamides formed of a cyclic amino group such as piperidine, morpholine, pyrrolidine or a piperazine optionally N- such as N-methyl piperazine.

Examples of Ra-Rb groups, wherein Ra is SO2, include alkylsulfonyl, heteroarylsulfonyl and arylsulfonyl groups, particularly monocyclic aryl and heteroaryl sulfonyl groups. Specific examples include methylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When Ra is NRC, Rb may be, for example, hydrogen or an optionally substituted C1-6 hydrocarbyl group or a carbocyclic or heterocyclic group. Examples of Ra-Rb, wherein Ra is NRC, include C1 -C4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C1 -C4 alkylamino (e.g., dimethylamino and diethylamino) and cycloalkylamino (e.g., cyclopropylamino, cyclopentylamino and cyclohexylamino).

Specific Embodiments and Preferences for A, E, R1 to R5 and R9 The " A "

In formula (I) A is a saturated carbonic hydrous ΡΕ1706385 linker group, containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum length of chain of 4 atoms extending between E and NR 2 R 3. Within these constraints, each of the components E and R1 may be attached to any location in group A. The term " maximum chain length " as used herein refers to the number of atoms lying directly between the two components and does not consider any branching of the chain or any hydrogen atoms which may be present. For example, in structure A below: CH 3 CH 3 CH 2

And R (A) the chain length between R1 and NR2R3 is 3 atoms, while the chain length between E and NR2R3 is 2 atoms.

In general, it is presently preferred that the linker group has a maximum chain length of 3 atoms (e.g., 1 or 2 atoms).

In one embodiment, the linker group has a chain length of 1 atom, extending between R1 and NR2R3. 44 ΡΕ1706385

In another embodiment, the linker group has a chain length of 2 atoms, extending between R1 and NR2r3.

In another embodiment, the linker group has a chain length of 3 atoms, extending between R1 and nr2r3.

It is preferred that the linker group has a maximum chain length of 3 atoms, extending between E and NR 2 R 3.

In a specifically preferred group of compounds, the linker group 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.

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

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

In one embodiment, the carbon atom to which the R1 group is attached is replaced by an oxygen atom. 45 ΡΕ1706385

In another embodiment, R 1 and E are attached to the same carbon atom of the linker group and a carbon atom extending between E and NR 2 R 3 is replaced by an oxygen atom.

When a nitrogen or oxygen atom is present, it is preferred that the nitrogen or oxygen atom and the nr2r3 group are spaced apart from each other by at least two intervening carbon atoms.

In a specific group of compounds within Formula (I), the linker atom, attached directly to the group E, is a carbon atom and the linker group A has a major carbon backbone.

The carbon atoms of the linker group A may optionally contain one or more substituents selected from oxo, fluoro and hydroxy provided that the hydroxy group is not located on a carbon atom α with respect to the group NR 2 R 3 and also provided that the oxo group is located on an α-carbon atom with respect to the NR 2 R 3 group. Typically, the hydroxy group, when present, is located in a β position with respect to the NR 2 R 3 group. In general, there will be no more than one hydroxyl group present. Where fluorine is present, it may be present as a single fluoro substituent or in a difluoromethylene or trifluoromethyl group, for example. In one embodiment, a fluorine atom is located in a β position with respect to the NR 2 R 3 group. 46 ΡΕ1706385

It should be noted that when an oxo group is present on the carbon atom adjacent to the NR 2 R 3 group, the compound of Formula (I) will be an amide.

In one embodiment of the invention, there are no fluorine atoms present in the linker group A.

In another embodiment of the invention, hydroxy groups are not present in linker group A.

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

In a group of compounds of Formula (I), no hydroxy or fluorine groups are present in the linker group A, for example, linker group A is unsubstituted.

Preferably, when a carbon atom in the linker group A is replaced by a nitrogen atom, the group A contains not more than one hydroxy substituent and, preferably, does not contain hydroxy substituents.

When there is a chain length of four atoms between E and NR 2 R 3, it is preferred that the linker group A does not contain nitrogen atoms and preferably has a complete carbon backbone. In order to modify the susceptibility of the compounds to metabolic degradation in vivo, the linker group A may have a branched configuration at the carbon atom attached to the NR 2 R 3 group. For example, the carbon atom attached to the NR 2 R 3 group may be attached to a pair of gem-dimethyl groups.

In a specific group of compounds of Formula (I), the R1-A-NR2 R3 part of the compound is represented by Formula R1- (G) n - (CH2) m W-Ob- (CH2) n - (CR6 R7) P -NR2 R3, wherein G is NH, NMe or O; W is attached to the group E and e is selected from (CH 2) j-CR, (CH 2) j -N and (NH) j -CH; b is 0 or 1, j is 0 or 1, k is 0 or 1, m is Ooul, 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; R6 and R7 are the same or different and are selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group; and R 20 is selected from hydrogen, methyl, hydroxy and fluoro;

In another sub-group of the compounds of Formula (I), the R1-A-NR2 R3 part of the compound is represented by Formula R1- (G) k- (CH2) mX- (CH2) n - (CR6 R7 ') p -NR2 R3, wherein G is NH, NMe or O; X is attached to the group E and is selected from (CH 2) j -CH, (CH 2) j -N and (NH) j -CH; j is 0 or 1, k is 0 or 1, m is 0 or 1, n is 0, 1, 2 or 3, or the sum of j, k, m, n and p does not exceed 4; and R6 and R7 are the same or different and are selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group.

A specific group CR6R7 is C (CH3) 2. 48 ΡΕ1706385

Preferably X is (CH2) j -CH.

Specific embodiments, wherein the R 1 -? -NR 2 R 3 part of the compound is represented by the formula R 1 - (G) k - (CH 2) m X - (CH 2) n - (CR 6 R 7 -) p -NR 2 R 3, are those in which: k is 0, m is 0, n is 0, 1, 2 or 3 ep 0. • k is O, m is O, m is O, 1 or 2 and p is 1 • X is (CH 2) j -CH, k is 1, m is 0, n is 0, 1, 2 or 3 and p is 0. ) j is CH, k is 1, m is 0, n is 0, 1 or 2 and ep is 1. • X is (CH2) j -CH, G is O, k is 1, m is 0, n is 0, 1, 2 or 3 ep0.

Specific embodiments, wherein the R 1 -A-NR 2 R 3 part of the compound is represented by the Formula R 1 (G) k- (CH 2) m X- (CH 2) n - (CR 6 R 7 ') P -NR 2 R 3, are those in which: k is 0, m is 0, w is (CH2) j-CR20, j is 0, R20 is hydrogen, b is 1, n is 2 and p is 0. j is 0, R20 is hydroxy, b is 0, n is 1 and p is 0, m is 0, m is 0, w is (CH2) j-CR20, j is 0, R20 is methyl, b is 0, n is 1 and p is 0. • k is 0, m is 0, w is (CH2) j-CR20, j is 0, R20 is fluoro, b is O, nelepeO. 49 ΡΕ1706385

In a preferred embodiment, the R1-A-NR2 R3 part of the compound is represented by the formula Rx-X- (CH2) n -NR2 R3, wherein X is attached to the group E and is a CH group and n is 2.

Specific examples of the linker group A, together with the R1, E and NR2R3 groups attachment points, are shown in Table 1 below.

50 ΡΕ1706385

Preferred groups presently include Al, A 2, A 3, A 6, AIO, All, A 22 and A 23.

A specific set of groups includes Al, A2, A3, A10 and All.

An additional specific set of groups includes A2 and All.

Another specific set of groups includes A6, A22 and A23. 51 ΡΕ1706385

An additional set of groups includes Al, A2 and A3.

In group A2, the asterisk designates a chiral center. Compounds having the R configuration at this chiral center represent a preferred subgroup of compounds of the invention. R1 is aryl or heteroaryl group and may be selected from the list of such groups given in the section entitled General Preferences and Definitions. R1 may be monocyclic or bicyclic and, in a preferred embodiment, it is monocyclic. Specific examples of monocyclic aryl and heteroaryl groups are aryl and heteroaryl six-membered groups containing up to 2 members on the nitrogen ring and five five-membered heteroaryl groups containing up to 3 members on the hetero atom selected from O, S and N .

Examples of such groups include phenyl, naphthyl, thienyl, furan, pyrimidine and pyridine, with phenyl being presently preferred. The R1 group may be unsubstituted or substituted by up to 5 substituents and examples of substituents are those listed in the group R10 above. 52 ΡΕ1706385

Specific substituents include hydroxy; C1-C4 acyloxy; fluorine, chlorine; bromo; trifluoromethyl; cyano; CONH2; nitro; C 1 -C 4 hydrocarbyloxy and C 1 -C 4 hydrocarbyl, each optionally substituted by C 1 -C 2 alkoxy, carboxy or hydroxy; C1-C4 acylamino; benzoylamino; pyrrolidino-carbonyl; piperidinocarbonyl; morpholinocarbonyl; pipera-zinocarbonyl; five- and six-membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S; phenyl; phenyl-C1 -C4 alkyl; phenyl-C1 -C4 alkoxy; heteroaryl-C1 -C4 alkyl; heteroaryl-C 4 -C 4 alkoxy and phenoxy, wherein the heteroaryl, heteroaryloxy, phenyl, phenyl-C 1 -C 4 alkyl, phenyl-C 1 -C 4 alkoxy, heteroaryl C 1 -C 4 alkyl, heteroaryl C 1 -C 4 alkoxy and phenoxy groups are each one optionally substituted with 1, 2 or 3 substituents selected from C 1 -C 2 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, CONH 2, C 1 -C 2 hydrocarbyloxy and C 1 -C 2 hydrocarbyl, each optionally substituted by methoxy or hydroxy.

Preferred substituents include hydroxy; C1-C4 acyloxy; fluorine; chloro; bromo; trifluoromethyl; cyano; C1 -C4 hydrocarbyloxy and C1 -C4 hydrocarbyl, each optionally substituted by C1 -C2 alkoxy or hydroxy; C1-C4 acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; five- and six-membered heteroaryl groups containing one or two heteroatoms selected from N, O and S, heteroaryl groups being optionally substituted by one or more C4-55 alkyl substituents; phenyl; pyridyl; and phenoxy, wherein the phenyl, pyridyl and phenoxy groups are each optionally substituted by 1, 2 or 3 substituents selected from C 1 -C 2 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, C 1 -C 2 hydrocarbyloxy and C 1 -C 2 hydrocarbyl, each optionally substituted by methoxy or hydroxy.

In a subgroup of compounds, the substituents for R1 are chosen from hydroxy; C1-C4 acyloxy; fluorine; chloro; bromo; trifluoromethyl; cyano; C 1 -C 4 hydrocarbyloxy and C 1 -C 4 hydrocarbyl, each optionally substituted by C 1 -C 2 alkoxy or hydroxy.

While up to 5 substituents may be present, more typically 0, 1, 2,3 or 4 substituents, preferably 0, 1, 2 or 3, more preferably 0.1 or 2.

In one embodiment, the group R 1 is unsubstituted or substituted by up to 5 substituents selected from hydroxy; C1-C4 acyloxy; fluorine; chloro; bromo; trifluoromethyl; cyano; C 1 -C 4 hydrocarbyloxy and C 1 -C 4 hydrocarbyl, each optionally substituted by C 1 -C 2 alkoxy or hydroxy.

In another embodiment, the group R1 may have one or two substituents selected from hydroxy, fluoro, chloro, cyano, phenyloxy, pyrazinyloxy, benzyloxy, methyl and methoxy. 54 ΡΕ1706385

In another embodiment, the R1 group may have one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy.

When R1 is a phenyl group, specific examples of substituent combinations include mono-chlorophenyl and dichlorophenyl.

Other examples of substituent combinations include those wherein R1 is hydroxyphenyl, fluorchlorophenyl, cyanophenyl, methoxyphenyl, methoxy-chlorophenyl, fluorophenyl, difluorophenyl, phenoxyphenyl, pyrazinyloxy-phenyl or benzyloxyphenyl.

When R1 is a six membered aryl or heteroaryl group, a substituent may advantageously be present at the para-position of the six-membered ring. Where a substituent is present in the para position, it preferably has a dimension greater than a fluorine atom. R2 and R3

In a group of compounds of Formula (I), R 2 and R 3 are independently selected from hydrogen, C 1 -C 4 hydrocarbyl and C 1 -C 4 acyl, wherein the hydrocarbyl and acyl components are optionally substituted by one or more substituents selected from fluoro, hydroxy, amino, methylamino, dimethylamino and methoxy. 55 ΡΕ1706385

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

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

Typically the hydrocarbyl group, whether substituted or unsubstituted, is an alkyl group, generally a C 1, C 2 or C 3 alkyl group and, preferably, a methyl group. In a specific subgroup of compounds, R 2 and R 3 are independently selected from hydrogen and methyl and, consequently, NR 2 R 3 may be an amino, methylamino or dimethylamino group. In a specific embodiment, NR 2 R 3 may be an amino group. In another specific embodiment, NR 2 R 3 may be a methylamino group.

In an alternative embodiment, the C1-C4 hydrocarbyl group may be a cyclopropyl, cyclopropylmethyl or cyclobutyl group.

In another group of compounds, R 2 and R 3 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 member in the heteroatom ring, selected from O and N.

In another group of compounds, 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 ring member selected from O and N. The saturated monocyclic heterocyclic group may be unsubstituted or substituted by one or more substituents R10 as defined above in the Preferences and General Definitions section of this application. Typically, however, any substituents on the heterocyclic group will be relatively small substituents such as C1 -C4 hydrocarbyl (e.g., methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, sec-butyl and tert-butyl ), fluoro, chloro, hydroxy, amino, methylamino, ethylamino and dimethylamino. Specific substituents are methyl groups. The saturated monocyclic ring may be an azacycloalkyl group, such as an azetidine, pyrrolidine, piperidine or azepan 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 on the ring, it may form part of an NH group or an N-C 1 -C 4 alkyl group, such as an N-methyl, N-ethyl, N-propyl or N-isopropyl group.

Where NR 2 R 3 forms an imidazole group, the imidazole group may be unsubstituted or substituted, for example, by one or more relatively small substituents such as C 1 -C 4 hydrocarbyl (e.g. methyl, ethyl, propyl, cyclopropyl and butyl) , fluoro, chloro, hydroxy, amino, methylamino, ethylamino and dimethylamino. Specific substituents are methyl groups.

In another group of compounds, 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 a second heteroatom ring member selected from 0 and N.

Examples of such compounds include compounds wherein NR 2 R 3 and A form a unit of Formula:

in which tu are each 0, 1, 2 or 3, provided that the sum of t and u is within the range of 2 to 4.

Further examples of such compounds include compounds wherein NR2 R3 and A form a cyclic group of Formula: ΡΕ1706385 58

R

Wherein n and v are each 0, 1, 2 or 3, provided that the sum of v and e is within the range of 2 to 5. Specific examples of cyclic compounds are those in which vew are both 2.

Further examples of such compounds include compounds wherein NR 2 R 3 and A form a cyclic group of Formula:

And wherein x and w are each 0, 1, 2 or 3, provided that the sum of x and w is within the range of 2 to 4. Specific examples of cyclic compounds are those wherein x is 2 and w is 1. 4 R '

In formula (I), R 4 is selected from hydrogen halogen, saturated C 1 -C 5 hydrocarbyl, saturated C 1 -C 5 hydrocarbyloxy, cyano and CF 3. 59 ΡΕ1706385

More typically, R 4 is selected from hydrogen, halogen, C 1 -C 5 saturated hydrocarbyl, cyano and CF 3. Preferred values for R4 include hydrogen and methyl. In a specific embodiment, R 4 is hydrogen. R9

In formula (I), R 5 is selected from hydrogen, halogen, saturated hydrocarbyl, C 1 -C 5 saturated hydrocarbyloxy, cyano, COOH, CONHR 9 and NHCONHR 9; NHCONHR 9 wherein R 9a is a group R 9a or (CH 2) R 9a, wherein R 9a is an optionally substituted monocyclic or bicyclic group, which may be carbocyclic or heterocyclic.

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

Typically, the carbocyclic and heterocyclic groups are monocyclic.

Preferably, the carbocyclic and heterocyclic groups are aromatic.

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

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

Most preferably, R 5 is selected from hydrogen, halogen, saturated C 1 -C 5 hydrocarbyl, cyano, CF 3, NH 2, NHCOR 9 and NHCONHR 9, wherein R 9 is optionally substituted phenyl or benzyl. The group R 9 is typically phenyl or optionally substituted benzyl, or phenyl or benzyl substituted by 1, 2 or 3 substituents selected from halogen; hydroxy; trifluromethyl; cyano; carboxy; C1 -C4 alkoxycarbonyl; C1-C4 acyloxy; amino; mono or di-C1 -C4 alkylamino; C1-C4 alkyl optionally substituted by halogen, hydroxy or C2-C2 alkoxy; C1 -C4 alkoxy optionally substituted by halogen, hydroxy or C1 -C2 alkoxy; phenyl, five- and six-membered heteroaryl groups containing up to 3 heteroatoms selected from O, N and S; and carbo-cyclic and saturated heterocyclic groups containing up to 2 heteroatoms selected from O, S and N.

Specific examples of the R5 component include hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, cyano, CF3, NH2, NHCOR9b and NHCONHR9b, wherein R9b is phenyl or benzyl optionally substituted by hydroxy, C1-C4 acyloxy (e.g., alkoxy) and fluorine, chlorine, bromine, trifluoromethyl, cyano, C1 -C4 hydrocarbyloxy (for example, alkoxy) and optionally substituted by C1 -C2 alkoxy or hydroxy.

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

Group " E "

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

Preferred E groups 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, more specifically a phenyl, pyridine ring , pyrazine or pyrimidine and, more preferably, a pyridine or phenyl ring.

Examples of bicyclic groups include benzo-fused and pyrido-fused groups, wherein the A group and the pyrazole ring are both attached to the benzo or pyrido component.

In one embodiment, E is a monocyclic group. 62 ΡΕ1706385

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

A subset of monocyclic aryl and heteroaryl groups comprises phenyl, thiophene, furan, pyridine and pyridine.

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

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

The E groups may be unsubstituted or may have up to 4 R8 substituents which may be selected from the group R10 as hereinbefore defined. More typically, however, the substituents R8 are selected from hydroxy; oxo (when E is not aromatic); halogen (e.g., 63 ΡΕ1706385 chlorine and bromine); trifluoromethyl; cyano; C1-C4 hydrocarbyloxy optionally substituted by C1-C2 alkoxy or hydroxy; and C 1 -C 4 hydrocarbyl, optionally substituted by C 1 -C 2 alkoxy or hydroxy.

Preferably, there are 0-3 substituents, more preferably 0-2 substituents, for example 0 or 1 substituent. In one embodiment, the E group is unsubstituted. E may be other than: a substituted pyridone group; a substituted thiazole group; a substituted or unsubstituted pyrazole or pyrazolone group; a substituted or unsubstituted bicyclic fused pyrazole group; a phenyl ring fused to a thiophene ring or a six-membered nitrogen-containing heteroaryl ring fused to a thiophene ring; a substituted or unsubstituted piperazine group; The group E may be an aryl or heteroaryl group having five or six members and containing up to three heteroatoms selected from O, Ne S, the group E being represented by the formula: ## EQU1 ##

where * indicates the point of attachment to the pyrazole group and " a " indicates the bonding of group A; r is 0, 1 or 2; U is selected from N and CR12a; and V is selected from N and CR12b; wherein R 12a and R 12b 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 nonhydrogen atoms present in R 12a and R 12b, together, do not exceed ten; or R 12a and R 12b together with the carbon atoms to which they are attached form an unsubstituted five to six membered saturated or unsaturated ring containing up to two heteroatoms selected from O and N; and R 10 is as hereinbefore defined.

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

II

where * indicates the point of attachment to the pyrazole group and " a " indicates the bonding of group A; P, Q and T are the same or different and are selected from N, CH and NCR10, provided that the group A is attached to a carbon atom; and U, V and R10 are as previously defined.

Examples of R 12a and R 12b include hydrogen and substituent groups R 10 as previously defined, having not more than ten non-hydrogen atoms. Specific examples of R 12a and R 12b include methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, chloro, methoxy, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, difluoroethoxy, trifluoromethoxy, 2,2,2-trifluoromethyl, cyano , amino, methylamino, dimethylamino, CONH 2, CO 2 Et, CO 2 H, acetamido, azetidinyl, pyrrolidino, piperidino, piperazino, morpholino, methylsulfonyl, aminosulphonyl, mesylamino and trifluoroacetamido.

Preferably, when U is CR 12a and / or V is CR 12b, the atoms or groups of R 12a and R 12b, which are directly attached to the ring members of carbon atom C, are selected from Η, O (for example as in methoxy) , NH (for example as in amino and methylamino) and CH2 (for example, as in methyl and ethyl).

Specific examples of the linker group E, together with their attachment points to the A (a) group and the pyrazole ring (*), are shown in Table 2 below. ΡΕ1706385 66

Table 2

In the table, the substituent group R 13 is selected from methyl, chloro, fluoro and trifluoromethyl.

The following optional exclusions may apply to the definition of E in any of formulas (I), (Ia), (Ib), (II), (III), (IV) and (V) and any of its subgroups or sub-definitions, as defined herein: • E may not be a phenyl group having a 67 ΡΕ1706385 sulfur atom attached to the para position with respect to the pyrazole group. • And may not be a substituted or unsubstituted benzimidazole, benzoxazole or benzothiazole group.

A subgroup of compounds of Formula (I) has the general Formula (II): A-N,

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 with respect to Formula (I) and its subgroups, examples and preferences; and R8 is a substituent group as defined herein. 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 the para position of the benzene ring.

Within formula (II), a specific subgroup of compounds of the invention is represented by Formula (III): ## STR1 ##

(I.e.

i RJ

ÍÍI

RtYVR

N-N: ni)

H wherein A 'is the residue of group A and R 1 through R 5 are as defined herein.

In formula (III), a preferred group of compounds is represented by formula (IV):

R / SI3 R3

(Iv) wherein z is 0, 1 or 2, R 20 is selected from hydrogen, methyl, hydroxy and fluoro and R 1 to R 5 are as defined herein, provided that when z is 0, R 20 is not hydroxy.

Another group of compounds within Formula (III) is represented by Formula (V): 69 ΡΕ1706385

(V) wherein R 1 and R 3 to R 5 are as defined herein.

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

In each of formulas (II) to (V), R1 is preferably a phenyl group optionally substituted as defined herein.

In another subgroup of compounds of the invention, A is a saturated hydrocarbon linker group, containing from 1 to 7 carbon atoms, the linker group having 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 of the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally contain one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group, when present, is not located on a carbon atom α with respect to the group NR 1 R 2 ; and R5 is selected from hydrogen, C1 -C5 saturated hydrocarbyl, cyano, CO2 NH2, CF3, NH2, NHCOR9 and NHCONHR9.

For the avoidance of doubt, it should be understood that each general and specific preference, embodiment and example of the R 1 groups may be combined with each general and specific preference, embodiment and example of the R 1 and / or R 2 and / or R 3 groups and / or R5 and / or R9 and that all such combinations are covered by this application.

The various functional groups and substituents composing the compounds of Formula (I) are usually chosen such that the molecular weight of the compound of Formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, per 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.

Specific compounds of the invention are as illustrated in the examples below and are selected from: 1-phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine; 2-phenyl-2- [3- (1H-pyrazol-4-yl) -phenyl] -3-propionitrile; 71 ΡΕ1706385 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-chlorophenyl) -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; 72 ΡΕ1706385 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- {- [1- (4-Chloro-phenyl) -2-pyrrolidin-1-yl-ethyl] -phenyl} -1H-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); 73 ΡΕ1706385 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} -1H-pyrazole; - {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] -ethylamine; 2- (4-chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} -ethylamine; 74 ΡΕ1706385 4- {4- [1- (4-Chloro-phenyl) -3-pyrrolidin-1-yl-propyl] -phenyl} -1H-pyrazole; 4- {4- [3-azetidin-1-yl-1- (4-chloro-phenyl) -propyl] -phenyl} -1H-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-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] diazepane; {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} -1H-pyrazole;

4- [4- (3-imidazol-1-yl-1-phenoxy-propyl) -phenyl] -1H-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; 75 ΡΕ1706385 {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-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; phenyl) -ethylamino] -ethanol; (2- (4-Chloro-phenyl) -2- (4- (1H-pyrazol-4-yl) -phenyl) -2- (4- (1H-pyrazol- ) -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 4- (4-chloro-phenyl) -4- [4- (3-methyl-1H-pyrazol-4-yl) -phenyl] -piperidine; 4-chloro-phenyl) -2- (4- (1H-pyrazol-4-yl) -phenyl] -morpholine; (4- {4- [4- (1H-pyrazol-1-yl) -phenyl] - piperazine-4-yl} -phenoxy) -acetic acid methyl ester (4- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -phenoxy) -acetic acid methyl ester; 4- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzonitrile; {2- (4-chloro-phenyl) -2- [4- (1H-pyrazole -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-py razol-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; 77 ΡΕ1706385 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; and C- (4-chloro-phenyl) -C- [4- (1H-pyrazol-4-yl) -phenyl] -methylamine; and their salts, solvates, tautomers and N-oxides. 78 ΡΕ1706385

In one embodiment, the compound of 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; and 2- (4-chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine.

Another subset of compounds of Formula (I) is 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. 79 ΡΕ1706385

Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters, Prodrugs and Isotopes

In this section, as in all other sections of this application, unless otherwise indicated in the context, references to Formula (I) include references to formulas (Ia), (Ib), (II), (III), (IV) and (V) and all other subgroups, preferences and examples thereof, as defined herein.

Unless otherwise specified, a reference to a specific compound also includes ionic forms of salt, solvate and protected forms thereof, for example, as set forth below.

Many compounds of Formula (I) may exist in the form of salts, for example acid addition salts or, in certain cases, organic and inorganic bases, such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention and references to compounds of Formula (I) include the salt forms of the compounds. As in the preceding sections of this application, all references to Formula (I) are to be understood as referring also to Formula (II) and its subgroups, unless otherwise indicated in the context.

The salt forms may be selected and prepared according to methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl 80 (ed.), 1701 (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026 -8, Hardcover, 388 pages, August 2002. For example, acid addition salts may be prepared by dissolving the free base in an organic solvent, wherein a given salt form is insoluble or weakly insoluble, the required salt is then filled into an appropriate solvent so that the salt precipitates out of the solution.

The acid addition salts may be formed with a wide variety of 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 (e.g., L-ascorbic), L-aspartic, benze-sulfonic, benzoic , 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+) - (1S) -camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane- (e.g., L-glutamic), α-oxoglutaric, glycolic, hippuric, glycogenic (e.g., D-glucuronic), glutamic acid, (±) -L-lactic acid and (±) -DL-lactic acid), lactobionic, maleic, malic, (-) - L-malic, malonic, DL-mandelic, methanesulfonic, naphthalenesulfonic (e.g., naphthalene-2-sulfonic), naphthalene-1,5-disulfonic, 1- hydroxy-2-naphthoic, nicotinic, nitric, oleic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino salicylic, sebacic, stearic, succinic, (e.g., p-toluenesulfonic), undecylenic and valeric, as well as acylated amino acids and cation exchange resins.

A specific group of acid addition salts includes salts formed with hydrochloric, hydrochloric, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, valeric, acetic, , propanoic, butanoic, malonic, glucuronic and lactobionic.

Another group of acid addition salts includes salts formed from acetic, adipic, ascorbic, aspartic, citric, DL-lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, meta-sulfonic, sebacic, stearic , succinic and tartaric acids.

The compounds of the invention may exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed. In stronger acids, the basic pyrazole nitrogen as well as the nitrogen atom of the NR 2 R 3 group may form part of salt formation. For example, where the acid has a pKa of less than about 3 (e.g., 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. 82 ΡΕ1706385

If the compound is anionic or has a functional group which may be anionic (for example, -COOH may be -COCT), then a salt may 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 cations such as Ca 2+ and Mg 2+ and other cations such as Al 3+. Examples of suitable organic cations include but are not limited to ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., nh3r +, nh2R2 +, 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 such as lysine and arginine. An example of a common quaternary ammonium ion is N (CH 3) 4+.

When the compounds of Formula (I) contain an amine function, they may form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known in the art. Such quaternary ammonium compounds are within the scope of Formula (I).

Compounds of Formula (I) containing an amine function, may also form N-oxides. Reference herein to a compound of Formula (I) which contains an amine function also includes the N-oxide. 83 ΡΕ1706385

When a compound contains several amine functions, one or more of a nitrogen atom may be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

The N-oxides may be formed by treatment of the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (for example, a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th . Editing, Wiley Interscience, pages. More particularly, the N-oxides can be prepared by the procedure of L. w. Deady (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent, such as dichloromethane.

The compounds of Formula (I) may exist in numerous different geometric isomeric and tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound may exist in a variety of geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are however encompassed by Formula (I).

For example, in the compounds of Formula (I), the pyrazole group may take one or other of the following two tautomeric forms A and B.

For the sake of simplicity, General Formula (I) illustrates Form A, but the formula is to be taken to encompass both Form A and Form B.

When the compounds of Formula (I) contain one or more chiral centers and may exist as two or more optical isomers, references to compounds of Formula (I) include all their optical isomeric forms (e.g., enantiomers and diastereoisomers), as individual optical isomers or mixtures of two or more optical isomers, unless otherwise indicated in the context.

For example, group A may include one or more chiral centers. Thus, when E and R1 are both attached to the same carbon atom of the linker group A, said carbon atom is typically chiral and, accordingly, the compound of Formula (I) will exist as a pair of ΡΕ1706385 enantiomers (or more than a pair of enantiomers, wherein more than one chiral center is present in the compound).

Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers) or can be characterized in terms of their absolute stereochemistry, using the nomenclature " R and S " developed by Cahn, Ingold and Prelog, see Acvanced Organic Chemistry by Jerry March, 4a. Ed., John Wiley and Sons, New York, 1992, pp. 109-114, see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated by numerous techniques, including chiral chromatography (chromatography on a chiral support) and such techniques are well known to one skilled in the art.

As an alternative to chiral chromatography, optical isomers can be separated by the formation of diastereoisomeric salts with chiral acids, such as (+) - tartaric acid, (-) - pyroglutamic acid, (-) - ditoluoyl-L-tartaric acid , (+) - mandelic acid, (-) - malic acid and (-) - camphorsulfonic acid, the diastereoisomers being separated by preferential crystallization and then dissociating the salts to provide the individual enantiomer of the free base. When the compounds of Formula (I) exist as two or more optical isomeric forms, one enantiomer of one pair of enantiomers may exhibit advantages over the other enantiomer, for example in terms of biological activity. Thus, in certain circumstances, it may be desirable to use only the therapeutic agent of a pair of enantiomers, or only one of a plurality of diastereomers. Therefore, the invention provides compositions containing 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) are present as a single optical isomer (e.g., enantiomer or diastereoisomer). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of Formula (I) may be present as a single optical isomer (e.g., enantiomer or diastereoisomer). Esters, such as carboxylic acid esters and acyloxy esters of the compounds of Formula (I) containing a carboxylic acid group or a hydroxyl group are also encompassed by Formula (I). In one embodiment of the invention, Formula (I) includes within its scope esters of compounds of Formula (I) containing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, Formula (I) does not include esters of compounds of Formula (I) containing an 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 C 1 -C 7 alkyl group, a C 3 -C 20 heterocyclic group or a C 5 -C 20 aryl group, preferably a ΡΕ1706385

C1 -C7 alkyl. Specific examples of ester groups include, but are not limited to, -C (= O) OCH 3, -C (= O) OCH 2 CH 3, -C (= O) -OC (CH 3) 3 and -C (= O) O Ph. Examples of acyloxy (inverse ester) groups are represented by -O C (= O) R, where R is an acyloxy substituent, for example a C 1 -C 7 alkyl group, a C 3 -C 20 heterocyclyl group or a C 5 -C 20 aryl group , preferably a C1-C7 alkyl group. Specific examples of acyloxy groups include, but are not limited to, -OC (= O) CH 3 (acetoxy), -O C (= O) CH 2 CH 3, -OC (= O) C (CH 3) 3, -O and -OC (= O) CH2 Ph.

Also encompassed by Formula (I) are any polymorphic forms the compounds, solvates (e.g., hydrates), complexes (e.g., inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of compounds and prodrugs of compounds. " Pro-drugs " means, 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 (for example, a physiologically acceptable, metabolically unstable ester). During metabolism, the ester group (-C (= O) O) 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) of the parent compound, with, where appropriate, prior protection of any other reactive groups present in the precursor compound , followed by deprotection, if necessary.

Examples of such metabolically unstable esters include those of Formula -C (= O) OR, where R is:

C1-7 alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C1 -C8 aminoalkyl (e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C1 -C7 alkyl (e.g., acyloxymethyl, acyloxyethyl, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1- (1-methoxy-1-methyl) ethylcarbonyloxyethyl, 1- (benzoyloxy) ethyl isopropoxycarbonyloxymethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, 4-tetrahydropyranyloxy) carbonyloxyethyl- (4-tetrahydropyranyl) carbonyloxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl).

Some prodrugs are enzymatically activated to produce the active compound or a compound which, in further chemical reaction, produces the active compound (for example, as in antigen-targeting enzyme prodrug (ADEPT) therapy, (GDEPT) and ligand-targeted enzyme prodrug therapy (LIDEPT). For example, the prodrug may be a sugar derivative or other glucoside conjugate, or may be an ester derivative of amino acid. METHODS FOR PREPARATION OF FORMULA COMPOUNDS (I)

In this section, as in all other sections of this application, unless otherwise indicated in the context, references to Formula (I) include references to formulas (a), (Ib), (II), (III), (IV) and (V) and all other subgroups, their preferences and examples as defined herein.

The compounds of Formula (I) may be prepared by reacting a compound of Formula (X) with a compound of Formula (XI) or an N-protected derivative thereof:

in which A, E and R1 to R5 are as hereinbefore defined, one of the groups X and Y is chloro, bromo or iodo or a trifluoromethanesulphonate (triflate) group and the other of the groups X and Y is a boronate residue, a boronate ester or a boronic acid residue. The reaction may be carried out under conditions

Suzuki coupling, in the presence of a palladium catalyst, such as bis (tri-t-butylphosphino) palladium and a base 90 æE1706385 (for example, carbonate, such as potassium carbonate). The reaction may be carried out in an aqueous solvent system, for example aqueous ethanol, and the reaction mixture is typically subjected to heating, for example at a temperature exceeding 100 ° C.

An exemplary synthetic route involving a Suzuki coupling step is shown in Scheme 1. The starting material for the synthetic route of scheme 1 is the halo-substituted aryl or heteroarylmethyl nitrite (XII), wherein X is a chlorine atom , bromine or iodine or a triflate group. The nitrile (XII) is condensed with the aldehyde R1 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 performed at room temperature. The resulting substituted acrylonitrile derivative (XIII) is then treated with a reducing agent which will selectively reduce the double alkene linkage, without reducing the nitrile group. A borohydride, such as sodium borohydride, may be used for this purpose, to provide the substituted acetonitrile derivative (XIV). The reduction reaction is typically carried out in a solvent, such as ethanol, and usually with heating, for example, at a temperature up to about 65 ° C. Reduced nitrile (XIV) is then coupled to the pyrazole boronate ester (XV) under the coupling conditions ΡΕ170638591

Suzuki described above, for Formula (I), wherein A-NR 2 R 3 is substituted. R1 is a group consisting of acetonitrile (XII)

X (XIII)

NaBH 4 EtOH

Me Me

(XVI) (XVII)

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 gives amino compounds of Formula (I), wherein the aryl or heteroaryl group E is attached to the β-position of the A group relative to the amino group. In order to provide amino compounds of Formula (I), wherein R1 is attached to the β position relative to the amino group, the functional groups of the two starting materials of the condensation step can be reversed, so that a compound of Formula XE- CHO, wherein X is bromo, chloro, iodo or a triflate group, is condensed with a compound of Formula R1 -CH2-CN to provide a substituted acrylonitrile derivative which is then reduced to the corresponding acetonitrile derivative prior to the coupling with the pyrazole boronate (XV) and reduction of the cyano group to an amino group.

The compounds of Formula (I), wherein R1 is attached to the α position relative to the amino group, may be prepared by the sequence of reactions shown in Scheme 2.

In Scheme 2, the starting material is a halo-substituted aryl- or heteroarylmethyl Grignard (XVIII, X = bromo or chloro) reagent, which reacts with the nitrile R1-CN in a dry ester, such as diethyl ether, to provide an intermediate imine (not shown) which is reduced to provide the amine (XIX) using a reducing agent such as lithium aluminum hydride. The amine (XIX) may be reacted with the boronate ester (XV) under the Suzuki coupling conditions described above, to afford the amine (XX). 93 ΡΕ1706385

(i) R 1 -CN X-E-CH 2 -MgBr Et 2 O, R 1 (XVIII) (ii) LiAIH * X ΝΗξ (XIX)

Scheme 2

The compounds of Formula (I) may also be prepared from the substituted nitrile compound (XXI):

94 ΡΕ1706385 wherein PG is a protecting group, such as a tetrahydropyranyl group. The nitrile (XXI) may be condensed with an aldehyde of Formula R 1 - (CH 2) r -CHO, where r is 0 or 1 and the resulting substituted acrylonitrile is subsequently reduced to the corresponding substituted nitrile under conditions analogous to those set out in Scheme 1 above . The PG protection group can then be removed by a suitable method. The nitrile compound may subsequently be reduced to the corresponding amine by the use of a suitable reducing agent, as described above. The nitrile compound (XXI) may also be reacted with a Grignard reagent of Formula R 1 - (CH 2) m - MgBr under Grignard reaction conditions, followed by deprotection to provide an amino compound of the invention, having the structure shown in Formula (XXII).

In the above-mentioned preparative procedures, coupling of the aryl or heteroaryl E group to the pyrazole is carried out by reacting a halo-pyrazole or halo-aryl or heteroaryl compound with a boronate or boronic acid ester in the presence of a catalyst and palladium base. Many boronates suitable for use in preparing the compounds of the present invention are commercially available, for example, from Boron Molecular Limited of Noble Park, Australia, or Combi-Blocks Inc. of San Diego, USA. Where boronates are not commercially available, they may be prepared by methods known in the art, for example as described in the recapitulation article of N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2557. Thus, the boronates may be prepared by reacting the corresponding bromo compound with an alkyl lithium, such as butyl lithium and then reacting with a borate ester. The resulting boronate ester derivative may, if desired, be hydrolyzed to provide the corresponding boronic acid.

The compounds of Formula (I), wherein the group A contains a nitrogen atom attached to the group E, may be prepared by well-known synthetic procedures of the compounds of Formula (XXIII) or a protected form thereof. Compounds of Formula (XXIII) may be obtained by a Suzuki coupling reaction of a compound of Formula (XV) (see Scheme 1) with a compound of Formula Br-E-NH 2, such as 4-bromoaniline. NH I '

AND

N-N (XXIII)

H

The compounds of Formula (I), wherein R1 and E are 96 ΡΕ1706385 attached to the same carbon atom, can be prepared as shown in Scheme 3. Base, CO2 O (XXIV)

(I) hydrolysis (ii) decarboxylation (XXVII)

(XXVI) amide coupling reaction with a reduction of amide XHNNR3 R3 (XXVIII) (XXIX)

Me Me Mev.

Suzuki Coupling

(D) (XV) H Pd (D) (XV)

CH 3 NR 3 R 3

E R1

(XXX) (XXXI)

Scheme 3 97 ΡΕ1706385

In Scheme 3, an aldehyde compound (XXIV), wherein X is bromo, chloro, iodo or a triflate group, is condensed with ethyl cyanoacetate in the presence of a base, preferably a non-hydroxy, such as piperidine, by heating under Dean Stark conditions. The cyanoacrylate intermediate (XXV) is then reacted with a Grignard reagent R1 MgBr, suitable for introducing the R1 group by Michael addition to the carbon-carbon double bond of the acrylate component. The Grignard reaction can be carried out in a non-protic polar solvent, such as tetrahydrofuran, at a low temperature, for example, at about 0 ° C. The product of the Grignard reaction is the cyano propionic acid ester (XXVI) and this is subjected to hydrolysis and decarboxylation to provide the propionic acid derivative (XXVII). The steps of hydrolysis and decarboxylation may be carried out by heating an acid medium, for example a mixture of sulfuric acid and acetic acid. The propionic acid derivative (XXVII) is converted to the amide (xxv -1) by reaction with an amine hr2r3 under conditions suitable to form an amide bond. The coupling reaction between the propionic acid derivative (XXVII) and the amine HNR 2 R 3 is preferably carried out in the presence of a reagent of the type normally used in the formation of peptide bonds. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) 98 ΡΕ1706385 (Sheehan et al., J. Amer. Chem. Soc. 1955,77, 1067), 1-ethyl-3- (3'-dimethylaminopropyl) (referenced herein as EDC or EDAC) (Seehan et al, J. Org. Chem., 1961, 26, 2525), coupling agents based on uronium, such as O- (7-azabenzotriazol-1-yl) - (HATU) and phosphonium-based coupling agents, such as 1-benzo-triazolyloxytris (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) (LA Carpino, J. Amer. Chem. Soc., 1993, 115, 399) or 1-hydroxybenzotriazole (HOBt) ( Konig et al, Chem. Ber., 103, 708, 2024-2034). Preferred coupling reagents include EDC (EDAC) and DCC, in combination with HOAt or HOBt. The coupling reaction is typically carried out in a non-aqueous, non-protic solvent, such as acetonitrile, dioxane, dimethylsufoxide, dichloromethane, dimethylformamide or N-methylpyrroline, or in an aqueous solvent, optionally together with one or more miscible cosolvents . The reaction may be carried out at room temperature or, where the reactants are less reactive (for example in the case of electron-deficient anilines containing electron withdrawing groups, such as sulfonamide groups) 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. 99 ΡΕ1706385

Where the amine HNR2R3 is ammonia, the amide coupling reaction may be carried out using 1,1'-carbonyldiimidazole (CDI) to activate the carboxylic acid prior to addition of the ammonia.

Alternatively, a reactive derivative of the carboxylic acid, for example an anhydride or acid chloride, may be used. Reaction with a reactive derivative, such as an anhydride, is typically carried out by stirring the amine and anhydride at ambient temperature in the presence of a base, such as pyridine. The amide (XXVIII) can be converted into a compound of Formula (XXX) (corresponding to a compound of Formula (I), wherein A has an oxo substituent near the NR2 R3 group) by reaction with a boronate (XV) under conditions of Suzuki coupling, as described above. The amide (XXX) may subsequently be reduced using a hydride reducing agent such as lithium aluminum hydride in the presence of aluminum chloride to provide an amine of Formula (XXXI) (corresponding to a compound of Formula (I ), wherein A is CH-CH 2 -CH 2 -). The reduction reaction is typically carried out in an ether solvent, for example diethyl ether, with heating at the reflux temperature of the solvent.

Instead of reacting the amide (XXVIII) with the boronate (XV), the amide may instead be reduced with lithium aluminum hydride / aluminum chloride, for example, in a 100æl ether-solvent at room temperature, to provide the amine (XXIX), which is then reacted as boronate (XV) under the Suzuki coupling conditions described above, to provide the amine (XXX). In order to obtain the amine homologue (XXIX) containing at least one methylene group, the carboxylic acid (XXVII) can be converted to azide by standard methods and subjected to a Curtius rearrangement, in the presence of an alcohol such as benzyl alcohol, to to provide a carbamate (see Advanced Organic Chemistry, 4th edition, by Jerry March, John Wiley and Sons, 1992, pages 1091-1092). The benzylcarbamate may function as a protecting group for the amine during the subsequent Suzuki coupling step and the benzyloxycarbonyl component of the carbamate group may then be removed by standard methods after the coupling step. Alternatively, the benzylcarbamate group may be treated with a hydride reducing agent, such as lithium aluminum hydride, to provide a compound wherein NR2 R3 is a methylamino group, instead of an amino group.

The intermediate compounds of Formula (X), wherein the component X is a chlorine, bromine or iodine atom and A is a CH-CH 2 - group, can be prepared by the reductive amination of an aldehyde compound of Formula (XXXII):

AND

I

With an amine of Formula HNR 2 R 3 under standard reductive amination conditions, for example in the presence of sodium cyanoborohydride in an alcohol solvent such as methanol or ethanol. The aldehyde compound (XXXII) may be obtained by oxidation of the corresponding alcohol (xxxill) using, for example, Dess-Martin periodinane (see Dess, D.B., Martin, J.C. J. Org. Soc. 1983, 48, 4155 and Organic

Syntheses, Vol. 77, 141).

R1 = CH2 CH2 OH

AND

I

V (XXXIII)

Compounds of Formula (I), wherein A, N and R 2 together form a cyclic group, may be formed by the Suzuki coupling of a boronate compound of Formula (XV) with a cyclic intermediate of Formula (XXXIV) or a its N-protected derivative.

AND

I (XXXIV)

The cyclic intermediates of Formula (XXXIV), wherein R1 is an aryl group, such as an optionally substituted phenyl group, may be formed by Friedel Crafts alkylation of an aryl compound with a compound of Formula (XXXV) :

R 3

HO

X (XXXV) Alkylation is typically carried out in the presence of a Lewis acid, such as aluminum chloride at a reduced temperature, for example, less than 5 ° C. The Friedel-Crafts reaction has been found to be generally applicable in the preparation of a range of intermediates of Formula (X). Thus, in a general method of producing compounds of Formula (X), a compound of Formula (LXX)

R2HOx xNx A IE IX

R (LXX) is reacted with a compound of Formula R2-H under Friedel Crafts alkylation conditions, for example in the presence of an aluminum, halide (e.g., AlCl3).

In another method, for the preparation of a compound of Formula (I), wherein the NR 2 R 3 component is attached to a CH 2 group of component A, an aldehyde of Formula (XXXVI) may be coupled with an amine of Formula HNR 2 R 3 in 103 ΡΕ1706385 conditions reductive amination, as described above. In formulas (XXXVI) and (XXXVII), A 'is the residue of group A - that is, the components A' and CH2 together form the group A. The aldehyde (XXXVII) may be formed by oxidation of the corresponding alcohol using for example, Dess-Martin periodinane.

R1 = OHA2 (XXXVI)

(XXXVII)

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

Scheme 4

Br-E ^ J (XXXVIII)

The starting material for the synthetic route shown in Scheme 4 is epoxide (XXXVIII), which may be either commercially available or produced by methods well known in the art, for example by reaction of the aldehyde Br- E-CHO with trimethylsulphonium iodide. The epoxide (XXXVIII) is reacted with an amine HNR 2 R 3 under conditions suitable for a ring-opening reaction with the epoxide, to provide a compound of Formula (xxxix). The ring-opening reaction may be carried out in a polar solvent, such as ethanol, at ambient temperature or, optionally, with gentle heating and typically with a large excess of the amine. The amine (XXXIX) then reacts with an aryl compound RXH, typically a phenyl compound, capable of being part of a Friedel Crafts alkylation (see, e.g., Advanced Organic Chemistry, by Jerry March, pages 534-542). Thus, the amine of Formula (XXXIX) is usually reacted with the aryl compound R1 +, in the presence of an aluminum chloride catalyst at or about room temperature. Where the compound aryl R 3 H is a liquid, for example, as in the case of a methoxybenzene (e.g., anisole) or a halobenzene, such as chlorobenzene, the aryl compound may serve as solvent. On the other hand, a less reactive solvent, such as nitrobenzene, may be used. Friedel Crafts alkylation of the compound RXH with the amine (XXXIX) provides a compound of Formula (XL), which corresponds to a compound of Formula (X), wherein x is bromine and A is CHCH2. The hydroxy intermediate (XXXIX) of Scheme 4 may also be used to prepare the compounds of Formula (X), wherein the carbon atom of the hydrocarbylated linker group A, adjacent to the group R1, is substituted by a oxygen. Thus, the compound of Formula (XXXIX) or an N-protected derivative thereof (where R2 or R3 are hydrogen) may be reacted with a phenol compound of Formula R1OH under Mitsunobu alkylation conditions, for example in the presence of azocarboxylate and triphenylphosphine . The reaction is typically carried out in a polar non-protic solvent, such as tetrahydrofuran, at a moderate temperature, such as room temperature.

Another use of the intermediate-hydroxy (XXXIX) is for the preparation of the corresponding fluoro compound. Thus, the hydroxy group may be replaced by fluorine by reaction with pyridine complex: hydrogen fluoride (Olah reagent). The fluorinated intermediate may then be subjected to a Suzuki coupling reaction to provide a compound of Formula (I) with a fluorinated hydrocarbon group A. A fluorinated compound of Formula (I) could alternatively be prepared by coupling first the hydroxy intermediate (XXXIX), or a protected form thereof, with a pyrazole boronic acid or boronate under Suzuki conditions and then substituting the hydroxyl group of the resulting compound of Formula (I) with fluorine using pyridine complex: hydrogen.

The compounds of Formula (I), wherein the component: ΡΕ1706385

R 1 is a group

R

R 1 CH-O-A " -N I \ 3

E R where A " is the hydrocarbon residue of group A, can be prepared by the sequence of reactions shown in

Scheme 5. p1 R1MgBr2

X-E-CHO-X-E-CH-OH (XXIV) (XLI)

Scheme 5 107 ΡΕ1706385

As shown in Scheme 5, the aldehyde (XXIV) reacts with a Grignard reaction R 2 MgBr under standard Grignard conditions, to provide the secondary alcohol (XLI). The secondary alcohol may then react with a compound of Formula (XLII), wherein R 2 'and R 3' represent the groups R 2 and R 3 or an amine-protecting group, A " is the residue of group A and X 'represents a hydroxy group or a leaving group. The amine protecting group may be, for example, a phthaloyl group, in which case NR 2 ', R 3' is a phthalimido group.

When X 'is a hydroxy group, the reaction between compound (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 then reacts with the compound (XLII) . The resulting compound of Formula (XLIII) is then subjected to a Suzuki coupling reaction with the pyrazole boronate reagent (XV), under typical Suzuki coupling conditions of the type described above, to provide a compound of Formula (XLIV). The protecting group may then be removed from the protected amine group NR 2, R 3 <, to provide a compound of Formula (I).

The compounds of Formula (I), wherein the component: ΡΕ1706385 108

R 1 is a group

R

R 1 -O-CH-A " -N 1 N 3 E R 3 wherein A " is the group A hydrocarbon residue, can be prepared by the sequence of reactions shown in Scheme 6. The A " -C1 NaBH4

E I X (XLV)

E ^ (XLVI)

DEAD

Ph3P

R 1,

R1 -O. , A " -N

HNR 2 R 3 R 1 -O. JV'-CI R " (XLVIII)

X

E I X (XLVII)

The starting material of Scheme 6 is the chloroacyl compound (XLV), which may be prepared by literature methods (for example, the method described in J. Med. Chem. 2004, 47, 3924-3926) or analogous methods. The 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 phenol compound of Formula F-OH under Mitsunobu alkylation conditions, for example in the presence of diethyl azodicarboxylate and triphenylphosphine, as described above, to afford the aryl ether compound (XLVII). The chlorine atom of the aryl ether compound (XLVII) is then displaced by reaction with an amine HNR2 R3, to provide a compound of Formula (XLVIII). The nucleophilic displacement reaction can be carried out by heating the amine with the aryl ether in a polar solvent, such as an alcohol, at an elevated temperature, for example approximately 100 ° C. Heating can advantageously be achieved 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 provide compound (XLIX).

In a variation of the reaction sequence shown in Scheme 6, the secondary alcohol (XLVI) can be subjected to a nucleophilic displacement reaction with an amine 110 ΡΕ1706385 HNR2R3, before introducing the R1 group by the Mitsunobu ether formation reaction.

Another route for the compounds of Formula (I), wherein E and R1 are attached to the same carbon atom of group A, is illustrated in Scheme 7.

R H0_. (I.e.

R

Me R5

CN I E

N-N

PG

Me N N-N (LV)

Scheme 7 111 ΡΕ1706385

In scheme 7, an N-protected pyrazolyl boronic acid (L) reacts under Suzuki coupling conditions with the cyano compound X-E-CN, wherein X is typically a halogen such as bromine or chlorine. The protecting group PG at the 1-position of the pyrazole ring may be, for example, a triphenylmethyl (trityl) group. Boronic acid (L) may be prepared by employing the method described in EP 1382603 or methods analogous thereto. The resulting nitrile (L1) can then react with a Grignard reaction R4 MgBr, to introduce the R1 group and form the ketone (LII). The ketone (LII) is converted to the enamine (LIV) by reaction with the diphenylphosphinoylmethylamine (LIII) in the presence of a strong base, such as an alkyl lithium, particularly butyllithium. The enamine (LIV) is then subjected to hydrogenation over a palladium or charcoal catalyst, to reduce the double bond of the enamine and remove the 1-phenethyl group. When the protecting group PG is a trityl group, the 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 a chiral separation. Removal of the protecting group 2-phenethyl and protecting group PG then provides an optically active form of the compound of Formula (LV). 112 ΡΕ1706385

Intermediates of Formula (X), wherein A and R2 bond to form a ring containing an oxygen atom, may be prepared by the general method shown in Scheme

Scheme 8

In Scheme 8, a ketone (LVI) is reacted with trimethylsulphonium iodide to form the epoxide (LVII). The reaction is typically performed in the presence of a hydride base, such as sodium hydride in a polar solvent, such as dimethylsulfoxide. 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 (e.g. isopropanol), usually with gentle warming (for example to about 50 DEG C. The resulting secondary alcohol is then cyclized to form the morpholine ring by treatment with concentrated sulfuric acid in a solvent such as dichloromethane and ethanolic The morpholine intermediate (LIX) can then react with the boronate ( XV) under Suzuki coupling conditions to provide the compound of Formula (LX), which corresponds to a compound of Formula (I), wherein A-NR 2 R 3 forms a morpholine group.

Instead of reacting the epoxide (LVII) with ethanolamine, it may instead react with mono- or dialkylamines, thereby providing a pathway for the compounds containing the component:

Compounds wherein R2 and R3 are both hydrogen may be prepared by reacting the epoxide (LVII) with potassium phthalimide in a polar solvent, such as DMSO. 114 ΡΕ1706385

During the Suzuki coupling step, the phthalimide group may undergo partial hydrolysis to provide the corresponding phthalamic acid, which may be cleaved using hydrazine, to provide the amino group NH2. Alternatively, the phthalamic acid may be recycled to the phthalimide employing a standard amide forming reagent, and the phthaloyl group then removed using hydrazine to provide the amine.

Another synthetic route for the compounds of Formula (I), wherein A and NR 2 R 3 combine to form a cyclic group, is illustrated in Scheme 9.

Scheme 9

In Scheme 9, the starting material (LXI) is typically a di-aryl- / heteroaryl methane, wherein one or both of the aryl / heteroaryl groups is capable of establishing 115 ΡΕ1706385 or facilitating the formation of an anion formed in the methylene group between E and R1. For example, R1 may advantageously be a pyridine group. The starting material (LXI) is reacted with the N-protected bis-2-chloroethylamine (LXII) in the presence of a strong non-interfering base such as sodium hexamethyl disilazide in a polar solvent such as tetrahydrofuran at a reduced temperature ( for example, around 0 ° C) to afford the N-protected cyclic intermediate (LXIII). The protecting group may be any standard amine protecting group, such as a Boc group. After cyclization, the intermediate (LXIII) is coupled to a boronate of Formula (X) under coupling conditions Suzuki is then deprotected to provide the compound of Formula (I)

The compounds of Formula (I), wherein the component: R2

R 1 -A

And R is a group:

Alk

R1-C-CH-N I 2 Vs where " Alk " is a small alkyl group, such as methyl or ethyl and may be formed by the synthetic route shown in Scheme 10. ΡΕ1706385 116

MeOH / H + R1n + XO2M0 X (LXV)

LDAAfc-I

T R1

Alk, co2h! Alk C02Me

E X (L-XVII) HNR2 R3 and X (LXVI)

LiAIH, R1

Alk ^ Rd N u E R "

X (LXVIII) (LXIX)

Scheme 10

In Scheme 10, a carboxylic acid of Formula (LXIV) is esterified by treatment with methanol in the presence of an acid 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 (e.g., between 0 ° C and -78 ° C). The branched ester (LXVI) is then hydrolyzed to (LXVII) acid and coupled with 117 ÅE 1707038 an amine HNR 2 R 3 under standard amide forming conditions, of the type described above. The amide (LXVIII) can then be reduced in the amine (LXIX) using lithium aluminum hydride and the amine (LXIX) then reacted with a pyrazole boronate or boronic acid under Suzuki coupling conditions to provide a compound of Formula I).

Once formed, many compounds of Formula (I) may be converted into other compounds of Formula (I) by employing standard functional group interconversions. For example, the compounds of Formula (I), wherein the NR 2 R 3 forms are part of a nitrile group, may be reduced to the corresponding amine. Compounds wherein NR 2 R 3 is a NH 2 group may be converted to the corresponding alkylamine by reduced alkylation or to a cyclic group. Compounds wherein R1 contains a halogen atom, such as chlorine or bromine, may be used to introduce an aryl or heteroaryl substituent within the R1 group through a Suzuki coupling reaction. Further examples of interconversions of a compound of Formula (I) in another compound of Formula (I) can be found in the examples below. Additional examples of functional group interconversions and reagents and conditions for carrying out such conversions may be found, for example, in Advanced Organic Chemistry, by Jerry March, 4a. 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). 118 ΡΕ1706385

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

A hydroxy group may be protected, for example, as an ether (-OR) or an ester (-OC (= O) R), for example as a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC (= O) CH 3, -OAc). An aldehyde or ketone group may be protected, for example, as an acetal (R-CH (OR) 2) or ketal (R2C (OR) 2), respectively, wherein the carbonyl group (> C = O) is converted in a diether (> C (OR) 2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid. An amine group may be protected, for example, as an amide (-NR0-R) or a urethane (-NRC0-R), for example as: a methyl amide (-nhco-CH3); a benzyloxy amide (-NHCO-OCH2, -NH-Cbz); as a t-butoxy amide (-NHCO-OC (CH 3) 3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC (CH 3) 2 C 6 H 4 C 6 H 5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroverathoyloxy amide (-NH- , as a 2-trimethylsilyleloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-119 ΡΕ1706385

Alloc), or as a 2- (phenylsulfonyl) ethyl oxy amide (-NH-Psec). Other protecting groups for amines, such as cyclic amines and N-H heterocyclic groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups and benzyl groups, such as a para-methoxybenzyl (pmb) group. A carboxylic acid group may be protected as an ester, for example, as: a C1 -C7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1 -C7 haloalkyl ester (e.g., a C1 -C7 alkyl ester (e.g. methyl ester, a t-butyl ester), a C7 -C7 haloalkyl ester (e.g., a C1 -C7 trihaloalkyl ester), a triC1- C 1 -C 7 alkyl ester, or a C 5 -C 20 aryl-C 1 -C 7 alkyl ester (e.g., a benzyl ester, a nitrobenzyl ester), or as an amide, for example as a methyl amide. for example as a thioether (-SR), for example as: a benzyl thioether, an acetamidomethyl ether (-S-CH 2 NHC (= O) CH 3) The 1-position of the pyrazole group in the compounds of Formula I) or its precursors may be protected by a variety of groups, the protecting group being selected according to the nature of the reaction conditions to which the group is exposed. Examples of protecting groups for NH pyrazole include tetrahydropyranyl, benzyl and 4-methoxybenzyl.

Many of the chemical intermediates described above are novel and these novel intermediates form a further aspect of the invention. ΡΕ1706385 120

PHARMACEUTICAL FORMULATIONS

While it is possible for the active compound to be administered alone, it is preferred to present it as a pharmaceutical composition (e.g., formulation) comprising at least one active compound of the invention together with one or more carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, pharmaceutically acceptable lubricants or other materials well known to those skilled in the art, and optionally other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions as defined above and methods of producing a pharmaceutical composition comprising mixing at least one active compound as defined above together with one or more carriers, excipients, buffers, adjuvants, stabilizers or other materials as described in the present disclosure. The term " pharmaceutically acceptable " as used herein pertains to compounds, materials, compositions and / or dosage forms which are within the scope of what is considered to be healthily suitable for use in contact with tissues or with an individual ( for example, human) without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each vehicle, excipient etc. must also be " acceptable " 121 ΡΕ1706385 in the sense of being compatible with the other ingredients of the formulation.

Therefore, in another aspect, the invention provides compounds of Formula (i) and subgroups, 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, intravaginal or transdermal administration. When the compositions are for parenteral administration, they may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous or direct delivery into an organ or tissue by injection, infusion or other delivery means.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit or multi-dose containers, for example, sealed ampoules and vials and may be stored freeze-dried (lyophilized), requiring only the addition of the sterile liquid carrier, for example water for injections, immediately before use. 122 ΡΕ1706385

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

In another preferred embodiment, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.

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

Suitable pharmaceutical dosage forms for oral administration include tablets, capsules, capsule-shaped tablets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and patches.

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, the tablet compositions may contain a unit dosage of active compound, together with an inert diluent or carrier, such as a sugar or sugar alcohol, for example, lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derivative diluent, such as 123 ΡΕ1706385 sodium carbonate, calcium phosphate, calcium carbonate or a cellulose or derivative thereof, such as methyl cellulose, ethyl cellulose, hydroxypropylmethylcellulose and starches such as corn starch. The tablets may also contain such standard ingredients as agglutination and granulating agents, such as polyvinylpyrrolidone, disintegrants (for example, crosslinkable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (for example, stearates), preservatives (e.g. para- biores), antioxidants (for example, BHT), buffering agents (for example, phosphate or citrate buffers) and effervescent agents, such as citrate / bicarbonate mixtures. Such excipients are well known and need not be examined in detail herein.

The capsule formulations may be of hard gelatin variety or soft gelatin and may contain the active component in solid, semi-solid or liquid form. The gelatin capsules may be formed from animal or synthetic gelatin or their plant derived equivalents.

Solid dosage forms (for example, tablets, capsules, etc.) may be coated or uncoated, but typically have a coating, for example a protective film coating (e.g., a wax or lacquer) or a control coating of liberation. The coating (for example, an Eudragit ™ type polymer) may be designed to release the active component into a desired location within the gastrointestinal tract. Thus, the coating may be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively compounding the stomach or the ileum or duodenum.

Instead of or in addition to a coating, the medicament may be presented in a solid matrix comprising a release-controlling agent, for example, a delay-release agent, which may be adapted to selectively release the compound, under conditions of varying acidity or alkalinity within the gastrointestinal tract. Alternatively, the matrix material or coating to retard release may take the form of an erosive polymer (for example, a maleic anhydride polymer), which is considerably and continuously eroded when the dosage form passes through the gastrointestinal tract. When there is a further alternative, the active compound may be formulated into a delivery system which provides osmotic control of the release of the compound. The osmotic release and other sustained or sustained release formulations may be prepared according to methods well known to those skilled in the art.

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid droplets and inserts (for example, intraocular inserts). Such compositions may be formulated according to known methods. 125 ΡΕ1706385

Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or thin suspensions or may be provided in finely divided sterile powder form for extemporaneous composition with sterile water for injection.

Examples of formulations for rectal or intravaginal administration include pessaries and suppositories, which may be, for example, formed from a shaped waxy or molded material containing the active compound.

Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and may be administered in standard form using powder inhaler devices or aerosol delivery devices. Such devices are well known. For administration by inhalation, the powder formulations typically comprise the active compound together with an inert solid powder diluent, such as lactose.

The compounds of the invention in general terms will be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a 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 milligrams to 2 grams of active ingredient, more usually from 10 126 ΡΕ1706385 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 (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

Inhibitory activity of the kinase protein The activity of the compounds of the present invention as inhibitors of protein kinase A and protein kinase B can be measured using the assays given in the examples below and the level of activity exhibited by a given compound can be defined in terms of value IC50. Preferred compounds of the present invention are compounds having an IC 50 value of less than 1 μΜ, more preferably less than 0.1 μΜ, against protein kinase B.

THERAPEUTIC USES

Prevention or Treatment of Proliferative Disorders

The compounds of Formula (I) are inhibitors of protein kinase A and protein kinase B. As such, they are expected to be useful in providing a means of preventing the growth or induction of apoptosis of neoplasms. Therefore, it is anticipated that the compounds will prove to be useful in treating or preventing proliferative disorders such as cancers. In particular, tumors with deletions or inactivating PTEN mutations or loss of PTEN expression or rearrangements in the TCL-1 gene (T-cell lymphocyte) may be particularly sensitive to PKB inhibitors. Tumors that have other abnormalities resulting in upwardly regulated PKB pathway signal 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, which result in an increase in the basal activity of the enzyme in question, or upregulation or overexpression or mutational activation of a growth factor receptor selected from epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), receptor insulin-like growth factor-1 (IGF-1R) and vascular endothelial growth factor receptor (VEGFR) families. It is also contemplated that the compounds of the present invention are useful in the treatment of other disorders resulting from proliferation or survival disorders, such as viral infections and neurodegenerative diseases, for example. PKB plays an important role in maintaining the survival of immune cells during an immune response and therefore PKB inhibitors could be particularly beneficial in immune disorders including autoimmune conditions. 128 ΡΕ1706385

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, glucose breakdown, energy storage and fat, such as metabolic disease and obesity.

Examples of cancers that may be inhibited include, but are not limited to, carcinoma, for example a bladder, breast, colon carcinoma (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidneys, epidermal, liver , lungs, for example, adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, esophagus, gall bladder, ovaries, pancreas, e.g., exocrine pancreatic carcinoma, stomach, cervix, endometrium, thyroid, prostate or skin , for example, squamous cell carcinoma; hematopoietic tumor of the lymphoid lineage, for example, leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma or Burkett's lymphoma; a hematopoietic tumor of the myeloid lineage, for example, acute and chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia; thyroid follicular cancer; a tumor of mesenchymal origin, for example, fibrosarcoma or habdomiosarcoma; a tumor of the central nervous or peripheral nervous system, for example, astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; semi-noma, teratocarcinoma; osteosarcoma; xenoderoma pigmen-toso; keratoctantoma; thyroid follicular cancer; or Kaposi's sarcoma.

Thus, in the pharmaceutical compositions, uses or methods of this invention for treating a disease or disorder comprising abnormal cell growth, the disease or disorder comprising abnormal cell growth in an embodiment is a cancer.

Specific subsets of cancers include breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell cancer, and non-small cell lung carcinomas.

Another subset of cancers include breast cancer, ovarian cancer, prostate cancer, endothelioma, and glioma. It is also possible that some protein kinase B inhibitors may be used in combination with other anticancer agents. For example, it may be beneficial to combine an inhibitor which induces apoptosis with another agent acting through a different mechanism to regulate cell growth, thus treating two of the characteristic features of cancer development. Examples of such combinations are given below. ΡΕ1706385 130

Immune Disorders

Immune disorders for which PKA and PKB inhibitors may be beneficial 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, hypersensitivity reactions Eczema, asthma, COPD, rhinitis and upper respiratory tract disease.

Other Therapeutic Uses PKB plays a role in apoptosis, proliferation, differentiation and therefore PKB inhibitors could also be useful in the treatment of the following diseases other than cancer and those associated with immune dysfunction; viral infections, e.g., herpes viruses, smallpox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; cardiovascular diseases, for example, cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, ritinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, myocardial infarction associated with ischemic injury, 131 ΡΕ1706385 stroke and reperfusion injury, degenerative diseases of the musculoskeletal system, eg, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases.

METHODS OF TREATMENT

Compounds of Formula (I) are believed to be useful in the prophylaxis or treatment of a range of diseases or disorders mediated by protein kinase A and / or protein kinase B. Examples of such diseases or disorders are given above.

The compounds of Formula (I) are generally administered to a subject in need of such administration, for example, a human or animal patient, preferably a human.

The compounds will typically be administered in amounts which are therapeutically or prophylactically useful and which in general are non-toxic. However, in certain situations (e.g. in the case of life threatening diseases) the benefits of administering a compound of Formula (I) may overcome the disadvantage of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.

The compounds may be administered for an extended period of time to maintain beneficial or only therapeutic effects for a short period. Alternatively, they may be administered in a pulsatile 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, when necessary. Finally, the amount of the compound administered will be commensurate with the nature of the disease or physiological disorder being treated and will be left to the discretion of the physician.

The compounds of Formula (I) may be administered as the sole therapeutic agent or may be administered in combination therapy with one or more other compounds for treatment of a specific disease, for example a neoplastic disease, such as a cancer, such as hereinbefore defined. Examples of other therapeutic agents or treatments, which may be administered together (either concomitantly or at different time intervals) with the compounds of Formula (I), include, but are not limited to:

• topoisomerase I inhibitors • antimetabolites • tubulin bleaching agents 133 ΡΕ1706385

• Inhibitors of binder and topoisomerase II

DNA • Alkylating agents • Monoclonal antibodies • Anti-hormones • Signal transduction inhibitors • Proteasome inhibitors • Methyl transferases of DNA • Cytokines and retinoids • Radiation therapy.

In the case of protein kinase A inhibitors or protein kinase B inhibitors combined with other therapies, the two or more treatments may be given in individually variable dose programs and through different pathways.

When the compounds of Formula (I) are administered in combination therapy with one or more other therapeutic agents, the compounds may be administered simultaneously or sequentially. When administered sequentially, they may be administered at closely spaced intervals (for example, for a period of 5-10 minutes) or at larger intervals (for example, 1, 2, 3, 4 or more separate hours or even longer, when necessary), the dosage regimen needs to be combined with the properties of the therapeutic agent (s). 134 ΡΕ1706385

The compounds of the present invention may also be administered in combination with non-chemo-therapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy; surgery and controlled diets.

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

One skilled in the art would know, by their common general knowledge, the dosage regimens and combination therapies to be used.

DIAGNOSTIC METHODS

Prior to administration of a compound of Formula (I), a patient may be evaluated to determine whether a disease or disorder of which the patient is or may be suffering would be amenable to treatment with a compound having activity against protein kinase A and / or protein B kinase.

For example, a biological sample taken from a 135 ΡΕ1706385 patient may be analyzed to determine whether a disease or disorder, such as cancer, of which the patient is or may be suffering, is characterized by a genetic abnormality or expression of abnormal protein, which results in the positive regulation of PKA and / or PKB or the sensitization of a pathway to normal PKA and / or PKB activity, or to the positive regulation of a PKA and / or PKB signal transduction component current, such as in the case of the receptor PKB, P13K, GF and PDK 1 & 2.

Alternatively, a biological sample taken from a patient may be analyzed for loss of a PKB pathway negative regulator or suppressor, such as PTEN. In the present context, the term " loss " encompasses the elimination of a gene encoding the regulator or suppressor, truncation of the gene (e.g. by mutation), truncation of the transcribed product of the gene, or inactivation of the transcribed product (e.g., by point mutation) or sequestration by another product. The term "positive regulation" includes high expression or overexpression, including genetic amplification (i.e., multiple copies of the gene) and increased expression by a transcriptional effect, and hyperactivity and activation, including mutations. Thus, the patient may undergo a diagnostic test to detect a PKA and / or PKB positive regulatory marker characteristic. The term diagnosis includes assessment. By labeling we include genetic markers, including, for example, the measurement of the 136 ΡΕ1706385 DNA composition, to identify PKA and / or PKB mutations. The term "marker" also includes tags that are characteristic of PKA and / or PKB positive regulation, including enzyme activity, enzyme levels, enzyme status (e.g., phosphorylated or not) and rNA levels of the above-mentioned proteins.

The above diagnostic tests and evaluations are typically conducted on a selected biological sample of tumor biopsy samples, blood samples (isolation and enrichment of spilled tumor cells), fecal biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, or urine. Identification of an individual containing a PKA and / or PKB mutation or a TCL-1 rearrangement or loss of PTEN expression may mean that the patient would be particularly suitable for treatment with a PKA and / or PKB inhibitor. Tumors may preferably be evaluated for the presence of a PKA and / or PKB variant prior to treatment. The evaluation process will typically involve direct sequencing, oligonucleotide microforming analysis or a specific mutant antibody. Methods of identification and analysis of mutations and positive regulation of proteins are known to a person skilled in the art. Methods of evaluation could include, but are not limited to, standard methods, such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization. 137 ΡΕ1706385

In the RT-PCR assay, the level of tumor mRNA is estimated by creating a cDNA copy of the mRNA, followed by amplification of the cDNA by PCR.

Methods of PCR amplification, selection of primers and conditions for amplification are known to a person skilled in the art. Nucleic acid manipulations and PCR are performed by standard methods, as described for the example of 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, 3a. Ed., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a kit commercially available for RT-PCR (for example, Roche Molecular Biochemicals) may be used or in the methodology as set forth in U.S. Patent 4,666,828; 4,683,202; 4,801,531; 5,222,659, 5,272,057, 5,882,864 and 6,228,529, incorporated herein by reference.

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

In general terms the in situ hybridization 138 ΡΕ1706385 comprises the following major steps: (1) fixation of the tissue to be analyzed; (2) pretreatment of the sample, to increase the accessibility of the target nucleic acid and to reduce non-specific binding; (3) hybridizing the nucleic acid mixture to the nucleic acid of the biological framework or tissue; (4) post-hybridization washes, to remove unbound nucleic acid fragments in the hybridization, and (5) detection of hybridized nucleic acid fragments. Probes used in such amplifications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100 or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid (s) under stringent conditions. Standard methods for performing FISH are described in Ausubel, F. M. et al., Eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc. and Fluorescence In Situ Hibridization: Technical OverView by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd. ed .; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

Alternatively, the protein products expressed by the mRNAs can be assayed by immunohistochemistry of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and 139 ΡΕ1706385 other known methods in the technique for detection of specific proteins. Methods of detection would include the use of site-specific antibodies. One skilled in the art will appreciate that all such well known techniques for detecting PKB upregulation or detection of PKB variants could be applicable in the present case.

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

For example, as stated above, it has been found that PKB beta is 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 contemplated that PKB inhibitors and, in particular, PKB beta inhibitors, can be used to treat ovarian and pancreatic cancers. 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 contemplated that PKB inhibitors, and in particular PKB alpha inhibitors, may be used to treat human gastric, prostate and breast cancer. Increased PKB gamma activity has been observed in independent breast and prostate cell lines 140 ΡΕ1706385 steroids (Nakatani et al., 1999, J. Biol. Chem. 274, 21528-21532). Therefore, inhibitors of PKB and, in particular, gamma PKB inhibitors can be used to treat cancers of the breast and prostate-independent steroids.

EXPERIMENTAL The invention will now be illustrated, but not limited, with reference to the specific embodiments described in the following procedures and examples.

The starting materials for each of the procedures described below are commercially available, unless otherwise specified.

In the examples, the compounds prepared were characterized by liquid chromatography, mass spectroscopy and 1H nuclear magnetic resonance spectroscopy, using the systems and operating conditions described below.

Proton magnetic resonance (1 H NMR) spectra were recorded on a Bruker AV400 instrument, operating at 400.13 MHz, in Me-d2 -OD at 27øC, unless otherwise noted, and are reported as follows: chemical shift δ / ppm (number of protons, multiplicity where s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). The residual proton solvent MeOH (δ = 3.31 ppm) was used as the internal reference. 141 ΡΕ1706385

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

In each of the examples, when the compounds are isolated or formed as the free base, they may be converted to a salt form, such as an acetic acid or hydrochloric acid salt. In contrast, when the compounds are isolated or formed as a salt, the salt can be converted to the corresponding free base by methods well known in the art and then optionally converted into another salt.

Numerous liquid chromatography systems have been used and these are described below.

Platform System

HPLC System: Waters 2795

Detector Espc. Massa Micromass Platform LC

PDA Waters 2996 PDA Detector

Acid Analytical Conditions 1:

Eluent A: H 2 O (0.1% Fumaric Acid)

Eluent B: CH 3 CN (0.1% Formic Acid)

Gradient: 5 - 95% eluent B above 3.5 minutes

Flow 1.5 ml / min

Column: Phenomenex Synergi 4μ Max-RP 80A, 50x4.6 mm 142 ΡΕ1706385

Acid Analytical Conditions 2:

Eluent A: H 2 O (0.1% Formic Acid)

Eluent B: CH 3 CN (0.1% Formic Acid)

Gradient: 5-95% eluent B above 3.5 minutes

Flow rate: 0.8 ml / min

Column: Phenomenex Synergi 4μ Max-RP 80A, 50x2.0 mm

Acid Analytical Conditions 3:

Eluent A: H 2 O (0.1% Formic Acid)

Eluent B: CH 3 CN (0.1% Formic Acid)

Gradient: 5-95% eluent B above 15 minutes

Flow rate: 0.4 ml / min

Column: Phenomenex Synergi 4μ Max-RP 80A, 50x2.0 mm

Basic Analytical Conditions 1:

Eluent A: H 2 O (10 mM NH 4 HCl 3 buffer adjusted to pH = 9.5 with ΝΗ 4)

Eluent B: CH 3 CN

Gradient: 05-95% Eluent B above 3.5 minutes

Flow rate: 1.5 ml / min

Column: Waters XTerra MS Cys 5 pm 4.6x50 mm 143 ΡΕ1706385

Basic Analytical Conditions 2:

Eluent A: H 2 O (10 mM NH 4 HCl 3 buffer adjusted to pH = 9.5 with NH 4 OH)

Eluent B: CH 3 CN

Gradient: 05-95% Eluent B above 3.5 minutes

Flow rate: 0.8 ml / min

Column: Thermo Hypersil-Keystone

BetaBasic-18 5 pm, 50x2.1 mm

Basic Analytical Conditions 3:

Eluent A: H 2 O (10 mM NH 4 HCl 3 buffer adjusted to pH = 9.5 with NH 4 OH)

Eluent B: CH 3 CN

Gradient: 05-95% Eluent B above 3.5 minutes

Flow rate: 0.8 ml / min

Column: Phenomenex Luna C18 (2) 5 pm, 50 x 2.0 mm

Basic Analytical Conditions 4:

Eluent A: H 2 O (10 mM NH 4 HC03 buffer adjusted to pH = 9.2 with NH 4 OH)

Eluent B: CH 3 CN

Gradient: 05-95% Eluent B above 3.5 minutes

Flow rate: 0.8 ml / min

Column: Phenomenex Luna C18 (2) 5 pm, 150x2.0 mm 144 ΡΕ1706385

Polar Analytical Conditions

Eluent A: H 2 O (0.1% Formic Acid)

Eluent B: CH 3 CN (0.1% Formic Acid)

Gradient: 00-50% eluent B over 3 minutes Flow: 1.5 ml / min

Column: Phenomenex Synergi 4 μ Hydro 80A, 50x4.6 mm

MS Conditions:

Capillary voltage 3.5 kV or 3.6 kV Cone voltage: 30 V

Temperature Source: 120 ° C Range Scan: 165 - 700 amu

ElectroSpray Ionization Negative, Positive or Positive & Negative

FractionLynx System

System: Waters FractionalLynx (dual analytical / prep)

HPLC pump: Waters 2525

Injector-Auto Sampler: Waters 2767 Spec. Mass: Waters-Micromass ZQ

PDA Waters 2996 PDA Detector

Acid Analytical Conditions:

Eluent A: H 2 O (0.1% Formic Acid)

Eluent B: CH 3 CN (0.1% Formic Acid)

Gradient: 5-95% eluent B above 5 minutes

Flow rate: 2.0 ml / min

Column: Phenomenex Synergi 4 μ Max-RP 80A, 50x4.6 mm 145 ΡΕ1706385

Polar Analytical Conditions:

Eluent A: H 2 O (0.1% Formic Acid)

Eluent B: CH 3 CN (0.1% Formic Acid)

Gradient: 5-95% eluent B above 5 minutes

Flow rate: 2.0 ml / min

Column: Phenomenex Synergi 4 μM Max-RP 80A, 50x4.6 mm

MS Parameters for acid and polar analytical conditions

Capillary voltage: 3,5 kV

Voltage Cone: 25 V Temperature Source: 120 ° C Scanning Range: 125-800 amu

Ionization Mode: ElectroSpray Positive or

ElectroSpray Positive & Negative

Chiral Analytical Conditions:

Eluent: MeOH + 0.1% NH 4 / TFA Flow: 1.2 ml / min

Total time: 16.00 min

Inj. Volume: 10 μΐ

Cone. sample: 2 mg / ml

Column: Astec, Chirobiotic V; 250x4.6 mm The mass spectrometer was removed from the line.

Agilent System

HPLC System: Agilent 1100 Series 146 ΡΕ1706385

Detector Espc. Mass: Agilente LC / MSD VL

Muiti Detector

Wavelength: Agilent series 1100 MWD

Software: HP Chemstation

Chiral Analytical Conditions:

Eluent: MeOH + 0.2% NH 4 / AcOH at room temperature

Flow rate: 2.0 ml / min

Total time: 8.5 min

Inj. Volume: 20 μΐ

Cone. sample: 2 mg / ml

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

Chiral Preparative Conditions 1:

Eluent: MeOH + 0.1% NH 4 / TFA at room temperature

Flow rate: 6.0 ml / min

Total time: 10.00 min

Volume In j. : 100 μΐ

Cone. sample: 2 mg / ml

Column: Astec, Chirobiotic V; 250x10 mm

Chiral Preparative Conditions 2:

Eluent: MeOH + 0.2% NH 4 / AcOH at room temperature

Flow rate: 20.0 ml / min

Total time: 19 min

Inj. Volume: 950 μΐ ΡΕ1706385 147

Cone. sample: 25 mg / ml

Column: Astec, Chirobiotic V; 250x21.2 mm

MS Conditions (analytical method only):

3000 V capillary voltage

Shredder: 150

Gain: 1.00 Drying gas: 12.0 1 / min

T gas drying: 350 ° C

Nebulizer Pressure: 2.46 (kg / cm 2)

Scan Range: 125 - 800 amu

Ionization Mode: Positive ElectroSpray

In the examples below, the following key is used to identify the LCMS conditions. PSA Platform System - Analytical Conditions 1 PS-A2 Platform System - Analytical Conditions Basic Analytical Conditions PS-B3 Platform System Basic Analytical Conditions PS-B3 Platform System Basic Analytical Conditions PS-B3 Platform System Basic Analytical Conditions PS-B3 Platform System Basic Analytical Conditions analytical conditions FL-C FractionlLynx System analytical conditions FL-C FractionlLynx System analytical conditions AG-CP Agilent System - preparative conditions 1 AG-CP2 Agilent System - 1 2-Phenyl-2- [4- (1H-pyrazol-4-yl) -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 149æl 1707038 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) was added followed by potassium carbonate (415 mg, 3.0 mmol, 6 equiv) in water (2.5 ml). The mixture was purged with nitrogen and sealed. The reaction mixture was heated in a CEM Explorer ™ microwave at 135 ° C for 15 minutes using 50 Watts power. The solvents were removed and the residue 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 (SiO2) eluting with a mixture of dichloromethane (90 ml): methanol (18 ml): acetic acid (3 ml): H2 O (2 ml) to afford the title compound. title 14 mg (9%); LCMS (PS-A) Rt 1.79 min; m / z [M + H] + 264. EXAMPLE 2 3-Phenyl-2- [3- (1H-pyrazol-4-yl) -phenyl] -propionitrile 2A. 2- (3-bromo-phenyl) -3-phenyl-propionitrile

150 ΡΕ1706385

A solution of 40% KOH (2.83 g in 5.0 mL H 2 O) 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%). The crude 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 held at this temperature for a further 2 hours. Upon 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 afford the desired product (1.80 g, 52%), which was used without purification. 2B] -3-Phenyl-2- [3- (1H-pyrazol-4-yl) -phenyl] -propionitrile

2- (3-Bromo-phenyl) -3-phenyl-propionitrile was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, followed by the procedure set forth in Example 1, 151 ΡΕ1706385 to provide the title compound. (LC / MS: (PS-A) Rt 2.98 [M + H] + 274). EXAMPLE 3 2- [4- (3,5-Dimethyl-1H-pyrazol-4-yl) -phenyl] -2-phenyl-ethylamine

Following the procedure of Example 1, but using 3,5-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxa-borolan-2-yl) -1H- pyrazole (Boron Molecular D03-BM152) in place of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole provided the title compound. (M + H) + 292. Example 4 2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] ] -ethylamine

152 ΡΕ1706385

Following the procedure of Example 1, but using 2,2-bis- (4-chloro-phenyl) -ethylamine in place of 2- (4-chlorophenyl) -2-phenylethylamine hydrochloride provided the title compound ( LC / MS: (PS-A) Rt 1.99 [M + H] 298). * This starting material can be produced by the method described in J. Amer. Chem. Soc., 1983, 105, 3183-3188. EXAMPLE 5 2- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -phenyl] -1-phenyl-ethylamine 5A. 2- (3-Bromo-phenyl) -1-phenyl-ethylamine

N III C ço * ô

Br

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 under reflux for 2 h, 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 heated under reflux for a further 16 h. Upon cooling, the reaction was quenched by cautious addition in drops of water (5 ml) and then partitioned between water (20 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO & > 4), filtered and concentrated. Purification by ion exchange chromatography afforded the desired compound (420 mg, 31%). 5B. 2- [3- (3,5-Dimethyl-1H-pyrazol-4-yl) -phenyl] -1-phenyl-ethylamine

The product of 5B was reacted with 3,5-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-pyrazole following the procedure set forth in Example 1 to provide the title compound (LC / MS: (PS-B) Rt 2.54 [M + H] + 292). EXAMPLE 6 3-Phenyl-2- [3- (1H-pyrazol-4-yl) -phenyl] -propylamine

154 ΡΕ1706385

To a solution of the product of 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 of the water suspension) and the reaction mixture was subjected to a nitrogen atmosphere for 17 h. The mixture was filtered through Celite (R) and the mother liquor was concentrated under reduced pressure to provide the title compound, which was purified by preparative liquid chromatography. (LC-MS: (PS-A) Rt 1.89 [M + H] + 278). EXAMPLE 7 3-Phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -propylamine 7A.2 - (4-Bromo-phenyl) -3-phenyl-propionitrile

Br

Following the procedure described in Example 2A, but substituting 4-bromophenylacetonitrile for 3-bromophenylacetonitrile provided the title compound, which was used in the next step without further purification. 7B] -3-Phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -propionitrile 155 ΡΕ1706385

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] -pro-

The nitrile product of Example 7B was reduced using the conditions described in Example 6 to provide the title compound. (M + H) + 278. EXAMPLE 8 3- (4-Chloro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] ] -propyl} -methyl-amine 8A 3- (4-Bromo-phenyl) -2-cyano-acrylic acid ethyl ester (J. Med. Chem, 1983, 26, 935-947) 156 ΡΕ1706385

4-Bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 mL, 17.84 mmol) in toluene was added piperidine (27 μ) and the reaction mixture was refluxed for 1 h with a separator Dean-Stark. The solvent was removed under reduced pressure, the residue triturated with ethyl acetate, filtered to afford 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, 6.95 mmol) at 0 ° C. The reaction mixture was heated at 85 ° C for 3 h, poured onto ice, acidified with 1 N HCL and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, crude product 157E1706385 was purified by flash silica chromatography, eluting petroleum ether to ethyl acetate / petroleum ether (5.95) to afford the desired product 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 silica chromatography eluting with ethyl acetate / petroleum ether (1: 1) to provide the desired product (0.82 g , production of 50%). LC / MS: (PS-A2) Rt 3.39 [M + H] " 338, 86. 8D. 3- (4-bromo-phenyl) -3- (4-chloro-phenyl) -N-methyl-

158 ΡΕ1706385

A mixture of 3- (4-bromo-phenyl) -3-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 prior to addition of methylamine (40% solution in water, 0.11 μ, 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 partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), filtered and concentrated to provide 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] -

In a nitrogen atmosphere, crude 3- (4-bromo-phenyl) -3- (4-chloro-phenyl) -N-methyl-propionamide was cooled to 0øC, lithium aluminum hydride (0.075 g, 1.97 mmol) and diethyl ether (3 ml) were added. Upon cooling, the aluminum chloride (0.23 g, 1.69 mmol) was dissolved in 159 ΡΕ1706385 diethyl ether (2 mL) and added. The reaction mixture was stirred for 16 h, quenched with water addition, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified by Phenomex-Trata_SCX column chromatography eluting with methanol, followed by 2N ammonia in methanol, to provide the desired product (0.254 g, 62% for steps 1D and 1E combined). LC / MS: (PS-B3) Rt 3.20 [M + H] + 339.85. 8F. {3- (4-Chloro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine

HN

Cl

[3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) -propyl] -methyl-amine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2- borolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-B3) Rt 2.63 [M + H] + 326.00. 1 H NMR (Me-d 3 -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 (1H, br s - due to formic acid). EXAMPLE 9 {3- (3,4-Difluorophenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -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 3,4-difluorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. LC / MS: (PS-A2) Rt 3.12 [M + H] + 355.84. 9B. 3- (3,4-Difluoro-phenyl) -N-methyl-3- [4- (1H-pyrazol-

3- (4-Bromo-phenyl) -3- (3,4-difluoro-phenyl) -N-methyl-1 H -propionamide was reacted with 4- (4,4,5,5-tetramethyl- dioxa-borolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide 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 solution of aluminum chloride at 0 ° C under a nitrogen atmosphere. Toluene was added and the reaction mixture was heated at 70 ° C for 18 h. Upon cooling, the reaction was quenched with the addition of water, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the desired compound. LC / MS: (PS-A2) Rt 2.15 [M + H] + 328.06. 1 H NMR (Me-d 3 -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). EXAMPLE 10 {3- (3-Chloro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine

n-n H

Following the procedure described in Example 8, but substituting 3-chlorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. LC / MS: (PS-B3) Rt 2.67 [M + H] + 326.00. NMR (Me-d 3 -OD) δ 2.43-2.50 (2H, m), 2.68 (3H, s), 2.94 (2H, m), 4.13 (1H, t), 7.24 (1H, m), 7.27-7.36 (3H, m), 7.41 (2H, d), 7.66 (2H, d), 8.50 (2H, s). EXAMPLE 11 3- (4-Chloro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propionamide

163 ΡΕ1706385

Following the procedure described in Example 9A and 9B, but substituting 3,4-difluorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. NMR (Me-d 3 -OD) δ 2.95 (2H, d), 4.53 (1H, t), 2.54 [M + H] + 326. LC / MS: (PS- 7.27 (6H, m), 7.50 (2H, d), 7.91 (2H, s). EXAMPLE 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 1,1'-carbonyldiimidazole (0.24 g, , 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 h, the solvent removed under reduced pressure and the residue was purified by flash silica chromatography eluting with ethyl acetate / petroleum ether (1: 4) to provide the title compound 09lg, production of 36%). LC / MS: (PS-A2) Rt 3.08 [M + H] + 339.93. * This starting material can be produced by the method described in Example 8A at 80 ° C. ΡΕ1706385 164 12B. 3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) -propylamine

Following the procedure described in Example 8E, however substituting 3- (4-Bromo-phenyl) -pyrrolidin-3- (4-bromophenyl) -3- (4-chloro-phenyl) -N- 3- (4-chloro-phenyl) -propionamide, the title compound was obtained. LC / MS: (PS-B2) Rt 3.88 [M + H] + 359, 87. 12C, 3- (4-Chloro-phenyl) -3- [4- (1H-pyrazol-4-yl) - phenyl] -propylamine

3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) -propylamine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -pyrazole following the procedure set forth in Example 1 to provide the title compound. LC / MS: (PS-B3) Rt 2.54 [M + H] + 312.04. NMR (Me-d 3 -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). ΡΕ1706385 EXAMPLE 13 3- (3,4-Dichloro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propylamine

Following the procedure described in Example 12, but substituting 4-chlorophenylmagnesium bromide for 3,4-dichlorophenylmagnesium bromide, the title compound LC / MS: (PS-A2) Rt 2.17 [M + H] + 345.95 NMR (Me-ds-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). EXAMPLE 14 4- (4-Chloro-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine 14A. 4- (4-Bromo-phenyl) -4- (4-chloro-phenyl) -piperidine

Br

H N

J

Br '

Cl 166 ΡΕ1706385

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 h, quenched by the addition of ice, then methyl t-butyl ether was added. After stirring for 1 h, the precipitate was collected by filtration, washed with water, methyl t-butyl ether and water to provide the title compound (5.59 g, yield 92%). LCMS: (PS-B3) Rt 3.57 [M + H] + 350, 352. 14B, -4- (4-Chloro-phenyl) -4- [4- (1H-pyrazol-4-yl) - phenyl] -piperidine

4- (4-Bromo-phenyl) -4- (4-chloro-phenyl) -piperidine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -pyrazole, following the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-A3) Rt 7.22 [M + H] + 338.08 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). EXAMPLE 15 4- (4-Methoxy-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

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; NMR (Me-d 3 -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). EXAMPLE 16 4- (4-Chloro-phenyl) -1-methyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine 16A. 4- (4-Bromo-phenyl) -4- (4-chloro-phenyl) -piperidine-1-carboxylic acid ethyl ester

168 ΡΕ1706385

In 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 , 45 mL, 3.2 mmol) and ethyl chloroformate (0.085 mL, 0.88 mmol). The reaction mixture was stirred for 3 h, diluted with ethyl acetate and washed with 1N HCl, saturated sodium hydrogen carbonate and brine. The organic layer was separated, dried (MgSO 4), filtered and concentrated to afford the title compound (0.29 g, yield 94%). LCMS: (PS-A2), Rt 4.02 [M + H] + 422, 424. This starting material can be produced by the method described in Example 14A. 16B, 4- (4-Bromo-Phenyl) -4- (6-chloro-phenyl) -1-methyl-piperidine

In a nitrogen atmosphere, 4- (4-Bromo-phenyl) -4- (4-chloro-phenyl) -piperidine-1-carboxylic acid ethyl ester (0.28 g, 0.66 mmol) and (0.051 g) were suspended in tetrahydrofuran (5 ml) and stirred for 2 h. The reaction mixture was quenched with addition of water, the solvent removed under reduced pressure, the residue partitioned between ethyl acetate and 2N NaOH. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to provide 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-phenyl) -1-methyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

4- (4-Bromo-phenyl) -4- (4-chloro-phenyl) -1-methyl-piperidine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxol-rolano- 2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. NMR (Me-d 3 -OD) d 2.41-2.53 (2H, m), 2.82 (3H, (2H, m), 7.28 (2H, s), 7.34 (1H, m), 7.96 (1H, (1H, d), 7.75 (1H, d), 8.52 (2H, d), 7.61 (1H, d) ). EXAMPLE 17 4-Phenyl-4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

170 ΡΕ1706385

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. title. NMR (Me-d 3 -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). EXAMPLE 18 4- [4- (3,5-Dimethyl-1H-pyrazol-4-yl) -phenyl] -4-phenyl-piperidine

Following the procedure described in Example 1, however substituting 4- (4-chloro-phenyl) -4-phenyl-piperidine and 3,5-dimethyl-4- (4,4,5,5-tetramethyl- [ 1,3,2] dioxaborolan-2-yl) -1H-pyrazole for 2- (4-chlorophenyl) -2-phenylethylamine hydrochloride and 4- (4,4,5,5-tetramethyl- dioxaborolan-2-yl) -1H-pyrazole, the title compound was obtained. NMR (Me-d 3 -OD) δ 2.22 (6H, s), 2.66-2.76 (4H, m) m), 3.16-3.28 (4H, m), 7.19-7.44 (9H, m). EXAMPLE 19

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

Following the procedure described in Example 1, but substituting bromoferinamine maleate for 2- (4-chlorophenyl) -2-phenylethylamine chloridide gave the title compound LC / MS: (PS-B2) Rt 2.29 [M + H] 307. 1 H NMR (Me-d 3 -OD) δ 2.44-2.54 (1H, m), 2.59-2.70 (1H, m) (2H, m), 4.20 (1H, t), 7.25-7.28 (1H, m), 7.32-7.36 (3H, m), 7.54 (2H, d), 7.75 (1H, dt), 7.94 (2H, br s). EXAMPLE 20 {2- (4-O-chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -dimethyl-amine 20A. 2,2-Bis- (4-chloro-phenyl) -N, N-dimethylacetamide

172 ΡΕ1706385 Bis- (4-Chloro-phenyl) -acetic acid was reacted with dimethylamine following the procedure set forth in Example 8D to provide the title compound. LC / MS: (PS-A2) Rt 3.40 [M + H] + 309.95. 20B. [2,2-Bis- (4-chloro-phenyl) -ethyl] -dimethyl-amine

Following the procedure described in Example 8E, but substituting 3- (4-Bromo-phenyl) -3- (4-chlorophenyl) -2,2- bis- (4-chlorophenyl) -N, N-dimethylacetamide chloro-phenyl) -N-methyl-propionamide, there was obtained the title compound LC / MS: (PS-B2) Rt 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-amine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -pyrazole, following the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-B2) Rt 173 ΡΕ1706385 3.07 [M + H] + 325.99. 1 H NMR (Me-ds-OD) δ2.5 (6H, s), 2.98 (2H, dd), 4.34 (1H, t), 7.31-7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s). EXAMPLE 21 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -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. 1 H-NMR (Med3-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, br s). EXAMPLE 22 {2- (4-O-chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] ethyl} -methyl-amine (R)

174 ΡΕ1706385

Prepared by employing the same procedure as Example 21, but the enantiomers separated by preparative chiral HPLC using the AG-CP2 method. LCMS: (AG-CA) Rt 5.58 min, 97.4% ee. 1 H NMR (Me-ds-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). EXAMPLE 23 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine (S)

Prepared using the same procedure as Example 21, but the enantiomers separated by preparative chiral HPLC using the AG-CP2 method. LCMS: (AG-CA) Rt 4.51 min, 98.0% ee. 1 H-NMR (Me-d 3 -OD) δ 2.75 (3H, s), 3.79 (2H, d), 4.51 (1H, t), 7.37-7.44 (4H, m), 7.49 (2H, d), 7.73 (2H, d), 8.66 (2H, s). EXAMPLE 24 4- {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -morpholine 175 ΡΕ1706385

Following the procedure described in Example 20, but replacing morpholine with dimethylamine gave the title compound. LC / MS: (PS-B3) Rt 3.07 [M + H] + 368, OS / HRMN (Me-d3-OD) δ 2.50 (4H, m), 2.97 (2H, m), 3.60 (4H, t), 4.26 (1H, t), 7.27 (6 H, m), 7.49 (2H, d), 7.89 (2H, s). EXAMPLE 25 4- {4- [1- (4-Chloro-phenyl) -2-pyrrolidin-1-yl-ethyl] -phenyl} -1H-pyrazole

Following the procedure described in Example 20, however, substituting pyridine for dimethylamine gave the title compound LC / MS: (PS-A2) Rt 2.06 [M + H] + 354.01. 1 H NMR (Me-d 3 -OD) δ 1.85 (4H, m), 2.87 (4H, m), 3.47 (2H, d), 4.31 (1H, 37 (6H, m), 7.54 (2H, d), 7.92 (2H, s). ΡΕ1706385 EXAMPLE 26 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -isopropyl-amine

Following the procedure described in Example 20, but substituting dimethylamine for isopropylamine, the title compound was obtained. NMR (Me-d 3 -OD) δ 1.31 (6H, d), 3.38-3.45 (1H, m), 3.65-3.74 (2H, m), 4.39 (1H, br t), 7.37 (6H, m), 7.59 (2H, d), 7.94 (1H, 2H, s). EXAMPLE 27

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

N-N H 177 ΡΕ1706385

Following the procedure described in Example 20, the title compound was obtained. NMR (Me-d 3 -OD) δ 2.25 (6H, s), 2.95-3.04 (2H, m) (2H, d), 7.89 (2H, d), 7.20 (1H, t), 7.16 (1H, , s) . EXAMPLE 28 {2,2-Bis- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl}

Following the procedure described in Example 20, the title compound LC / MS: (PS-B2) Rt 2.45 [M + H] + 358.11. NMR (Me-d3-OD) δ (2H, d), 4.43 (1H, t), 7.39 (4H, d), 7.57 (4H, d), 7.93 (4H, , s). EXAMPLE 29 (2,2-Bis- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine

178 ΡΕ1706385

Following the procedure described in Example 21, the title compound was obtained. NMR (Me-d 3 -D) δ 2.65 (3H, s), 3.60 (2H, d), 4.34 (1H, t), 7.36 (4H, d), 7.59 (4H, d), 7.94 (4H, s). EXAMPLE 30 2- (4-Chloro-phenyl) -2-4- (1H-pyrazol-4-yl) -phenyl] -ethylamine (R)

Prepared by employing the same procedure as Example 4, but the enantiomers separated by chiral preparative HPLC using the AG-CP1 method. LCMS: (FL-C) R t 10.97 min, 95.7% ee. Δ NMR (Me-d 3 -OD) δ 3.65 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.16 (2H, s). EXAMPLE 31 2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine (S)

179 ΡΕ1706385

Prepared by employing the same procedure as Example 4, but the enantiomers separated by chiral preparative HPLC using the AG-CP1 method. LCMS: (FL-C) R t 9.63 min, 100% ee. NMR (Me-d 3 -OD) δ 3.66 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.15 (2H, s). EXAMPLE 32 2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide

Following the procedure described in Example 12A, followed by 12C, but substituting 3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) -acetic acid for bis- (4-chloro-phenyl) propionic acid, the title compound was obtained. R f 2.53 [M + H] + 312. 1 H NMR (Me-d 3 -OD) δ 4.99 (1H, s), 7.30-7.33 (6H, m), 7.55 (2H, d), 7.86-8.02 (2H, br s). EXAMPLE 33 1- (2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl] -piperazine Ethylbis- (4-chloro-phenyl) ) -acetaldehyde

Periodinane Dess-Martin (3.17 g, 7.49 mmol) was added in a solution of 2,2-Bis- (4-chloro-phenyl) -ethanol in dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 17 h in nitrogen, 2N NaOH (15 ml) 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. more purification. LC / MS: (PS-B3) Rt 3.62 [M + H] + 262.91. 33b. 4- [2,2-Bis- (4-chloro-phenyl) -ethyl] -piperazine-1-carboxylic acid tert -butyl ester

To a solution of bis- (4-chloro-phenyl) -acetaldehyde (3.74 mmol) in methanol in a nitrogen atmosphere was added N-BOC-piperazine (1.05 g, 5.61 mmol) 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 hours, water (3 ml) was added and the solvent removed under pressure. The residue was partitioned between dichloromethane and water, the organic layer was separated, dried (MgSO4), filtered and concentrated. Purified by flash silica chromatography 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- [2,2-Bis- (4-chloro-phenyl-ethyl] -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 hour, the solvent was removed under reduced pressure to provide the title compound as the HCl salt. 33D. 1- {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -piperazine

(4-chloro-phenyl) -ethyl] -piperazine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-B3) Rt 2.63 [M + H] + 326.00. Δ NMR (Me-d 3 -OD) δ 3.55-3.68 (8H, m), 3.74 (1H, 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). EXAMPLE 34 1- {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -piperidine

Following the procedure described in Example 33A, 33B and 33D, but substituting N-BOC-piperazine for piperidine gave the title compound. NMR (Me-d 3 -OD) δ 1.44 (2H, m), 1.53 (4H, m) , 2.39-2.57 (4H, m), 2.94-3.99 (2H, m), 4.26 (1H, t), 7.22-7.35 (6H, m), 7 , 50 (2H, d), 7.91 (2H, s). EXAMPLE 35 4- (4- [2-Azetidin-1-yl-1- (4-chloro-phenyl) -ethyl] -phenyl} -1H-pyrazole 183 ΡΕ1706385 35 2- (4-Chloro-phenyl) -2- - [4- (1H-pyrazol-4-yl) -phenyl] -ethanol

2,2-Bis- (4-chloro-phenyl) -ethanol was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, followed the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-A2) Rt 2.72 [M + H] + 299.00. 35B. (4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -acetaldehyde

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

Following the procedure described in Example 33B, but substituting (4-chloro-phenyl) -acetaldehyde and N-BOC-piperazine for (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. 1 H NMR (Me-d 3 -OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71-3.77 (1H, m), 4. (2H, m), 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, , d), 8.69 (2H, br s). EXAMPLE 36 1-Phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine

N-N

H

Following the procedure described in Example 5, 185 ΡΕ1706385 but substituting 3-bromobenzylmagnesium bromide and 3,5-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan- 2-yl) -1H-pyrazole for 4-bromobenzylmagnesium bromide and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole provided the title compound of the title. 1 H NMR (Me-d 3 -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). EXAMPLE 37 [4- (5-Methyl-3-trifluoromethyl-1H-pyrazol-4-yl) -phenyl] -acetonitrile

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 p-toluene sulfonic acid monohydrate mg, 0.62 mmol, 0.1 equiv). The solution was cooled to 0øC 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 h and the solvents were removed under reduced pressure. The crude mixture was purified by column chromatography (SiO2) eluting with 25% EtOAc-gasoline through a linear gradient to provide the title compound 1.4 g (59%). LCMS (PS-A) Rt 3.72 min [M + H] + 314. 37B (4- [5-Methyl-1- (tetrahydro-pyran-2-yl) -3-trifluoromethyl-1H-pyrazol- 4-yl] -phenyl} -acetonitrile

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

In {4- [5-Methyl-1- (tetrahydro-pyran-2yl) -3-triisopropyl] -ethyl] -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 hour. The solvents were removed under reduced pressure and the title compound was purified by column chromatography (SiO2) eluting with a linear gradient (30% ethyl acetate gasoline) 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 1 to provide 2- [4- (5-methyl-1- (tetrahydro-pyran-2-yl) -3-trifluoromethyl-1H-pyrazol-4-yl) -phenyl] -3- propionitrile which can be deprotected by removal of the 1-tetrahydropyranyl group under the conditions set forth in Example 37C to provide 2- [4- (3-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 method of Example 6 then, where necessary, deprotected according to the method of Example 41C) to provide 2- [4- (5-methyl-3-trifluoromethyl-1H-pyrazol-4-yl) -phenyl] -3-phenyl-propylamine . 188 ΡΕ1706385 The product of Example 37B may also be reacted with benzyl magnesium bromide or phenyl magnesium bromide under the conditions and Grignard reaction described in Example 5 to provide (next to deprotection by the method 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-phenyl-ethylamine, respectively. EXAMPLE 38

Construction of the Pirazol 38A Ring System. Synthesis of 4- (4-Bromo-phenyl) -3-methyl-1H-pyrazole

N, N-dimethylformamide dimethyl acetal (11.3 mL, 84.6 mmol, 3 mmol) was added in 4-bromophenylacetone (5.0 g, 23.5 mmol, 1.0 equiv) (Acros Organics 34216) 6 equiv) and the mixture was heated at 90 ° C for 6 hours. The solvents were removed and the resulting gum was dissolved in ethanol (235 ml) with further heating. Hydrazine hydrate (1.37 ml, 28.2 mmol, 1.2 equiv) was added and 189 Ρ E1706385 the mixture was heated under reflux for 15 h. The solvents were removed under reduced pressure and the solid triturated with dichloromethane to provide the title compound, 2.24 g (40%); LCMS (PS-A) Rt 2.87 min [M + H] + 238. More material could be isolated from the mother liquor. 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 the 1-position of the pyrazole ring, by formation of the tetrahydropyranyl (THP) derivative, following the procedure set forth in Example 38A. A Grignard reagent may then be prepared from the bromophenyl component by treatment of the protected magnesium derivative in an ether solvent in standard mode (see J. March, Advanced Organic Chemistry, 4th Edition, 1992, John Wiley, New York, pp. 622-625). The Grignard reagent can be reacted with nitroestrene (the nitrostyrene having been prepared by a standard method, such as the method described in Organic Syntheses, Collective Volume 1, page 413) and the resulting nitroethyl compound reduced to give 2- { 4- [3-methyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-4-yl] -phenyl} -2-phenyl-ethylamine. Removal of the tetrahydropyranyl group, using the method of Example 8C, affords 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), wherein group A 190 ΡΕ1706385 contains a nitrogen atom which is attached to the group F. The introduction of a nitrogen containing entity may be carried out by reaction of the compound of Example 38A with [3- (4-chloro-phenylamino) -propyl] -methyl-carbamic acid tert -butyl ester under conditions of palladium catalyzed amination of the type described in Organic Letters, 2002 , vol. 4, No. 17, pp. 2885-2888, followed by removal of the t-butyloxycarbonyl protecting group by standard methods. EXAMPLE 39 [3- (1H-Pyrazol-4-yl) -phenyl] -acetonitrile

N-N

H

Following the procedure set forth in Example 1, but using 3-bromophenyl-acetonitrile 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 as described in Example 5. EXAMPLE 40 2- (4-Chloro-phenyl) -N-methyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide

Following the procedure described in Example 12A, followed by 12C, but substituting bis (4-chloro-phenyl) -acetic acid for 3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) ) -propionic acid and methyl amine by ammonia gave the title compound. NMR (Me-d 3 -OD) δ 2.79 (3H, s), 4.94 (1H, br s), 7.26-7.35 (6H, m), 7.55-7.57 (2H, m), 7.96 (2H, br s). EXAMPLE 41 N-Methyl-2,2-bis- [4- (1H-pyrazol-4-yl) -phenyl] -acetamide

192 ΡΕ1706385

Following the procedure described in Example 40, the title compound was obtained. LC / MS (PS-A2): Rt 2.19 [M + H] + 358. 1 H NMR (Me-d 3 -OD) δ 2.80 (3H, s), 4.95 (1H, br s) , 7.32 (4H, d), 7.56 (4H, d), 7.98 (4H, br s). EXAMPLE 42 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine 42A. 1- (4-Bromo-phenyl) -2-methylamino-ethanol

A solution of 2- (4-bromophenyl) oxirane (0.5 g, 2.51 mmol) in methylamine (6.6 mL, 33 volume% in ethanol, 25.12 mmol) was stirred at ambient temperature under an atmosphere of nitrogen. After 18 h the solvent was removed in vacuo and the residue purified on flash silica eluting with dichloromethane: ethanol: acetic: water (120: 15: 3: 2) to provide the desired compound as the acetic acid salt. Further purification through Phenomenex_Strata_SCX column eluting with methanol, followed by 2N ammonia in methanol, provided the desired product. LC / MS: (PS-B3) Rt 2.52 [M + H] + 230. ΡΕ1706385 193 42Β. [2- (4-Bromo-phenyl) -2- (4-chloro-phenyl) -ethyl]

Aluminum chloride (278 mg, 2.087 mmol) was added portionwise in a stirred solution of 1- (4-Bromo-phenyl) -2-methylamino-ethanol (160 mg, 0.666 mmol) in chlorobenzene (3 mL) and the mixture of The reaction was stirred at room temperature for 17 h. Water (2 ml) was added dropwise and the reaction mixture was then partitioned between dichloromethane (100 ml) NaHCO3 (30 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified by PhenomexStrata_SCX column chromatography, eluting with methanol, followed by 2N ammonia in methanol, to afford the desired product. LC-MS: (PS-B3) Rt 3.58 [M + H] + 324. 42C, (2-4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) nyl] -ethyl} -methyl-amine

194 ΡΕ1706385

A solution of [2- (4-Bromo-phenyl) -2- (4-chloro-phenyl) -ethyl] -methyl-amine (6.1 g, 13.716 mmol), 4- (4,4,5,5 2-yl) -1H-pyrazole (5.3 g, 27.431 mmol) and K 3 PO 4 (10.19 g, 48.00 mmol) in ethanol (7.5 mL) methanol (11.5 ml), toluene (7.5 ml) and 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 purged with nitrogen for an additional 2 minutes. The mixture was then heated at 80 ° C under nitrogen for a period of 17 h. Solvents were removed and the residue 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 (SiO2) eluting with dichloromethane: methanol: acetic: water (90: 18: 3: 2) to provide the title compound (3.6 g); LCMS (PS-A2) Rt 2.08 min [M + H] + 312. EXAMPLE 43 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] - ethyl} -ethylamine

195 ΡΕ1706385

Following the procedures described in Examples 42A to 42C, but substituting methylamine for ethylamine gave the title compound. NMR (Me-d 3 -D) δ 1.15 (3H, t), 2.83 (2H, q), 3.35 (2H, m), 4.25 (1H, t), 7.30-7.48 (6H, m), 7.57 (2H, d), 7.95 (2H, s). EXAMPLE 44 4- {4- [1- (4-Chloro-phenyl) -2-imidazol-1-yl-ethyl] -phenyl} -1H-pyrazole

Following the procedures described in Examples 42A to 42C, but replacing imidazole with methylamine afforded the title compound. 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 (1H, s), 8.05 (2H, s), 9.0 (1H, 1H, s). EXAMPLE 45

Methyl- {2- (4-phenoxy-phenyl) -2- [4- (1 H -pyrazol-4-yl) -phenyl] -ethyl} -amine Î »E1706385 196 45Â °. [2- (4-Bromo-phenyl) -2- (4-phenoxy-phenyl) -ethyl] -methyl-amine

Following the procedure described in Example 42b, but replacing diphenyl ether with chlorobenzene and using nitrobenzene as solvent gave the title compound. Methyl- {2- (4-phenoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -piperazin- phenyl] -ethyl} -amine

Following the procedure described in Example 42C, however substituting [2- (4-bromo-phenyl) -2- (4-phenoxy-phenyl) -ethyl] -methyl-amine for [2- (4-bromo- phenyl) -2- (4-chloro-phenyl) -ethyl] -methyl-amine, the title compound was obtained. 1 H-NMR (Me-d 3 -OD) δ 2.75 (3H, s), 3.75 (2H, d) , 4.38 (1H, t), 6.98 (4H, dd), 7.12 (1H, t), 7.33-7.40 (6H, m), 7.61 (2H, d), 7.95 (2H, s). EXAMPLE 46 {2- (4-Methoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine 46A. [2- (4-Bromo-phenyl) -2- (4-methoxy-phenyl) -etll] -methyl-amine

Following the procedure described in Example 42B, but substituting anisole for chlorobenzene, the title compound was obtained as a mixture of regioisomers (ca 4: 1) with the corresponding ortho-methoxy analogue. LC / MS: (PS-B3) Rt 3.24 [M + H] + 320. 46B. [2- (4-Bromo-phenyl) -2- (4-methoxy-phenyl) -ethyl] -methyl-amine

(4-methoxy-phenyl) -ethyl] -methyl-amine (and its regioisomer) was added in a solution of [2- 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 / ether and petroleum (1: 9) to afford the intermediate BOC-protected compound as the sole 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 afforded the title compound as the HCl salt. LC / MS: (PS-B3) Rt 3.21 [M + H] + 320. 46C. 2- (4-Methoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine

Following the procedure described in Example 42C, however substituting [2- (4-bromo-phenyl) -2- (4-methoxy-phenyl) -ethyl] -methyl-amine for [2- (4-bromo- phenyl) -2- (4-chloro-phenyl) -ethyl] -methyl-amine, the title compound was obtained. LC / MS: (PS-B3) Rt 2.52 [M + H] + 308. NMR (Me-d3-OD) δ 2.75 199 ΡΕ1706385 3H, s), 3.75 (2H, dd), 3.80 (3H, s), 4.38 (1H, t), 6.95 (2H, d), 7.32 (2H, d), 7.45 (2H, d), 7.70 2H, d), 8.52 (2H, s). EXAMPLE 47

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

Boron tribromide (7.8 ml, 1.0M in dichloromethane) was added slowly in 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 NaHC03 solution. The organic layer was dried (MgSO4), filtered and concentrated to afford the desired product. LCMS: (PS-B3) Rt 2.76 [M + H] + 306. 200 ΡΕ1706385 47Β. [2- (4-Bromo-phenyl) -2- (4-hydroxy-phenyl) -ethyl] -methyl-carbamic acid tert -butyl ester

(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 the crude product was purified by column chromatography (SiO2) eluting with ethyl acetate / petroleum ether (1: 4) to give the title compound . R f 3.85 [M + H] + 406. 47C 2- (4-Bromo-phenyl) -2- [4- (pyrazin-2-yloxy) -phenyl] - 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 K 2 CO 3 (213 mg, 1.54 mmol) in dimethylformamide (8 mL) was heated at 100 øC for 17 h. On cooling, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated NaHCO 3 solution. The organic layer was dried (MgSO4), 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 Phenomenextract_SCX column chromatography eluting with methanol, followed by 2N ammonia in methanol to provide the desired product (82 mg). (M + H) + 384. Methyl- {2- [4- (pyrazin-2-yloxy) -phenyl] -2- [4-1H-pyrazol- 4-yl) -phenyl] -ethyl} -amine

Following the procedure described in Example 42C, however substituting {2- (4-Bromo-phenyl) -2- [4- (pyrazin-2-yloxy) -phenyl] -ethyl} -methyl-amine for [2- (4-Bromo-phenyl) -2- (4-chloro-phenyl) -ethyl] -methyl-amine gave the title compound. NMR (Me-d 3 -OD) δ 2.80 (3H, s), 3.75-3.90 (2H, m) 7.50 (4H, t), 7.75 (2H, d), 8.12 (1H, d), 7.50 (1H, 8.33 (1H, d), 8.42 (2H, s), 8.48 (1H, s). EXAMPLE 48

Methyl- {2-phenoxy-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -amine 48A. [2- (4-Bromo-phenyl) -2-hydroxy-ethyl] -methyl-carbamic acid tert -butyl ester

BOC 20 (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 ether (1: 4) to afford the desired product (2.1 g). (M + H) + 330. 48B [2- (4-Bromo-phenyl) -2-phenoxy-ethyl] -methyl-amine

203 ΡΕ1706385

Diethyl azodicarboxylate (358 μΐ, 2.27 mmol) was added dropwise to a solution of [2- (4-Bromo-phenyl) -2-hydroxy-ethyl] -methyl-carbamic acid tert -butyl ester (500 , and triphenylphosphine (596 mg, 2.27 mmol) and phenol (285 mg, 3.03 mmol) in tetrahydrofuran (10 mL) and the reaction mixture stirred at room temperature under a nitrogen atmosphere, for 17 h. The solvent was then removed under reduced pressure and the residue partitioned between ethyl acetate and saturated NaHCO3. 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 afford 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 afforded the title compound as the HCl salt. Further purification by chromatography of PhenomexStrata_SCX column, eluting with methanol, followed by 2N ammonia in methanol afforded the desired product as the free base (94 mg). (M + H) + 406. 48C Methyl- {2-phenoxy-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl }-the mine

204 ΡΕ1706385

Following the procedure described in Example 42C, but substituting [2- (4-Bromo-phenyl) -2-phenoxy-ethyl] -methylamine for [2- (4-Bromo-phenyl) -2- ( 4-chloro-phenyl) -ethyl] -methyl-amine, the title compound was obtained. 1 H-NMR (Me-d 3 -OD) δ 2.50 (3H, s), 2.90 (1H, dd) (1H, dd), 6.85 (1H, t), 6.90 (2H, d), 7.18 (2H, t), 7.40 (1H, 2H, d), 7.55 (2H, d), 7.93 (2H, s). EXAMPLE 49 2 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} -ethylamine

49A, (4-Bromo-phenyl) - (4-chloro-phenyl) -methanol OH

4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether) was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81 mmol) in tetrahydrofuran (25 ml) at 0 ° C, atmosphere. The reaction mixture was allowed to warm to room temperature and was 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 205 æL -1706385 1N HCI solution. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate / petroleum ether (1: 9), to afford the title compound (2.30 g). LC / MS: (PS-B3) Rt 3.49 [M-H3] + 297. 49B. 2- {2 - [(4-Bromo-phenyl) - (4-chloro-phenyl) -methoxy] -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 (560 mg, 2.94 mmol) in toluene (50 mL) was heated under reflux under Dean-Stark conditions for 17 h. On cooling, the solvent was removed and the residue partitioned between ethyl acetate and water. The organic layer was then dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (SiO4), eluting with ethyl acetate / petroleum ether (1: 4), to afford the title compound (1.95 g). LC / MS: (PS-B3) Rt 4.07 ion of unobservable mass. 49C. N- (2 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} -ethyl) -phthalamic acid ΡΕ1706385 206 ci

Following the procedure described in Example 42C, however substituting 2- {2 - [(4-bromo-phenyl) - (4-chloro-phenyl) -methoxy] -ethyl} -isoindole-1,3-dione for [2- (4-Bromo-phenyl) -2- (4-chloro-phenyl) -ethyl] -methyl-amine gave the title compound. LC / MS: (FS-A) Rt 2.85 [M-H] + 474. 49D. 2 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} -ethylamine

Hydrazide monohydrate (159.1, 3.28 mmol) was added in a solution of N- (2 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} (260 mg, 207 Ρ TE1706385 0.55 mmol) in methanol (6 ml) and the reaction mixture stirred at 80 ° C for 16 h. Upon cooling, the solvent was removed under reduced pressure and the crude product was purified by column chromatography (SiO2) eluting with dichloromethane: methanol: acetic acid (90: 18: 3: 2). Further purification by Phenomex-Trata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol afforded the desired product as a free base (120 mg). NMR (Me-d, -OD) δ 2.85 (2H, t), 3.55 (2H, t, J = ), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95 (2H, s). EXAMPLE 50 4- {4- [1- (4-Chloro-phenyl) -3-pyrrolidin-1-yl-propyl] -phenyl} -1H-pyrazole

Following the procedure described in Example 8, but substituting pyridine for methylamine gave the title compound. LC / MS: (PS-A2) Rt 2.25 [M + H] + 366. NMR (Me-d3-OD) [delta] 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). ΡΕ1706385 Example 51 4- {4- [3-Azetidin-1-yl-1- (4-chloro-phenyl) -propyl] -phenyl} -1H-pyrazole

Following the procedure described in Example 8, but substituting pyridine for methylamine gave the title compound. NMR (Me-ds-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). EXAMPLE 52

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

Following the procedure described in Example 8, but substituting 2-naphthylmagnesium bromide for 209 Å AND 1706385 4-chlorophenylmagnesium bromide, the title compound was obtained. NMR (Me-d 3 -OD) δ 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) > δ (4H, m), 8.70 (2H, s). EXAMPLE 53

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

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 4- (N, N-dimethyl) anilinomagnesium bromide gave the title compound. (M + H) + 335. NMR (Me-d 3 -OD) δ 2.46-2.60 (2H, m), 2.69 (3H, (2H, t), 3.27 (6H, s), 4.25 (2H, t), 7.45 (2H, d), 7.60-7.72 (6H, m) ), 8.50 (2H, s). EXAMPLE 54 {3- (4-Fluoro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine 210 ΡΕ1706385

Following the procedure described in Example 8, but substituting 4-fluorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. NMR (Me-d 3 -OD) δ 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). EXAMPLE 55 4- {4- [4- (4-Chloro-phenyl) -piperidin-4-yl] -phenyl} -1H-pyrazole-3-carbonitrile

Following the procedure of Example 1, but using 4- (4-Chloro-phenyl) -4- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2- yl) -phenyl] -piperidine in place of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and 211E1706385 4-bromo-1H-pyrazol- 3-carbonitrile instead of 2- (4-chlorophenyl) -2-phenylethylamine hydrochloride provided the title compound LC / MS: (PS-A2) Rt 2.22 [M + H] + 363. 1 H 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). EXAMPLE 56 3- (4-Phenoxy-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propylamine

Following the procedure described in Example 8, but substituting 4-phenoxyphenylmagnesium bromide for 4-chlorophenylmagnesium bromide and ammonia for methylamine, there was obtained the title compound LC / MS: (PS-A2) Rt 2.28 [M + H] + 370, 34. NMR (Me-d 3 -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, δδ 7.14 (1H, t), 7.30-7.39 (6H, m), 7.55-7.58 (2H, ), 7.90-7.97 (2H, br s), 8.54-8.60 (1H, br s). EXAMPLE 57 1 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methyl} -piperazine 212 ΡΕ1706385

Following the procedure described in Example 1, but substituting 1- (4,4'-dichloro-benzhydryl) -piperazine for 2- (4-chlorophenyl) -2-phenylethylamine hydrochloride there was provided the title compound LC / MS: (PS-B3) Rt 2.82 [MH] + 351.27. NMR (Me-d 3 -OD) δ 3.0-3.25 (4H, m), 3.45-3.65 (4H, m), 5.05-5.25 (1H, br s), 7 , 40-7.50 (2H, d), 7.65-7.83 (6H, m), 8.45 (2H, s). EXAMPLE 58 1-Methyl-4- {phenyl- [4- (1H-pyrazol-4-yl) -phenyl] methyl} - [1,4] diazepane

Following the procedure described in Example 1, but substituting 1- [p-chlorodiphenylmethyl] -4-methyl-1,4-diazacycloheptane hydrochloride for 2- (4-chlorophenyl) -2-phenylethylamine hydrochloride provided The title compound, LC-MS: (PS-B3) Rt 2.85 [M + H] + 347.18. 1 H NMR (Me-d 3 -OD) δ 2.25-2.60 (2H, brm), 3.00 (3H, s), 3.40-4.18 (8H, br m), 5.78 ( 1H), 7.40-7.48 (1H, m), 7.49-7.55 (2H, t), 7.75-7.80 (2H, d) 98 (4H, m), 8.32 (2H, s). EXAMPLE 59 {3- (3-Chloro-phenoxy) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine 59A. 1- (4-Bromo-phenyl) -3-chloro-propan-1-ol (J. Med. Chem, 2004, 47, 3924-3926)

To a solution of 1- (4-Bromo-phenyl) -3-chloro-propan-1-one (1g, 4.04 mmol) in tetrahydrofuran (9 mL) and water (0.58 mL) was added sodium borohydride , 16g, 4.28 mmol). The reaction mixture was stirred at room temperature for 2 h, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgSO 4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC / MS: (PS-A2) Rt 3.07 [M + H] + without ionization. 214 ΡΕ1706385 59Β. [3- (4-Bromo-phenyl) -3- (3-chloro-phenoxy) -propyl] -chloride

hcl XI

V

3-Chlorophenol was reacted with 1- (4-Bromo-phenyl) -3-chloro-propan-1-ol following the procedure set forth in Example 48B to provide the title compound which was used in the next step without more purification. 59C. [3- (4-Bromo-phenyl) -3- (3-chloro-phenoxy) -propyl] -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, employing a power of 50W. The solvent was removed and the crude product was purified through Phenomenex_Strata_SCX ion exchange column, eluting with methanol, followed by 2N ammonia in methanol. The product was purified by column chromatography (S102), eluting with dichloromethane 215 ΡΕ1706385 to dichloromethane: methanol: acetic: water (90: 18: 3: 2), using biotage SP4 to provide the title compound. LC / MS: (PS-B3) Rt 3.42 [M + H] + 356.19. 59D. {3- (3-Chloro-phenoxy) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine

[3- (4-Bromo-phenyl) -3- (3-chloro-phenoxy) -propyl] -methyl-amine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2- borolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-B3) Rt 2.80 [M + H] + 342.26. 1 H NMR (Me-d 3 -OD) δ 2.19-2.30 (1H, m), 2.30-2.45 (1H, m), 2.72 (3H, S), 3.10- (2H, m), 5.40-5.47 (1H, m), 6.80-6.88 (1H, d), 6.88-6.94 (1H, d) , 6.96 (1H, s), 7.15-7.20 (1H, t), 7.38-7.45 (2H, d), 7.57-7.65 (2H, d), 7 , 98 (2H, s). EXAMPLE 60

Methyl-2- {2-phenyl-2- [6- (1H-pyrazol-4-yl) -pyridin-3-yl] -ethyl} -amine 216 ΡΕ1706385 60 Ρ. 6- (3-methyl-1-trityl-1H-pyrazol-4-yl) -nicotinamide

N

II

To a solution of 6-chloro-nicotinonitrile (0.2 g, 1.49 mmol) and 3-methyl-1-trityl-1H-prazol-4-boronic acid (0.5 g, 1.36 mmol) in ethylene glycol dimethyl ether (3 mL) was added sodium carbonate (0.36 g, 3.39 mmol) in water (1.5 mL). The reaction mixture was degassed with nitrogen before the addition of tetrakis (triphenylphosphino) palladium (0) and then heated in a CEM microwave at 135øC for 30 minutes (50W potency). The reaction was partitioned between water and ethyl acetate, basified with water with 2N NaOH, the organic extracts were combined, dried (MgSO4) and the solvent removed. The crude product was suspended in small volume methanol, the white precipitate was filtered to provide the title compound (0.32 g, 53% yield). LC / MS: (PS-A2) Rt 4.52 [M + H] + 427.26. * This starting material can be produced by the method described in EP1382603A1. 60B, (4-chloro-phenyl) - [6- (3-methyl-1-trityl-1H-pyrazol-4-yl) -pyridin-3-yl] -methanone 217 ΡΕ1706385

To a solution of 6- (3-methyl-1-trityl-1H-pyrazol-4-yl) -nicotinonitrile (0.5 g, 1.17 mmol) in tetrahydrofuran (4 ml) was added 4-chlorobenzenemagnesium bromide , 52 mL, 1.52 mmol, 1M in diethyl ether); the reaction mixture was stirred under nitrogen for 16 hours. The reaction was quenched to a pH below 2 by the 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 (MgSO4), solvent removed and the residue purified by column chromatography (SiO2) eluting with petrol to ethyl acetate: petroleum ether (15:85) to afford the title compound (0.49 mg, yield 77%). LC / MS: (PS-A2) Rt 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 (1-phenyl-ethyl) - amine 218 ΡΕ1706385

n-Butyllithium (0.47 ml, 0.76 mmol, 1.6 M in Hexanes) was added dropwise in a solution of (R) (Diphenylphosphinoylmethyl) -methyl- (1-phenyl-ethyl) , 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, , 25 mmol) in tetrahydrofuran (0.9 ml) was added and the reaction mixture was stirred for another 30 minutes at -15øC before heating to room temperature for 1 hour. The reaction mixture was quenched with water, extracted with diethyl ether, the organic extracts were combined, dried (MgSO4) and concentrated to afford the title compound, which was used in the next step without further purification. * This starting material can be produced by the method described in Tetrahedron Asymmetry, 2003, 14, 1309-1316. 60D. Methyl- {2-phenyl-2- [6- (1H-pyrazol-4-yl) -pyridin-3-yl] -ethyl} -amine 219 ΡΕ1706385

In a solution of {2- (4-Chloro-phenyl) -2- [6- (3-methyl-1-trityl-1H-pyrazol-4-yl) -pyridin-3-yl] -vinyl} -methyl- ( 1-phenyl-ethyl) -amine in ethanol was added 10% by weight of palladium on activated carbon and the reaction mixture was subjected to an atmosphere of hydrogen for 17 h. The residue was purified by column chromatography (SiO2), eluting with dichloromethane: methanol: acetic acid: water (240: 20: 3: 2) to dichloromethane: methanol: acetic acid: water (90: 18: 3: 2) to give the title compound. LC / MS: (PS-A2) Rt 1.59 [M + H] + 293.18. 1 H NMR (Me-d 3 -OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (1H, t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80 (1H, s), 8 , 38 (1H, s). EXAMPLE 61 4- {4- [1- (4-Chloro-phenyl) -3-imidazol-1-yl-propyl] -phenyl} -1H-pyrazole-E1706385 220 61 °. 1- (4-bromo-phenyl) -3-imidazol-1-yl-propan-1-ol

HO

Br

Cl

HC

Br

O

A solution of 1- (4-Bromo-phenyl) -3-chloro-propan-1-ol (1.5 g, 6.01 mmol) and imidazole (1.23 g, 18.03 mmol) in dimethylformamide (18 ml) was heated at 100 ° C for 18 h, 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 provide the title compound (0.75 g, 44% yield). LC / MS: (PS-B3) Rt 2.48 [M +] + 281.14, 283.11. * This starting material can be produced by the method described in Example 43A. 6lB. 1- [4-Bromo-phenyl) -3- (4-chloro-phenyl) -propyl] -imidazole

Br br

Chlorobenzene (5 ml) was reacted with 1- (4-Bromo-phenyl) -3-imidazol-1-yl-propan-1-ol (0.41 mg, 1.46 mmol), followed by 221 ΡΕ1706385 if the procedure in Example 42B, to give the title compound (0.37 g, 67% yield). LC / MS: (ps-A2) Rt 2.40 [M + H] + 375.16, 377.17. 61C. 4- {4- [1- (4-Chloro-phenyl) -3-imidazol-1-yl-propyl] -phenyl} -1H-pyrazole

1- [3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) -propyl] -1H-imidazole was reacted with 4- (4,4,5,5-tetramethyl- dioxa-borolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. LC / MS: (PS-A2) Rt 2.21 [M +] + 363.28. 1 H NMR (Me-d 3 -OD) δ 2.55-2.70 (2H, m), 3.85-3.95 (1H, m), 3.95-4.10 (2H, m), 7 , 5 (1H, s), 7.10-7.60 (9H, m), 7.65 (1H, s), 7.90-8.00 (2H, d). EXAMPLE 62 4- [4- (3-Imidazol-1-yl-1-phenoxy-propyl) -phenyl] -1H-pyrazole 62A] - [3- (4-Bromo-phenyl) -3-phenoxy-propyl] -1H-imidazole 222 ΡΕ1706385

Phenol was reacted with 1- (4-Bromo-phenyl) -3-imidazol-1-yl-propan-1-ol following the procedure set forth in Example 48B to provide the title compound. LC / MS: (PS-A2) Rt 2.30 [M + H] + 357.26, 359.27. * This starting material can be produced by the method described in Example 47A. 62B 4- [4- (3-Imidazol-1-yl-1-phenoxy-propyl) -phenyl] -1H-pyrazole

1- [3- (4-Bromo-phenyl) -3-phenoxy-propyl] -1H-imidazole was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. NMR (Me-d 3 -OD) δ 2.30-2.55 (2H, m), 4.25 (1H, (2H, m), 5.10-5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s), 7.15-7, (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d), 7.85 (1H, s) , 7.95 (2H, s). ΡΕ1706385 223 EXAMPLE 63 4- {4- [4- (1H-Pyrazol-4-yl) -phenyl] -piperidin-4-yl} -phenol

Following the procedure described in Example 14, but substituting phenol for chlorobenzene using nitrobenzene as the solvent, the title compound was obtained. NMR (d6-DMSO) δ 7.97 (2H, s), 7.49 (2H, d), 7.25 (1H, (2H, d), 7.10 (2H, d), 6.68 (2H, d), 2.840 (4H, bs), 2.366 (4H, bs). EXAMPLE 64 1 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methyl} -piperazine

Following the procedure described in Example 57, the title compound was obtained. LCMS: (PS-A3) Rt 6.38 [M + H] + 319. NMR (Me-d3-OD) δ 8.53 (2H, s), 7.90 (2H, d), 224 Îμ17063857, (2H, d), 7.40-7.30 (3H, m), 5.70 (1H, s), 3.68 (4H, bs), 3.51 3.48 (4H, m). EXAMPLE 65 {2- (4-Fluoro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine 65A. [2- (4-Bromo-phenyl) -2- (4-fluoro-phenyl) -ethyl] -carbamic acid benzyl ester

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 added sequentially triethylamine (561 μ, 4.02 mmol) in acetone (1.6 mL) and ethyl chloroformate (43 μL, 4.64 mmol) in acetone (1.6 mL). The reaction was allowed to warm to room temperature, stirred for 30 minutes before being cooled again 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 addition of water (10 ml) and diethyl ether (10 ml). The aqueous layer was separated and further extracted with ethyl acetate (10 ml). The combined organic liquors were washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in anhydrous toluene (12 mL) prior to the addition of benzyl alcohol (567 μL, 9.27 mmol) and heating at 80 ° C for 40 minutes. The reaction was allowed to cool to room temperature before the addition of ethyl acetate (50 ml) and saturated sodium bicarbonate (50 ml). The organic liquors were separated and washed with more bicarbonate solution (50 ml), hydrochloric acid (2N, 100 ml) and saturated brine (50 ml) before drying (MgSO4) and concentration in vacuo. The residue was purified by column chromatography (SiO2), eluting with ethyl acetate / petrol gradient (5:95), to provide the title compound (594 mg, 45%). LCMS: (PS-A2) Rt 3.18 Sem

Ionization.

This starting material can be produced by the method described in Example 8A at 8C, substituting 4-fluorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide. 65B. {2- (4-Fluoro-phenyl) -2- [4- (1H-pyrazol-4-yl] -phenyl] -ethyl} -carbamic acid benzylic acid benzyl ester.

N-N H

F

[2- (4-Bromo-phenyl) -2- (4-fluoro-phenyl) -ethyl] -carbamic acid benzyl ester was reacted with 4- (4,4,5,5-tetrazol-1,3,2- dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to provide the title compound. (4-Fluoro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -piperazin- -ethyl} -methyl-amine

F

The title compound was prepared according to the procedure described in Example 1. The title compound was prepared according to the procedure described in Example 1, using a solution of lithium aluminum hydride (5.3 ml, 5.30 mmol, 1M in tetrahydrofuran) yl) -phenyl] -ethyl} -carbamic acid tert-butyl ester (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 (2 x 20 ml). The combined organic liquors were washed with saturated aqueous brine, then dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO 2) eluting with dichloromethane: methanol: acetic: water (120: 15: 3: 2) to (90: 18: 3: 2) gradient to provide the title compound, which was subsequently converted to the hydrochloride salt (100 mg, 32%). LC / MS: (PS-A2) ΡΕ1706385 227

NMR (Me-d 3 -OD) δ (2 H, d), 7.34-7.29 (4H, m), 7.02 (2H, 2H), 2.65 (3H, s), 8.20 (2H, s), 7.57 (t), 4.32 (1H, t) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine

Following the procedure described in Example 65, but substituting 3-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide, the title compound was obtained. LC / MS: (PS-A3) Rt 4.92 [M + H] + 312. 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). EXAMPLE 67 4- [4- (2-Methoxy-ethoxy) -phenyl] -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine 67A. 4- (4-Bromo-phenyl) -4- (4-hydroxy-phenyl) -piperidine-1-carboxylic acid tert-butyl ester 228 ΡΕ1706385

Following the procedure described in Example 47B, but substituting 4- [4- (4-Bromo-phenyl) -piperidin-4-yl] -phenol * with 4- [1- (4-Bromo-phenyl) - 2-methylamino-ethyl] -phenol, the title compound was obtained. 1 H NMR (d 6 -DMSO) δ 7.45 (2H, d), 7.25 (2H, d), 7.11 (2H, d), 6.68 (2H, d) 18 (4H, m), 2.31-2.20 (4H, m), 1.38 (9H, s). * This starting material can be produced by the method described in example 63. 67B. 4- (4-Bromo-phenyl) -4- [4- (2-methoxy-ethoxy) -phenyl] -piperidine-1-carboxylic acid tert-butyl ester

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 at 50 ° C for 30 minutes using a power of 50 229 ΡΕ1706385 watts . The reaction was poured into sodium hydroxide (2N, 4 mL), stirred for 5 minutes, then extracted into ethyl acetate (2 x 30 mL). The combined organic liquors were dried (MgSO4), concentrated and the residue purified by column chromatography (SiO2) eluting with ethyl acetate / petrol gradient (25:75) to (50:50) to provide the title compound. (82 mg). LCMS: (PS-A2) Rt 4.00 [M + H] + 490. 4- [4- (2-Methoxy-ethoxy) -phenyl] -4- [4- (1H-pyrazol-4-yl) -phenyl-piperidine

4- (4-Bromo-phenyl) -4- [4- (2-methoxy-ethoxy) -phenyl] -piperidine-1-carboxylic acid tert-butyl ester was reacted with 4- (4,4,5- 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, substituting tetracis triphenylphosphine palladium (0) as the catalyst, the title compound was obtained. LC / MS: (PS-A2) Rt 3.27 [M + H] + 478. 4- [4- (2-Methoxy-ethoxy) -phenyl] -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine 230 ΡΕ1706385

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 was concentrated. The residue was dissolved in ethyl acetate, then extracted into hydrochloric acid (2N, 2 x 20 ml). The combined aqueous fractions were washed with ethyl acetate, then basified (2N NaOH) before back-extracting in ethyl acetate (2 x 20 mL). The combined organic liquors were washed with saturated brine, then dried (MgSO4) and concentrated to give the title compound (66 mg). LCMS: (PS-A3) Rt 6.08 [M + H] + 378. 1 H NMR (Me-d 3 -OD) δ 7.92 (2H, s), 7.51 (2H, d), 7.31 (2H, t), 3.73 (2H, t), 3.42 (3H, s), 7.25 (2H, d) , 2.94 (4H, bs), 2.44 (4H, bs). EXAMPLE 68 4- [4- (3-Methoxy-propoxy) -phenyl] -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine 68A. 4- (4-Bromo-phenyl) -4- [4- (3-methoxy-propoxy) -phenyl] -piperidine-1-carboxylic acid tert-butyl ester 231 ΡΕ1706385

Tosyl chloride (572 mg, 3.0 mmol) was added to a solution of 3-methoxypropanol (191 μg, 2.0 mmol) in pyridine (1 mL). This was stirred at room temperature for 5.5 h, then diluted with ethyl acetate (20 ml) and washed with hydrochloric acid (2N, 3 x 10 ml) and saturated brine (10 ml). The liquors were dried (MgSO4) and concentrated to provide 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 phenyl) -piperidine-1-carboxylic acid methyl ester (100 mg, 0.231 mmol). The resulting mixture was stirred at 100 ° C for 4 h. Once cooled, water (20 ml) was added and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic liquors were washed with brine (10 mL) before drying (MgSO4) and concentration. The residue was purified by column chromatography (SiO2), eluting with a gradient of 10-20% ethyl acetate / petrol, to provide the title compound as a colorless oil (131 mg). LCMS: Rt 4.20 [M + H] + 504. This starting material can be produced by the method described in Example 67A. 232 ΡΕ1706385 68Β. 4- [4- (3-Methoxy-propoxy) -phenyl] -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

Following the procedure described in Example 67C and 67D, but substituting 4- (4-Bromo-phenyl) -4- [4- (3-methoxy-propoxy) -phenyl] -piperidinoic acid tert -butyl ester (4-Bromo-phenyl) -4- [4- (2-methoxy-ethoxy) -phenyl] -piperidine-1-carboxylic acid tert-butyl ester, there was obtained title. LCMS: Rt 6.65 [M + H] + 392. NMR (Me-d 3 -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, , 24-3.22 (4H, m), 2.67-2.66 (4H, m). EXAMPLE 69 3- (3,4-Picloro-phenyl) -3- [4- (1H-pyrazol-4-yl) phenyl] -propionamide

233 ΡΕ1706385

Following the procedure described in Example 9A and 9B, but substituting 3,4-dichlorophenylmagnesium bromide for 3,4-difluorophenylmagnesium bromide, the title compound was obtained. LC / MS: (PS-A3) Rt 9.82 [M + H] + 360.14, 362.12. 1 H NMR (Me-d 3 -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) EXAMPLE 70 2- (4- {2- -Methylamino-1- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -phenoxy) -isonicotinamide

Following the procedure described in Example 47, but substituting 2-chloro-4-cyanopyridine for 2-chloropyrazine, the title compound was obtained. LC / MS: (PS-B3) Rt 2.27 [M + H] + 414. 1 H NMR (Me-d 3 -OD) δ 2.45 (3H, s), 3.55 (1H, (1H, d), 7.10 (2H, d), 7.30-7.38 (3H, m), 7.40 (2H, d) (1H, d), 7.56 (2H, d), 7.95 (2H, s), 8.22 (1H, d). ΡΕ1706385 234 EXAMPLE 71 {2- (4-Chloro-phenoxy) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine

Following the procedure described in Example 48, but substituting 4-chlorophenol for phenol, the title compound was obtained. NMR (Me-d 3 -OD) δ 2.50 (3H, s), 2.86 (1H, dd) (2H, d), 7.50 (1H, dd), 5.35 (1H, dd), 6.89 (2H, d), 7.17 2H, d), 7.93 (2H, s). EXAMPLE 72 3- (2- (4-Oloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamino} -propan-1-ol

235 ΡΕ1706385

Following the procedure described in Example 20, but substituting dimethyl amine for 3-aminopropan-1-ol, the title compound was obtained. LC / MS: (PS-A2) Rt 2.05 [M + H] + 356. 1H. NMR (Me-d 3 -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). EXAMPLE 73 2- {2-4-Chloro-phenyl) -2- [4-1H-pyrazol-4-yl) -phenyl-

Following the procedure described in Example 20, but substituting dimethyl amine for 2-aminoethan-1-ol, the title compound was obtained. LC / MS: (PS-A2) Rt 2.05 [M + H] + 342. 1 H NMR (Me-d 3 -OD) δ 1.98 (AcOH, s), 3.10 (2 H, s), (2H, t), 4.39 (1H, t), 7.36 (2H, d), 7.38 (4H, s), 7.61 (2H, , d), 7.97 (2H, s). EXAMPLE 74 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -cyclopropylmethyl-amine 236 ΡΕ1706385

Following the procedure described in Example 20, however substituting dimethylamine for cyclopropylmethyl amine, the title compound was obtained. (M + H) + 352. 1RMN (Me-d 3 -OD) δ -0.4 - 0.3 (2H, m), 0.35-0, (2H, m), 2.78 (1H, m), 2.42 (2H, d), 3.15-3.25 (2H, m) ), 7.16-7.27 (6H, m), 7.45 (2H, d), 7.82 (2H, s). EXAMPLE 75

Methyl- [2- [4- (1H-pyrazol-4-yl) -phenyl] -2- (4-pyridin-3-yl-phenyl) -ethyl] -amine

Following the procedure described in Example 1, however substituting 4- (4,4,5,5-Tetramethyl-11,3,2] dioxaborolan-2-yl) -pyridine for 4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and coupling to {2- (4-methyl-1H-im]

Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine, the title compound was obtained. 1 H NMR (Me-d 3 -OD) δ 1.94 (AcOH, s), 2.72 (3 H, s), 3.72 (3H, (2H, d), 7.61 (2H, d), 4.46 (1H, t), 7.41 (2H, d), 7.51-7.56 (3H, (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d). * This starting material can be produced by the method described in Example 21. EXAMPLE 76 4- {3-Methylamino-1- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -phenol

Following the procedure described in Example 8, but substituting 4-anisylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound can be obtained. 1 H-NMR (Me-d 3 -D O) δ 1.92 (AcOH, s), 2.34-2.43 (2H, m) (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). EXAMPLE 77 3- (4-Methoxy-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propylamine 238 ΡΕ1706385

Following the procedure described in Example 8, but substituting 4-anisylmagnesium bromide for 4-chlorophenylmagnesium bromide and ammonia for methylamine (2M in methanol), the title compound was obtained. LC / MS: (PS-A2)

NMR (Me-d 3 -OD) δ 2.23-CN CN CN (2H, m) 2.74 (2H, dd), 3.65 (3H, (2H, d), 7.71 (2H, s), 7.17 (2H, d), 7.41 (2H, d), 7.71 (2H, s), 8.41 (HC02H, br s). EXAMPLE 78 4- (4-Chloro-phenyl) -4- [4- (3-methyl-1H-pyrazol-4-yl) -phenyl] -piperidine 78A. 4- (4-Chloro-phenyl) -4- [4- (3-methyl-1-trityl-1H-pyrazol-4-yl) -phenyl] -piperidine

4- (4-Bromo-phenyl) -4- (4-chloro-phenyl) -piperidine hydrochloride was reacted with 3-methyl-1-trityl-1H-pyrazole-4-boronic acid *, followed by the procedure set forth in Example 1, but using tetracis (triphenylphosphino) palladium (0) as the catalyst, to provide the title compound. LC / MS: (PS-B3) Rt 2.78 min [M + H] + 594. This starting material can be produced by the method described in EP 1382603 78B. 4- (4-Chloro-phenyl) -4- [4- (3-methyl-1H-pyrazol-4-yl) -phenyl] -piperidine

A suspension of 4- (4-chloro-phenyl) -4- [4- (3-methyl-1-trityl-1H-pyrazol-4-yl) -phenylpiperidine (178 mg, 0.30 mmol) in 5N hydrochloric acid (5mL), THF (5mL) and methanol (5mL) was stirred for 140 minutes. The organic solvents were removed in vacuo, then the resulting solution was diluted with 2N HCl and washed with ether. The aqueous phase was basified by the addition of sodium hydroxide pellets, then extracted with ethyl acetate. This organic extract was washed with brine, dried (MgSO4), filtered and concentrated to provide a residue, which was purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) and dichloromethane. 240 ΡΕ1706385 The product was further purified by preparative HPLC to afford the title compound, which was converted to its dihydrochloride salt (84 mg, 80%); LCMS (PS-A3) Rt 6.86 min [M + H] + 352. 1RMN (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). EXAMPLE 79 2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -morpholine 79A. 2- (4-Chloro-phenyl) -2- (4-iodo-phenyl) -oxirane

Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placed in N2, then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g, 3.2 mmol) was added as a solid after 15 min, followed, after a further 30 min, by (4-chloro-phenyl) - (4-iodo-phenyl) -methane. The mixture was stirred at room temperature for 24 h, then diluted with ethyl acetate and washed with 1: 2 water / brine, water and brine (x2). The organic phase was dried (MgSO4), filtered and concentrated to afford 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- (4-Chloro-phenyl) -2- (2-hydroxy-ethylamino) -1- (4-iodo-phenyl) -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 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated potassium carbonate / water solution (1: 9). The aqueous phase was extracted a second time with ethyl acetate, then the combined extracts were washed with brine, 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-phenyl) -2- (4-iodo-phenyl) -morpholine

242 ΡΕ1706385

A solution of 1- (4-chloro-phenyl) -2- (2-hydroxy-ethylamino) -1- (4-iodo-phenyl) -ethanol (701 mg, 1.68 mmol) in DCM (10 mL) was treated with H2 SO4> 4 (0.1 mL, 1.9 mmol). After 20 hours, another portion of H 2 SO 4 (1.0 mL, 19 mmol) was added and the mixture stirred for an additional 2 hours. The mixture was diluted with ethyl acetate and washed with saturated potassium carbonate and brine, then dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (SiO2) eluting with 0.5% triethylamine and ethyl acetate to give the title compound (290 mg, 43%); LCMS (PS-A2) Rt 2.40 min [M + H] + 400. 79D .2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -morpholine

2- (4-chloro-phenyl) -2- (4-iodo-phenyl) -morpholine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H pyrazole, following the procedure set forth in Example 1, but using tetracis (triphenylphosphine) palladium (0) as the catalyst to provide the title compound. LCMS (PS-A3) Rt 6.88 min [M + H] + 340. 1RMN (Me-d3-OD) 243 ΡΕ1706385 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, br.s). EXAMPLE 80

(4- {4- [4- (1H-Pyrazol-4-yl) -phenyl] -piperidin-4-yl} -phenoxy) -acetic acid methyl ester and (4- {4- [4- (4-Bromo-4-yl) -phenyl] -piperidin-4-yl} -phenoxy) -acetic acid ethyl ester 80A, {4- [4- (4-Bromo-phenyl) -piperidin- -phenoxy} -acetic acid

EtOAc:

+

Following the procedure described in Example 42B, but substituting chloro-benzene for ethyl phenoxyacetate and using nitrobenzene as the solvent, the title compound was obtained. LCMS (PS-A2) Rt 2.37 min [M + H] + 418. 80B. (4- {4- [4- (1H-Pyrazol-4-yl) phenyl] -piperidin-4-yl} -phenoxy) -acetic acid methyl ester and (4- {4- [4- pyrazol-4-yl) -phenyl] -piperidin-4-yl} -phenoxy) -acetic acid methyl ester 244 ΡΕ1706385

Et02C

{4- [4- (4-Bromo-phenyl) -piperidin-4-yl] -phenoxy} -acetic acid ethyl ester was reacted with 4- (4,4,5,5-tetramethyl- dioxaborolan-2-yl) -pyrazole following the procedure set forth in Example 1, but using tetracis (triphenylphosphine) palladium (0) as the catalyst and heating at 80 ° C for 30 min to afford a mixture of the title compounds. In the preparation, the basic aqueous extract was neutralized with hydrochloric acid and extracted with ethyl acetate (x2), then these organic extracts were combined and washed with brine, dried (MgSO4), filtered and concentrated to provide a crude product which was Recrystallized from water to give (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. 1 H NMR (DMSOd 6) δ 2.22-2.26 (4H, m), 2.67-2.71 (4H, (2H, d), 7.11 (2H, d), 7.24 (2H, d), 7.46 (2H, 96 (2H, br.s). The material which was not extracted on base was converted to methanol in simple compound, {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -phenoxy) -acetic. This was purified by preparative HPLC to provide the title compound (18 mg, 7%); (M + H) + 392. 1 H NMR (Me-d 3 -D) 2.34-2.45 (4H, m), 2.87 (4H, (2H, d), 7.21 (2H, d), 7.26 (2H, d), 7.47 (2H, d), 7.89 (2H, s). EXAMPLE 81 4- {4- [4- (1H-Pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzonitrile 81A. 4- (4-chloro-phenyl) -4- (4-iodo-phenyl) -piperidine

Following the procedure described in Example 42B, but substituting chlorobenzene for iodobenzene, the title compound was obtained. LCMS (PS-A2) 2.68min [M + H] + 398.81B. 4- [4- (4-Chloro-phenyl) -piperidin-4-yl] -benzo nitrile

Cl Cl 246 ΡΕ1706385

A mixture of 4- (4-chloro-phenyl) -4- (4-iodo-phenyl) -piperidine and copper (I) cyanide in DMF was heated at 140 ° C under nitrogen for 6 h, then cool. The mixture was diluted with ethyl acetate, washed with a conc. and brine (x 5), dried (MgSO 4), filtered and concentrated to afford a residue which was partially purified by column chromatography (SiO 2), eluting with a gradient of 2M ammonia in methanol (5% to 10%) and dichloromethane , to provide the title compound (46 mg, < 16%). This was taken to the next reaction without further purification. LCMS (PS-A2) Rt 2.39 min [M + H] + 297. 81C. 4- {4- [4- (1H-Pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzonitrile

4- [4- (4-chloro-phenyl) -piperidin-4-yl] -benzylamine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) (triphenylphosphine) palladium (0) was prepared as the catalyst and heating at 100 ° C for 15 minutes afforded the title compound. LCMS (PS-A3) Rt 6.68 min [M + H] + 329. NMR (Me-d3-OD) [delta] 2.65-2.73 (4H, 247 Î'E1706385 m), 2.77-2, (2H, d), 7.68 (2H, d), 7.71 (2H, d) d), 8.42 (2H, br.s) EXAMPLE 82 {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine 82A. Bis (4-chloro-phenyl) -acetic acid methyl ester

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 the addition of 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 brine, dried (MgSO 4), filtered and concentrated to provide the residue, which was purified by column chromatography (SiO 2), eluting with 10% ethyl acetate / petrol, to provide the title compound as a colorless oil (3.57 g, 78%); LCMS (PS-B3) Rt 3.79 min, No Ionization. 1 H NMR (CDCl 3) δ 3.74 (3H, s), 4.96 (1H, s), 7.20-7.23 (4H, m), 7.28-7.32 (4H, m) . 248 ΡΕ1706385 82Β. 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 minutes, then after a further 20 minutes, iodomethane (0.63 mL, 10.1 mmol) was added. added. After 4 hours, the reaction was quenched by the 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 / petrol 1: 4 and washed with saturated ammonium chloride solution, then brine, dried (MgSO4), filtered and concentrated to provide a residue which was purified by column chromatography (SiO2) eluting with a gradient of ethyl acetate / petrol (1% to 2%), to provide the title compound as a colorless oil (210 mg, 17%); LCMS (PS-B3) Rt-1 Omin, No Ionization. NMR (CDCl 3)? 1.88 (3H, s), 3.73 (3H, s), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m). ΡΕ1706385 249 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 at room temperature for 5 days, then concentrated in vacuo. The residue was partitioned between ethyl acetate and 2N hydrochloric acid, then the organic phase was washed with brine, dried (MgSO 4), filtered and concentrated to give the title compound (186 mg, 93%) as a yellow solid, which was used without further 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 ) -propionic acid, the title compound was obtained. LCMS (PS-B3) Rt 3.40 min [M + H] + 308. ΡΕ1706385 250 82E. [2,2-Bis-4-chloro-phenyl) -propyl] -methyl-amine

Cl

N H

Cl

N H

Cl

Cl

Following the procedure described in Example 8E, but substituting 3- (4-Bromo-phenyl) -3- (4-chloro-phenyl) -2,2- bis- (4-chlorophenyl) -N- -phenyl) -N-methyl-propionamide, the title compound was obtained. LCMS (FL-A) Rt 2.35 min [M + H] + 294. 82F. {2- (4-Chloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine

N-N H

[2,2-Bis- (4-chloro-phenyl) -propyl] -methyl-amine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H -pyrazole, following the procedure set forth in Example 1, to provide the title compound. LCMS (PS-A3) Rt 6.94 251 ΡΕ1706385 min [M + H] + 326. 1 H NMR (Me-d 3 -OD) δ 1.86 (3H, s), 2.77 (3H, s), 3 (2H, d), 8.35 (2H, d, J = 8Hz), 8.68 (2H, s) . EXAMPLE 83 1- (4-Chloro-phenyl) -2-methylamino-1- [4- (1H-pyrazol-4-yl) -phenyl] -ethanol

H

Following the procedure described in Example 79A, 79B and 79D, but substituting methylamine with ethanolamine gave the title compound. LCMS (PS-A3) Rt 5.28 min [M + H] + 328. [M-H20 + H] + 310. 1 H NMR (Me-d 3 -OD) δ 2.38 (3H, s) (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, 2H, s). EXAMPLE 84 2-Amino-1- (4-chloro-phenyl) -1- [4- (1H-pyrazol-4-yl) -phenyl] -ethanol 84A. 2- [2- (4-Chloro-phenyl) -2-hydroxy-2- (4-iodo-phenyl) -ethyl] -isoindole-1,3-dione ΡΕ1706385 252 Ο

The 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 ) and DMSO (2 mL) was heated at 100 ° C for 20 h. The mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water and brine (x2), dried (MgSO4), filtered and concentrated to give a crude product, which was purified by column chromatography (SiO2), eluting with ethyl acetate / petrol gradient (2.5% to 100%), then 10% methanol / dichloromethane, to provide the title compound (273 mg, 34%); LCMS (PS-A2) Rt 3.22 min [M + H] + 504.

* This starting material can be produced by the method described in Example 79A 84B. N- {2- (4-Chloro-phenyl) -2-hydroxy-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -phthalamic acid

2- [4-Chloro-phenyl) -2-hydroxy-2- (4-iodo-phenyl) -ethyl] -isoindole-1,3-dione was reacted with 4- (4,4- 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, but using tetrakis (triphenylphosphine) palladium (0) as the catalyst, for to give the title compound. LCMS (PS-A2) Rt 2.62 min [M-H] - 460. 2-Amino-1- (4-chloro-phenyl) -1- [4- (1H-pyrazol-4-yl) -phenyl] -ethanol

Following the procedure described in Example 49D, but substituting N- {2- (4-chloro-phenyl) -2-hydroxy-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl } -phthalamic acid for N- (2 - {(4-Chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} -ethyl) -phthalamic acid, there was obtained the title compound . LCMS (PS-A3) Rt 6.29 min [M-H2O + H] + 296. 1 H NMR (Me-d 3 -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). EXAMPLE 85 4- (3,4-Dichloro-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

Following the procedure described in Example 14, but substituting chloro-benzene for 1,2-dichlorobenzene, the title compound was obtained. LCMS (PS-B4) Rt 7.20 min [M + H] + 372. 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 (1H, dd), 7.46-7.52 (3H, m), 7.53 (1H, d), 7.72 (2H, d), 8.56 (2H, s). EXAMPLE 86 4- (3-Chloro-4-methoxy-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

255 ΡΕ1706385

Following the procedure described in Example 14, but substituting chlorobenzene for 2-chloroanisole, the title compound was obtained. LCMS (PS-B4) Rt 6.24 min [M + H] + 36. NMR (Me-d3-OD) δ 2.62-2.75 (4H, m), 3.23 (4H, apparent t) (1H, d), 7.30 (1H, dd), 7.34 (1H, d), 7.45 (2H, d), 7.69 (1H, 2H, d), 8.57 (2H, s). EXAMPLE 87 4- (4-Chloro-3-fluoro-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine 87A, 4- (4-Chloro- -3-fluoro-phenyl) -4-hydroxy-piperidine-1-carboxylic acid

OH

A solution of 4-chloro-3-fluorophenylmagnesium bromide (15 mL, 7.5 mmol, 0.5 M in THF) was added, in nitrogen, to 4-oxo-piperidine- 1-carboxylic acid (1.02 g, 5.1 mmol). After 24 h, a saturated ammonium chloride solution was added, then the organic solvent was removed in vacuo. The mixture was extracted with ethyl acetate, then this extract was washed with brine, dried (MgSO 4), filtered and concentrated to provide a residue which was purified by column chromatography (S 1 O 2), eluting with a gradient of 256 æE1706385 ethyl acetate / petrol (0% to 20%) to provide the title compound (511 mg, 30%). NMR (Me-d 3 -OD) δ 1.48 (9H, s), 1.67 (2H, br.d), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99 (2H, br.d), 7.27 (1H, dd), 7.38 (1H, dd), 7.42 (1H, t). 87B. 4- (4-Bromo-phenyl) -4- (4-chloro-3-fluoro-phenyl) -

Following the procedure described in Example 42B, but substituting chlorobenzene for bromobenzene, the title compound was obtained. LCMS (PS-A2) Rt 2.43 min [M + H] + 368. 87C. 4- (4-Chloro-3-fluoro-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

4- (4-Bromo-phenyl) -4- (4-chloro-3-fluoro-phenyl) -piperidine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxol-257 ΡΕ1706385 2-yl) -1H-pyrazole, following the procedure set forth in Example 1, but using tetrakis (triphenylphosphine) palladium (0) as the catalyst, to give the title compound. LCMS (PS-A3) Rt 7.11 min [M + H] + 356. 1 H NMR (Me-d 3 -OD) δ 2.62-2.80 (4H, m), 3.18-3.30 partially overlap with solvent, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30 (1H, dd ), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s). EXAMPLE 88 4- {4- (1H-Pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzoic acid 88A. 4- (4-Carboxyphenyl) -4- (4-chloro-phenyl) -piperidine-1-carboxylic acid tert-butyl ester

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-butyllithium (1.5 mL, 1.6 M in hexanes) was added dropwise and the mixture maintained at this temperature for 25 minutes. Carbon dioxide gas (generated from ice and dried by passage through a column of calcium chloride pellets) was bubbled through the anionic solution for 80 minutes, 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 also being dried (MgSO4), filtered, combined with ethereal extract and concentrated to provide 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 produced by the method described in Example 14A, followed by Example 48A. 88B. 4- (4-Carboxy-phenyl) -4- [4- (1H-pyrazol-4-1-phenyl] -piperidine-1-carboxylic acid tert-butyl ester

4- (4-Carbóxy-259α, 17β-phenyl) -4- (4-chloro-phenyl) -piperidine-1-carboxylic acid tert-butyl ester was reacted with 4- (4,4,5,5-tetramethyl- 3,2-dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, to give the title compound. LCMS (PS-A2) Rt 2.92 min [M + H] + 448. 88C. 4- [4- [4- (1H-Pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzoic acid

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 afford the title compound as the dichloride salt (22 mg, 90%); NMR (Me-d 3 -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). EXAMPLE 89 4 - [4- (1H-Pyrazol-4-yl) -phenyl] -1,2,3,4,5,6-hexahydro- [4,4 '] bipyridinyl 260 ΡΕ170638589Α. 4- (4-Chloro-phenyl) -3,4,5,6-tetrahydro-2H- [4,4 '] bipyridinyl-1-carboxylic acid tert -butyl ester

In nitrogen, a solution of bis- (2-chloroethyl) -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 two minutes later by a solution of sodium hexamethyldisilazide (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0 ° C for 3.5 h, then allowed to warm to room temperature and stirred for a further 20 h. Methanol was added, then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (x3) and brine, dried (MgSO4), filtered and concentrated to provide a residue which was purified by column chromatography (S102), eluting with gradient 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2) eluting with 50% ethyl acetate / petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M + H] + 373. This starting material can be produced by the method described in J. Chem. Soc., Perkin Trans., 1, 2000, p. 3444-3450 261 ΡΕ1706385 89Β. 4- [4- (1H-Pyrazol-4-yl) -phenyl] -1,2,3,4,5,6-hexahydro- [4,4 '] bipyridinyl

4- (4-Chloro-phenyl) -3,4,5,6-tetrahydro-2H- [4,4 '] bipyridinyl-1-carboxylic acid tert -butyl ester was reacted with 4- (4,4,5- , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, following the procedure set forth in Example 1, followed by treatment with 4M HCl in dioxane to provide the title compound. LCMS (PS-B4) Rt 4.28 min [M + H] + 305. 1 H NMR (Me-d 3 -OD) δ 2.76 (2H, br.t), 3.01 (2H, br.d) , 3.29 (2H, br.d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d), 8.37 (2H, s), 8.82 (2H, d). EXAMPLE 90 3- (3-Chloro-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propylamine

Following the procedure described in Example 8, 262 ΡΕ1706385 but substituting 3-chlorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide and ammonia for methylamine, the title compound was obtained. LCMS (PS-B3) Rt 2.60 min [M + H] + 312. 1 H NMR (Me-d 3 -OD) 2.44 (2H, apparent qd), 2.87 (2H, (2H, m), 7.34 (1H, t), 7.42 (2H, d), 7.68 (1H, (2H, d), 8.58 (2H, s). EXAMPLE 91 2-Methylamino-1- (4-nitro-phenyl) -1- [4- (1H-pyrazol-4-yl) -phenyl] -ethanol

Following the procedure described in Example 83, however substituting (4-bromo-phenyl) - (4-nitro-phenyl) -methanone for (4-chloro-phenyl) - (4-iodo-phenyl) -methanone, the title compound was obtained. NMR (Me-d 3 -OD) δ 8.27 (2H, d), 7.98 (2H, s), 7.80 (2H, d, J = ), 7.65 (2H, d), 7.52 (2H, d), 4.00 (2H, dd), 2.73 (3H, s) . EXAMPLE 92 2- (3-Chloro-4-methoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine 263 ΡΕ1706385

Following the procedure described in Example 87B and Example 42C, but substituting 2-amino-1- (4-bromo-phenyl) -ethanol and chlorobenzene for 1- (4-bromo-phenyl) -2- chloroanisole, the title compound LCMS (PS-B3) Rt 2.55 [M + H] + 328, 20. NMR (Me-d3-OD) δ 3.65-3.70 (2H, d), 3.90 (3H, s), 4.30-4.35 (1H, t), 7.05-7.10 (1H, d), 7.30-7.35 (1H, d) , 7.40 (1H, s), 7.45-7.50 (2H, d), 7.70-7.75 (2H, d), 8.60 (2H, s). EXAMPLE 93 2- (4-Chloro-phenyl) -2-fluoro-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine 93A. 2,2-Bis- (4-chloro-phenyl) -2-fluoro-ethylamine

OH

Cl > NH,

F

NH,

Cl

Cl 2 -Amino-1,1-bis- (4-chloro-phenyl) -ethanol (293 mg, 264 æE1706385, 1.04 mmol) was dissolved in pyridine-HF (2 ml) with cooling. After 24 h, the mixture was diluted with 1N sodium hydroxide solution and extracted with DCM (x3). Each extract was dried (MgSO4) and filtered before being combined and concentrated to provide a residue which was purified by column chromatography (SiO2) eluting with 0.5% triethylamine in ethyl acetate to afford the title compound ( 192 mg, 65%); LCMS (PS-B3) Rt 3.34 min [M-F -] + 266. NMR (DMSO-d 6) δ 3.41 (2H, d), 7.39-7.46 (8H, m). 93B, 2- (4-Chloro-phenyl) -2-fluoro-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine

nh2

(4-chloro-phenyl) -2-fluoro-ethylamine was reacted with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- pyrazole following the procedure set forth in Example 1, except heating was carried out at 100 ° C for 5 minutes, using a power of 300W in a CEM microwave to give the title compound. NMR (Me-d 3 -OD) δ 4.04 (2H, d), 7.47-7.55 (6H, m) , 7.77 (2H, d), 8.41 (2H, d). 265 ΡΕ1706385 EXAMPLE 94 3- (3,4-Dichloro-phenyl) -3- [6- (1H-pyrazol-4-yl) -pyridin-3-yl] -propylamine

Following the procedure described in Example 60 but substituting 6-chloro-nicotinonitrile for 6-chloro-pyridine-3-carbaldehyde and substituting 3-methyl-1-trityl-1H-pyrazole-4-boronic acid for -ethyl-1H-pyrazole-4-boronic acid, and then following the procedure described in Example 8, the title compound could be obtained. EXAMPLE 95 2- (4-Chloro-3-fluoro-phenyl) -2- [4- (1H-pyrazol-4-yl) phenyl] -ethylamine

Following the procedure described in Example 87, but substituting 4-oxo-266α-androstane-1-carboxylic acid tert-butyl ester for (2-oxo-ethyl) -carbamic acid tert -butyl ester, the compound of the title could be obtained. EXAMPLE 96 4- (2-Chloro-3-fluoro-phenyl) -4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidine

Following the procedure described in Example 14, but substituting 1-chloro-2-fluoro-benzene for chlorobenzene, the title compound could be obtained. EXAMPLE 97 1 - {(3,4-Dichloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methyl} -piperazine 97A. (4-Chloro-phenyl) - (3,4-dichloro-phenyl) -methanol

Cl

Cl 267 ΡΕ1706385

Commercially available chlorophenyl magnesium bromide and 3,4-dichloro-benzaldehyde may react with each other according to the method described in J Medicinal Chem., (2000), 43 (21), 3878-3894, to provide the title compound . 97B. 1,2-Dichloro-4- [chloro- (4-chloro-phenyl-methyl] -benzene

Cl

Cl Cl

The product of Example 97A can be reacted with SO2 Cl2 according to the method described in Organic Letters, 2003, 5 (8), 1167-1169, to provide the title compound. 97Ç. 1 - {(3,4-Dichloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methyl} -piperazine

The title compound can be prepared from the compound of Example 97C using the method and conditions described in Zhongguo Yaowu Huaxue Zazhi (2002), 12 (3), 125-129. ΡΕ1706385 268 EXAMPLE 98 2- (3,4-Dichloro-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine

Following the procedure described in Example 42, however, in Example 42B, substituting 1,2-dichloro-benzene for chlorobenzene, the title compound can be obtained. EXAMPLE 99 {2- (3-Chloro-4-methoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine

Following the procedure described in Example 42, however, in step 42B, substituting 2-chloroanisole for chlorobenzene gave the title compound. LC / MS: (PS-A2) 269 ΡΕ1706385

Rt 2.03 [M + H] + 342. 1 H NMR (Me-ds-OD) δ 2.45 (s, 3h, S), 3.22 (2H, d), 3.85 (3H, s) (1H, d), 7.15 (1H, d), 7.27-7.34 (3H, m), 7.55 (2H, d) , 7.92 (2H, s) EXAMPLE 100 4- {4- [2-Azetidin-1-yl-1- (4-chloro-phenoxy) -ethyl] -phenyl} -1H-pyrazole

Cl

N0

Following the procedure described in Example 42A, but replacing methylamine with azetidine and following the procedure of Example 45, the title compound could be obtained. EXAMPLE 101 3- (3-Chloro-4-methoxy-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propylamine

270 ΡΕ1706385

Following the procedure described in Example 61 but replacing imidazole with potassium phthalimide in step 61A and replacing chlorobenzene with 1-chloro-2-methoxybenzene in 61B, and then removing the phthaloyl protecting group under the conditions set forth in Examples 84B and 84C, the title compound can be prepared. EXAMPLE 102 {3- (3-Chloro-4-methoxy-phenyl) -3- [4- (1H-pyrazol-4-yl) -phenyl] -propyl} -methyl-amine

NH

Following the procedure described in Example 61 but replacing imidazole with methylamine in Example 61A and substituting 1-chloro-2-methoxy-benzene for chlorobenzene in Example 61B, the title compound can be obtained. EXAMPLE 103 1 - [(3-Chloro-4-methoxy-phenyl) - (4-chloro-phenyl) -methyl] -piperazine ΡΕ1706385 271 103A. (3-Chloro-4-methoxyphenyl) - (4-chloro-phenyl) -methanol

OH

The title compound can be prepared using the method of Example 97A, however substituting 3-chloro-4-methoxybenzaldehyde for 3,4-dichlorobenzaldehyde. 103B. 2-Chloro-4- [chloro- (4-chloro-phenyl) -methyl] -1-methoxy-benzene

Cl

The hydroxyl compound of Example 103A can be converted to the title chloro compound, following the method of Example 97B. 3 - [(3-Chloro-4-methoxy-phenyl) - (4-chloro-phenyl) -methyl] -piperazine

H

The title compound can be prepared from the product of Example 103B by following the method of Example 97C. EXAMPLE 104 C- (4-Chloro-phenyl) -C- [4- (1H-pyrazol-4-yl) -phenyl] -methylamine

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 could be obtained. EXAMPLE 105 {2- (4-O-chloro-phenyl) -2- [4- (3-methyl-1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine 105A. 2- (4-Chloro-phenyl) -N-methyl-2- [4- (3-methyl-1-trityl-1H-pyrazol-4-yl) -phenyl] -acetamide

273 ΡΕ1706385 2,2-Bis- (4-chloro-phenyl) -N-methyl-acetamide was prepared by reaction of the corresponding carboxylic acid with commercially available methylamine using the method of Example 21a. The N-methyl-acetamide compound was then converted to the title compound by the method described in Example 1. LCMS (PS-B3) Rt 4.21 min, m / z [M + H] + 582. 105B. 2- (4-Chloro-phenyl) -N-methyl-2- [4- (3-methyl-1H-pyrazol-4-yl) -phenyl] -acetamide

The trityl protected compound from Example 104A was deprotected by the method described in Example 60D to provide the title compound. LCMS (PS-B3) Rt 2.41 min; m / z [M + H] + 340. 1 H NMR (methanol-d4) δ 2.40 (3H, s), 2.78 (3H, s), 4.95 (1H, s), 7.29- 7.34 (6H, m), 7.41 (2H, d), 7.69 (1H, s). 105C. (2- (4-Chloro-phenyl) -2- [4- (3-methyl-1H-pyrazol-4-yl) -phenyl] -ethyl} -methyl-amine 274 ΡΕ1706385

Following the procedure described in Example 20B the title compound was provided. LCMS (PS-B3) Rt 2.80 min; m / z [M + H] + 326. 1 H NMR (methanol-d 4) δ 2.52 (3H, s), 2.75 (3H, s), 3.80 (2H, d), 4.46 1H), 7.41 (4H, s), 7.49 (2H, d), 7.54 (2H, d), 8.24 (1H, s).

BIOLOGICAL ACTIVITY EXAMPLE 106

Measurement of Inhibitory Activity of PKA Kinase (ICso)

The compounds of the invention can be tested for PK inhibitory activity using the PKA catalytic domain of Upstate Biotechnology (# 14-440) and the PKA residue specific peptide 9 (GRTGRRNSI) also from Upstate Biotechnology (# 12-257), as the substrate. A final concentration of 1 nM enzyme is used in a buffer which includes 20 mM MOPS pH 7.2, 40 μΜ / γ33Ρ-ΑΤΡ and 5 μΜ substrate. Compounds are added in dimethylsulfoxide solution (DMSO) at a final DMSO concentration of 275æl TE1706385 2.5%. The reaction is allowed to proceed for 20 minutes before the addition of excess orthophosphoric acid to stop the activity. unincorporated γ33Ρ-é is then separated from the phosphorylated proteins on a Millipore MAPH filter plate. The plates are washed, scintillant is added and the plates are then counted in a Packard Topcount. The percent inhibition of PKA activity is calculated and plotted to determine the concentration of test compound required to inhibit 50% of PKB activity (ICso)

The compounds of Examples 1, 4, 43, 44, 45, 46, 47, 48, 49, 52, 54, 59, 63, 66, 67, 73, 78, 79, 81, 82, 83, 84, 86 and 90 have IC 50 values less than 1 μ, while the compounds of Examples 5, 7 and 80 have IC 50 values of less than 15 μ. EXAMPLE 107

Measurement of Inhibitory Activity of PKB Kinase (ICso) Inhibition of protein kinase B activity by the compounds can be determined essentially 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 is 276 ΡΕ1706385 purified and activated with PDK1, as described by Yang et al. The AKTide-2T peptide obtained from Calbiochem (#; 123900) is used as a substrate. The peptide AKTide-2T (h-a-r-e-r-ee-s-f-g-h- A final enzyme concentration of 0.6 nM is used in a buffer, which includes 20 mM MOPS pH 7.2, 30 μΜ / γ33Ρ-ΑΤΡ and 25 μ substra substrate. Compounds are added in DMSO solution to a final DMSO concentration of 2.5%. The reaction is allowed to proceed for 20 minutes before the addition of excess orthophosphoric acid to stop the activity. The reaction mixture is transferred to a phosphocellulose filter plate, where the peptide and the unused atp is bound by washing. After washing, scintillant is added and the incorporated activity measured by scintillation counting. Percent inhibition of PKB activity is calculated and plotted to determine the concentration of test compound required to inhibit 50% of PKB (IC 50) activity

Following the protocol described above, it was found that 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 The results of the present invention are shown in Figures 1 and 2, which are shown in Figures 1 and 2, respectively. 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 each has IC 50 values below 50 μΜ. ΡΕ1706385 277

PHARMACEUTICAL FORMULATIONS EXAMPLE 108 (i) Tablet Formulation

A tablet composition containing a compound of Formula (I) is prepared by mixing 50 mg of the compound with 197 mg lactose (BP) as the diluent and 3 mg of magnesium stearate as a lubricant and compressing to form a tablet of the known form. (ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of Formula (I) with 100 mg of lactose and placing the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injectable Formulation I

A parenteral composition for injection administration may be prepared by dissolving a compound of formula (I) (for example in a salt form) in water containing 10% propylene glycol to provide an active compound concentration of 1.5% by weight. The solution is then sterilized by filtration, placed into an ampoule and sealed. ΡΕ1706385 278

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving in water a compound of formula (I) (for example as a salt) (2 mg / ml) and mannitol (50 mg / ml), the solution being sterile filtered and placing into sealed 1 ml vials or ampoules. (iv) Subcutaneous Injection Formulation

A composition for subcutaneous administration is prepared by mixing a compound of Formula (I) with pharmaceutical grade corn oil to provide a concentration of 5 mg / ml. The composition is sterilized and placed into a suitable container.

Equivalents

The foregoing examples are presented for purposes of illustration of the invention and should not be construed as imposing any limitation to the scope of the invention. It will be apparent that numerous modifications and modifications can be made to the specific embodiments of the invention described above and illustrated in the examples, provided that the basic principles of the invention are not deviated from. This request covers all such modifications and changes.

Lisbon, December 15, 2010

Claims (53)

A compound of the formula (I): or a salt, solvate, tautomer or N-oxide thereof, wherein A is a saturated hydrocarbon linker group containing having 1 to 7 carbon atoms, the linker group having 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 of the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally contain one or more substituents selected from oxo, fluoro and hydroxy, provided that the hydroxy group, when present, is not located on a carbon atom α with respect to the group NR 2 R 3 and from that the oxo group, when present, is located on a carbon atom α with respect to the NR 2 R 3 group; E is a cyclic or bicyclic cyclic or heterocyclic bicyclic group, wherein E is unsubstituted or has up to 4 R8 substituents selected from hydroxy, oxo (when E is not aromatic), chlorine, bromine, trifluoromethyl, cyano, C4- C4 hydrocarbyloxy and C1-C4 hydrocarbyl, optionally substituted by C1 -C2 alkoxy or hydroxyl; R 1 is an aryl or heteroaryl group which is unsubstituted, or has one or more substituents selected from hydroxy, C 1 -C 4 acyloxy; fluorine; chloro; bromo; trifluoromethyl; cyano; CONH2; nitro; C1 -C4 hydrocarbyloxy and C1 -C4 hydrocarbyl, each optionally substituted by C4 -C2 alkoxy, carboxy or hydroxy; C1-C4 acylamino; benzoyl-amino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholino-carbonyl; piperazinocarbonyl; five- and six-membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S; phenyl; phenyl-C1 -C4 alkyl; phenyl-C1 -C4 alkoxy; heteroaryl-C1 -C4 alkyl; heteroaryl-C1 -C4 alkoxy and phenoxy, wherein the heteroaryl, heteroaryloxy, phenyl, phenyl-C1 -C4 alkyl, phenyl-C1 -C4 alkoxy, heteroaryl-C1 -C4 alkyl, heteroaryl-C1 -C4 alkoxy and phenoxy groups are, each optionally substituted by 1, 2 or 3 substituents selected from C 1 -C 2 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, CO 2 NH 2, C 1 -C 2 hydrocarbyloxy and C 4 -C 2 hydrocarbyl, each being optionally substituted by methoxy or hydroxyl . R 2 and R 3 are independently selected from hydrogen, C 4 -C 4 hydrocarbyl and C 4 -C 4 acyl, wherein the hydrocarbyl and acyl moieties are optionally substituted by one or more substituents selected from fluoro, hydroxy, amino, methylamino, dimethylamino and methoxy; 3 Ρ E1706385 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second member of heteroatom ring, 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second ring member heteroatom selected from O and N; or NR 2 R 3 and the carbon atom of the linker group A to which it is attached together form a cyano group; R4 is selected from hydrogen, halogen, C1 -C5 saturated hydrocarbyl, saturated C1 -C5 hydrocarbyloxy, cyano and CF3; and R5 is selected from hydrogen, halogen, saturated C1-C5 hydrocarbyl, C1-C5 saturated hydrocarbyloxy, cyano, CONH2, CONHR9, CF3, NH2, NHCOR9 or NHCONHR9; R 9a is a group R 9a or (CH 2) R 9a, wherein R 9a is a monocyclic or bicyclic group, which may be carbocyclic or heterocyclic; the carbocyclic group or heterocyclic group R9a, being optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1 -C4 hydrocarbylamino; a Ra-Rb group wherein Ra is a bond, X2C (X2), C (X2) X2, X1C (X2) X1, s, SO, SO2, NRC, SO2NRc or NRcS02; and Rb is selected from hydrogen, heterocyclic groups having from 3 to 12 ring members and a C1 -C8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino , mono- or di-C1 -C4 hydrocarbylamino, carbocyclic and heterocyclic ring having 3 to 12 ring members and wherein one or more carbon atoms of the C1 -C8 hydrocarbyl group may optionally be substituted by O, S, SO, SO 2, NRC, X 1 C (X 2), C (X 2) X 1 or X 3 C (X 2) X 1; R c is selected from hydrogen and C 1 -C 4 hydrocarbyl; and X 1 is O, S or NRC and X 1 is = O, = S or = NRC. A compound according to claim 1 of formula (Ia): (ia) or a salt, solvate, tautomer or N-oxide thereof wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms, R 1 is selected from the group consisting of R 1 and NR 2 R 3 and a maximum chain length of 4 atoms, extending between E and NR 2 R 3, wherein one of the carbon atoms of the linking group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally contain one or more substituents selected from oxo, fluoro and hydroxy, provided that the hydroxy group, when present, is not located on a carbon atom α with respect to the group NR 2 R 3, and provided that the oxo group, when present, is located on a carbon atom α with respect to the NR 2 R 3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group, wherein E is unsubstituted or has up to 4 substituents R8 as defined in claim 1; R1 is an aryl or heteroaryl group which is unsubstituted or substituted as defined in claim 1 R2 and R3 are independently selected from hydrogen, C1 -C4 hydrocarbyl and C1 -C4 acyl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated heterocyclic monocyclic group having 4-7 ring members and optionally containing a second heteroatom 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 heterocyclic monocyclic group having 4-7 ring members and optionally containing a second ring member heteroatom selected from O and N; or NR 2 R 3 and the carbon atom of the linker group A to which it is attached together form a cyano group; R4 is selected from hydrogen, halogen, saturated C1 -C5 hydrocarbyl, cyano and CF3; and 6ΡE1706385 R5 is selected from hydrogen, halogen, C1-C5 saturated hydrocarbyl, cyano, CONH2, CONHR9, CF3, NH2, NHCOR9 or NHCONHR9; R9 is phenyl or benzyl, each optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono or di-C1 -C4 hydrocarbylamino; a group Ra-Rb, wherein Ra is a bond, O, CO, XbC (X2), C (X2) X1, X1C (X2) X1, S, SO, SO2, NRC, SO2NRc or NRcS02; and Rb is selected from hydrogen, 3- to 12-membered ring heterocyclic groups and a C 1 -C 8 hydrocarbyl group optionally substituted by one or more substituents selected from the hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, or di-C1 -C4 hydrocarbylamino, carbocyclic and heterocyclic, 3- to 12-membered ring members and wherein one or more carbon atoms of the C1 -C8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRC , Χ20 (Χ2), 0 (Χ2) Χ2 or X1C (X2) X1; R c is selected from hydrogen and C 1 -C 4 hydrocarbyl; and X 1 is O, S or NRC and X 2 is = O, = S or NRC. 7 ΡΕ1706385 substituted by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally have one or more substituents selected from fluoro and hydroxy, provided that the hydroxy group, when present, is not located on a carbon atom α with respect to the group NR 2 R 3; and R 5 is selected from hydrogen, halogen, saturated C 1 -C 5 hydrocarbyl, cyano, CONH 2, CF 3, NH 2, NHCOR 1 23 and NHCONHR 3. A compound according to any one of claims 1 to 3, wherein the linker group A has a maximum chain length of 3 atoms, extending between R1 and NR2R3. A compound according to claim 4, wherein the linker group A has a maximum chain length of 2 atoms, extending between R1 and NR2R3. A compound according to any one of claims 1 to 5, wherein the linker group A has a chain length of 3 atoms, extending between E and nr2r3. A compound according to claim 6, wherein the linker group A has a chain length of 23 to 3 atoms extending between R 1 and NR 2 R 3 and a chain length of 2 to 3 atoms extending between E and NR 2 R 3. ΡΕ1706385 A compound according to any one of the preceding claims wherein the linker atom attached directly to the E group is a carbon atom, and the linker group A has an entire carbon backbone. A compound according to any one of claims 1 to 7, wherein the R1-A-NR2 R3 part of the compound is represented by Formula R1- (G) kW-Ob- (CH2) n - (CR6 R7 ') P -NR 2 R 3, wherein G is NH, NMe or O; W is attached to the group E and is selected from (CH 2) j-CR 20, - (CH 2) j -N and (NH) j -CH; b is 0 or 2, j is Ooul, k is Ooul, m is O, 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; R6 and R7 are the same or different and are selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group; and R 20 is selected from hydrogen, methyl, hydroxy and fluoro. A compound according to any one of claims 1 to 7, wherein the moiety R1-A-NR2 R3 is represented by the formula R1- (G) k- (CH2) mX- (CH2) n - (CR6 R7) p- NR 2 R 3, wherein G is NH, NMe or O; X is attached to the group E and is selected from (CH 2) j -CH, (CH 2) j -N and (NH) j -CH; j is 0 or 1, k is O0, m is O, n is 0, 1, 2 or 3 is the sum of j, k, m, n and p does not exceed 4; and R6 and R7 are the same or different and are selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group. A compound according to claim 10, wherein (i) k is O, m is 0, n is 0, 1, 2 or 3 is 0; or (9) is 170, (ii) k is 0, m is 0 or 1, n is 0, 1 or 2 and p is 1. A compound according to claim 10, wherein (i) X is (CH 2) j -CH, k is 1, m is 0, n is 0, 1, 2 or 3 and p is 0; or (ii) (CH2) j -CH, kel, m0, n0, lou2ep1. A compound according to claim 10 or 12, wherein (i) j is 0; or (ii) j is 1; or (iii) CR6R7 is C (CH3) 2. A compound according to claim 10, wherein the R1-A-NR2 R3 part of the compound is represented by Formula Rx-X- (CH2) n -NR2 R3, wherein X is attached to the group E and is a group CH , en is 2. The compound according to claim 1 or 2, wherein R 3 -A (E) -NR 2 R 3 is selected from the groups AI to All below: 10 ΡΕ1706385 A compound according to any one of the preceding claims, wherein E is a monocyclic group. A compound according to any one of the preceding claims, wherein E is an aryl or heteroaryl group, each of which is substituted or not by up to 4 substituents R8 as defined in claim 1. The compound of claim 17 selected from optionally substituted phenyl, thiophene, furan, pyrimidine and pyridine groups each of which is unsubstituted or substituted by up to 4 substituents R 8 as defined in claim 1. The compound according to claim 18, wherein E is a phenyl group which is unsubstituted or substituted by up to 4 substituents R 8 as defined in claim 1. 11 ΡΕ1706385 A compound according to any one of the preceding claims, wherein the group A and the pyrazole group are attached to the group E in a relative meta or para orientation; i.e., A and the pyrazole group are not attached to the adjacent ring members of the E group. A compound according to claim 20, wherein E is selected from 1,4-phenylene, 1,3-phenylene, 2,5-pyridylene and 2,4-pyridylene, 1,4-piperazinyl and 1,4- each of which is unsubstituted or substituted by up to 4 R8 substituents as defined in claim 1. A compound according to any one of the preceding claims, wherein E has 0-3 substituents. The compound of claim 22, wherein E is 0-2 substituents. The compound of claim 23, wherein E has 0 or 1 substituent. The compound of claim 24, wherein E is unsubstituted. A compound according to claim 19 having the formula (II): wherein R 1, R 2, R 3, '< (ii) wherein group A is attached at the meta or para position of the benzene ring and q is 0-4. The compound of claim 26, wherein q is 0, 1 or 2. The compound of claim 27, wherein q is 0 or 1. The compound of claim 28, wherein q is 0. The compound of claim 19 of formula (III): 4 (III) wherein A 'is the group A residue, and R 1 to R 5 are as defined in any one of the preceding claims. A compound according to claim 19 of formula (IV): wherein z is 0, 1 or 2, R 20 is selected from hydrogen, methyl, hydroxy and fluoro, provided that, when z is 0, R 20 is other than hydroxy. The compound of claim 19 of formula (V): H (v) wherein R 3 is selected from hydrogen and C 1 -C 4 hydrocarbyl. 14 ΡΕ1706385 The compound of claim 32, wherein R 3 is hydrogen. A compound according to any one of the preceding claims, wherein R1 is selected from phenyl, naphthyl, thienyl, furan, pyrimidine and pyridine, each optionally substituted as defined in claim 1. The compound of claim 26, wherein R1 is phenyl. A compound according to any one of the preceding claims, wherein R 1 is unsubstituted or substituted by up to 5 substituents selected from hydroxy, C 1 -C 4 acyloxy, fluoro, chloro, bromo, trifluoromethyl, cyano, C 1 -C 4 hydrocarbyloxy and C1 -C4 hydrocarbyl, optionally substituted by C1 -C2 alkoxy or hydroxy. The compound of claim 36, wherein the R1 group has one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy. The compound of claim 37, wherein R1 is a mono-chlorophenyl or dichlorophenyl group. A compound according to any one of the preceding claims, wherein R 4 is selected from hydrogen and methyl. 15 ΡΕ1706385 A compound according to any one of the preceding claims, wherein R 5 is selected from hydrogen, methyl and cyano. The compound of claim 40, wherein R 5 is hydrogen or methyl. A compound according to any one of the preceding claims, wherein R 1 and R 2 are independently selected from hydrogen, C 1 -C 4 hydrocarbyl and C 1 -C 4 acyl. The compound of claim 42, wherein R1 and R2 are independently selected from hydrogen and methyl. The compound of claim 43, wherein R1 and R2 are both hydrogen. A compound according to any one of the preceding claims having a molecular weight of less than 525. The compound according to claim 1 of Formula (I) which is: 1-phenyl-2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine; 2-phenyl-2- [3- (1H-pyrazol-4-yl) -phenyl] -propionitrile; 16 ΡΕ1706385 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-chlorophenyl) -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 Ethyl 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- {- [1- (4-Chloro-phenyl) -2-pyrrolidin-1-yl-ethyl] -phenyl} -1H-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-yl) -phenyl] -acetamide; 18β]] - 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} -1H-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] -ethylamine; 2 - {(4-chloro-phenyl) - [4- (1H-pyrazol-4-yl) -phenyl] -methoxy} -ethylamine; 4- {4- [1- (4-Chloro-phenyl) -3-pyrrolidin-1-yl-propyl] -phenyl} -1H-pyrazole; 19 ΡΕ1706385 4- {4- [3-azetidin-1-yl-1- (4-chloro-phenyl) -propyl] -phenyl} -1H-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-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] diazepane; {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} -1H-pyrazole; 4- [4- (3-imidazol-1-yl-1-phenoxy-propyl) -phenyl] -1H-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; 20 E] 1706385 (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-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; phenyl) -ethylamino] -ethanol; (2- (4-Chloro-phenyl) -2- (4- (1H-pyrazol-4-yl) -phenyl) -2- (4- (1H-pyrazol- ) -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-pyrazole (4-chloro-phenyl) -4- [4- (3-methyl-1H-pyrazol-4-yl) phenyl] piperidine; (4-chloro-phenyl) -2- (4- (1H-pyrazol-4-yl) -phenyl] -morpholine; (4- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -phenoxy) -acetic acid methyl ester; 4- {4- [4- (1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -benzonitrile; {2- (4-chloro-phenyl) -2- [4- (1H-pyrazole -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) nyl) -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- (1H-pyrazol-4-yl) -phenyl] -ethanol; 2- (3-chloro-4-methoxy-phenyl) -2- [4- (1H-pyrazol-4-yl) -phenyl] -ethylamine; 22 ΡΕ1706385 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; and C- (4-chloro-phenyl) -C- [4- (1H-pyrazol-4-yl) -phenyl] -methylamine; and their salts, solvates, tautomers and N-oxides. The compound of Claim 46 which is 2-amino-1- (4-chloro-phenyl) -1- [4- (1H-pyrazol-4-yl) -phenyl] -ethanol or a salt, solvate , tautomer or N-oxide thereof. 23 ΡΕ1706385 The compound of any one of the preceding claims in the form of a salt, solvate, ester or N-oxide. A compound according to any one of claims 1 to 48 for use in medicine. A compound according to any one of claims 1 to 48 for use in (i) prophylaxis or treatment of a protein kinase β-mediated disorder or disease; or (b) prophylaxis or treatment of a protein kinase A mediated disorder or disease. A compound as defined in any one of claims 1 to 48 for use in the prophylaxis or treatment of a disorder or disease selected from a carcinoma of the bladder, breast, colon, epidermis, liver, esophagus, gallbladder, ovary, pancreas, stomach, cervix, endometrium, thyroid, prostate, or skin, a hematopoietic lymphoid lineage tumor, a hemato-poietic myeloid lineage tumor, thyroid follicular cancer, a tumor of mesenchymal origin, a central or peripheral nervous system tumor , melanoma, seminoma, terato-carcinoma, osteosarcoma, xeroderma pigmentosum, keratoc-tantoma, thyroid follicular cancer or Kaposi's sarcoma. A compound as defined in any one of claims 1 to 48 for use in the prophylaxis or treatment of a disorder or disease selected from 24 ΡΕ1706385 breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous cell cancer and non-small cell lung carcinomas. The use of a compound as defined in any one of claims 1 to 48 for: (a) the manufacture of a medicament for the prophylaxis or treatment of a protein kinase B mediated disorder or disease; or (b) the manufacture of a medicament for the prophylaxis or treatment of a protein kinase A mediated disorder or disease; or (c) the manufacture of a medicament for the prophylaxis or treatment of a disorder or disease resulting from abnormal cell growth; (d) the manufacture of a medicament for the prophylaxis or treatment of a disease in which there is a disorder or proliferation, apoptosis or differentiation. A pharmaceutical composition comprising a novel compound as defined in any one of claims 1 to 48 and a pharmaceutically acceptable carrier. A process for the preparation of a compound of Formula (I) as defined in any one of claims 1 to 48, which process comprises: (a) reacting a compound of Formula (X) with a compound of Formula (XI ) or an N-protected derivative thereof: ΡΕ1706385 25 / And X (X) (XI) wherein A, Ε and R1 to R5 are as defined in any one of the preceding claims, one of the groups x and Y is selected from chlorine, bromine, iodine and trifluoromethanesulfonate and the other of the groups X and Y is a residue boronate, for example, a boronate ester or boronic acid residue, in the presence of a palladium catalyst and a base; (b) reductive amination of a compound of Formula (XXXVI): (XXXVI) with HNR 2 R 3, in the presence of a reducing agent; and optionally, (c) converting a compound of Formula (I) into another compound of Formula (I). Lisbon, December 15, 2010 ι ΡΕ1706385 REFERENCES CITED IN DESCRIPTION This list of references cited by the applicant is for the reader's convenience only. It is not part of the European patent document. While due care has been taken in compiling references, errors or omissions may not be excluded and the IEP declines any liability in this regard. Patents cited in the disclosure of the disclosure are hereby incorporated by reference in their entirety. Patents cited in the disclosure are hereby incorporated by reference. Patents cited in the disclosure of the disclosure include: WO 1917S4A; WO 9733280 · US 5332864 A Î »WCs 0§8562 ° L: 5 5213528 EP 13826034 4 Non-patent literature cited in the Description * Harffi, S .; Hanics »S, Tfte PrsiBto Sfese Fssis δ · ::; ·. ··. 5 asní SS. Asadesafe Press, 1895; Ka, ks, S, K; ttantw. T, FASES J., 135, wi. 9, S7S-SS6; KnlghfoR et al., Sssfrc® .; 1SS1 vol 253, 407-414, Miies et al. Csil im ¥ & 70, 419428; K2, K2 and st, Cs3: 1SS3. Vol. 73, $ 85-596. esters-Busfos et al., EMSO J., 16S, 4, ve. 13, 2352-336; Case Report, Casey Res & mk, 19S7, 57, 3, 3S, 3, 4, 5, 6, 5, 6, 57,4397 * BeSreoss et al. ; J. .. Cmssr. 193S, vsi. 64, 260-255 (Cheagma et al., 1994, 9, 9: 3,3635-3641). Yuan et al., Owocog. iS < 2324-2330 * st & LPms. 5034-5337 * Shis st, Am. J Pafeoi, 2001, 159, 435-437. Nakatani et al., J. Bi. Chem., 89, ss. 274, 21528-25532 Aanalu, E, M, Auteusi, P .; Sáitem 8, S, Wtiiter. F *; Fntotta, 8, S .; Hansae®, V *; Taaksn. K. Pfstm sisas® Atpe 5 stsspfsfsfsfssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss PHASES tsm 5 * 1 8SS-862 »Strain, CJL; Che-Ctog, V, S, Psateas Kmase. Bt & tsc. , 2SS2, voU2, SS-S2 * Li, O ,; Zyt, S-D, CyrfS, and Tcpphs. 2,830-871 * Pfstein Alasse A and Hííítssí? Oiseass. There is more to York York, than York. 2382, vol. §88 * Fft & Stiftings Ssfts: Piupertiss, Seiefe, srsd Use, August2802, 886 * Jtny Mareí. Advanced Group. Wky Ssíers-asnce * L, W, Daady. S) Chem., 1377, vol. 7, 588-514 * Jear SSarch. Crystallized. Jato Wisy & Ssrss. 1382.108-114 * Cefm; ingestion: Preg. Aagm. Ctoem, M Bi. Î ±, Î ±, β, β, β, β, β, β, β, β, , 1355, v. F7. 1067 * StiseBas et al. Cti & 5661, 128.2525. Castrosi et al. 8.48 (1H, d, J = 8Hz). * L. JL Caspino. J. Amer. Cbem. Ssc., 1993, 115, 4707, Ken, et al. Up. " • 83 (70δ), 2024-28M * 4 IbbA AakmssiOrgsmc: CAscssèt /, Wiigy & SoBS, 1862,1601-1602 * Oess, Ο, Β ,; ilwtin, UC. J. Oi§. Sse ·.,. 198¾. '148, 41SS * Grgassffi Syllab., Ls * & 5. voi, 77.41 * Jewy Msrei). Agave® 5S Orgsiste 534-542 * j.md.Ctwn.t 2004, sqU7 > 3824-3823 * Tstf & liotim :; Asymimiiyt 2063, vof, 14, 13SS-131S Jeny Sarsi, Adianoná Organte Chssnsby, Wstsy fktgrsaaice, vsi. 118 2 ΡΕ1706385 ΡΕ7066 F Ρ1 F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F F Jo & RVKgy, voi, 1-1? * Ofsjjjjjjjssssss, Joirsrs Wâey, et, 1 -8 * T. &hr; P, Weis. Pfotess® Gfoups in Osssyts Syrfesis. Jie Wiie $ assd Sons. 1998 * * * * * * * * * * * * * Cysteine Cysteine Cysteine Cysteine B & ísgy, Jatay & Safss Sic, 2SM PCP. Pratossta: s guiSe io o-ies: ssd espgífcsfeios, dos dewc Press ,. 1 H NMR (CDCl3):? & 4otacatar Gtatasg; A Lsbersíoty taajissi Cotei Spmg Hsrfeo? Lsberstas? Press, 20i31 Angle, & & Enigmai, 1W, vfe ;. 152.643 * Csrst Prctooata * rs teisteoifer Bsásgv, Jataí Wley & Behavior, 2084 Physicians and Immunologists: Physicians, Physicians, Physician, Physician, Physician, Physician, Physician, Physician, Physician, Physician, Physician, Physician, € ssss * f. fttethffiis sfsd Pratois, telsireh: 2SQ4, • 377-QSS * Sun «t si. Am. J. Pstetei. 20S1, woi. 153, 431437; Cfc & Sas., 1SS3, vol. 105, 3183-: 1188. 3. C, 25 :. 335-947 * J, Hrsrah, Aphasnced Otganfc Cbfimisíry, Mm WAe & 1892 < '22-S2S * Qrgsnis · Synthesis, vol. 1 413 * Qrgmic LMms 2302, m. 4 i i 7). , Pp. 2585-2888, J. Chem., 2, M. 47, 3324-332. Tefsfo K & teymmatep, 2303, vete 1388-1318 J. Chern Sm Sm Ps. &Amp; 1, 3444-3453, J.M., et al., 2333. 43 (21), 387843894. 2) 03, vs. 5S), 1167-1188 * Yttrium Yatmt Hsmym Zazta. 2382, v < & 12% 125-128 ° C # MS, MS, 1 st. IS, 5081-5072. Bskm-2502, vol. 9, 840944