SA05260179B1 - Pyrazole-containing aryl-and heteroaryl-alkylamine compounds that inhibit or modulate the activity of proten kinase A (PKA) and protein kinase B (PKB) - Google Patents

Abstract

The invention provides compounds of the formula (I) having protein kinase B inhibiting activity: 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 NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, wherein one of the carbon atoms in 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 bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the NR2R3 group and provided that the oxo group when present is located at a carbon atom a with respect to the NR2R3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R1 is an aryl or heteroaryl group; and R2, R3, R4 and R5 are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds and their use as anticancer agents.

Description

Y —_ _ aryl alkylamine and aryl heteroaryl alkylamine compounds containing pyrazole inhibit or modify the activity of its protein kinase (PKA) and protein kinase (PKB) B Pyrazole-containing aryl-and heteroaryl-alkylamine compounds that inhibit or modulate the activity of protein kinase A (PKA) and protein kinase B (PKB) FULL DESCRIPTION BACKGROUND This invention relates to aryl- and heteroaryl-alkylamine compounds containing pyrazole of protein kinases (PKB) B kinases (PKA) activity as related to the use of these compounds in the treatment or prevention of conditions caused by PKB PRA, 1 and new compounds with inhibitory activity or Modification of PKA 5 PKB Pharmaceutical formulations containing compounds and new chemical intermediates are also introduced. Protein kinases are a large family of enzymes that are structurally related; 3 It is responsible for controlling a wide range of translocations in the cell: (Hardie, 6. and Hanks, 5. (1995) The Protein Kinase Facts Book.

I and II, Academic Press, San Diego, CA). ¢ and lipids; &) 0 It has been determined that the repeat units of the sequence correspond as Fale to each of these kinase families: Apapa

trampled

(e.g., Hanks, S.K., Hunter, T., FASEBJ., 9:576-596 (1995); Knighton, et al, Science, 253:407-414 (1991); Hiles, et al., Cell, 70: 419-429 (1992); Kunz, et al, Cell, 73:585-596 (1993); Garcia-Bustos, et al., EMBOJ., 13 12352-2361 (1994)) The proteome according to its regulatory mechanisms. These mechanisms include, for example, kinase, phosphorylation and phosphorylation compounds, “autophosphorylation” and protein-to-protein interactions; polynucleotide s and protein–lipid interactions; protein interactions

0s 0 Kinase is defined by more than one mechanism. The kinase compounds regulate various processes in the cell; Including but not limited to 0 Reproduction, Differentiation, and Cell Death 800005159; movement; copying; transmission and other signal transmission operations; By adding a phosphate group to the target proteins. These phosphorylation events act as A on/off switches where Jes can regulate or regulate the biological function of the target protein. Phosphorylation of the target proteins occurs in response to several extracellular signals (hormones + neurotransmitters ¢ 1). growth factors, differentiation, etc.) cada cycle events and nutritional or environmental stressors; etc. The appropriate protein kinase in the signaling pathways activates or inactivates (either directly or indirectly); metabolic enzyme or a regulatory protein; or future; or a cytoskeletal protein; ion channel or pump; or transcription factor; So for example. The uncontrolled process of signaling is the result of improper control of protein phosphorylation - responsible for many coal pads, for example inflammation and cancer.

M cancer and allergies Allergy / asthma Asthma Diseases and conditions of the immune system Diseases and conditions of the immune system Diseases and conditions of the central nervous system ¢ And the formation of vessels. angiogenesis 0 Apoptosis or programmed cell death is considered; An important physiological process that eliminates the existence of cells that are no longer required for the organism. This process is important in the early development of the fetus allowing for controlled cracking to occur that is not fatal. The removal and recovery of cell components and the elimination of cells by apoptosis is also an important process in maintaining the chromosomal and genomic cohesion of developing cell populations. There are many known test points in the cell development cycle when DNA damage and genomic cohesion are carefully monitored. The goal of the response is to detect abnormalities at these test points to restrict the growth of these cells and initiate the repair process. if the damage or abnormalities cannot be repaired; fan cases of cell death by the destroyed cell so that the spread of defects and errors can be prevented. Cancer cells usually contain many mutations. and errors or modifications in their chromosomal DNA. It is widely believed that this is due, in part, to the fact that most tumors contain a defect in one or more of these vo processes responsible for Adee initiation of cell death. JB's natural control mechanisms cannot kill cancer cells; Chromosomal errors, or DNA oi, continue to proliferate. As a result; Restoring these signals associated with cell death or dysregulated survival signals is an attractive avenue for cancer treatment. It has long been known that the signal transduction pathway containing the enzymes 3-kinase (PI3K) 0¢ and 1g1t; PKB among others” mediates an increased resistance to death

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Cellular or survival responses in many cells. There is a large amount of information indicating that this pathway is an important pathway for survival that is used by many growth factors to suppress cell death 0 apoptosis and enzyme 6 is activated by many growth and survival factors »EGP Jie PDGF and through the generation of compounds jan » polyphosphatidylinositols activate post-Lo signaling events, including the activity of protein kinase s kinase PDKI complexes B (PKB), also known. This also applies to host tissues; such as vascular endothelial cells in addition to emerging tumors. PKB is a protein kinase thr/ser kinase consisting of a kinase domain with an N-terminal PH domain and a C-terminal regulatory domain. The PKB enzyme itself is phosphorylated at 308 thr. By PDKI and at 473 Ser b©10085 Not yet tagged. Full activation of 0 requires phosphorylation at both sites, while complete conjugation of the PH 5 domain of PIP3 is required to bind the enzyme to the cytoplasmic face of the lipid membrane to provide access.

Ideal for enzyme-influenced materials. In turn, PKB (Jill) phosphorylates a group of substances under its influence, which contributes to the overall survival response. Although we cannot be certain that we understand all of the 1 mediator factors in the PKB-dependent survival response, some important actions are thought to be the phosphorylation and inactivation of BAD caspase 9. 5 and phosphorylation of FKHR transcription factors Ji Forkhead leads to their exclusion from “bl gill” and activation of the NfkappaB pathway by phosphorylation of the CLS kinase y” post-phosphorylation in

successive group.

In addition to the anti-apoptotic and pro-survival actions of the PKB pathway, the enzyme plays an important role in promoting cell proliferation. This action is also likely to occur through multiple procedures; Some of them, phosphorylation, inactivation of the cyclin-dependent kinase inhibitor IL2N, phosphorylation of 210511012000, and activation of mTOR 1026 are believed to control several features of cell growth. The enzyme phosphatase PTEN, which phosphorylates and suppresses 0.00, is a major tumor suppressor protein; Normally regulates survival pathway (Sars .01316/ PKB) Evaluation of the role of the PISK/ PKB pathway in tumorigenesis from the observation that PTEN is one of the most common targets of mutation in human tumors; mutations in this gil phosphatase Its presence in about 750 melanomas (Cairns et al 1997, Cancer Research 57, 3660-3663(0 p:©6105) and advanced prostate cancers (Cairns et al 1997 Cancer Research 57, 4997) indicates that and others have indicated that a large number of human tumors depend on Gall PKB activity for their growth and survival and will respond

PKB for suitable inhibitors of Ladle alpha, beta, and gamma, which studies indicate aud 263 and there are closely related genetic equivalents that have specific, albeit overlapping, functions. Evidence indicates that each of them can be 1 Uw PKB, for example, it turns out that . cancer separately that plays a role in ovarian cancer in ovarian cancers 746-10 Excessive genetic expression or activation of it in . pancreatic cancers and the pancreas (Bellacosa et al 1995, nt J. Cancer 64, 280 - 285; Cheng et al 1996, PNAS 93, 3636- 3641; Yuan et al 2000, Oncogene 19, 2324 - 2330).

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1- PKB is amplified in human gastrointestinal tract cancers, prostate cancer16 and breast cancer:

(Staal 1987, PNAS 84, 5034 - 5037; Sun et al 2001, Am.

J.

Pathol. 159, 431-437) and it was done

Monitoring increased PKB-gamma activity in a non-dependent prostate and breast cell lineage

steroid (Nakatani etal 1999, J.BioLChem. 274, 21528-21532)° The PKB pathway influences normal tissue growth and survival and can be regulated during normal biological functions to control cell and tissue function. Thus, disorders associated with unwanted proliferation and survival of cells and tissues can be therapeutically more beneficial than treatment with PKB. Examples of such disorders can be mentioned associated immune cell disorders

ye of prolonged expansion and survival of cell populations leading to a prolonged or controlled immune response. and for example; The response of a By T lymphocyte to homologous antigens or homologous growth factors interleukin-2 Jie¢ activates the 21312/0103 pathway and is responsible

On maintaining the survival of antigen-specific lymphocyte clones during the immune response. And under conditions in which Led lymphocytes respond to improper antigens, either

1 was subjective or alien; or in which other anomalies trigger prolonged activation; The PKB pathway contributes to a survival-critical signal that inhibits the normal mechanisms by which the immune response is terminated by cell death. A fair amount

Evidence showing lymphocyte cleat Aa response to autoantigens in autoimmune conditions Jie multiple sclerosis and arthritis. and extension of effector lymphocyte populations

0 Improper exposure to foreign antigens is characteristic of a range of conditions such as special responses

M -

Allergy and asthma. In summary of the above; It can be said ob inhibition of PKB can

It gives a useful treatment for immune disorders. Other examples include cases that are not suitable for expansion, growth, and reproduction. tissue hyperplasia;

survival of normal cells in which PRB may play a role; The following include, but are not limited to, cardiac myopathy, plaque atherosclerosis, atherosclerosis: 0 . glomerulonephritis and myopathy glomerulonephritis:

Because of its role in cell growth and survival, the PKB pathway influences the control of glucose uptake by insulin.

Available controls from mice deficient in the isoforms of alpha and l beta

PKB indicates that this verb is mediated by the equivalent form, beta. As a result; PKB activity modifiers may find use in the treatment of diseases that are associated with impaired glucose metabolism and energy storage.

,. obesity, obesity, metabolic disease, diabetes, diabetes, Jie

threonine | serine cyclic protein kinase is an AMP dependent protein kinase (PKA)

It phosphorylates a large number of substances under its influence and is involved in the regulation of many

La cellular processes including cell growth; cell differentiation; and cion-channel connectivity1, gene transcription, and release from ganglia of neurotransmitters. in his inactive form; the

The universal enzyme (PKA) is a four-subunit complex that includes two regulatory subunits

.two catalytic subunits and two catalytic subunits

PKA acts as a link between the signaling transduction events of protein© and the cellular processes involved

organize it. The binding of the ligand-hormone complex glucagon Jia to the transmembrane receptor activates the receptor-associated protein ©_PR=6 (hydrolysate-binding protein-077). When activated, the unit

- oq and activate it; Which, in turn, adenylate cyclase of protein 6 disintegrates and binds to the enzyme A sub-produced in this way by binding camp, and then the (camp) cyclic AMP converts to ATP, which leads to the dissolution of the subunits United catalytic. As for the PKA regulatory subunits, which are inactive when combined with the PKA subunits, the catalytic subunits of the phosphorylation regulatory proteins; It becomes active upon degradation and participates in the phosphorylation of other oo. phosphorylation kinase phosphorylates PKA eg; The catalytic sub-unit of the enzyme, Phosphorylase phosphorylation, is involved in the phosphorylation of kinase Phosphorylase. glucose to release glycogen responsible for breaking down and inhibiting the phosphorylation enzyme 3 duds glucose Cb sia in the regulation of PKA also participates 0 (PKA) (which are modifiers that can increase or decrease the activity of PRA and so the activity modifiers glycogen and energy storage glucose may be useful in the treatment or treatment of metabolic disorders obesity, metabolic diseases, and obesity diabetes Jie et al. As a PKA inhibitor, the opinion has been established that, on the basis of HIV induced by T in the disruption of PRA type 1 cell type 1, the possible role of 1, which is more camp 7 cells from patients infected with 1177 had elevated levels of sensitivity to 0-like inhibition compared to normal 7 cells.As a result of the studies they carried out on pend 7 cell disruption of type 1 PKA, they concluded that the increased activation of PKA could therefore Be a possible target for HIV-1 (PKA)-based therapy in patients with immunomodulation. ©

1and

Aandahl, E.M., Aukrust, P., Skalhegg, B.S., Miiller, F., Freland, 5.S., Hansson, V.,

Tasken, K. Protein kinase A type I antagonist restores immune responses of T cells from

HIV-infected patients. FASEB J. 12, 855-862 (1998) can lead to activation of PKA and it has also been shown that mutations in the regulatory subunit of . endocrine tissue Superior endocrine tissue © camp As a messenger in cell regulation; The abnormal responses to PRA due to its diversity and importance can lead to many human diseases such as irregular growth and reproduction of the cell. (Stratakis, C.A.; Cho-Chung, Y.S.; Protein Kinase A and human diseases. Trends Endrocri. Metab. 2002, 13, 50-52) in many human cancer cells including PKA, increased transgene expression of 0 has been seen and therefore . colon or breast extracts from patients with ovarian or breast cancer as an entry point for cancer treatment, PRA is inhibition (Li, Q.; Zhu, G-D.; Current Topics in5 Medicinal Chemistry, 2002, 2, 939-cancer 971). in human diseases; See, for example, PKA and for a review of Role 1

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

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Several classes of compounds have been shown to have PKA inhibitory activity. For example; 4% of the isoquinolinyl-sulphonamido-diamines were disclosed in the international patent 11/511784. © International Patent (Chiron) 197949/00 discloses substituent pyrazole compounds with estrogen receptor antagonist activity. He described the compounds as useful in treating or preventing breast cancer1 that occurs via the estrogen receptor; This is among other things, but the inhibitory ability of PKB has not been revealed. The international patent (Searle) + “FY + TF” discloses substituted pyrazole compounds as kinase P38 antagonists of 0 pyrazolone of a class of inhibitors (Cephalon) + 0/7775 and the international patent discloses and discloses About (X-Ceptor Therapeutics) 0/1 94484 As for the international patent. kinase as modulators of nuclear receptors. N-substituted as pyridine Compounds substitutable as pyridones Compounds ge ¥/eTAYY International patent reveals

P38 MAP has rates of 0 on a class of (Dr Reddy's Research Foundation) 176837/00 and International Patent Disclosure for Use as In situ 1 phenyl substituent compounds 0782016 contains an anti-inflammatory. And in group 60 (1m-1) it is replaced by a sulfur-containing substitution group. A sulphonyl or a sulphonamide is in the form of a sulfur group.

GENERAL DESCRIPTION OF THE INVENTION The invention provides compounds having inhibitory or modulatory activity towards protein kinase 8 (PKB) and protein (PKA) A which are useful in preventing or treating pathological conditions caused by PKB or PKA and in characteristic first; The invention provides compounds of the formula (0: 2 R / 1 R—A-—N Rr E HN R® / N —N ° 0 0 salt; or soluble or a tautomer or ta N-oxide where the 8-4-1828 part of a compound is represented by the formula -,17-0-(0()012)-1 Cua (CH)(CRR) -NR'RY 6 is NH, Nme, or 0; group E is connected IW and is selected from (CHo)Ns (CH2)-CR™ and 011-(0011); b is 0 0 or 1 − and 0 is 0 or 1; k is zero or 1 and “ is zero or 1 or “or 1” and m is zero or 1; the sum of ta Ky is zero or 1; The sum of a zygote and “and” does not exceed the number ;; 85 and 7 are the same or different and are chosen from methyl and ethyl “or form a cyclopropyl group; 1829 is selected from hydrogen and fluorine 5 hydroxy s methyl ; and AE 0 monocyclic aryl group or heterocyclic aryl group which are selected from pyridines pyrimidine s furans thiophene s phenyl groups ; each having no

substituting or even having § a select RE substitution group of hydroxy, bromine chlorine, hydrocarbyloxy Cia cyano trifluoromethyl and hydrocarbyl having an optional substitution by R alkoxy or hydroxyl ¢ R! aryl de jana or selected aryl heterocyclic group of phenyl and naphthyl pyridines pyrimidine furan | thienylg©; The aryl group or hetero-aryl group is unsubstituted or bears one or more substituent groups selected from: hydroxy .; and acyloxyCi4 0 ; and fluorine.; and 2"coc"; bromine 0.; trifluoromethyl .; cyano .; 0; d-nitro eo ¢ and hydrocarbyl Cis hydrocarbyloxy Ci 0 each having an optional substitution by Cry alkoxy or carboxy or hydroxy ; and YY Cm

0. ml acylamino; and benzoylamino 0 ; and pyrrolidinocarbonyl 0 ; and piperidinocarbonyl.; and © b morpholinocarbonyl; f - aryl heterocyclic heterocyclic oxy-heteroaryls of five or six atoms containing one or more hetero-atoms selected from 11, 0, and 5; and phenyl .; and phenyl - bin alkyl; and 0l phenyl - per alkoxy ; and aryl .hetero-alkyl Cia ;?; and aryl 0 hetero-ber alkoxy ; and phenoxy 0. ¢ where each of the aryl groups is heterocyclic aryly heterocyclic phenyl oxy phenyls 0 — phenyls alkyl - ber aryly alkoxy hetero- ber aryl s alkyl Heterocyclic- phenoxy s alkoxy Cis has an optionally substituted by 1 or ? Or ¥ ic gona replace selected trifluoromethyl 5 bromine 3 chlorine y fluorine acyloxy Cia

— \ o —

hydrocarbyloxy Cis CONH2 5 cyano s and hydrocarbyl ware each with a substitution by

methoxy or hydroxy ¢ f

C and 3 each selected separately from hydrocarbyl Cras hydrogen and acyl ¢ and

CLSS saturated hydrocarbyl and 01-5 « halogens <hydrogen are selected from rR

hydrocarbyloxy 0 saturated ¢ CF3 5 ¢ cyano gs and

hydrocarboxy Cj.s.s saturated hydrocarbyl and halogens «hydrogen selected from R’

NH, s ramtel CONHR’ 5 CONH, 5 cyano g saturated

SNHCONHR® 5 NHCOR® f

R is a R® Cus (CHp) RJ R™ group is a monocyclic or a bicyclic group 0 can be carbonaceous or heterocyclic; And

It can be in the cyclic carbon group or the non-contiguous group “38 substituents

Optional with one or more replacement kits. Selected from hydroxys halogen;

mono- or di-Cl-4 or "complete" and specialized ¢ and ¢ nitrog) and 7800 ¢ trifluoromethyl 5

0, CO, XCD), COAX, is an R* bond where RAR” is 4c sens; or hydrocarbylamino and be hydrogen from RP and choose NSO, NO, or S, SO, 80 « NRC, a vo

In non-contiguous groups there is between ¥ and 71 atoms per ring; and is in the group Crs

hydrocarbyl facultatively substituted with one or more hydroxy substituents to be selected ;

mono- or di-Cj4 and ¢ amino ¢ carboxys ¢ and s ¢ cyano ¢ halogens ¢ 0X0

hydrocarbylamino ¢ and carbonic cyclic groups and hetero-groups having between

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_— a" \ — ¥ and 11 atoms in the ring, where S, SO, SO, NRC, X'C(X), C(XHX' Dla) ,0 orX'C(XHX') can replace an atom One or more carbons in the hydrocarbyl group Cj..p are selected from hydrogen and hydrocarbyl ¢ and 2X 0, 5, or 118m is an axial quantitative see =NRC The invention also provides the following : Component of ead aa of the form av) or any other subset or form of form (1) as Apel here. Component of form ( ) or (07) or any do sans subset of them as diel here 0 For use in the treatment or prevention of Alla pathogens caused by protein kinase B Use a compound of formula () or (IV) or any Ae sana subunit thereof as defined herein for use in the treatment or prevention of a disease condition caused by protein kinase B. A compound of Formula () or (IV) or any subgroup or form thereof as defined herein for use in the treatment or Prevention of a pathological condition caused by protein kinase A 0 0 Use of a compound of formula ( ) or SAV) any subset or form thereof as Ada herein For use in the treatment or prevention of Alla pathogens The protease kinase A 6 is not the only one

- unless \ _

. Use a compound of form (0 or SAV) any subset thereof as defined herein.

For the manufacture of a drug or for the prevention or treatment of a disease or condition involving, or arising from, the growth of

Normal cell death or suppressed cell death Apoptosis.

0 - A pharmaceutical composition comprising a new compound of formula (0) or (AV) or any combination

A subset thereof as defined herein with a pharmaceutically acceptable carrier.

. A compound of Formula ( ) or AV or any subset thereof as defined herein for use as a drug.

The use of a compound of Formula ( ) or (AV) any subset thereof as defined herein to manufacture a drug for the prevention or treatment of any of the diseases or conditions disclosed

0 here. . the use of a compound of formula (0; or Jv) Fav) Sam Sm Sap) Sa) any subset thereof as defined herein for the manufacture of a drug for the treatment of; or prevention of; disease or condition in a patient examined Sais that he suffers from or Jas that he suffers from; a disease or condition that could respond to treatment with a compound that has protein kinase wa activity 5. ee use a compound of formula 0; or JW) Savy Sam San Ja) Sa) any subset thereof as defined herein for the manufacture of a remedy. or prevention of a disease or condition in a patient tested datas that he has or is likely to suffer com a disease or condition that could respond to treatment with a compound that has activity against protein kinase A definitions and general preferences: 6 th

- 1, 5, and 8 through to A The following definitions and preferences will apply to each of the Parts and any sub-definition; or a subset or form of terminator unless the context otherwise requires Rs. Any other subset (IV) and any reference to formula ( ) herein will also refer to formula _ of compounds within the scope of formula ( ) unless otherwise stated In context otherwise. and as an SS - unless otherwise specified in the context in general; These groups can be monocyclic or bicyclic; It may contain, for example, atoms in a ring. 01 atoms in a ring; And usually from © to 17 and Ge Example - at what ranges Examples of monocyclic groups can be mentioned groups that contain , 4, 8, or 0 and better © or 6 atoms in the ring. It is 1 atoms in the ring. The most common from © to A, 9, 10, 11, 11 and better A. Examples of bicyclic groups can be mentioned those that contain atoms in the ring. for heterogeneous 1H with between © and 71 atoms; The best ranges from aryl groups of 0 as used here to an aryl' carbon group between © and 10 atoms in the ring. The term “heterocyclic” as used herein refers to a cyclic aryl’ with aromatic properties; the term “heterocyclic” aryl’s “aryl’” refers to a heterogeneous group with aromatic properties. rings, for example) where one or more groups of these rings are non-aromatic, provided that at least one ring is aromatic.

and 1 - lila] the group can be connected via an aromatic or via a non-aromatic ring. The aryl 5 aryl heterocyclic groups can be monocyclic or dicyclic and may be either unsubstituted or have one or more substituent groups substituted; For example, one or more groups of RY as previously defined. © The term non-aromatic group means unsaturated cyclic systems without an aromatic property; Carbon and heterogeneous ring systems that are partially saturated and not saturated at all. The expressions “unsaturated” and “a saturated” mean rings in which the cyclic structures contain atoms sharing more than one bond i.e. the ring contains one multiple bond on “C=C Jie” JN or “C=C” or N=C 'fully saturated' means rings that do not have multiple bonds between the atoms of the ring. Partially saturated cyclocarbons cle gana 1 include cycloalkenyl groups as previously defined, such as cyclooctenyl 5 cycloheptenyl s « cyclopentenyl . Examples of heterocyclic groups are monocyclic and monocyclic groups that contain between © and 1 atom per ring; from © to .01 is best for example a heterocyclic group can be a ring with five or six atoms or two Vo rings each fused Each ring can contain about *hetero-atoms specifically chosen from nitrogen and oxygen s sulfur Typically a hetero-ring contains up to* heteroatoms, most commonly up to 7 atoms; For example, one heteroatom.In one embodiment, the aryl heterocyclic ring contains only one nitrogen atom in the ring. The nitrogen atom in the heterocyclic aryl rings can be basic, as is the case with imidazole or pyridine ¢, or non-basic, Ll, as is the case with the nitrogen atom

in 00016 or pyrrole . and as le is the number of basic © atoms present in the aryl heterocyclic group including any amino substituent group in the ring; will be less than 0 Examples of aryl heterogroups having © atoms include - but not limited to Qo: pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole Examples of heterocyclic aryl groups with 7 atoms include - but are not limited to - .pyridine, pyrazine, pyridazine, pyrimidine and triazine 0 and a non-heteroaryl aryl group can be chosen A congener, for example, of the following: 0) a benzene ring fused to a © ring or 7 atoms containing 1, 7, or ? heterocyclic atoms. b) a pyridine ring fused to a © or 7 ring Contains 1 or JY ? heterocyclic atom in the ring. (z 0) a pyrimidine ring fused to a ring of © or 6 atoms containing 1 or ? or * heterocyclic atoms. d pyrrole ring fused to a ring of © or + atoms containing 1 or LEAT FY Homogenous in the loop

0) a generic “rum_ ring fused to a ring of © or 7 atoms containing 1, ?, or * heterocyclic atom in the ring. and an imidazole ring fused to a ring of © or + atoms containing 1, 7, or * atoms BAY is a heterocyclic ring.°g An oxazole ring fused to a ring with © or 1 atoms containing 1 or JY non-cyclic atom

congruent in the loop. h isoxazole ring fused to a ring with © or 1 atoms containing 1 or ? or * a heterocyclic atom in the ring. +( a thiazole ring fused to a © ring or 7 atoms containing 1 or JY ? a non atom

0 is homogeneous in the loop. 4) An isothiazole ring fused to a © ring or 7 atoms containing 1 or JY * heterocyclic atom in the ring. 4) A thiophene ring fused to a © ring or 1 atoms containing 1 OR ? or FY is heterogeneous in the loop.

(J \o) furan ring fused to a ring with © or “> atoms containing 1, Y, or 7 heterocyclic atoms in the ring. (p) oxazole ring fused to a ring with e or + atoms containing 1, Y, or ' heteroatom in the ring.

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®@isoxazole ring fused to a ring with © or 1 atoms containing 1 or 1 or * heterocyclic atom in the ring. Q) A cyclohexyl ring fused to a ring of © or 7 atoms containing 1 or ? or “a P atom of a cyclopentyl ring fused to a © ring or 7 atoms containing 1 or SAT JY heteroatom in the ring. Examples of dicyclic heterocyclic aryl groups containing a ring with 6 atoms fused to a ring with © atoms include, but are not limited to, benzfuran, benzthiophene, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, 01 purine (as indazole, benzodioxole and pyrazolopyridine 5 (adenine, guanine). Examples include dicyclic heterocyclic aryl groups containing 2 fused rings with 1 atoms - on but not limited to TT quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, yo isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine We Lm

— S Examples of aryl 5 aryl heterocyclic polycyclic groups containing an aromatic ring and a non-aromatic ring include: tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran, 2,3-dihydro-benzo[1,4]dioxine, benzo [1,3]dioxole, 4,5,6,7- tetrahydrobenzofuran, indoline and indane ° Examples include cyclic aryl carbon groups include: phenyl, naphthyl, indenyl, and tetrahydronaphthyl Examples include cyclic non-aromatic groups Heterogeneous those groups that have between? and 71 atoms per ring, most commonly between © and 10 atoms per ring, and these groups can be mono or binary 0 ring for example; Typically, it has between 1 and © heteroatoms in the ring (most commonly 1, ?, ©, or ; heteroatom in the ring); It is usually selected from nitrogen oxygens and sulfur sulfur. It can, for example, contain heterocyclic groups; on the cyclic ether moieties LS) is the case in “(tetrahydrofuran and dioxane) and cyclic thioether moieties (as is the case for 0 (tetrahydrothiophene and dithiane) and cyclic amine moieties (As in o(pyridine and LS) cyclic sulphones as in sulfolene (s) and cyclic sulphoxides ¢ and cyclic sulphonamides and combinations thereof (thiomorpholine Jie). Other examples of groups include Non-aromatic heterocyclic amide (LS) cyclic parts is Jal. In pyrrole it is written (0) and WS) cyclic ester parts is the case in butyrolactone 00. YyYyst

— ¢ 7b Examples of monocyclic heterocyclic non-aromatic groups include monocyclic heterocyclic groups with ©, 76, and 1 atoms. Particular examples include: morpholine, thiomorpholine and its S-oxide (particularly thiomorpholine (¢ 1-piperidinyl, 2-piperidinyl 3-piperidinyl and 4-piperidinyl Jie) 5 pyridine) and N- alkyl piperidines such as N-methyl piperidine, piperidone, pyrrolidine ° dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N- alky!piperazines such as N-methyl piperazine, N-ethyl piperazine and N-isopropylpiperazine. piperidinyl and 4-piperidinyl), piperidone, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, Vo dihydrofuran , dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazone, piperazine, and N-alkyl piperazines such as N-methyl piperazine YYsH

Y o — — and as le the non-aromatic heterocyclic groups include pyrrolidine 5 pyridine piperazine s « morpholine azetidine and N-alkyl piperazines . Another particular example is non-aromatic and heterocyclic groups; Which also forms part of the preceding group of non-aromatic and heterocyclic groups, which is azetidine©. Examples of heterocyclic and non-aromatic groups include the Jie cycloalkane cyclohexyl, cyclopentenyl Jie ¢ cycloalkenyl 3 + cyclopentyl and cycloalkenyl groups cycloheptenyl s and asa and ma'an in addition to cyclooctatetraene 5 « cyclohexadienyl ¢ and decalinyl 5 tetrahydronaphthenyl . Optionally, each definition of carbon and non-homocyclic groups in this specification may exclude any part or combination of two or more of the following: — Substitutable or non-substituted pyrrolidone rings. - pyrrolo[1,2-a]pyrimid-4-ones are either substitutable or not. = pyrazolones with or without substitution. And when heterocyclic carbon groups are referred to; Unless otherwise indicated, I can be in the 1 carbon ring or heterocycle substituted or have one or more RY groups substituted from hydroxy s halogen and trifluoromethyl amino s carboxy s nitro s cyano s, mono- or di-C1-4 hydrocarbylamino, carbonaceous and heterocyclic groups with from © to 11 atoms per ring; And the R® Cus RER® group is a bond of 5 R 115750 to titanium SO, SOz, NRE, 8, to be set: EDAH, 1160 CO, 0, Yves

B 4 + Y B_ RO is selected from hydrogen and carbon and heterocyclic groups with which of ? to 11 atoms in the hydrocarbyl© ring, dc ganas can have an optionally substituted with one or more substituent groups to be chosen from hydroxy e”e cyanos halogens carboxy y nitro s and trimer and hydrocarbylamino 014 -tel mono- or 0-carbocyclic and heterocyclic groups having 11 JY carbon atoms and where one or more carbon atoms can be substituted in hydrocarbyl Crs — 5, 50 , 80 , 115716000 , © Arto-Eight COAX or RC are selected from hydrogen and hydrocarbyl fibers; and aX 0 or 8 or 185 and 0 TMV RV J No - . Cua The RY substituent group comprises a carbon or heterocyclic group; This carbon or heterocyclic group may not have or be substituted with one or ST of other substituent groups RY and in one of the subgroups of compounds of formula oT) such other RY substituent groups may include carbon or heterocyclic groups which may not be the same containing a substitution. In another subgroup of compounds of formula (I) the other substituent groups do not include carbon or heterocyclic groups but are chosen from the groups already mentioned in the definition RI

The substituent group RY can be chosen to contain no more than 71 atoms other than hydrogen 0 and for example; Via greater than V0 is a non-hydrogen atom; For example, no more than 11” or 01 or q or A or neither or 1 or © atoms other than hydrogen . When carbon and heterocyclic groups have a pair of substituent groups on two adjacent 0 atoms in Alla (the two Jain groups) can bond so that a cyclic group is formed. and for example; An adjacent pair of substituent groups on two adjacent atoms in the ring can be bonded by one or more heteroatoms and optionally substituted alkylene groups to form a fusion group: oxa-, dioxa-, aza-, diaza- or oxa- aza-cycloalkyl 0 Examples of such associated substituent groups include: 0 0 Tn pS, x) 0 0 0 0 for N F pe TI TX F N H Examples of groups include substituting with iodine s bromine y chlorine y fluorine halogen “ .chlorine 5 fluorine is particularly preferred Detailed description vo in the definition of compounds of formula (I) above; As used hereinafter, 'hydrocarbyl' ual' is a general term that includes aliphatic, cyclic, fatty, and aromatic groups, which have a main chain

Y A — _ of carbon; Unless otherwise stated. In special cases; As defined by Hana, one or more of the carbon atoms that make up the main carbon chain can be replaced by a particular atom or group of atoms. Examples of groups include: alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl° and these groups may not be substitutable; or when it is provided for; It can have one or more substitution groups replaced as defined here. The examples and preferences expressed below apply to all hydrocarbyl substituent groups or substitution groups containing hydrocarbyl groups referred to in the various definitions of 0 -substitution groups of compounds of formula (I) unless otherwise stated. As dale and for example; Can be in hydrocarbyl groups up to about A carbon atoms ¢ unless otherwise required by the text and within the subset of hydrocarbyl groups having from 1 to A carbon atoms Specific examples are for Cis hydrocarbyl such as Libra Jw) hydrocarbyl from hydrocarbyl Ci, hydrocarbyl and the yo specific examples ke 5 for a discrete value or combination of values chosen from C35 Cos Cr hydrocarbyl Css Cis Ces Css Cys The term alkyl' gives both straight and branched chain alkyl groups. Examples of groups include: Yyen methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methy!butyl, and n-hexyl to 4 alkyl 1 atoms and within the subgroup of the isomers and their isomers Ciz that alkyl (such as fer alkyl such as b alkyl Cg le sana carbon sub-examples include (alkyl): those derived from cycloalkyl and include examples of groups and within cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane will have a cycloalkyl group, the cycloalkyl sub-group of . cycloalkyl carbon atoms and special examples of this from A to : but not limited to alkenyl and examples of groups include 0 ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl , buta-1,4-dienyl, pentenyl, and hexenyl carbon atom” A5Y (alkenyl) The alkenyl group and within the alkenyl subgroups will have a Jie alkenyl Cog body, and special examples of that are: but not limited to cycloalkenyl Examples of groups 0 and within include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl

Ve have cycloalkenyl groups, the cycloalkenyl subgroup of . cycloalkenyl Css to 8 carbons; Specific examples of this are groups

Yen

‎VY. — - alkynyl groups = include but are not limited to - ile gana : ethynyl and 2-propynyl (propargyl) and within subgroups of alkynyl groups that have an A IY carbon atom, special examples of These are the Jie alkynyl Cas groups the alkynyl Coa groups. E Examples of carbocyclic aryl groups include but are not limited to AY groups that may be substituted by unsubstituted: -phenyl, naphthyl, indane and indene Examples include cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl include: phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl 01 and when present; or more to be selected from: hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C 1-4 hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic vo in it from 11 JF (typically from ? to 01 and most commonly from © to ve) atoms in the ring. Preferred substituent groups include the fluorine Je halogen. Thus for example the substituent hydrocarbyl group could be fluorinated 3 fluorine partially or over perfluorinated 3 fluorine such as difluoromethyl or trifluoromethyl and in one embodiment include

1 — 8 — preferred substituent groups Cyclic and heterocyclic carbon groups groups with 1 IY atoms in the ring. And when this is stipulated; One or more of the carbon atoms in the hydrocarbyl group can optionally be substituted with or XCCXAX ! including both SO, 0 , 5 , 50 (4 © a subset of them) where + ! and 2 as above elegy pet provided that at least one carbon atom remains from the hydrocarbyl group. For example, an atom or a group of the aforementioned can replace 1 or SY JY ; a carbon atom in the hydrocarbyl group; The atoms or groups that are substituted can be the same or different. In dle terms the number of linear or main chain carbon atoms that can be replaced by other atoms will 0 correspond to the number of linear or main chain carbon atoms in the group they replace. Examples of groups in which one or more carbon atoms or groups have been substituted include: ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X'C(X ?) or cxHXH, sulphones and sulphoxides (C replaced by SO or S0O,), amines (C replaced by NR®).Vo Other examples include carbonates 3 ureas and carbamates (C-C-C replaced by X1C(X2) (X1).

Did not - and when the amino group has two hydrocarbyl substituent groups can - with each other and with an A nitrogen atom bonded to E and optionally with another heterocyclic atom nitrogen Je or sulfur or © or linked to form a cyclic structure of 7- 4 atoms. The definition of “8-82 as used here either for substituent groups present in a carbonic cyclic fraction or heterocyclic fraction or for other substituent groups present elsewhere on compounds of formula (+) includes, among others, compounds in which BR? SELECTED FROM SCINR ASSOCIATION, SURVIVAL CO, OC(0), SC(0), NREC(0), OC(S), SC(S), NR“C(S), 0 NRCCNRS), C(0)0, C(0)S, C(O)NRE, C(S)0, C(S)S, C(S) NRE, CINR)0, CNRS, CINROHNRE, 0C(0)0, SC(0)0, NREC(0)0, OC(S)0, SC(S)0, NRC(S)0, OCINRYO, i» SC(NRS)0, NREC) NR)0, OC(0)S, SC(0)S, NREC(0)S, OC(S)S, SC(S)S, NRC(S)S, OCNRS)S, SCINRE)S, NRECINRE)S, OC(O)NRE, SC(O)NR®, NRC(0) NRE, OC(S)NRS, SC(S) NRE, NREC(S)NRE, OCINRONRE, SCINRONRE, NRECINRNRS, 5 , SO, SO, NR", SO,NR® and NR°SO, 0 where WSR is previously defined. Fragment 18 can be hydrogen or a group selected from carbon or heterocyclic groups having from © to 11 atoms in the ring (typically from ' to 10' atoms and most commonly from © to 01) The ,© hydrocarbyl group has an optional substitution as previously defined. Examples of hydrocarbyl groups, carbonyl cyclic groups, and non-heterocyclic vo groups are as above.

Secret _- and when it is 18 is Rs O it and 0 0 hydrocarbyl form 3s and remove with each other the hydroxy carbyl group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy groups (Jie) alkoxy Jie of 0 alkoxy and most commonly ethoxy Jie alkoxy; Especially cyclopropyloxy Ji cycloalkoxy Cig Jw) cycloalkoxy “( methoxy and cyclobutyloxy © and cyclohexyloxys cyclopentyloxy ( and Css Jie) cycloalkyalkoxy - and alkoxy such as the (cyclopropylmethoxy) and can be in Hydrocarbyloxy groups can be substituted with different substituent groups as previously defined.For example, the alkoxy groups can have .substituted with halogen (LS) is Jal in difluoromethoxy and hydroxy s) is trifluoromethoxy. (as in (hydroxyethoxy 0 wer Ls) alkoxy is in Cia = hydroxy “( methoxyethoxy alkyl) (as in (hydroxyethoxyethoxy or cyclic Jie) cycloalkyl group or A non-aromatic and heterocyclic group as previously defined) 0 Examples of alkoxy groups that carry a non-aromatic and heterocyclic group as a substitution group are those whose heterocyclic group Led is a saturated cyclic amine such as: piperazine s pyrrolidine 5 pyridines morpholine Vo and compounds of ben alkyl-piperazines and compounds of tetrahydropyran 5 cycloalkyl-piperazines or DC gana tetrahydrofuran alkoxy are 0 alkoxy and more specifically group: © methoxy Jie alkyl i.e. ethoxy or 0 N-Propoxy and there can be a substitution in “alkoxy groups” for example - with a monocyclic 0 group such as piperazine s morpholine pyridine 5 pyrrolidine and substituent derivatives

On a nitrogen atom, such as: N-benzyl, N-C, 4 acyl and N-C.4 alkoxycarbonyl groups, and special examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy, where 16 is the Rs bond and is the hydrocarbyl group Cig and examples on hydrocarbyl cule gana RR? How defined is Lin and can hydrocarbyl groups be saturated as cycloalkyl m alkyls ; The special andy on these groups includes cyclopropyl 5 ethyl s methyl . The (alkyl Ji) hydrocarbyl groups can be substituted by many groups and atoms as previously defined. Examples of alkyl groups substituted include alkyl groups substituted with one or more halogen atoms such as chlorine s fluorine (special examples include: bromoethyl, chloroethyl, difluoromethyl, 2,2,2-trifluoroethy! and perfluoroalkyl and alkyl trifluoromethyl Jia 0 (or Cis ¢( ethyl hydroxys methyl hydroxy Ji) hydroxy amino _y ¢ ( acetoxymethyl and benzyloxymethyl Jie) acyloxy and Jie mono- and dialkylamino : aminoethyl udder, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and butylaminomethyl (Ji) alkoxys 0 of the alkoxy as methoxy - as in methoxy ethyl ) and cyclic groups such as cycloalkyl ¢ groups and aryl and aryl groups heterocyclic and heterocyclic aromatic groups as already mentioned). Specific examples of alkyl groups substituted with a cyclic group include those in which the cyclic group is a saturated cyclic amine such as:

— Mg Ag — morpholine, piperidine, pyrrolidine, piperazine, C). 4-alkyl-piperazines, Cj.7-cycloalkyl- piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is alkyl Cg; More specifically, alkyl C13 such as ethyl methyl and n-propyl . Specific examples of alkyl groups substituting 0e include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N-substituted forms as previously defined here. Specific examples of alkyl groups substituted with aryl groups and the aryl 0 heterocycle include .benzyl, phenethyl and pyridylmethyl groups and where 188 is 502185 and 18 is for example; hydrogen or an optionally substituted hydrocarbyl Cis group or a carbonyl and heterocyclic group. Examples of R%RP where “18” is 50:08 include: Group: aminosulphonyl, C4 alkylaminesulphony! and di-C;. 4 alkylamine sulfony! Vo groups, and sulphonamides consisting of an aminocyclic group Jie: piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine with an optional substitution such as 0 N-methyl piperazine

Examples of RAR where 188 is SO; include: aryls sulphonyl alkyl groups heterocyclic 0 sulphonyl aryls sulphonyl and especially monocyclic and heterocyclic sulphonyl groups. Specific examples include sulphonyl phenyl s ¢ methyl sulphonyl toluenesulphonyl s . m and when 188 is NRC it can be 8; For example; hydrogen or a hydrocarbyl Cig group having “Jad” or a heterocyclic carbon or heterocyclic group. Examples of RR “where 183 is pi” include: amino, C;.4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino), di-C;.4 alkylamino (e.g. dimethylamino). and dithylamino) and cycloalkylamino (e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino). SPECIFIC EXAMPLES OF PREFERRED Es A 8 through 18 and 87 group “A” : according to the invention in formula ol) the fragment 2-4-0828 of the compound will be represented by the formula 8-G Cus (G )k-(CH2)-W-Ob-(CH2),- (CR'R")p-NR?R? is NH or Nme or tO and 17 is associated with group 2 and is selected from bs (NH)-CHs (CH)-Ns “(CHDJ-CR® is zero or 1 and zhi is zero or 1 and 16 is ia or amy) zero or 1 and” is zero or 1 or Pye SY is 0 and 1; the sum of a and ka is 0 or 1; the sum of g and 18 y' and 'and 7 does not exceed ; or CRR7 is a cyclopropyl ¢ group and 12 is selected from hydrogen and hydroxy s methyl fluorine;

— vv —_

One of the special groups for 08587 is group .C(CH3);

and special distributions that led is part 81-4-8287 of the compound represented by the formula RAG)

(CH) W-Ob(CH)(CRRT),-NRR is one where:

ms ja 4 K . is zero; Wy is (CH-CR® and g is zero; Rs is hydrogen 0 and 5 is Any) ? And 7 is zero.

hydroxy is RY, g is zero «(CH%)j-CR*®, 10 is yellow, and 0 is ha AK 0.

bs ¢ is zero ns is \Ps is zero .

bs methyl is R¥ 5 zero oa js «(CH?)j-CR® is W is zero my Jia is K .

is zero ns is \ Ps is zero. K 0 is zero my is zero Wy is «(CHp)j-CRy- and g is zero 5 R¥ is fluorine »

0 is zero Ps \v ng is zero bs

and in one of the favored arrangements; The REANRIR? fraction of the compound is represented by the formula RI-X-

X Cua (011), 7 is attached to group 1 and is group “CH” and 1 is ?.

particular examples of bonding group 8; With its contact points with groups © Es {NR?R® 5 yo are shown in the following table 1 :

YY

1 table m a m

ARTY

E R E R E R

A3 A2 2 Me Me 2 Me Me , 1 | 1_R R R

R NI R N N hg R ls ly : N ER How much ER with a gram of 2 g of 3 E "in meters R? E A10 A A 2

R? 5 1 ak N and NT ~ 3c a 3

E R E

7 pm 8 pm

RL. 0 2 ty f

E Rr?

Al9

Me OH

R'_R? A_R? : ;

E then E R

_? 9 _ A. A

F

Aj_R? \

E Rr

A25_R? 1c _ 2

YY TO)

E Rr E Fr

A3 A2 Current favorite combinations include Ass Ass Ap and Rit. And in group A; the sign andl means the presence of a GDS center. The compounds having a +1 distribution at this asymmetric center represent (sa) the preferred subgroups of the compounds of the invention. :R! The R! group is a heterocyclic aryl or aryl group selected from select phenyl pyridines pyrimidines furans thienyl s naphthyl ¢ and the aryl group or heterocyclic aryl group has no substitution or tolerance one or more replacement groups selected from; hydroxy 0 ; and “000 of acyloxy; and fluorine 0; and Yyén

'chlorine

bromine 0 ; And

trifluoromethyl 0 ; And

Cyano. and ¢CONH, 0 oo and

nitro 0 ¢ f

hydrocarbyloxy Ci 0 and fiber© JS hydrocarbyl has an optional substitution by ©

alkoxy, carboxy, or hydroxy; And

0 but acylamino ¢ and benzoylamino 00; And

pyrrolidinocarbonyl 0 ; And

piperidinocarbonyl; And

morpholinocarbonyl 0 ; And

0 aryl heterocyclic aryls heterocyclic oxy heterpalate groups of five or 1 six atoms containing one or more heteroatoms selected from N, E, and 5; and

phenyl 0 ; And

1 - - phenyl - bitter alkyl; and phenyl 0-br alkoxy; and aryl .heterocyclic- 0:4 alkyl ; and aryl .hetero- :0 alkoxy ¢ and phenoxy *© ¢ : where both aryl groups are aryly heterocyclic phenyly oxy phenylys alkyl C4 - phenyl 4 - aryl alkoxy hetero-br alkyl and aryl hetero- 0:4 phenoxy alkoxy optionally substituted by 1 or Y or ¥ ic gana substitution selected from trifluoromethyl s bromine s chlorine s fluorine s acyloxy Cia cyanos 0 0011112 and from hydrocarbyloxy and hydrocarbyl Cp, each Lie has a substitution by methoxy, i.e. hydroxy; and the set RY may not have a substitution or have a substitution of up to © substitution groups; Preferred substitution groups include: : \o per acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; ben hydroxy; hydrocarbyl through hydrocarbyloxy and can be in each of them substituted by:

acylamino; benzoylamino; pyrrolidinocarbonyl;bitter alkoxy or hydroxy; of piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; and aryl groups heteroatoms with 0 or 7 containing one or two heteroatoms are chosen from 17, 0, and 5 and there can be a test substitution in the 0 heteroatom aryl groups with one or more of alkyl cry; phenyls; and pyridyl; ua phenoxy s can be in both phenyl and 1 and does phenoxys replace 1 or ? or ¥ substituent groups to be chosen from bromine s chlorine s fluorine acyloxy Cio and trifluoromethyl cyano such as hydrocarbyloxy and hydrocarbyl ; which (Say) each have a methoxy or hydroxy substitution. acyloxy; or 10" or OR substitution groups; preferably zero or 1 or oF and more preferably zero or 1 or Y and in one embodiment there is no substitution in RY or is have substituents with up to * 0 combinations to be selected from fluorine 5 ¢ acyloxy Cj. ¢ hydroxy fluorine 5 ¢ acyloxy Cj ¢ hydroxy; In Kv., of which it is replaced by alkoxy Crp, i.e. hydroxy 7:1.

Ay is another model in which the RY group can have one or more substituent groups chosen from: hydroxy, fluorine, chlorine, cyano, phenyloxy, pyrazinyloxy, benzyloxy, methyl and methoxy oo and in the AT form The !© group can have one or two substituent groups chosen from fluorine s fluorine , trifluoromethyl and methoxy 3 methyl . and when it is 18 it is the phenyl group; Special examples of substitution group combinations include mono-chlorophenyl and dichlorophenyl. Other examples of combinations of substituent groups include those in which RY is: hydroxyphenyl, fluorochlorophenyl, cyanophenyl, methoxyphenyl, methoxy- 01 chlorophenyl, fluorophenyl, difluorophenyl , phenoxyphenyl, pyrazinyloxyphenyl or benzyloxyphenyl.RY Cua is an aryl or aryl heterocyclic group with T atoms; And a substitution group can be located at the para position on the hexagonal ring. And when there is a substitution group in 1 position with paras, it is preferable that it be larger in size than a fluorine atom. 2 and 3 are each selected from 12 Ry separately from hydrogen, hydrocarbyl, and acyl ; and A 777

— $ _ and typically; the hydrocarbyl group is an alkyl group; The most common is the Ci alkyl group, ©, or B, preferably the methyl group. and in one of the vehicle subgroups; R? is chosen - each separately - from methy 15 hydrogen so 118283 could be an amino » that is, a methylamino or a dimethylamino group + and in one special embodiment it could be 10828 an amino group . and in a preferred AT form; (Sa to be 108287 0 methylamino group and in synonymous form”; B:© hydrocarbyl group can be cyclopropyl, methyl cyclopropyl, or cyclobutyl. R* 0 in formula (1); choose hydrocarbyl Cis halogens «hydrogen (je R*) unsaturated; or hydrocarbyloxy unsaturated -CF35 cyano and more specifically select R* from hydrogen halogens and bitter© hydrocarbyl Saturated CF35 cyano. The preferred values for “18” include halogen and methyl. In a special embodiment 58 is 0 hydrogen R5 ve in formula (1); 8 is selected from hydrocarbyl Crs halogens hydrogen saturated; Cis CONHR's CONH,5 cyano sada hydrocarbyloxy ri NH,s5 111060877 (NHCONHR® where 111100111187 is group 89 or “89” or (CH)R™ where R™ is Yvyen

agnome - a monocyclic or bicyclic group that has an optional substitution and can be cyclic or heterocyclic carbonaceous groups Examples of carbonaceous and heterocyclic groups are already described in the "General Definitions and Preferred Materials" section. ° Typically, the carbonaceous and heterocyclic groups are monocyclic. The heterocyclic and cyclic carbonaceous groups are preferably aromatic. Specific examples of the R group are phenyl and i-benzyl groups that can have an optional substitution. Preferably select R from hydrogen halogens R saturated hydrocarbyl 3 cyano and :01111 NHCONHR® 5 NHCOR® 5 NH, 5 CF; CONHR'; 0 where 18 can have an optional substitution of benzyl J phenyl . It is much better to choose R® from saturated hydrocarbyl Cis « halogens hydrogen; NHCONHR® 5 (NHCOR® 5 (NH, 5 CF 5) “cyano s” where 8 “can have an optional substitution of benzyl. 1 and the AR group is - typically - phenyl or benzyl unsubstituted, phenyl or benzyl substituted with 1, 7, or ¥ substituent groups to be chosen from: acyloxy;ber halogen; hydroxy; trifluoromethyl; cyano; carboxy; C 14alkoxycarbonyl; amino; mono- or di-Cy.4 alkylamine, YYer

— $9 —; alkyl Cru has optionally substituted with hydroxy s « halogen or yip Cras ¢ alkoxy alkoxy 44 optionally substituted with hydroxy s 6 halogen i.e. alkoxy Ci, ¢ and the embodiment and congener aryl groups have 0 or + atoms containing up to * heteroatoms selected from 0, 11 and 5; and saturated cyclic and heterocyclic carbonaceous groups containing up to “heteroatoms selected from 0, 5, or a. Particular examples of the fragment include methyl y bromine y chlorine 5 fluorine s hydrogen R® NHCOR®® NH, 5s CF35 cyanos methoxy methyl s ethyl hydroxy s ethyl and NHCONHR® where R® is phenyl or Les benzyl optionally substituted for hydroxy and ben cyano trifluoromethyl 5 bromine 5 chlorine 4 fluorine 5 « acyloxy and alkyl Ji) hydrocarbyl C4 (alkoxy Jie) hydrocarbyloxy Cis 0 ) and may optionally have a substitution of hydroxy sf alkoxy Cia. Preferred examples include hydrogen RY and ductility of cyanos. Preferably RY is a hydrogen or methyl group “EM vo in the formula ED) a monocyclic aryl group or a heterocyclic aryl group which is selected from the phenyl groups and the number of pyridine pyrimidine 5 furan ; each of them has no replacement or even has; de gana select 8 substitutions of chlorine s hydroxy cyano s trifluoromethyl 5 bromine s lord hydrocarbyloxy rin hydrocarbyl optional substitution by alkoxy C.; or hydroxyl ¢

It is preferable that group A and group 08 are not attached to two adjacent carbon atoms in the ring in the © group. For example Jal the pyrazole group can be attached to group 15 in the meta or para position with respect to it. Examples of such groups include: 1,4-phenylene, 1,3-phenylene, 2,5-pyridylene and 2,4-pyridylene, 1,4-piperazinyl, and 1,4-piperazonyl. ° Other examples include pentagonal rings which have a double substitution in the two positions Fo) and groups 5 may not have or may even have ; Substitution groups RE bromine «chlorin) ¢ hydroxy ( ¢ and cyano ¢ trifluoromethyl ware hydrocarbyloxy can have an optionally substituted with alkoxy Cia or hydrocarbyl Cia ¢ hydroxy can have Ye Optional substitution with alkoxy Cio or hydroxy Preferably there are 0 to * substituent groups; preferably 0 to 7 substituent groups; such as 0 to 1 and in one embodiment the group is non-substituting. Include Examples of the bonding group BE with its connection points to group A (2) and the pyrazole ring (*) are shown in the following table:

(Y) Table 3 a a 11 m ap. © BI * B2 * B3 a a a a 13

MeOR ". 89 B10 811 B12 fluorine s chlorine s methyl from RP and in this table + the substitution group is selected. trifluoromethyl s

LIV) a subset of compounds can be represented by the formula (ITT) and within the formula 2 20g R

R (CHIN ;

R

RA y 5g / N—N : 1 av) hydroxy s methyls hydrogen from RY and choose oY or 1 where 7 is zero or yi then 20g should be pea (AZ Laie is as previously defined, provided that R' R's fluorine s .hydroxy is YY S$

In formula (IV) the !© phenyl group has an optional substitution as defined herein. PE. 2 . : In order to avoid confusion, it must be understood that each type is specific (Janda) and the © collections model and example can be combined with each preferred or generic sale; collections models and examples are located 22 and/or 83 and/or m J/sR 'F The functional groups and substitution groups that make up the compounds of formula (1) are typically chosen so that the molecular weight of the compound of formula (0) does not exceed Veen, and the most common is that the molecular weight is not less than 50, as if 701 or less than 150 or less than 101 or less than 0+©.It is most preferred that the molecular weight be less than 75© and be - for example - less than 0.001.The compounds are chosen of the invention and are illustrated in the following examples: 2-phenyl-2-[4-(1 H-pyrazol-4-yl)-phenyl] -ethylamine; 2-[4-(3,5-dimethyl-1 H) 2-(4-chloro-phenyl)-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethylamine; 2-[3-(3,5-dimethyl-1 H-pyrazol-4-yl)-phenyl]-1 -phenyl-ethylamine; 3-phenyl-2-[3-(1 H-pyrazol-) 4-yl)-phenyl] -propylamine; Vo 3-phenyl-2-[4-(1 H-pyrazol-4-yl)-phenyl]-propylamine; {3-(4-chloro-phenyl) -3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl} -methyl-aminc;

— 0. — {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]-propylamine; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 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); {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -isopropyl-amine; 1 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); z l 1H-pyrazol-4-yl)-phenyl]-ethylamine (S); Vo

- oy — 1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazo 1-4-y])-phenyl]-ethyl }-methyl-amine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl } -ethyl-amine; methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazo 1-4-yl)-phenyl]-ethyl} -amine; {2-(4-methoxy-phenyl)-2-{4-(1H-pyrazo]-4-y1)-phenyl]-ethyl} -methyl-amine; ° methyl-{2-[4-(pyrazin-2-yloxy)-phenyl}-2- [4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -amine; methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; 2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4 -yD)-phenyl]-methoxy}-ethylamine; methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl }-amine; dimethyl-(4-{3-methylamino-1-[4-(1H-pyrazo 1-4-y1)-phenyl}-propyl}-phenyl)-amine; 01 {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol -4-yl)-phenyl]-propyl}-methyl-amine; 3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; {3-(3-chloro-phenoxy)-3-[4-(1H-pyrazo 1-4-yl)-phenyl]-propyl} -methyl-amine; methyl-{2-phenyl-2-[6-(1H-pyrazo ]-4-y])-pyridin-3-yl]-ethyl }-amine; {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine; Vo sold a door

- of - {2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-m ethyl-amine; 2-(4-{2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -phenoxy)-isonicotinamide; {2-(3-chloro-phenoxy)-2-[4-(1H-pyrazo]-4-y)-phenyl]-ethyl}-methyl-amine; {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazo 1-4-y1)-phenyl}-ethyl}-cyclopropylmethyl-amine; 4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl} -phenol; 3-(4-methoxy-phenyl)-3-[4-(1H-pyrazo 1-4-yl)-phenyl]-propylamine; ° {2-(4-chloro-phenyl)-2- [4<( 1H-pyrazol-4-yl)-phenyl]-propyl} -methyl-amine; 1-(4-chloro-phenyl)-2-methylamino-1- [4-(1H-pyrazol-4-yl)-phenyl]-ethano 8 2-amino-1 -(4-chloro-phenyl)- 1- [4-(1H-pyrazol-4-yl)-phenyl] -ethanol; 3-(3-chloro-phenyl)-3-[4-(1H-pyrazo 1-4-yl)-phenyl]-propylamine; 2-methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 01 2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazo I-4-yl)-phenyl]-ethylamine; 2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazo 1-4-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;

- ov — 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; 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-pyrazo[-4-yl)-phenyl]-methyl}-piperazine; and

C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine; and salts, sulphates, tautomers and N-oxides thereof. °

In one embodiment, the compound of the formula (I) is selected from the group consisting of: {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl}-ethyl } -methylamine (R); 3-(4-chloro-phenyl)-3- 4 (1H-pyrazol-4-yl)-phenyl]-propyl amine; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 01 {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. It consists of (I) and another group of compounds of formula

—- $ 0 —— 2-(4-chloro-phenyl)-2-[4-( 1H-pyrazol-4-yl)-phenyl]-ethylamine (R isomer); and its salts, solutes and N-oxides its tautomeric. salts; the solutes; tautomeric ¢ and isomers; esters 3 « N-oxides s; prodrugs and analogues 0 in this section; As in other sections of this application; unless the context provides otherwise; References to formula (1) include references to formula (IV) and all other subgroups, preferred species and examples thereof given herein. Unless otherwise at, reference to a particular compound also includes the ionic, salt and soluble forms and the protected forms thereof For example, as previously discussed. All such salts are within the scope of this invention; references to the compounds of formula (I) include the salt forms of the compounds. As in the preceding sections of this cll all references to formula (D) shall be taken to refer also to Formula (AV) 1 and subgroups thereof unless otherwise indicated in the context.Salts may be selected according to the methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille

G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002

- oo — For example, acid addition salts can be prepared by dissolving the free base in an organic solvent in which the form of the salt of interest is not soluble or in which the solubility is greasy, and then the salt is removed from the solution. i Adding the required acid in suitable solvent so that the acid addition salts can be formed using a wide range of acids; whether inorganic or organic. Examples of addition acids include those consisting of © acid: chosen from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.

L-ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor- sulphonic, (+)-(1S)-camphor-1 0-sulphonic, capric, caproic, caprylic, cinnamic (e.g.

D-glucuronic), glutamic (e.g.

L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (+)-DL-lactic), lactobionic, maleic, malic, (-) -L-malic, malonic, (+)-DL- mandelic, methanesulphorc naphthalenesulphonic (e.g. naphthalene-2-sulphonic), yo naphthalene-1 ,5-disulphonic, 1 -hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic , oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino- salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, toluenesulphonic ba door

A — m - (such as valericy undecylenic “( P-TOLUENESULPHONIC) in addition to acyl group-containing amino acids and cation exchange resins. One special group of acid addition salts includes the ASIA salts with hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic , glucuronic and lactobionic acids. Another group of acid addition salts includes salts consisting of: acetic, adipic, ascorbic, aspartic, citric, DL-Lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, methanesulphonic, sebacic, stearic, succinic KE and tartaric acids. The compounds of the invention can exist as mono or binary salts according to the Pha of the acid of which the salt is formed. In strong acids, eld) pyrazole nitrogen in addition to the nitrogen atom 8 group 008283 can co-form the salt. For example (JE, when the acid has a Pka less than about ¥Je) for example an acid such as hydrochloric acid + or sulfuric acid or trifluoroacetic acid (the compounds of the present invention will be - Typically - salts with ?molecular equivalent of acid.If the compound is anionic, or has a functional group it can be anionic (Ju) COOH — gives 600); The salt can be formed using an appropriate cation. Examples include coc

cov - : inorganic cations = to name a few. Alkali metal ions such as K+ 5 Nat cations s alkali earth Jue +082 and Mg2+ and other wedmnah such as JAR including but not limited to (NH4+ Jie) ammonium ion ammonium 5 ions in which there is a substitution (NR4+ 5 < NHR3+ 5 «NH2R2+ 5 NH3R+ Jue) 0. Examples of some suitable substituted ammonium ions include those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, in addition to arginine lysine Jie amino acids. Common examples of quaternary 0 ammonium ions are N(CH3)4+ and when a compound of formula (T) contains an amine functional group; they can be quaternary ammonium salts; It also occurs when interacting with an alkylating agent according to methods known to those with experience in this field. These quaternary ammonium compounds fall within the range of formula -(D 10). Compounds of formula (I) containing an amine functional group can also form Neoxides. It can be noted here that formula (I ), which contains an amine functional group, which contains Lad, an N-oxide.

A —_ 0 — and when a compound contains several amine functional groups; One or more nitrogen atoms can be oxidized to form N-oxide particular examples include the N-oxide of a tertiary amine or atom 10 in a nitrogen-containing heterocyclic ada . The N-oxides can be made by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or peroxycarboxylic acid Ji. See, for example: Advanced Organic Chemistry, by Jerry March, 49 Edition, Wiley Interscience, pages and with more specificity »N-oxides can be done with the procedure followed by: (LW.

Deady (Syn.

Comm. 1977, 7, 509-514) where an amine is reacted with 0” m-chloroperoxybenzoic acid (MCPBA) for example; in an inert solvent such as dichloromethane | 0 . Compounds of formula (I) can exist in a number of geometric, isomeric and tautomeric forms; References to compounds of formula (I) include all such forms. 3 £ £ £ For the avoidance of confusion; and when a compound may exist in several isomeric or tautomeric forms and only one of them is explained, all such forms are included in the scope of formula (I) 1. For example; For in compounds of formula ( ) the pyrazole group can take one of those tautomeric forms having By $M | door

_ 9 0 — Re Re _N MG RL.

No SR? B 3 C SA E E R ON R 5 A R 5 \ / N—N N—N H H A B For simplicity; The general form (1) shows form (A), but the formula must be taken into account that it models both forms Bs A and when compounds of formula (1) contain one or more non-Ala centers and 0 can exist In the form of two or more optical isomers, the reference to compounds of formula (1) includes all of their isomer forms (such as isomers 65 and diastereoisomers) “either as independent optical isomers or as mixtures of two or more optical isomers Unless otherwise required by the text, for example, group M can include one or more asymmetric centers, and so on 0 When each of the 15 RS bonds to the same carbon atom on bonding group A, that carbon atom is not Typically isomeric and thus the compound of formula (D) exists as a pair of enantiomers (or more than one pair of isomers where there is more than one asymmetric center in the present compound). Optical isomers can be distinguished and identified by their optical activity (i.e., isomers + and -) or they can be distinguished in terms of their absolute spatial distribution using the nominalities with “8” and 87” that were developed by “Prelog s Ingold 5 Chan.” See: YY en.

EE

Advanced Organic Chemistry by Jerry March, 4™ Edition, John Wiley & Sons, New York, 1992, pp. 109-114.

Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl, 1966, 5, 385-415 Techniques including day optical isomers (asymmetric supported Sas) and such techniques as sale asymmetric chromatography are well known to those with experience in In this field, by forming salts of Optical isomers and as an alternative to the chromatography technique, optical isomers can be separated: such as ALS with non-diastereoisomers of (+)-tartaric acid, (-)-pyroglutamic acid, (- )-di-toluloyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulphonic 1 Then separate the 005 stereoisomers by preferential crystallization, then analyze the salts to obtain separate isomers of the free base. In two or more optical isomers, one (D) and when compounds of the active formula Jie are present in the enantiomer can exhibit advantages over the other enantiomers - and so on under certain conditions It may be desirable to use as a therapeutic agent 0 biological 1 and only one of a pair of isomers; or only one of a group of dimers ( ) The invention therefore provides compositions containing the compound of formula ely. diastereoisomers or 65 or 01 (eg there is oo where there is at least 0 with one or more centers of asymmetry or at least 9) of the formula 1 compound as isomer 01 Jae or 5No or 86 or 0

Single photosynthesis (isotropic or dichotomous). In a general model, 14 # or more (i.e. almost all of them) of the total amount of the compound of formula (1) is present in the form of a single (isomer or dichotomous) optical isomer. Esters such as carboxylic acid esters and acyloxy esters of compounds Formula (I) bearing they are a carboxylic acid group or a hydroxyl group in the range of Formula 00 and in one embodiment of the invention; Formula (I) includes within the range of esters compounds of Formula ( ) having a carboxylic acid group or a hydroxyl group. .ay 0 Examples esters Compounds containing group 0(01-)0-, where R is the ester substituent group eg < alkyl Cig 6 group and a Wodon heterocyclic group; OR aryl Cs. group 6, preferably alkyl C7 Special examples of —ester ile gana include but are not limited to -C(=0)OCH3, -C(=0)OCH,CHj, -C( =0)0C(CH;); where R is the Jia acyloxy substituent group of an alkyl Crs group; a 0:20 heterocyclic group; or set 0520 aryl « or preferably set 0. alkyl Cig Specific examples include but are not limited to acyloxy groups ——OC(=0O)phs — OC(=0)C(CH3),.s ( acetoxy) - OC(=0) CH; And 6M011 (0-)00 -.

- 7+ - also falls within the scope of formula (1) any polycrystalline forms of compounds; and solutes (such as hydrates) and complexes (Jia) containment complexes or containment compounds with cyclodextrins Jia; or complexes with metals) for compounds; and vehicle prodrugs. By "prodrug" we mean any compound that transforms in vivo into an active compound of the image (I) © For example, some prodrugs are esters of the compound (Jill esters) that change by conformation and are pharmaceutically acceptable) . during metabolism; dais set ester(-C(=0)OR) to give a property Ni and such esters can be made by esterification; of any carboxylic acid group eg (-C(=0)OH) in the parent compound; when appropriate; Before protecting any other Ald groups in the parent compound; This is followed by removal of protection if necessary. 0 Examples of these esters that change during metabolism include those compounds with the formula R cua C(=0)OR: Me, -Et, -nPr, -iPr, -nBu, -sBu, - iBu, -tBu); C1-7 aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C.7alkyl (e.g., acyloxymethyl ; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1- Vo (benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)-carbonyloxyethyl). Y.

Lad also activates some prodrugs using enzymes to obtain an active compound; or a compound that, after another chemical activation, gives an active compound (as is the case for example with gall 45 antigen prodrug enzyme therapy (ADEPT) and allogen-directed prodrug enzyme therapy (010177). The prodrug is 0 a sugar derivative or a conjugated AT glycoside, or it can be an amino acid ester derivative Methods for preparing compounds of formula (1) in this section, as in other sections of this application, unless the context otherwise requires cells, references to formula ( ) include references to formula (IV) and all other subgroups; their preferred types and examples thereof are previously defined. 0 Compounds of formula (I) may be prepared by a compound reaction of formula ( X) with a compound of formula (XD) or a derivative protected at N of it. : 7 2 / 1 A 4 5 7 D R 1 N R / E N—N ( XD) 1 and m * where Es A has entered up to p as previously defined; sa) the X and 7 groups are chlorine, bromine, iodine, or the trifluoromethanesulphonate (triflate) group and the groups are The other ve from p3 and a is boronate ester Jie “boronate” or the structural unit of boronic acid. The reaction can be carried out under typical Suzuki pairing conditions in the presence of a Jie palladium catalyst:

- 1g .( potassium carbonate Fra Jia carbonate) with an aqueous bis(tri-z-butylphosphine)palladium base and typically the ethanol mixture is subjected and the reaction can be carried out in an aqueous solvent system as the reaction for heating; at more than 1,000 m for example. 1. It is shown in the Suzuki diagram and an illustrative synthesis method includes an aryl or aryl heterogeneous coupling step of 1 and the starting material for the synthetic route shown in the diagram 0 or bromine or chlorine is an X in which Cus (XII) halo has been substituted with methyl nitrile in the presence of R'CHO aldehyde with (XII) nitrile and is condensed. triflate ic seme or iodine call ethanol in an aqueous solvent system such as sodium or potassium hydroxide Jie is an alkaline substance and the reaction can be carried out at room temperature.

0 and then the substituent acrylonitrile (XII) derivative is treated with a reducing agent which will selectively reduce the double bond in the alkene without reducing the nitrile group and sodium borohydride Jie borohydride can be used for this purpose to obtain a derivative acetonitrile has a (XIV) substitution and typically the reduction reaction is carried out in a solvent such as ethanol usually with heating; And even a temperature of about 65C, for example.

(XV) pyrazole of the boronate ester with (XIV) reductant nitrile, and then a coupling is made for the previously explained 1 led to obtain a compound of formula (), which Suzuki is in conjugation conditions with substitution acetonitrile is the A-NR'R' group.

‎AE

o — 5 _ R' wag I eh X—E—CH;yCN KOH/EtOH E CN (XI) X (XI) NaBH, EtOH Me Me Me Me R' E CN 5 4 i xn NN 2 xv) Pd(0) catalyst 3 a" b b h p Ni/NH, 5 c Rach R RS EtOH NN NN (XVI) (Xvi) Scheme 1 Baie Substituted acetonitrile (XVI) can be reduced to Lhd amine (XVID) by treatment with a suitable reducing agent such as ammonia Raney nickel in ethanol The synthetic route shown in Scheme 1 leads to obtaining amino compounds of formula (I) 0 which are heterocyclic aryl de sane led 1 attached at position 8 of the m group with respect to the amino group. In order to obtain amino compounds of formula (1) in which a is attached at position 8 with respect to the amino group, the functional groups on the two starting materials in the condensation step can be reversed so that The compound of formula X-E-CHO is condensed where X is bromine, chlorine, iodine, or 011816 aa group A compound of formula E is condensed

ST

1-072-0 to obtain a substituent acetonitrile derivative and then be reduced to the corresponding acetonitrile derivative before conjugation with (XV) pyrazole boronate and reduction of the cyano group to . amino group and compounds of the formula ( ) can be prepared in which RY is attached to the position » with respect to the aminod! de saad by a series of reactions shown in the schematic diagram. And in a plan? The starting material is Grignard's modulus (it is an aryl or methyl aryl heterocyclic substituted with XVII) halo where X is bromine or (chlorine where it reacts with nitrile malformed in Dry ether diethyl ether Jie to obtain an intermediate amine (not shown) is 0 reduced to yield (XIX) amine using a reducing agent lithium aluminum Jie (Says .08) amine reaction work ( XIX) with boronate ester (XV) in the previously described (XX) amine coupling conditions for Suzuki

0 ivory X—E—CH;-MgBr Et,0 1 A Wood (XVIII) (i) LiATH, X NH, (XIX)

Me Me

Me started Me 00 8

RA R’ xv) NN

Pd(0) catalyst NH,

E

Se R® /

N—N

H

(XX)

Scheme 2 (XXD) containing a nitrile substitution of compound (I) and compounds of formula 2 N can also be prepared

E

RA R® /

N—N

PG (XX) and AAA

Where PG is a protective group such as the tetrahydropyranyl group. (XXI)nitrile can be condensed with an aldehyde of the form R'S(CH2)-CHO where ar is 0 or 1 and the resulting substituent acrylonitrile is then reduced to the corresponding substituent nitrile Under conditions similar to those illustrated in Figure 1 above. The protective © PG can then be removed in an appropriate manner. The nitrile compound can then be reduced to a jill amine using an appropriate reducing agent as described above. It is also possible to make a reaction of the (XXI) nitrile compound with (Grignard reagent formula: 1-000 under standard conditions for Grinard reagent, then followed by deprotection to obtain the amino compound of the invention, which has the structure shown in Formula ([60) RN.CH )r NH, E RA R® / N—N 1 H (XXII) and in the preceding preparations summarized; The conjugation of an aryl group or aryl heterocyclic E with pyrazole is carried out by the reaction of a pyrazole - halo compound or aryl = halo or an aryl heterocyclic compound with boronate ester or s * boronic acid having a catalyst of palladium and a base. Several boronates suitable for use in the preparation of the compounds of the invention are commercially available oe Jia those available from “Boron Molecular Limited of Noble Park, Australia at Leisy Combi-Blocks Inc, of San Francisco.” Boronates are not available. AR can be prepared

.N.

Miyaura and A.

Suzuki, Chem.

Rev. 1995, 95, 2457 and so on boronates can

It was prepared by the reaction of the bromine compound with butyl lithium Ji alkyl lithium, and then a reaction with

,. boronates ester It is possible to make a hydrolysis - if desired - of a derivative. boronates ester views. boronic acid for

e Compounds of formula 0 in which group (A) contains a nitrogen atom attached to group E can be prepared by known synthesis procedures from compounds of formula (XXII) or a protected form thereof. Compounds of formula (XXIII) can be obtained by conjugating Suzuki of a compound of formula (XV) (see diagram 1) with a compound of formula 4A-bromoaniline Jie Br-E-NH,

Ma 2 SN R® / N—N H (XXII) 0 Compounds of formula (D) to which Eg RY is attached to the same carbon atom can be prepared by the method shown in Scheme .

— VY. =

NC CO, et base

X—E—CHO + NC-CH;COEt —— = T

E (XXV) (XXIV) x

R'MgBr

COH

2 (i) hydrolysis NC. COE 1 (ii) decarboxylation OR effective

X (XXVI) x (XXVI) z amide coupling reaction

CONR®R’ reduction of amide [om x Hg 5 R’

X (XXVIII) X (XXIX)

Me Me Me, ie Me Me Ve, 0.0 : : 00 “BY Suzuki Coupling +

SN R® Py R®

N—-N (XV) (XV) N-N

H H

Pd) Pd(0) m jo ng gg gg

PN RS reduction of amide RN R® // replace N—N

H H

(XXX) (XXX)

Scheme 3

In the VF scheme, the (XXIV) aldehyde compound, where X is bromine, chlorine, iodine, or the triflate group, is condensed with the occlusive cyanoacetate in the presence of a base to give an intermediate compound consisting of (XXV) cyanoacrylate ester. Typically, condensation is performed in the presence of a base; pyridine jie non-hydroxide is preferred; By heating in Dean Stark conditions. Then the intermediate cyanoacrylate reaction (XXV) is made with the appropriate Grignard reagent R'MgBr to introduce the group! The Grignard reaction Jel can be carried out in a polar non-proton donor cule tetrahydrofuran Jie at a low temperature; For example at approx m row. The product of the Jeli Grinard reaction is cyano propionic acid ester (XXVI) 0, and it is subjected to hydrolysis and decarboxylation to obtain a derivative: Man (Sas propionic acid (XXVID). Decarboxylation by heating in an acidic medium “Je” a mixture of sulfuric acid and acetic acid. The derivative (XXVIII) amide “propionic acid (XXXVI) is converted by reaction with amine 1 1008283 in Suitable conditions for the formation of an amide bond.It is preferable to conduct the coupling reaction between the derivative of HNR?R® amine 5 propionic acid (XXVID) in the presence of a coefficient of the type usually used in the formation of peptide linkages, examples of such coefficients include: al, J.

Amer.

Chem Soc. 1953, 71, that 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan 1-ethyl-3-(3' -dimethylaminopropyl)-carbodiimide), 1067 Yyet

(4) Here WL is referred to as EDC or (Sheehan et al, J.

Org.

Chem., 1961, 26, 2525) (EDAC and Jie uronium-based couplings: O-(7-azabenzotriazol-1-yl)-N, N,N,N tetramethyluronium hexafluorophosphate (HATU) © And coupling materials based on Jie phosphonium: 1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). It is preferable to use coupling materials based on Carbodiimide. In combination with : 1-hydroxy-7-azabenzotriazole (HOA?) (L.

A.

Carpino, J.

Amer.

Chem.

Soc., 1993, 115, or 1-hydroxybenzotriazole (HOB) (Konig et al, Chem.

Ber., 103, 708, 2024- 01 (4397) 2034. Preferred couplings include DDC 5 EDC (EDAc) in combination with HOA or HOBt and the coupling reaction is typically performed in a non-aqueous and non-mil solvent For protonation such as: acetonitrile, dioxan, dimethylsulphoxide, dichloromethane, dimethylformamide or N- methylpyrrolidine Vo or in an aqueous solvent and optionally with one or more miscible solvents. The reaction can be carried out at RT when the reactants are OF active (eg in the case of electron-poor anilines carrying declension groups

Jie electrons have sulphonamide groups at appropriately high temperatures.

ef ja) enables the reaction in the presence of a base that does not interfere with the course of the reaction; tertiary amine Jie as triethylamine or N, N-diisopropylethylamine is the case with

When the HNR?R® amine is an ammonia, the amide conjugation of Jeli can be carried out using 1,1°-carbonyldiimidazole (CDI) 0 to activate the carboxylic acid before adding the ammonia.

Alternatively (lil), the active derivative, carboxylic acid, such as anhydride or acid chloride ¢ can be used.

use it. Typically, a reaction is carried out with an active derivative, anhydride Jie, by flipping the anhydride 5 amine.

at room temperature in the presence of a base such as pyridine.

(XXVID amide) can be converted to a compound of formula (XXX) (analogue to compound of formula (0) where A has an oxo-substituted group next to (NR°R' dc gana) by reacting with (XV ) carbonates

in Suzuki coupling conditions as previously explained. The (XXX) amide can then be reduced using aluminum chloride in the presence of lithium aluminum hydride as the reducing agent of

to give an amine of formula (XXX) (which corresponds to a compound of formula (I) where A is CH-

(CH,-CH;-) Typically, the reduction reaction is carried out in an ether solvent ¢ such as diethyl ether with yo heating and return of the solvent. Instead of the reaction of (XXVIID amide with (XV) boronates, the amide enables Ya to be reduced

b aluminum chloride [lithium aluminum hydride] at room temperature; to get

on (XXIX) amine which is then reacted under the previous Suzuki coupling conditions

Annotate it to get (XXX).

In order to obtain the (XXIX) amine isotope containing the “Ji methylene” group, the acid (XXVID) can be converted into an azide by standard methods and subjected to a modification process in the presence of benzyl alcohol Jie J eas to obtain a carbamate ¢ See: Advanced Orgainic Chemistry, 4 edition, by Jerry March, John Wiley & sons, 1992, pages 1091-1092) ° The benzylcarbamate acts as the amine group 485 during the next Suzuki conjugation step; The benzyloxycarbonyl moiety can then be removed by standard methods after the conjugation step. Alternatively, the benzylcarbamate group can be treated with a hydride reducing agent lithium aluminum Jie hydride to obtain a compound in which NRZR? is a methylamino group instead of an amino group \-. Intermediate compounds of formula ( ) in which the “chlorine X” part is bromine or iodine and A is the group CH-CHy- can be prepared by a reductive amination of the aldehyde compound from Formula (XXXII) Nr CHO 1 X (XXXII) vo with an amine of formula HNR'R® under reductive amination conditions; For example, in the presence of sodium borohydride cyano in an alcohol solvent such as methanol or ethanol. YY¢1

— MVv_ (XXX) aldehyde can be obtained by the (XXXII) oxidation of the corresponding alcohol using, for example, Dess-Martin periodinane. See: D.B.; Martin, J.C.

J.

Org.

Soc, 1983, 48, 4155 and Organic Syntheses, Vol. 77, 141 ,10655 CH,OH b R v X (XXXII) 5 The Friedel Crafts reaction was found to have dale applicability to the preparation of a range of intermediates of formula ©0. Accordingly; and in a general way of making compounds of the formula ©); A compound of formula H(LXX) 2 nor HO A R 7 X (LXX) 0 is reacted with a compound of formula 8-11 under alkylation conditions (Freidel Crafts alkylation) For example, in the presence of aluminum, halide (eg (AICI;). In an additional method for preparing a compound of formula (1) where part 10828 is conjugated to the CH group, Sa A part has an aldehyde conjugation of Formula (XXXVI) with amine of formula HNRZR? under reductive amination conditions as described before. In formulas (XXXVI) (XXXVIDs 0) 'has' is the remainder of the group /- No cracks form him and 0112 together

group him. (Say) formation of (XXXVI) aldehyde by oxidation of the corresponding alcohol using <Dress-Martin encirclement e.g. 1 ~CH,OH M LAS D E E 4 R A R Se R® N— N N—N A Freidel Crafts alkylation procedure of the type described above can also be used to analyze © intermediates of formula (XXXIV) to prepare intermediates of formula Cua (X) X is bromine An example of such a procedure is shown in Scheme 4. OH 23 0 2 — El — Br—E—<]] Br—E + and Ba (XXXIX) ((006/1) 2 a AlCI p s—e— N and Pa (XL) R Scheme 4 The starting material for the synthetic pathway shown in Scheme ¢ is epoxide (XXXVI), which can either be obtained commercially or can be alee by methods well known to a skilled person 0 eg by reacting Br-E-CHO aldehyde under conditions suitable for a ring-opening reaction with the alee

live

Shedd epoxide A compound of formula (XXXIX) The ring-opening reaction may be carried out in a polar solvent ethanol Jie at room temperature or optionally with mild heating; Typically, with a large increase of amine. The (XXXIX) amine is then reacted with a compound (R'H aryl) and typically a phenyl compound “0” capable of participating in the Friedel Crafts alkylation. See, for example: “Ady Advanced Organic Chemistry , by Jerry March, pages 534-542 An amine of the formula po (XXXIX) compound RH aryl is typically reacted in the presence of an aluminum chloride catalyst at or around room temperature. aryl 8/11 is a liquid; eg in the case of methoxybenzene (Je) eg anisole or chlorobenzene Jie halobenzene 0 ¢ the aryl compound acts as the solvent. Otherwise a less reactive solvent can be used Like nitro benzene Freidel Crafts alkylation gives R'H with X where is (X) which corresponds to a compound of formula (XL) A compound of formula (XXXIX) amine is bromine and A is .CHCH, (XXXIX) hydroxy compound in Scheme No. can also be used to prepare compounds of formula 00 in which the carbon atom of the hydrocarbon of the conducting group A is substituted next to the group R! by means of an oxygen atom.Thus, the compound of the formula XXXIX or its derivative protected at terminal N) Cua, where R? or RP is hydrogen, can be reacted with a phenolic compound of formula 1-011 under conditions of eg Mitsumobu alkylation; in the presence of azodicarboxylate and triphenylphosphine 016071. The reaction is typically carried out in YY solvent Z

Polar non-ile to protons such as tetrahydrofuran at a moderate temperature such as the ambient temperature. The use of hydroxy «Sel Al intermediate (XXXIX) is for the preparation of the fluorine compound and the corresponding cdl. The hydroxy group can be replaced by fluorine by reaction with a complex of hydrogen fluoride: pyridine (reactant (Olah) the fluorinew intermediate can then be subjected to a Suzuki coupling reaction to give a compound of formula (I) with a hydrocarbon group treated with LA fluorine. Alternatively, a fluorine of formula (1) can be prepared ) by first conjugating the intermediate hydroxy compound (XXXIX) or a protected die form with pyrazole boronic acid or boronate under Suzuki conditions and then substituting a hydroxy group 0 in the resulting compound of formula (I) with fluorine Using a complex -hydrogen fluoride : pyridine Compounds of formula (I) can be prepared in which the part: 2 / R—A—N Qa E R is a group: p R—CH-O—A"-N and Ba E R vo where AT is the hydrocarbon residue of group A by a sequence of reactions shown in Scheme No. 2 A » Lapp

R*MgBrR

X—E—-CHO Li X—E—CH-OH (XXIV) (XLI) rR”

Me Me | 1 /

MoE X—A Mag 5

R

3.5 (XLII)

B

RA R 5 R 1 R 2' / \ X—E-CH-O—A"-N xv) N and Ba (XLII Pd(0) a 2

R

CH-O—A"-N\gy

E R

RP R (X L IV)

N—N

H

Scheme §

Grignard with reactant (XXIV) aldehyde as shown in Scheme 0. (XLI) secondary alcohol is reacted under 10 standard conditions to give secondary alcohol 7: in which (XLIT) is a compound of formula ae The secondary alcohol can then react with the secondary alcohol (sie) and have a ¢ amine protecting dc gana or Rs 182 p and 83 groups or a leaving group. hydroxy group 8; representing 76 groups ,

As — - can be a protection group amine « eg; is a phthaloyl group where in this case 1182183 is a phthalimido group . when 36 is a hydroxyl group; The reaction between compound (XL) (XLII) 5 can take the form of a condensation reaction catalyzed by toluene sulphonic acid . by “dy” when 0 is © is a leaving group such as halogen ; Alcohol (XLI) can first be reacted with a strong base sodium hydride Jie to form an alcoholate, which then reacts with compound ((01). The resulting compound of formula (XLID) is then subjected to a Suzuki coupling reaction with a reactor (XV) pyrazole boronate under typical Suzuki conjugation conditions of the type described before to give a compound of formula Sa (XLIV) then All) the protective group of the protected amine 0 group 1182183 to give a compound of formula (I) (Sa) Preparation of compounds of formula (I) in which the fraction: R? / 1 R—A—N 3 \ E R ke 3 from the group: R R-0-CH-A"-N and B E R where AT is the hydrocarbon residue of group A by the sequence of reactions shown in Scheme A

B" NaBH, R —_— I 0 00/0 (XLV) DEAD | Ph,P R'OH 2c von 1 um R—O0. Designate R oN A Roe | (XLVI) E E x 0 (XLVI) Me Me 2 Mee R -N ;m (80)0 o_O R B E A R® RL_ ~ R® / / solve Fig. 11 for xv) Scheme 6 The starting material for Scheme 6 is (XLV) chloroacyl, which can be prepared by literature and documentation methods (eg the method described In: J.

Med.

Chem, 2004, 47, 3924-3926 or equivalent methods. The compound (XLV) is converted to (XLVI) secondary alcohol by reduction with the hydride reducing agent sodium borohydride Jie in the polar solvent tetrahydrofuran [ele Jie . The (XLVI) secondary alcohol can then be reacted with a phenolic compound of formula 1-011 under eg <Mitsumoba alkylation conditions; in the presence of

M - diethyl azodicarboxylate and triphenylphosphine ¢ as explained by (JB) to give (XLVI) aryl ether compound, then a chlorine atom in (XLVI) aryl ether compound is displaced by Jeli with amine HNR'R? to give a compound of formula (XLVI) The nucleophilic displacement reaction can be carried out by heating amine with (aryl ether) a polar solvent such as alcohol at elevated temperature; eg about 100 C. (Sa) The resulting amine (007-17110) was then subjected to the Suzuki coupling procedure with borons of formula (XV) as described above to give compound (0117). In a change to the reaction sequence shown in Scheme 1 Say the secondary alcohol (XLV) is subjected to a calf nucleophilic displacement reaction of amine ge 1108283 before the introduction of the L group by Mitsunoba Jel&0 to form ether. It is done in Scheme 1. Illustration of the AT pathway for compounds of formula (D) in which 1 and 8 are connected to the same carbon atom of group A Yvé¢n

CN

HO. __OH

B E

RAN R 5 X-E-CN R Rakha R 5 Iulbalsils 7SSSSSS /

N—N Pd(0) PG PG (LI) (L)

R'MgBr (LD 0 Me Me

Me Pree°0

R Love N AN Ph Ph R >

E Me E

R “AR 5 n-BuLi R “AR 5

LIV

N—N (LIV) N—N

PG PG

(LI)

Pd/C

H,

R! 1

E Me

RN rR’

NNW

Scheme 7 under (1) N protected at terminal pyrazolyl boronic acid deli in Scheme No. 7 - is typically an X in which the X-E-CN cyano with a Suzuki compound is pairing conditions for ring 1 in position PG the protecting group may be chlorine or bromine such as halogen .triphenylmethyl (trityl) ic gana for example; « pyrazole

(L) boronic acid may be prepared using the method described in EP No. 0877507 or equivalent methods. The resulting nitrile (LI) may then be reacted with the R'-MgBr Grignard reactor to introduce group R! and form (LI) ketone (LID) ketone is converted to (LIV) enamine By reaction with 0H diphenylphosphinoylmethylamine (LI) in the presence of a strong base alkyl lithium Jw ¢ and in particular butyl lithium. (LIV) enamine glad) is then hydrogenated using a palladium catalyst on charcoal to reduce the enamine double bond and remove the 91O16060P-1 group. Cua protection group PG is trityl Ae same ; The hydrogenation process also removes group 01; Which gives 0 a compound of formula (LV) alternatively; Enamine can be reduced by a hydride reducing agent under conditions described in 1309-1316 (2003) 14 Tetrahedron: Asymmetry and subjected to chiral separation. Removal of the protecting group 2-phenethyl and protecting group PG gives a photoactive image From a compound of formula (LV) Vo intermediate compounds of formula Cus (X) connected to A and 82 may be prepared to form a ring containing an oxygen atom by the general method shown in Scheme 8.

_AO —

R\__O RL__O oF 7115 L O E NaH E

X win X (LVI) oH

H,N b (LIX) 1c 07 concH,SO, b OH “No NH tbh R abrasive OH

H

Ev

X Pd(0) X (LVI)

Me Me

Me | Me A 0-5 0.0 So NH

E y / then rR?

XV 0 (XV) Na Ne

H

Scheme 8 0258 trimethylsulphonium iodide with (LVI) ketone Jeli is carried out “A in Scheme No. sodium Jw hydride p0<10m”._The reaction is typically carried out in the presence of (LVI) base. dimethylsulphoxide Ji in a polar solvent hydride of which mono- or dialkylamines with compounds « amine ethanol with epoxide (LVI) Jeli © may thus provide a path to compounds containing the part:

Oh

R? 1

E then

Compounds where R? and 83 are both hydrogens can be prepared by reacting epoxide (LVII) with potassium phthalimide in a polar solvent such as DMSO. During the coupling step Suzuki ¢ may pass the phthalimide group Partial hydrolysis to give the corresponding phthalamic acid, which (Sa) was cleaved using hydrazine to give an NH, amino group alternatively; 0. Rings of phthalamic acid can be reconstituted into phthalamic acid using a scaling reactor to form an amide and then removing the phthaloyl group with hydrazine to give amine 1 . E + X (LX) Cl (LX) base _PG NG R Tan X Scheme 9 Compounds of formula (I) can be formed in which the part: 1 / 2 R—A—N i \ 4 E R 0 is an R? unless 4 | + R—C—CH; N 3 \ E R YY ER

where “ALK” is a small alkyl group methyl Jie or ethyl formed by the schematic pathway shown in Scheme No. Do R\._COH R\_ _CO,Me MeOH/H* hg and E -— = E X (LXV) X (LXV) LDA Alk-| ~CO,Me 77 Ta 1 A X (LXV) X (LXV) HNR2R? Alk R 1g LAI, M Ak 5 Z Hob es P N _R ? p x R X (LXV) (LXIX) Scheme 10 in Scheme No. “Ve” (pe carboxylic acid of formula (LXIV)) is esterified by © treatment with methanol in the presence of a catalyst Hydrochloric acid Jie Mae ester (LXV) reacts with strong base lithium diisopropylamide (LDA) Ji and methyl Jie alkyl iodide A iodide low temperature Jo) way example; Between 0 C and -No 6 0 the branched ester (LXVD) is then hydrolyzed to acid (13071) and conjugated to amine 11018283 under

mm - standard conditions for amide formation .of the type described above. The (LXVII) amide can then be reduced to (LXIX) amine using “lithium aluminum hydride” and the (IXIX) amide is then reacted with pyrazole boronate or boronic acid under Suzuki coupling conditions. to give a compound of the formula ().

0 Once formed many compounds of formula ( ) can be converted into compounds into other compounds of formula (I) using standard functional group interconversions. For example; Compounds of formula (I) can be reduced as 118283 parts nitrile de gene to the corresponding amine. Compounds in which 118283 is a ;NH group can be converted to the corresponding alkyl amine by reductive alkylation to the corresponding alkylamine by alkylation

alkylation 0 reductive; or to a toroid. Compounds where !© contains a halogen atom such as chlorine or bromine the entry dc sane can be used as a substitution of an aryl group or a heterocyclic aryl to group A by a Suzuki pairing reaction . Additional examples of interconversions of a compound of formula (1) to an AT compound of formula ( ) can be found in the following examples. (Say) Additional examples of interconversions of functional groups, reactants and reaction conditions to implement such

1s conversions in; For example: 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) Yves

In many of the reactions described by JE it may be necessary to protect one or more groups to prevent the reaction from occurring at an undesired location on the molecule. Examples of protecting groups and methods of protecting and removing protection for functional groups can be found in: Protective Groups in Organic Synthesis (T.

Green and P.

Wuts; 3rd Edition; John Wiley and Sons, 1999) ° the hydroxy group ¢ may be protected for example”; Like “((OC(=O)R) ester 4 (-OR) ether For example: t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CHj3, -OAc). OR),) or ketal (RyC(OR),) respectively, in which a carbonyl group (>C=0) is converted to a diether (>C(OR),), by a reaction with; For example a primary alcohol 0 an aldehyde de sama or a ketone is easily determined by analysis Al using a large excess of water in the presence of an acid. The 1 amine group may be protected on eg 0 amide (-NRCO-R) or a urethane (-NRCO-OR), for example: methyl amide (-NHCO-CHj3); a benzyloxy amide (-NHCO-OCH,Cg¢Hs, -NH-Cbz) ; as: Yven t-butoxy amide (-NHCO-OC(CHj)s, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHj3),C¢H4CsHs, - NH-Bpoc), : or as 9-fluorenylmethoxy amide (-NH-Fmoc), Je : or as 6-nitroveratryloxy amide (-NH-Nvoc), : Jie or as 2-trimethylsilylethyloxy amide (-NH -Teoc), °

Je or allyloxy amide (-NH-Alloc), Jw or 2,2,2-trichloroethyloxy amide (-NH-Troc), 2-(phenylsulphonyl)ethyloxy amide (-NH-Psec). Cyclic and amine groups Jia ¢ amine compounds Other protecting groups of amine groups include: heterocyclic; 28. para-methoxybenzyl (PMB) or “(ester; a t-butyl ester « methyl ester eg Je) alkyl Cig ester eg see b ester b (¢ or trihaloalkyl ester eg Je) alkyl halo Cig ester alkyl C1- aryl Cs . ester « alkyl Cp; - silyl alkyl ester, for example; Je) triCy alkylsilyl-Cy.7alkyl ester; or a Cs. aryl-cig alkyl ester Vo may be done. amide methyl; for example » such as amide; or ( benzyl nitro ester ¢ benzyl benzyl e.g.; eg: Je thioether (-SR); eg thiol protecting (-S-CH,NHC(=0)CH3) ether methyl group. and esteramide

YyYst

_ a \ —

benzyl thioether; an acetamidomethyl ether (-S-CH,NHC(=0)CH).

The position (11(1) of the pyrazole group in compounds of formula (I) or their starting materials by a variety of

cle pend The protection group is chosen according to the nature of the reaction conditions to be exposed

dc gana for her. Examples of protecting groups for pyrazole 1111 include tetrahydropyranyl, benzyl and 4-methoxybenzyl© groups.

Many of the intermediate chemical constituents described above are new and form such

New intermediates are an additional feature of the invention.

Pharmaceutical formulations:

While the active compound can be given alone; it is preferable to present it in the form of a pharmaceutical formulation 0 (eg (formula JO) comprising at least one active compound of the invention with

One or more pharmaceutically acceptable substances of a carrier, adjuvant, excipient, diluent, or

Filler, pH 11C regulator, stabilizer, reducer, or lubricant

or another substance known to those skilled in the art and optionally other curative or prophylactic agents.

The present invention furthermore provides βDNA compositions as specified by ¢ and methods for making 1 pharmaceutical composition comprising mixing at least one active compound; as specified before; with

One or more pharmaceutically acceptable carriers, excipients, or

pH regulators, auxiliaries, stabilizers or other substances; as it is

described in this patent.

-ay-

The term 'pharmaceutically acceptable' as used herein relates to compounds, materials, compositions and/or

dose pictures which are; within the field of medical discretion; Suitable for use in contact with

patient tissue (eg a human) without excessive toxicity; or a prelude; or allergic response; or

A problem or other multiplier equivalent to a reasonable risk/benefit ratio. Each article must also be

carrier or excipient, etc.; 'acceptable' in the direction of being compatible with the other components of the formula.

ol Les In an additional feature; The invention provides compounds of formula (1) and subgroups thereof

As indicated in this patent in the form of pharmaceutical compositions.

Pharmaceutical compositions can be in any form suitable for oral administration; or road

non-intestinal localized or in the nose; or eye; ear or rectum; or inside the vagina; or 0 transdermal. where the formulations are intended for administration by non-enteric route; can be formulated

For intravenous, intramuscular or subcutaneous administration into the peritoneal cavity, or for direct delivery into

The target organ or tissue by injection, infusion, or other delivery method.

Pharmaceutical formulations for non-enteric administration include sterile aqueous solutions for injection

And non-aqueous, which may contain antioxidants and pH-regulating substances 1 _ and antibacterial sal and solutes that make the formula isotonic with the recipient's blood

intended; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents.

Formulas may be presented in unit-dose containers or multiple-dose containers; For example

hermetically sealed ampoules and vials; It may only be stored in freeze-drying conditions as needed

add a sterile liquid carrier; For example, water for injections; just before use.

DSU Improvised injection solutions and suspensions may be prepared from sterile powders, granules and tablets. In one of the preferred embodiments of the invention; The pharmaceutical composition is in a form suitable for subcutaneous administration (5.0). Pharmaceutical dosage forms suitable for administration by mouthpieces include tablets, capsules 0, minicapsules, tablets, rivets, syrups, solutions, powders, granules, elixirs, suspensions, lozenges, biscuits, smears or suplingual tablets. Pharmaceutical compositions containing compounds of formula (1) can be formulated according to techniques Known; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, “Jal! Easton, PA, USA 0” Therefore, tablet formulations may contain a unit dose of an active compound with an inert diluent or inert carrier Jie is a sugar or sugar alcohol; for example lactose, sucrose, or mannitol 0 sorbitol; and/or a diluent derived from non-sugar sodium carbonate (Jie or calcium phosphate or calcium carbonate or cellulose or its derivative such as hydroxypropyl methyl cellulose 5 cellulose ethyl s cellulose methyl 1 _and starch such as maize starch Tablets may also contain such standard ingredients as binding and granulating agents polyvinylpyrrolidone fie ¢ and disintegrants (eg “Jill crosslinked cellulose carboxy methyl Jie alll polymers”); lubricating agents (eg, stearates); and preservatives (Je) eg (JB) compounds (Jf sa g¢ (parabens) antioxidant (Je) eg (BHT) and pH regulating agents pH ov. (eg regulating substances for pH phosphate pH or ¢f citrate and agents

Yo -

effervescent as citrate/bicarbonate mixtures; Jie These excipients are well known nor Gala

To explain it in detail here.

Capsule formulas may be of the hard gelatin and soft gelatin variety

may contain the active ingredient in solid form; or semi-solid; or liquid. can be configured

Gelatin capsules of animal gelatin or its synthetic or vegetable-derived equivalents.

(Sa solid dose encapsulation Je) eg; tablets; capsules; etc) or not

encapsulated but typically have a wrapping) eg a protective film wrap (eg

eg wax or varnish) or release control coating. The cover can be designed (eg;

Budragit™ polymer to release the active ingredient at a desired location within the gastro-intestinal tract. Thus, the coating can be selected to degrade under certain pH conditions within

the gastrointestinal tract; This makes it selective for release of the compound into the stomach, ileum, or duodenum

Ten.

instead of or in addition to; casing; The drug may be presented in a rigid container containing a control agent

at launch; For example a delayed-release agent which may be configured to release the compound vo-selectively under altered acidic or alkaline conditions in the gastrointestinal tract. alternatively; maybe

The material of the container or delay-release casing is a corrosive polymer (le) eg;

(maleic hydride polymer) which is mainly carried out continuously by the AKG during the passage of the dose image

through the gastrointestinal tract. as an additional alternative; The active compound can be formulated into a delivery system that provides

Osmosis control of compound release. Osmosis release, other dase release© or continuous release formulations may be prepared according to methods well known to those skilled in the art.

$1 per

_4o —

Topical formulations include ointments, creams, sprays, patches, and gels

and liquid drops and inserts (eg intraocular inserts). Jia can formulate these combinations

according to known methods.

Compositions for non-enteric administration are typically provided as sterile aqueous or oily micro-solutions or suspensions; or 28 is supplied as a sterile powder fractionated 28 days to manufacture

Improvised with sterile water for injection.

Examples of formulations for rectal or intravaginal administration include vaginal suppositories and suppositories

which may be composed, for example, of a moldable or wax-containing material

active compound.

0 formulations for administration by inhalation may take the form of inhalable formulations or liquid or powder sprays; It can be given as standard using powder inhalers or 0.0 spray dispensers. Such devices are well known. For administration by inhalation “0” Powder formulations typically comprise the active compound with a diluted powdered inert solid as lactose .

\o Compounds of the invention will generally be presented as a 'de a' unit and by themselves 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 ng to (ada Y) for example 100 mg to ? gram of active ingredient; usually more than 10 mg to 1 gram; for example Ow Sl) mg to Can mg; Or 1 mg to Y mg.

— 9 4 —

The active ingredient will be administered to a patient who needs it (eg a human patient or a patient).

animal) in sufficient quantity to achieve the desired therapeutic effect.

Efficacy of inhibition of protein kinase:

The effectiveness of the compounds of the invention can be measured as inhibitors of 68 proteinase A kinases and protein B

0 using experiments shown in the following examples and the potency level of a known compound of ANY value can be set

0. The preferred compounds of the present invention are compounds with a dad of 1050 less than 1

micromolar and more preferably less than 600 µM versus protein kinase 8.

Therapeutic uses

Prevention or Treatment of Proliferative Disorders ye Compounds of formula (I) are inhibitors of protein kinase A proteinase 5; therefore als

It is expected to be useful in providing a means to prevent the occurrence or to prevent the induction of budding cell death. So it is

The compounds are expected to be useful in treating or preventing disorders of cellular proliferation such as cancer

cancer at. In particular, tumors with deletions or inactivating mutations in PTEN or

Loss of PTEN expression or alterations in the 1201-1 gene (fibroblast cell (T) can be particularly sensitive vo to PKB inhibitors.

The PKB signal has a controlled increase (Sash) that Lind is particularly sensitive to PKB inhibitors.

Examples of such anomalies include, but are not limited to, the overexpression of one

or more subunits 01316; An overexpression of one or more forms is equivalent to

PKB, or mutations in PBK, 20161, or PKB that increase the basal activity of the enzyme replaced

ay-attention” or controlled increase or mutational activation of a growth factor receptor such as a growth factor selected from an epicutaneous growth factor receptor. EGFR, primary fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R), and endothelial growth factor receptor 5 de (178078).

0 It is expected that the compounds of the invention will be useful in treating other cases of disorders in reproduction or survival such as viral infection; For example, neurodegenerative diseases. PKB plays an important role in maintaining the survival of immune cells during the immune response, so PKB inhibitors can be useful in immunological disorders, including autoimmune conditions.

0 Therefore, PKB may be useful in the treatment of diseases in which reproduction is disturbed; Or cell death, apoptosis, or differentiation. PKB inhibitors may also be useful in treating deficiencies caused by insulin resistance, allergy, and glucose blockage; Storing energy and fat Jie diseases related to metabolism and obesity Obesity.

1 Examples of cancers that can be inhibited include; For example, but not limited to cancerous tumors; Jue cancer of the bladder, breast, colon (such as Jia colorectal carcinomas, adenocarcinoma and rectal adenocarcinoma) and kidney cancer; epidermal skin; liver liver; the lung, such as adenocarcinoma; and small cell lung cancer

0 and non-small cell lung carcinomas and gallbladder

ovary ¢, pancreas, and pancreatic carcinoma in exocrine LOA; Cancers of the stomach, stomach, cervix, endometrium, thyroid gland, prostate, Jie skin, squamous cell carcinoma, tumor of the lymphoid lineage hematopoietic tumor of lymphoid lineage 0; Jie pall leukemia ¢ lymphocytic leukemia ¢ B-cell lymphoma ¢ lymphoma ¢ T-cell lymphoma; Hodgkin's lymphoma 1 and non-Hodgkin's lymphoma “hairy cell lymphoma” or Burkett's lymphoma; hematopoietic tumor of myeloid lineage ¢ like 3a gall leukemias of the myelin, whether acute or chronic acute and chronic myelogenous leukaemias; 1 myelodysplastic syndrome and promyelocytic leukaemia; thyroid follicular cancer ¢ and Lad Jie ¢ tumor of mesenchymal origin fibrosarcoma or habdomyosarcoma; Jie tumor of the central or peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma or schwannoma; teratocarcinoma; testicular seminoma, osteosarcoma, bone tumors, xenoderoma pigmentosum 0, chromosomal tumor 1810000008, keratoma + and follicular carcinoma of the thyroid gland

Kaposi's sarcoma or "thyroid follicular cancer."

di it is in pharmaceutical formulations; The uses and methods of this invention gad a disease or condition involving abnormal cellular growth; Or a disease or condition involving abnormal cell growth in one of the embodiments means cancer. Subgroups of particular interest include breast cancer, ovarian cancer0, Glaus colon Old prostate cancer, and esophageal cancer; WAY squamous cell carcinoma and non-small cell lung cancer. Another group of cancers includes breast cancer, ovarian cancer, prostate cancer, endometrial cancer, and gliomas. Some P3 kinase inhibitors may also be used in combination with other anti-cancer agents 0 eg; It can be useful to combine an inhibitor that induces cell death, apoptosis, with another agent that works by means of different all to regulate cellular growth, thus addressing two types of hallmarks of cancer development. Examples of such combinations are listed in Immune Disorders Sa vo that Immune Disorders for which PKA and 2108 inhibitors are useful led include but are not limited to JED Immunologic conditions ASU and chronic inflammatory diseases; (Je eg; systemic lupus erythematosus and glomerulonephritis which does not

- 11.

It is caused by autoimmunity; Rheumatoid arthritis, psoriasis, inflammatory bowel disease and diabetes associated with autoimmune transmission and asthma sly “Eczema hypersensitivity reactions” and rhinitis.

.upper respiratory tract disease and diseases of the upper respiratory tract

oo Other therapeutic uses PKB plays a role in cellular death, apoptosis, proliferation, and differentiation. Therefore, PKB inhibitors can also be useful in treating the following diseases other than cancer, such as those associated with immune disorders: Viral infections Jie virus Herpes virus, pox virus, Epstein-Barr virus, Sinddis virus, adenovirus, HIV HCV 5 (HPVs 0, HOMV) and preventing the development of AIDS in Cases infected with SHIV and cardiovascular diseases Jie cardiac hypertrophy » restenosis ¢ and atherosclerosis ¢ and neurodegenerative disorders « Jie Alzheimer's and AIDS-related dementia AIDS-related dementia + Parkinson's disease, amyotropic lateral sclerosis Vo, retinitis pigmentosa, spinal muscular atropy, cerebellar degeneration, glomerulonephritis glomerulonephritis, myelodysplastic syndromes, ischemic injury associated myocardial lil infarctions, stroke, reperfusion injury, degenerative diseases of the transverse skeletal system of the musculoskeletal system

_ \ 0 1 _

For example (Jha) osteoporosis, arthritis, aspirin-sensitive rhinosinusitis ¢, fibrosis ay all cystic fibrosis, multiple sclerosis, and kidney diseases. Methods and treatment

0 It is noted that the compounds of formula (1) will be useful in preventing - and treating = many pathological conditions that occur through protein kinase A and/or protein kinase 8. Examples of these diseases and conditions are mentioned below. In general, compounds of formula ( ) are given to a patient in need of such treatment, such as a human or animal patient, preferably humans.

) 0 is not fle or prophylactic and is in a Ladle capacity. Typically the compounds will be administered in amounts that are beneficial 0 are toxic. However; In certain situations (such as life-threatening illnesses) the benefits of administering a compound in which formula (1) duals may outweigh the disadvantages of any toxic effects or effects may be desirable to administer the compounds in amounts consistent with the degree of toxicity The compounds can be given over a long period to maintain the beneficial therapeutic effects, or they can be given

vo given over a short period of time. Alternatively, it can be given intermittently. The typical daily dose may range from 100 pg to 100 mg per kg body weight; Typically, it is between 01 nanograms and 01 mg per kg of body weight, and the best is between 1 microgram and 10 mg of body weight. Larger or lower doses can also be given when needed.

I am a father

0 Y —_ \ — Finally, the amount of the compound to be administered will be appropriate to the nature of the disease or physiological condition required to be treated and will be carried out under the supervision of the attending physician. The compounds of Formula (I) may be given as a single therapeutic agent or they may be given in combination for combination therapy in combination with one or more compounds to treat a specific disease condition; For example, oo is an emerging disease such as cancer, as previously defined. Examples include therapeutic agents or treatments that may be given in combination (either at the same time or at different time intervals). Topoisomerase inhibitors. Anti-metabolic products.Antimetabolites.oe.Targeting agents.Tubulin targeting agents. DNA binding and topoisomerase 11 inhibitors. Alkylating substances. 0. Monoclonal antibodies. 0. Anti-hormones. Signal Transduction Inhibitors. Proteasome inhibitors. DNA methyl transferase enzymes

— 1.

retinoids and cytokines.

. Radiotherapy

In the case of inhibitors of proteinase A or protein kinase B associated with ESA therapies, it can be

Giving compounds simultaneously or sequentially. And when given sequentially; May be given at short intervals (eg over 10 minutes) or at longer intervals (eg FY)

of an hour or more or even with a larger interval when the need arises). System will depend

The dosage used depends on the properties of the therapeutic agent or agents.

The compounds of the invention can also be administered in combination with non-chemotherapy treatments

Radiation, photodynamic therapy, gene therapy, surgery and controlled feeding systems.

0 For use in combination therapy with a therapeutic agent al the compound of formula (1) and one, two, three, four or more therapeutic agents may be formulated as a dose containing two, three, four or more therapeutic agents. Alternatively, [cll] therapeutic agents can be formulated separately and given together as a group; And optionally with instructions for use.

1 A person skilled in this field can know from his general knowledge the dosage regimens and combination therapies that can be used.

‎YYeH

EP

Diagnostic methods The patient can be examined to determine whether the disease or condition that the patient suffers from - or will suffer from - before administering the formula compound (ofl) will be treatable with a compound that has anti-protein kinase Ss activity8. Protease A 1188© A biosample from a patient can be analyzed to determine whether the case or Jha) and eg 0 abnormalities aE are cancer; which the patient has or will suffer from is Jie disease PKB and/or PKA gene or abnormal circulating protein expression leading to a controlled increase of the normal; or towards a controlled increase of PKB and/or PKA or sensitization of the pathway to activity of

PDK1s, 1316 and 07 PKB in the case of a PKB and/or PKA receiver Signal power check before

PDK250 A biosample from a patient can be analyzed for loss of a negative regulator or repressor oll and an alternative regulator or Fas In the current context the expression 'lost' includes deletion of the PTEN Jie PKB gene of the repressor pathway; or amputation inherited (for example by mutation); excision of the clone product of a water gene or inactivation of the clone (for example by point mutation) or salutation by another gene product. elevated or excess genetics including enlargement (i.e., multiple copies of a gene) and increased expression by transcriptional effect; hyperactivity and activism; Including activation by mutations. Thus, a patient can undergo a diagnostic test to discover the characteristics of the expression 'diagnostic' includes the screening process. We mean PKB and/or PKA characteristic of the controlled increase in DNA mutations of those profiles that include; for example Measurement of the structure of the "pela pal" © Aber p

— \ «Oo —

PKA and/or LS PKB The term “manifestation” includes those features that characterize the controlled increase of

PKA and/or PKB including enzyme activity, enzyme levels and enzyme status (whether phosphorylated

(YA) and mRNA levels of the aforementioned proteins.

Lhe od carry out diagnostic tests and pre-vital examinations to be selected from lie taken from tumors; And blood samples (isolation and enrichment of the obtained cells)

stool or sputum samples; or chromosome analysis; or wile crystalline membrane; or membrane fluid

peritoneum or urine. It can mean classifying someone as carrying a mutation in PRA and/or PKB or a modification in

TCL-1 or loss of PTEN expression indicates that the patient may be particularly susceptible to treatment with 0 PKA inhibitor and/or PKB and can preferentially screen tumors for the presence of the PKA variant.

and/or PKB before treatment. The screening process will typically include a direct sequencing

And an analysis of the fine stack of “oligonucleotide” or antibody specific for the mutation.

Methods for identifying and analyzing mutations and cases of controlled increase in proteins are known in this field.

Examination methods may include; To name a few - conventional methods (Jie 1 reverse polymerase chain reaction - Fill reverse transcriptase (PT-PCR) or in situ hybridization.

And when sorting by (PT-PCR), the level of mRNA in the tumor is evaluated by making a copy of cDNA

of mRNA, followed by amplification of cDNA by PCR

PCR amplification methods and primer selection; amplification conditions are known to those skilled in this field.

processing DNA and 7018 operations in standard ways; As explained, for example, in:

a

Ye" = - 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. ° An explanation of reactions and processing processes involving DNA techniques is also described in Sambrook et al., 2001, 3" Ed, Molecular Cloning. : A Laboratory Manual, Cold Spring Harbor Laboratory Press.

Alternatively a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) oi ced Sa, a commercially available kit for PT-PCR (Ji) that of Roche Molecular Biochemicals 0 may be used; The method described in the following US Patents: 1714 Rho OAAYATE, ©7181, ©097759, 5/8157, 54182777, and £1TTAYA used as our references here. Examples of in situ hybridization techniques for testing expression mRNA hybridization can be mentioned in (FISH) 5 fluorine 101 See 649:152 - (Angerer, 1987 Meth.

Enzymol., as ale The in situ hybridization process includes the following main steps: (1) immobilization of the tissue to be analyzed; (Y) pre-hybridization treatment of the sample to increase accessibility to the target DNA and to reduce non-specific binding; ( vii) crossbreeding of the mixture of nucleic acids in the biostructure or tissue;

- 1. In hybridization and (*5) the discovery of hybrid DNA fragments. The dag ll fluorine sensors used in applications are typically labeled; By using radioactive isotopes or transmitters

Yoo or 001 or 50 for example. The preferred tentacles are long; as if it is of a length or more; This is so that a qualitative hybridization of 0 nucleotides and even about “targeted” nucleotides and mint can be done in acid(s) conditions with the target DNA (or nucleic acids): we find it explained in a specific FISH. And the standard methods for implementing

Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley &

Sons Inc and Fluorescence In Situ Hybridization: It is reviewed in ed.; John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd 01

ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine can be evaluated by mRNA methods and alternatively; The expressed protein products from immunohistochemistry collections of tumor samples and solid-phase immunoassays using titer plates using 505 di-polyacrylamide gel and Western microelectrophoresis; soaking, flow cytometry, and other methods known in the art for the detection of specific proteins. Detection methods include the use of site-specific antibodies. An experienced person in this field will realize that all of those known techniques for controlled augmentation detection can be applied to the current situation.

YA -: - Therefore; These techniques can also be used to identify tumors, especially those that are receptive to treatment with PKB l/s PKA inhibitors, for example; As previously mentioned; PKB beta was shown to have a controlled increase of 0-66/ in ovarian and pancreatic cancers (Bellacosa et al 1995, Int.

J.

Cancer 64, 280 - 285; Cheng et al 1996, PNAS 93, 3636-° Yuan et al 2000, Oncogene 19, 2324 - 2330) ;3641 Therefore, it is intended that PKB inhibitors, in particular PKB beta inhibitors, can be used to treat ovarian and pancreatic cancers. 0 ovarian and pancreatic cancers, and PRB alpha is enlarged in cases of stomach, prostate, and breast cancer. In humans (Staal 1987, PNAS 84, 5034 - 5037; Sun et al 2001, Am.

J.

Pathol. 1 59,431 -437) © Therefore, it is conceivable that PKB inhibitors, particularly PKB alpha inhibitors, could be used in the treatment of stomach, prostate and breast cancer in humans. PKB-gamma activity has been observed in nonsteroid-dependent prostatic and breast cell lineages (Nakatani et al 1999, J.

Biol.

Chem. 274, 21528 - 21532) and therefore (ad) it is conceivable that PKB2 eo inhibitors and in particular PKB gamma could be used in the treatment of gastric, prostate and breast cancer in humans.

101.9 - - The invention will now be illustrated; By way of example, but not limited to, by reference to the specific models described in the following procedures and examples, starting materials for each of the procedures described below are commercially available unless otherwise specified.

m in examples; The prepared compounds were characterized by liquid chromatography, mass spectrometry, and H NMR spectrometry using systems and operating conditions indicated below. Proton magnetic resonance ('H NMR) spectra were recorded on a BrukerAV400 instrument operated at 7 MHz in Me-ds-OD at ©270; Unless otherwise SY is specified and reported as follows: chemical displacement S/PPm (number of protons; multiply where 5 = singular; l = binary; and “-

. bry = wide). MeOH proton donor residual solvent (8H 3.31 PPm) was used as an internal reference. For mass spectra; where chlorine is present the fractionated mass of the compound is CI chlorine) in each of the ABI where the compounds were isolated or formed as a free base; It can be converted into a salt form such as acetic acid or hydrochloric acid. On the contrary; Where Jie

ve compounds or their salt formation; The salt can be converted to the corresponding free base by methods known to a skilled person and then optionally converted to another salt. A number of liquid chromatograph systems have been used and these are described below.

Oh no

— and \ \ b Program System: Waters 2795 System | HPLC Mass Spectrometer Finder | Micromass Platform LC Finder Waters 2796 PDA 8 PDA Acid analytical conditions: 1 eluent A 8 (Formic Acid 7+.)) H,O ( Formic Acid /+)) CH;CN | ma | ( tg a 90-0 rinse aid b over v.00 min wee ee ed | ff 4.6x5 d 5 Waters XTerra MS 0 g 0 Acid analytical conditions ?: Rinse A 0 Formic Acid 61 ( H,O ) Formic Acid 26 01) CH;CN Hi ( wire puget foe || a ww ss Thermo Hypersil-Keystone BetaBasic-18 Sjam, 50x2. Imm | aed | acidic analytical conditions: eluent A (Formic Acid 7 01) (H20 HN) eluent B | Formic Acid 601 ( CH3CN (shake os) eluenta over 1 minute es Phenomenex Luna C18(2) 50m, 50x2.0mm A

11110 - - Basic analytical conditions: 1 sale elution a (V+) H20 mM 011411003 pH regulator pH adjusted to 8 by OH 11114. B 0 0 arn 95-0 rinse aid b over ©.? We ea Waters XTerra MS C18 Sum 4.6x50mm | ser | basic analytical conditions: 1 eluent A (01) H20 mM 1111411003 pH regulator pH adjusted to q.0 by NH4 OH cies oma oa | | 7955-0 eluent b over v0 min wm ea Thermo Hypersil-Keystone BetaBasic-18 50m, 50x2.1mm | ed | © Injection method — Autosampling method: 2767 Waters Mass Spectrum Finder: Waters - Micro mass ZQ Waters 2996 PDA: PDA Finder

111 - Acid analytical conditions: Rinse A Formic Acid 7 01( 0 BH ( Formic Acid /+.}) CH3CN | cama ( cm |[ a bridal shower lashes [es we a Phenomenex Synergi 4\i Max-RP 80A, 50x4.6mm | ae Polar analytical conditions: eluent A 0 0 Formic Acid 6 11( ( Formic Acid Z+.Y) CH3CN | oma | ( 1 Al-Tarraj ||

Max-RP 80A, 50x4.6mm | ned | © MS coefficients for acidic and polar analytical conditions: capillary potential | 5. kV mee ara 0 ae with me mm aa put mee ionization method 1 positive electric spraying or positive and negative electric spraying “no”

- 111017 - Chiral analytical conditions:

TFA/NH4 7+.) + MeOH | sn won sa en [sew see] ee] oe sts

Astec, Chirobiotic V; 250 x 4.6 mm | For Agilent Sound: Agilent 1100 series B HPLC System Agilent LC/MSD VL System Mass Spectrometer

Agilent1100 series MWD H is a multi-wavelength finder

HP Chemstation B software Chiral analytical conditions: AcOH/NH4 707 + MeOH I at room temperature ee Tae we we ses [se bo a

Astec, Chirobiotic V; 250 x 4.6 mm | friendliness

- 116 - 1: Chiral preparatory conditions, ms fo von || Dr. Rinse wn | sa ee. Taw hse gee deer sess] rE :7 Chiral preparatory conditions sumsgnorm rue | | wr ww [se wen lamar Roa Ed | ge

Sears | mss)

Avec Lamictal S || sed (just an analytical method): MS m voltage conditions | (Square inch is the device reading) eggs || Throat pressure for Lajes a aan best sa

Yysn

- 115 - In the following examples; The following key is used to specify the 10145 conditions used: esses and lesca ss ros mamas vu 1 which is d 0 some system - bottom extension conditions 1 general system - bottom extension conditions pe a a [ay eee woman || pene wees memes [time ees - am sat pr asus fms pr sums mimi |: ne swam [ile wwe times roo usw mms am 1] Example No. 2-Phenyl-2-[4-(1H-pyrazol-4- yl)-phenyl]-ethylamine©NH,

CO NH

He 6 ry A 2 0

HY 0 1 : equivalent (1 mmol; 105 mg; 174) to a suspension of

Yven

- 111 - 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride in 0 (A) mL) toluene added (71 pat) mol) (0) Sy (Strem) bis(tri-t) -butylphosphine)palladium purification of the mixture with nitrogen A suspension of 0 V was added (100 + mmol); 0110 equivalent): (Aldrich 52505-7) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in ethanol (Ja +. A) 0 followed by (£10 inc. 7 mM + eq) potassium carbonate in (©) Ja 0 water. The mixture was cleaned with nitrogen and sealed. The reaction mixture was heated in a microwave CEM Explorer™ to 176 m s 11 min using ov power 1 Watt The solvent was removed and the residue was divided between 1 N NaOH; ethyl acetate The aqueous layer was extracted with ethyl acetate and the Jue compacted organic layers by 0 brine; dried with 14850, and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (0:5 d); eluated with (950 (1) (Jo) ml ) 11:0 to give 7( : acetic acid (Ja ¥) : methanol (Je A) : dichloromethane ‎-LCMS (PS-A) Rt 1.79 min; m/z [M+H]" 264 mg; £9 (from the title compound; 1 ex. 3-Phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile 00 2-(3-Bromo-phenyl)-3-phenyl -propionitrile (iY)

JCU

Cr © Cs, 008 Cl Cay,

BrBrBr:

YY£1

:- 111 -

YAY) g v © mL KOH (H;0 740 in VY mL) ethanol was added to the solution

from Yo.0 «lia ©)5 benzaldehyde (Use eo YA da YAO) mmol)

43-bromophenylacetonitrile (9 ml) ethanol . The reaction mixture was then stirred in degrees

room temperature for 2 hours and the precipitate was collected by Lal filtration, washed by TAA (0 g); 7)) ethanol _ cold. (.45 grams” 17104 mmol) of the product was then dissolved

pla) in ethanol (Ja Yo) and heated to 66 . added (£09 110 cana mmol)

boro sodium hydride in portions and the mixture was maintained at this temperature for two hours

two additional. Upon cooling, water (Jo 01) was added and the solvent was removed under reduced pressure

The residue was divided between (de 001) water and (100_mL) ethyl acetate. The organic layer was separated, dried using MgSO, filtered, and concentrated to give (VAY (g; 757) of product

desired and used without purification.

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

J Cr 0

2-(3-Bromo-phenyl)-3-phenyl-propionitrile Jeli was made with 4-(4,4,5,5-tetramethyl-1,3,2- lols dioxaborolan-2-yl) -1H-pyrazole Vo the procedure shown in Example 1 to give a compound

.LCMS (PS-A) Rt 2.98 min; m/z [M+H]" 274 Title.

yven

- YYA - 2-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine : ¥ Example number H NH,

Me—_~ ) Me

N—N

H

: But using 1 following the example procedure gave 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole . 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole H by (PS-A) Rt 1.79 min; m/z [M+H]" 292 Example No. 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

Cl

Hy©

N—N

H

: but using 1 following the example procedure 0 gives 2,2-bis-(4-chloro-phenyl)-ethylamine in place of 2-(4-chlorophenyl)-2-phenylethylamine .LCMS (PS-A) Rt 1.99 min; m/z [M+H]" 298 Title compound.

1108 - - This starting material can be made by the method described in: Amer.

Chem.

Soc., 1983, 105, 3183-3188 for Example No. o 2-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-phenyl]- 1 -phenyl-ethylamine m ) ° { 2-(3-Bromo-phenyl)-1-phenyl-ethylamine N Il] © MgBr NH, BrBr added (0 inc. 5.049 mmol) benzonitrile dropwise into a solution of YY (a 8.818 mmol) bromobenzylmagnesium bromide (+.YVo -molar solution in diethyl ether in nitrogen at room temperature. It was then Reaction mixture 0 was heated to reflux for 2 hours and allowed to cool. At this point (do £.A0) 4 mmol (1m) lithium aluminum hydride in THF was carefully added and the reaction mixture was allowed to warm to The degree of reflux for an additional 176 hours. Upon cooling, the reaction (Ua) was quenched and (ela) Ja o was added dropwise and divided aie between (0a)Je water and (ethyl)Je / 00 acetate. The organic layer was separated, dried with MgSO, filtered, and concentrated. Purification by ion exchange chromatography (ZF) gave (71) cana on exchange of the desired compound. Yyét

- 17. 2-3-5 _Dimethyl- 1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine ( dp ) lm,

Me~) Me

N—N

H

The product from (DB) was reacted by following procedure with 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H- pyrazole -(LCMS (PS-B) Rt 2.54 min [M+H]" 292) to give the title compound. 1 shown in Example 0 6 Example 3-Phenyl-2-[3-(1H) -pyrazol-4-yl)-phenyl]-propylamine 6/

N—N

H

(Je Y°) eq.) product of example in 1 to a solution of no mg; 17. mmol; ae concentrate and (*.1 ml approx. aqueous suspension) nickel ammonia (Je +.0) ethanol were added 0 h. The reaction mixture was filtered through 11 minutes of nitrogen and the reaction mixture was subjected to an atmosphere and the mother liquor was concentrated under reduced pressure to give the title compound, which was purified © (LC/MS: (PS-A)R; 1.89 [ M+H]" 278 by a preparative liquid chromatography.

1171 - - Example No. 17 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine (7a) 2-(4-Bromo-phenyl)- 3-phenyl-propionitrile ~N Br 0 gave following the example procedure (Iv) but replacing 4-bromophenylacetonitrile with 3-bromophenylacetonitrile the title compound which was used in the next step 0 Unpurified (Lab) 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionitrile ~N CoC Z 7 N—N H 0 Following the procedure shown in Example 1 but substituting : 2-(4-Bromo-phenyl)-3-phenyl-propionitrile by : 2-(4-chlorophenyl)-2-phenylethylamine the title compound was obtained.

1177 - - ((AG) 3-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine NH, © N—N H Done Reducing the nitrile product of Example (oY) using the conditions described in Example A + to give the title compound. 278 -LCMS (PS-B) Rt 3.03 [M+H]" 0 Example A {3- (4-Chloro-phenyl)-3-[4~(1H-pyrazol-4-yl)-phenyl]-propyl } -methyl-amine 3-(4-Bromo-phenyl)-2-cyano-acrylic acid ethyl ester (iA) (J.

Med.

Chem., 1983, 26, 935-947) 0 \ > 0 oS | 0 0 New .or SA om Br Br 0 ol al) added (171 mmol) (V.4) 5 4-Bromobenzaldehyde filling 17.44 mmol) ethyl cyanoacetate in (µl V) toluene) piperidine and the reaction mixture was refluxed for 1 hour by a L-0680-5 separator. The solvent was removed under reduced pressure; the residue was pulverized with warm ethyl acetate; filtered to yield (¥ 0 g; yield 4) Desired product as ¥ 3.44 'LC/MS (PS-A2) Rt

177 - - (<A) : 3-(4-Bromo-phenyl)-3 -(4-chloro-phenyl)-2-cyano-propionic acid ethyl ester N 0 N 7 btech bin cl Ra and Br Br a solution of (¥ g) was added; 0.71 mmol) of : m toluene (da VY) 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester dry dropwise to (1) (Ja v4 1.97 mmol) ) 4-chlorophenylmagnesium bromide (0+ M solution in tetrahydrofuran 4 °C. The reaction mixture was heated to 1 Ao for ¥ hours”; poured on ice; acidified with 1 N HCI and extracted with ethyl The organic layer was separated, dried with MgSO, filtered and concentrated and the crude product 0 was purified by silica flash chromatography, rinsed with petroleum ether to petroleum ether / ethyl acetate (0:30) to give (1.9 mg (79) of desired product; LC/MS (PS-A2) Rt 3.78 [M+H]" 391.93 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)- propionic acid (MN) Na 0 0 oS OH ge 5 . 0 . \o Then reflux a mixture of (0.411 grams; mmol) : Yyén

174 - - 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethyl ester in (0 mL) (do ©) Sa sulfuric acid (Je©) « acetic acid water for two hours. the organic layer has been separated; dried, filtered, and concentrated using 14850, and the crude product was purified by silica flash chromatography; rinsing with Yo ) petroleum ether / ethyl acetate ( oo to give LAY) g; 50%( of desired product; 338.86 (PS-A2) Rt 3.39 [M+H] 10/15. 3-(4-Bromo-pheny!l)-3-(4-chloro-phenyl) -N-methyl-propionamide (2A) HN 0 OH 0 [ Br Cl Br | Ci then stirred a mixture of (5 zg; LYE mmol) : 3-(4-bromo- phenyl)-3-(4-chloro-phenyl)-propionic acid and VY 0 g; no amol) l-hydroxybenatriazole 0 in)¥ dichloromethane (Je) for Yo min before adding v1 ) μl mmol) amine methyl (solution / in )s (sla d fizzy CAA 0 mM 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (Use) The reaction mixture was stirred dela 11 sad, removing the solvent under reduced pressure” and dividing the residue between 1 ethyl acetate HCI, N. The organic layer was separated, dried with 14850, filtered, and concentrated i = 1 the title compound which was used in the next step without purification Additional LC/MS (PS-A2) Rt 3.20 [M+H]" 5 Yyén

_ 1 Y oo — [3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine (—2A)

HN” HN oT oC oA

Br cl Br cl: “nitrogen in the crude atmosphere has been cooled to zero; and 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide diethyl ether (Ja and (lithium aluminum hydride mmol)) 0.577 gr. .0 VO) add © (Js ¥) in aluminum hydride (mmol) 0.64 loa YF) with cooling; hour thawed; And quench it by adding VT water and adding it. Then the reaction mixture was stirred for diethyl ether

All standard ethyl acetate) were separated and extracted by 7 NaOH (basic) ales, filtered and concentrated ¢ and the crude product was purified using MgSO, organic; and dried with, followed by methanol and rinsing by Phenomenex-Strata-SCX column chromatography 0 proceeds of step d and e combined al a +. Yo! ) is standardized to give ¥ methanol in ammonia

LC/MS (PS-B3) Rt 3.20 [M+H]" 339.85 . (% Ty {3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl] -propyl }-methyl-amine (5 A) lo] 1, HN © H a }

Br 0 Ra Cl ©

N—N

H

- 177 - With [3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine reacted following the procedure described in 4-(4,4, 5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole

LC/MS (PS-B3) Rt 2.63 [M+H] "326 to give the title compound. 1 Example No. "HNMR (Me-d3-OD) 5 2.37-2.47 (2H, m), 2.66 (3H) , s), 2.91 (2H, 1), 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) ° 1 Example No. {3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl] -propyl }-methyl-amine 3-(4 -Bromo-phenyl)-3-(3 ,4-difluoro-phenyl)-N-methyl-propionamide 1 5 )

F

F

Uh .no © º Br but_by substituting (2A) to _example no. (1A)a, the procedure described in _example glib oy. Then, « 3,4-difluorophenylmagnesium bromide by 4-chlorophenylmagnesium bromide

LC/MS (PS-A2) Rt 3.12 [M+H] "355.84 Obtain the title compound. : (kb) 3-(3,4-Difluoro-phenyl)-N-methyl-3-[ 4-(1H-pyrazol-4-yl)-phenyl]-propionamide

197 - - 3 F J i F NS i J — Al © Br N-N 3-(4-Bromo-phenyl)-3-(3,4-) reacted difluoro-phenyl)-N-methyl-propionamide with 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure shown in example 1 to give the title boat. LC/MS (PS-A2) Rt 2.55 [M+H]'341.93 Y) 5 : {3-(3,4-Difluoro-phenyl)-3-[4-(1H-pyrazol-) 4-yl)-phenyl]-propyl}-methyl-amine F F F F Ca vinegar 0 7 7 7 N-N bees Lithium aluminum hydride was added to a suspension of: 3-(3,4 -Difluoro-phenyl)-N-methyl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide 0 in diethyl ether « followed by an aluminum chloride solution in diethyl ether at zero degrees under nitrogen atmosphere. Toluene was added and the reaction mixture was heated at 70 °C for YA h. Upon cooling, the reaction was quenched by adding water and rendering it basic (1 NaOH).

= YYA - the organic layer is separated; dried using . ethyl acetate standard) and extracted it by filtering and concentrating it to give the aforementioned compound. MgSO,

LC/MS (PS-A2) Rt 2.15 [M+H]" 328.06 "HNMR (Me-d5-OD) 8 2.19-2.29 (2H, m), 2.35 (3H, 5), 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, 5) 10° Example No. {3-(3-Chloro- phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

Ci

H

7)

N—N

H

4-chlorophenylmagnesium bromide but by substituting A following the procedure described in Example No. ; The title compound, 3-chlorophenylmagnesium bromide, was obtained by 0

LC/MS (PS-B3) Rt 2.67 [M+H]*326 "HNMR (Me-d5-OD) 6 2.43-2.50 (2H, m), 2.68 (3H, 5), 2.94 (2H, m), 4.13 (IH, 1), 4 (1H, m), 7.27-7.36 (3H, m), 7.41 (2H, d), 7.66 (2H, d), 8.50 (2H, s).

Yen

- 1" - 11 Example 3-(4-Chloro-phenyl)-3-[4-(1 H-pyrazol-4-yl)-phenyl]-propionamide cl

Lm 0 : 2 /

N—N

H

: Following the procedure described in Example 19 and (*b) but replacing ¢ 4-chlorophenylmagnesium bromide with: 3,4-difluorophenylmagnesium bromide M LC/MS (PS-A2) Rt 2.54 [M +H] "326 Then get the title compound. 111 (Me-d;-OD) 6 2.95 (2H, d), 4.53 (1H, 1), 7.27 (6H, m), 7.50 (2H, d) , 7.91 (2H, s).3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine : 11 Ex. phenyl)-3-(4-chloro-phenyl)-propionamide (i VY ) 0 NH,

Oh0

Br J | ClBr | Cl Vs : (Use mm YE g LY°) and then stir a solution of No. 0 g vv and 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl )-propionic acid* ml; ¥.TA) for £0 min before adding dichloromethane at 1,1'-carbonyldiimidazole mol)

— 1. The reaction mixture was stirred for a period of (methanol (? molar solution in mmol ammonia) silica two hours’, the solvent was removed under low pressure, and the residue was purified by chromatography, gram; 0.0 41) to give (€ 1): petroleum ether / ethyl acetate and luminous; rinsing with

LC/MS (PS-A2) Rt 3.08 [M+H] 339.93 of desired product; (77 to (4g).(1A) This starting material can be made by the method shown in example * 0 3 - (4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine (Ba1Y )

NH, NH, on OL C oa

Br cl Br Cl : By following the procedure explained in Example No. (4e) but by substituting : by 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionamide «3 was obtained -(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide 0 Title compound.

LC/MS (PS-B2) Rt 3.88 1+7 3-(4-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine @Y) al

NH, © NH,

Boo 0©

N—N

H

YYen

- 11 - With 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine reacted following the procedure described in 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole

LC/MS (PS-B3) Rt 2.54 [M+H]" 312.87 to give the title compound. 1 Example # 'H NMR (Me-d5-0OD) 6 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).° 7 Example No. 3-(3,4-Dichloro-phenyl) -3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine ci cl z om ©

N—N

H

. But by replacing 1" following the procedure explained in Example No. ¢ 3,4-dichlorophenylmagnesium bromide by 4-chlorophenylmagnesium bromide

LC/MS (PS-A2) Rt 2.17 [MHH] "345.95 Title compound obtained. 'H NMR (Me-d5-OD) 6 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).

- YY -

Ve Example No

Dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3 -pyridin-2-yl-propyl}-amine : 2 to SN > = 2 /

N—N

H

: but by replacing 1 following the procedure shown in Example brompheniramine maleate by 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride 0 -LC/MS (PS-B2) Rt 2.29 [M+H] 307 The title compound was obtained. 111 (Me-d3-OD) 6 2.44-2.54 (1H, m), 2.59-2.70 (1H, m), 2.77 (6H, s), 2.93-3.01 (2H, m), 4.20 (1H, 1), 7.25-7.28 (1H, m), 7.32-7.36 (3H, m), 7.54 (2H, d), 7.75 (1H, dt), 7.94 (2H, brs). : 1 o Example 1 {2-(4-Chloro-phenyl)-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethyl} -dimethyl-amine 2,2-Bis- (4-chloro-pheny!)-N,N-dimethyl-acetamide (I 1°)

Oy OH ON oa Cl cr_3 “Cl

Ary - - Bis-(4-chloro-phenyl)-acetic acid was reacted with dimethylamine following the procedure shown in Example A to give the title compound. 309.95 [11+11] 3.40 (PS-A2) Rt 1].0/115. )© b) [2,2-Bis-(4-chloro-phenyl)-ethyl]-dimethyl-amine - 5 5 Cl z z Cl Ci | 0 0 By following the procedure explained in Example No. (4e) but by substituting: 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide by: 2,2-Bis- (4-chloro-phenyl)-N,N-dimethyl-acetamide Je was obtained as the title compound. .LC/MS (PS-B2) Rt 3.75 [M+H] 295.99 : {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]- ethyl} -dimethyl-amine : (z©) Cl rr v go 9 AT UL, (2 N—N H \[2,2-Bis-) reacted 4-chloro-phenyl)-ethyl]-dimethyl-amine with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure described in Example #1 to give the title compound. 325.99 (PS-B2) Rt 3.07 [M+H] 1.0/115.

- 17 - “HNMR (Me-d;-OD) § 2.5 (6H, 5), 2.98 (2H,dd), 4.34 (1H, vt), 7.31-7.36 (6H, m), 7.50 (2H, d) , 7.92 (2H, s).01 Example No. {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl }-methyl-amine cl” 8

H

©

N—N

H 0 by dimethylamine but by substituting 710 following the procedure described in Example No. Obtaining the title compound. 5c amine methyl

LC/MS (PS-B2) Rt 2.83 [M+H]" 312.07 "HNMR (Me-d;-OD) 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). 0 º ' 117 Example No. {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine (R)

- \Yo-

Cl M H 7 / N-—N H enantiomers, but the VY enantiomers were separated using the same procedure as in Example No. AG-CP2. Preparative chiral preparation using the HPLC method by .ee/ LC/MS (AG-CA) Rt 5.58min,97.4 "HNMR (Me-d5-OD) § 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).

YA Example No. {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl } -methyl-amine (S) 0 -

H

2/

N—N

H enantiomers, but the YY enantiomers were separated. Prepared using the same procedure as in Example No. 0. Preparative Kerr Alli using the 0-072m method. HPLC by ee/ LC/MS (AG-CA) Rt 4.51min,98.0

11 - “HNMR (Me-d3-0OD) 2.75 (3H, 5), 3.79 (2H, d), 4.51 (1H, t), 7.37-7.43 (411, m), 7.49 (2H, d) , 7.73 (2H, d), 8.66 (2H, s).15 Example No. {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl ( -isopropyl-amine cl 9 0

H

©

N—N

H 0 by dimethylamine but by substituting Yoo The procedure described in Example glib .1.0115 (PS-A2) Rt 2.10 [M+H]" 340 The title compound was obtained. ¢ isopropylamine "HNMR (Me- d5-OD) & 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 (2H, s).

Y. Example No. ye.

Dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl } -amine on 0 © : N—N

H

Yven

- YY - Title complex .01 was obtained by following the procedure described in Example No. LC/MS (PS-B2) Rt 2.82 [M+H] 1 O NMR (Me-d5-OD) E ‎ 2.25 (6H, s), 2.95-3.04 (2H, m), 4.20 (1H, t), 7.16 (1H, t), 7.26- 7.33 (6H, m), 7.49 (2H, d), 7.89 (2H , s). 71 Example No. oo {2,2-Bis-[4-(1H-pyrazol-4-yl)-phenyl]}-ethyl ( -dimethyl-amine

HN nr 0©

N—N

H

LC/MS (PS- The title complex. 6H, s), 3.59 (2H, d), 4.43 (1H, t), 7.39 (4H, d), 7.57 (4H, \d), 7.93 (4H, s).

YY Example No. {2,2-Bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine

Yen

-AYA-

N= _ N and 2 8 © N—N H LC/MS (PS-B2) Rt 2.18 [M+H] 344.11 "HNMR (Me-d5-OD) 2.65 (3H, 5), 3.60 (2H, d), 4.34 (1H, t), 7.36 (4H, d), 7.59 (4H, d), 7.94 (4H, s).°

YY Example #2-(4-Chloro-phenyl)-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethylamine (R)

Cl - 0 N H, 7

N—N

H enantiomers No.; However, the JU isomers separated prepared using the same procedure as in the chiral preparation using the 0-001M method. HPLC by 0.ee/ LC/MS (FL-C) Rt 10.97min,95.7

- Ava - '"H NMR (Me-d5-OD) 3.65 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.16 (2H) , s).

YE Example #2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S)

QO

7 7

N—N

H o enantiomers prepared using the same procedure as in Example no. However, the isomers were separated by a chiral preparation using the 0-01.J HPLC method by .ee/.LC/MS (FL-C) Rt 9.63min,100 "H NMR (Me-ds-OD) 3.66 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.15 (2H, s).

Yo Example #2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide cl

Ud©

N—N

H

Yen

- 17.0 : but by replacing (2) Y) followed by (VY) following the procedure explained in Example No.: by 3-(4-Bromo-phenyl)-3-(4-chloro- phenyl)-propionic acid Then obtain the title compound.

IHNMR (Me-d3-0OD) 6 4.99 (1H, s), 7.30-7.33 (6H, m), 7.55 (2H, d), 7.86-8.02° (2H, brs). 1-Phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine : 7 Example No.

NH, 7

N—N

H

: Following the procedure described in Example No. © but with the substitution of 3-bromobenzylmagnesium bromide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl) -1H-pyrazole. By 4-bromobenzylmagnesium bromide and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole . Then get the title compound Vo

Yen:

1 - - 4 RTM 2.44 LC/MS (PS-B2) Rt THNMR(Me-d3-OD) 6 2.99 (2H, d), 4.13 (1H, t), 7.10 (2H, d), 7.20-7.38 (SH, m), 7.45 (2H, d), 7.91 (2H, s).Ja No. 1: [4-(5-Methyl-3-trifluoromethyl-1H-pyrazol) -4-yl)-phenyl]-acetonitrile ~~ © 37A. 4-Bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole { Y V) Br Br os AN or, Me / N—N —— A 2 N—N H ( 0 to a solution ( 4 g; TY mmol; 1 equivalent) of : BAR ) * [4-(5-Methyl-3-trifluoromethyl-1) H-pyrazol-4-yl)-phenyl]-acetonitrile ( chloroform | 0 added ) 14 mg OY mmol; 0.1 eq) 0 then the solution was cooled to pia and (0 4 ..filling 5.7 mMol 0.5 eq) 3,4-dihydro-2H-pyran was added drop by drop over © minutes. The mixture was allowed to warm to room temperature for 1 hour and the solvents were removed under reduced pressure. The crude mixture was purified by column chromatography “(S102) and eluted with zero-Yo/Yo-petroleum over a linear gradient to give al ya 084) Vo 09 0 from the heading compound 314 "'[11+11] platform. 2.72 .LC/MS (PS-A) Rt

- 1067 - : b Y v) {4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]-phenyl } - acetonitrile ~N b 9 CF,

N—N

O

Example Product No. (7?a) from Jeli M. Done: with 4-bromo-5 methyl- 1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole ¢ 4- (cyanomethylphenyl)boronic acid under the conditions described in the example (Combi-Blocks, San Diego, USA Cat. No. 2444-001) number 3 to give the title compound. 4-(5-Methyl-3-trifluoromethyl-1H- pyrazol-4-yl)-phenyl]-acetonitrile c) 71 01 c ~N 0 ’ —CF,

N—N

H

: equivalent) Yo mg; + mmol Yo) to a solution

Yven

{4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3 -trifluoromethyl-1H-pyrazol-4-yl] -phenyl}- acetonitrile | (Example No. (A in ethyl acetate (Da 1) HCI was added in ethyl acetate (Ja 1) and the mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the heading 0 compound was purified by column chromatography “(S5102) and rinsing (by zero-ethyl acetate 1 0 - petroleum) cana V1) 750);266 [14+11] LC/MS (PS-A) Rt 2.85min Y v)d Preparation of dye compounds 0 ( from : [4-(5-Methyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-phenyl]-acetonitrile 1) Example product No. (No "b) can be reacted with benzaldehyde under the conditions Described in Jha. 3- phenyl-propionitrile, which can be deprotected by removing the 1-tetrahydropyranyl group under the conditions shown in Example No. (YV) c to give: 2-[4-(5-methyl-3 -trifluoromethyl) -1H-pyrazol-4-yl)-phenyl]-3 -phenyl-propionitrile 01 can be reduced:

146 - - 2-[4-(5-Methyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-phenyl]-3-phenyl-propionitrile or its derivative 1-tetrahydropyranyl according to example method No. 1 (And from now on, according to the need to remove the protection according to the method of Example No. 41c) to give: 2-[4-(5-methyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-phenyl]- 3-phenyl-propylamine 0 Lad The product of Example No. (77b) can be reacted with: benzyl magnesium bromide and phenyl magnesium bromide under reaction conditions 2 described in Example No. © to give (after removal of protection by method Example A and C: 1-benzyl-2-[4-(5-methyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-phenyl]-ethylamine and 2- [4-(5-methyl) -3-trifluoromethyl-1 H-pyrazol-4-yl)-phenyl]-1 -phenyl-ethylamine 01 respectively. Example No. YA Constructing the pyrazole ring system (A) 0 ¥ a) Synthesis of 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole Br Br 1 —~Me y Me N A H

E21 - to )0 grams; 77.5 mM 1 “J sa eq) 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole (Acros Organics 3421 6) ALT (da VY) mmol added; YT equivalent): N,N-dimethylformamide dimethyl acetal and the mixture was heated to 1Vo for 7 hours. The solvents were removed and the resulting gum was dissolved in ethanol (Je "Yo) with further heating.

e Addition of 0 TV) filling 78.7 mM 011 eq) Hydrazine hydrate and the mixture was heated to

Reflux score for Vo hours. The solvents were removed under reduced pressure and the material was pulverized

solid by dichloromethane to give ) 4 grams; (X80 from title complex; LC/MS (PS-A) Rt 2.87min 1148

) into compounds of formula 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole b) YA conversion)

(1) 0 4-(4-Bromo-phenyl)-3-methyl-1H-pyrazole at position 1 of the pyrazole ring can be protected by formation of the (THP) tetrahydropyranyl derivative by the following procedure shown in Example 0.1 YA) Grignard reactant can then be prepared from the bromine and -phenyl moiety by treating the magnesium-protected derivative in an ether solvent in a standard way (see

J.

March,4dvanced Organic Cchemistry, 4h Edition, 1992, John Wiley, New York, pages 622-625 Vo by nitrostyrene (Nitrostyrene was prepared with Grignard reaction sala Jel can be reduced (Organic Syntheses , Collective Volume 1, page 413. A standard method explained in: The product to give nitroethyl compound Yyeen

165 - - 2-{4-[3-methyl-1-(tetrahydro-pyran-2-yl)-1 H-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine gives the removal of the group tetrahydropyranyl using the method described for Example No. (2A) Kay (7) 2-{4-[3-methyl-] H-pyrazol-4-yl]-phenyl }-2-phenyl-ethylamine compound conversion bromine and (for example YA) { to compounds of formula (1) in which group A contains a nitrogen atom 0 which is attached to group 8. The introduction of the nitrogen-containing entity can be carried out by means of a compound reaction Example number (78) with: [3-(4-chloro-phenylamino)-propyl]-methyl-carbamic acid tert-butyl ester under amination conditions stimulated by oe palladium, the type described in: “Organic Letters, 2002 ,vol.4, No 17, 002885-48 followed by removal of the protecting group £-butyloxycarbonyl |0 by standard methods Example 4: [3-(1H-Pyrazol-4-yl)-phenyl]-acetonitrile C Sy 2 N—N H following the procedure shown in Example 1 but using: 3-bromophenyl- acetonitrile instead of “2-(4-chlorophenyl)- 2-phenylethylamine and then get 0 to get the title compound. 184 LC/MS (PS-A) Rt 2.35min [M+H]"

VEY - - H-Pyrazol-4-yl)-phenyl]-acetonitrile 1 can be used as an intermediate in the preparation of compounds of formula (I) eg by an aldehyde condensation reaction as shown in Example ¥ Or the Grignard reaction as shown in Example No. 0 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid can be used as an intermediate in the preparation of compounds of formula “D” on For example by an aldehyde condensation reaction as shown in Example No. ? Or the Grignard reaction as shown in Example #. Example 01 2-(4-Chloro-phenyl)-N-methyl-2-[4-(1 H-pyrazol-4-yl)-phenyl]-acetamide AU N H 2 N-N H 0 following the procedure shown in Example (IVY) followed by (7 (2) but replacing: 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid instead of Bis-(4-chloro-phenyl)- acetic acid and ammonia instead of amine methyl + then obtaining the title compound. LC/MS (PS-A2) Rt 2.64min [ M+H]" 326 'H NMR (Me-d;-OD) 6 2.79 (3H, 5), 4.94, (1H, brs), 7.26-7.35 (6H, m), 71.55- 7 (2H, m), 7.96 (2H, br s). \o Yyén

- 1/8 -

N-Methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide : ¥) Example No.

N=

N=

ULE

N

0 7 /

N-N by following procedure c shown in example m and then obtaining the address complex .

LC/MS (PS-A2) Rt 2.19min [M+H]" 358 'H NMR (Me-d3-OD) 2.80 (3H, 5), 4.95, (1H, br), 7.32 (4H, d), 7.56 (4H, d), 7.98 (4H, m br s) Example No. YY {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl) -phenyl]-ethyl } -methyl-amine -(4-Bromo-phenyl)-2-methylamino-ethanol (ivy ) 0 1 oH H 0 solution jon Br Br A solution of (0.0 g; 7.01 mmol) 2-(4-bromophenyl)-oxirane in (1.1 “Ja You mmol) amine methyl (777 vol in ethanol) at room temperature in the atmosphere of

tq - - nitrogen . After YA 1 hour the solvent was removed under vacuum and the residue was purified with flash silica and rinsed with AY. ) ela : acetic acid : methanol : dichloromethane 1 (YoY no) to give the desired compound in the form of acetic acid salt. Additional purification was given using Phenomenex-Strata-SCX column and rinsing with methanol followed by ammonia. in Y methanol NM of desired product. 4-chloro-phenyl)-ethyl]-methyl-amine Ci OH H 0 for the solution Br Br YVAY (mg You AY mmol) Aluminum chloride was added part by part to the stirred solution 0 of (cana 0 2797+ mmol) 1-(4-Bromo-phenyl)-2-methylamino-ethanol in (¥ chlorobenzene (Ja)) and the reaction mixture was stirred at room temperature for 11 minutes. h. (JY) water was added dropwise and the reaction mixture was then partitioned between saturated dichloromethane (Jo 001( NaHCO; (Je Yo)). The organic layer was dried with MgSOy, filtered, and concentrated under reduced pressure. Then purify the residue by column chromatography: Phenomenex-Strata-SCX and rinse with methanol followed by ammonia in methanol ¥ Nm aed of desired product.324 LC/MS (PS-B3) Rt 3.58 [M+H]'

— .c 1 -_ {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine (z YY ) [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine f (0,772.471 la mmol)Ve)4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole g; EA 5 mmol) toluene (Ja V.¢) 5 methanol (Ja ¥Y.0) 5 ethanol (Ja V.0) HAK;PO, ele (Ja 0 °) by nitrogen for Two minutes. Nye added 0 11 mg; 77.6 mol) Bis(tri-t-butylphosphine)palladium (0) and the reaction mixture was cleaned with nitrogen for an additional 2 minutes. The mixture was then heated in nitrogen atmosphere for a period of VY hours. The solvent was removed and the residue was divided among 1 N NaOH 5 ethyl acetate. The aqueous layer 01 was extracted with ethyl acetate and the combined organic layers were washed with brine, dried with MgSO, and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (0:5) 0 and eluted by dichloromethane to dichloromethane: acetic acid: methanol: water (6 YF VA) to give (1© mg) of the title compound ; -LCMS (PS-A2) Rt 2.08 min; [M+H]" 312 1 _Ex. YY, {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol -4-yl)-phenyl]-ethyl}-ethyl -amine cl or H and 2 N—N H Yyén

— \ o \ _— amine methyl c) but by substituting (77) (IVY) following the procedure described in Examples Figures; the title compound. amine ethyl was obtained by LC/MS (PS-A2) Rt 2.11 [M+H]" 326 'H NMR (Me-d5-OD) 6 1.15 (3H, t), 2.83 (2H, q), 3.35-3.43 (2H, m), 4.25 (1H, t), 7.30- 7.48 (6H, m), 7.57 (2H, d), 7.95 (2H, s).° "HNMR (de-DMSO) 6 4.60 (1H, 1), 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, 5), 9.0 (1H, s).#4? Jha

Methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl }-amine [2-(4-Bromo-phenyl)-2-( 4-phenoxy-phenyl)-ethyl]-methyl-amine (iv ¢ ) 01

H N pd 4 Uo

H

. Br

Br with chlorobenzene but replacing («= YY) following the procedure explained in example numbers

LEMS as a solvent; The title compound was obtained. nitrobenzene using diphenyl ether (PS-A2) Rt 2.54 [M+H]" 382

_ \ o Y —

Methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -aminc (;ap)0) 0

Br77

N—N

H

: c) but by replacing YY) following the procedure explained in example numbers: by [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine done Obtaining [2-(4-Bromo-phenyl)-2-(4-phenoxy-phenyl)-ethyl]-methyl-amine 0 -LC/MS (PS-B3) Rt 3.04 [1+11] 370 compounds Title. 11 (Me-d5-OD) 6 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).

Yo {2-(4-Methoxy-phenyl)-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine 0 [2-(4-Bromo-) phenyl)-2-(4-methoxy-phenyl)-ethyl] -methyl-amine (iv ° ) 0 7

OH button ~ CJ

H 0 = ort = ~

Br Br Br ®

Yen

o Ag — \ — following the procedure described in Example numbers (VY) b) but replacing chlorobenzene by 6 + the title compound was obtained as a mixture of domain isomers (©: approx. 1) with an ortho-like -methoxy landscapes. 320 [11+11] 3.24 (PS-B3) Rt 1.0/115. Yo) b [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine ~o “0 b” oo hs 3 mL ~ b 1 © “!l pe het Br : (£4 mg; 4 mmol) 800 was added to a solution of (la VA) 5.708 mmol) [2-(4-Bromo-phenyl)- 2-(4-methoxy-phenyl)-ethyl]-methyl-amine (and its domain isomer) in dichloromethane (da 10). After stirring at room temperature for 11 hours, the solvent was removed under reduced pressure and the product was purified. the crude by flash chromatography 0 and rinsing with zy (3:) petroleum cther/ ethyl acetate (6 mg) of the compound protected by the intermediate BOC as the desired single isomer. The product was then stirred into a saturated solution of HCL in ¥ diethyl ether (Ja) + ¥ diethyl ether (Ja) for ¥ days. Removing the solvent under reduced pressure gave the title compound as HCL salt .LC/MS (PS-B3) Rt 3.21 [M+H]" 320 {2-(4-Methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl }-methyl-amine (z Ye) 0 following the procedure described in example numbers YY c) but by substituting:

1 © $ — - [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine by [2-(4-Bromo-phenyl)- 2-(4-methoxy-phenyl)-ethyl]-methyl-amine; The title compound has been obtained. 308:LC/MS (PS-B3) Rt 2.52 [M+H]" 'H NMR (Me-d5-0D) 6 2.75 (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 No. 7? [1-(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol (I 1 ) ~ OH 0 H H N 07 2 : Br Br 0 Done Add VA) mL; 1 M in dichloromethane (slowly) to a solution of (00 mg; 07 mmol) [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl )-ethyl]-methyl-amine in dichloromethane (Ja A) at 0°C in nitrogen. The reaction mixture was allowed to warm to room temperature and then stirred for an additional hour. The mixture was poured onto a slide and diluted Then by dichloromethane and a saturated NaHCO 2 solution the organic layer vo was dried with MgSO, filtered and concentrated to give the desired product.

— \ 00 —

LC/MS (PS-B3) Rt 2.76 [M+H]" 306 : B 1 ) [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl}-methyl-carbamic acid tert-butyl ester

Oh

0OH

N

> Mob “Jo” Bahra Rum

Br (1 1 mg 0.77 mmol) 300:0 was added to a solution of (71 0111 mM -(4-Bromo-phenyl)-2-methylamino-ethyl]-phenol ( Js 1]-4 in Yr) mL): dichloromethane . After stirring at room temperature for 11 hrs the solvent was removed under reduced pressure and the crude product was purified by column chromatography (Si0, 0) and eluted with: 1 (petroleum ether/ ethyl acetate) to produce the title compound. LC/MS (FL-A) Rt 3.85 [M+H] 406 0 : c v1) {2-(4-Bromo-phenyl)-2-[4-(pyrazin-2-yloxy)- phenyl]-ethyl} -methyl-amine

NE) NZ a J a rb" > . ore 0-62 ot

br br br

o 4 — 3 — A solution of ( NYO mg; 171 mmol) heated : [2-(4-Bromo-phenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl -carbamic acid tert-butyl ester ‎Yo.¥ )s mg; A mM 2-chloropyrazine (Use f (Y mg « 0. mmol) 100 in A) ml) dimethylformamide to Vos 5 for VY h. Upon cooling the solvent oo was removed under reduced pressure and the residue was divided between ethyl acetate and a saturated NaHCO; The organic layer was dried with MgSO, filtered, and concentrated. The crude product was then treated with HCl saturated in (diethyl ether) Ja 01 and stirred at room temperature VY sad 1 h. The solvent was then removed under reduced pressure and the crude product was purified by a Phenomenex-Strata-SCX column chromatography and rinsing with methanol followed by ammonia in Y methanol 0 N (AY) had mg) of the desired product. 3.17 LC/MS (PS-B3) Rt [IM+H]" 384 p(s) Methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[ 4-(1 H-pyrazol-4-yl)-phenyl]-ethyl} -amine ro NT) Nn JANN 0 0 C v H g H xl J p Br N—N H vo following the procedure described in example numbers (YY) c) but by substituting:

: - Yov - : by [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine then obtaining ¢ {2-(4-Bromo-phenyl) -2-[4-(pyrazin-2-yloxy)-phenyl]-ethyl }-methyl-amine .LC/MS (PS-B3) Rt 2.48 [M+H] 372 on the title compound.” HNMR (Me -d;-OD) & 2.80 (3H, s), 3.75-3.90 (2H, m), 4.50 (1H, 1), 7.23 (2H, d), 7.50 (4H, t), 7.75 (2H, d) °

YY Example No

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

OH OH or — drag churn

Br Br 0 mM 8.79 alga 7 (to a solution of BOCO (Use 8.54 cal a 1.90 mM) add cos 0 after dichloromethane (Je 01) in 1-(4-Bromo-) phenyl)-2-methylamino-ethanol (mol) h. The solvent was removed under reduced pressure and VT was stirred at room temperature for ethyl acetate and rinsed with (SiO). Purification of the crude product by column chromatography

LC/MS (PS-B3) Rt 3.16 [M+H]330 To produce the desired product. (0:1 ) petroleum ether/ [2-(4-Bromo-phenyl)-2-phenoxy-ethyl}-methyl- amine b yv) vo

Foy

Br 0 87 Br

118 - - Yo A (μl 7.77 mmol) Diethyl azodicarboxylate was added dropwise to a solution of (044 cana (1.0 mmol): [2-(4-Bromo-phenyl)- 2-hydroxy-ethyl]-methyl-carbamic acid tert-butyl ester, (oq mg cana YA©) triphenylphosphine (Y.YV 2.07 mmol) phenol in (do 01( tetrahydrofuran) The reaction mixture was stirred in As at room temperature under nitrogen for VY hours The solvent was then removed under reduced pressure and the residue was divided between ethyl acetate and a saturated NaHCO solution The layer was dried The crude product was then purified by column chromatography ¢(Si0;) and eluated with ethyl:1 (petroleum ether/ acetate 1) to produce the compound protected by BOC 0. which was then stirred in a saturated solution of HCI in diethyl ether (Ja 71) for 4 h. Removing the solvent under reduced pressure gave the title compound in the form of the HCl salt gave further purification by Phenomenex-Strata-column chromatography. SCX and rinsing with methanol followed by ammonia in methanol? Standard to give (94 mg) of the desired product as a free base. 406 [11+11] 4.04 (PS-B3) Rt 1.0/145. Vo (No 3 =( Methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine) © 7 Br i

Yyen

_ 9 m \ — following the procedure described in example numbers (YY) c) but replacing: [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine by : [2-(4-Bromo-phenyl)-2-phenoxy-ethyl]-methyl-amine The title compound was obtained. .LC/MS (PS-B3) Rt 2.73 [M-PhO+H]" 200 (3H, 5), 2.90 (1H, dd), 3.15 (1H, dd), 5.40 (1H, dd), 6.85 (1H, 0 2.50 NMR (Me-d5-OD) y, t), 6.90 (2H, d), 7.18 (2H, t), 7.40 (2H, d), 7.55 (2H, d) , 7.93 (2H, 5). Example YA 2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy} -ethylamine (4) -Bromo-phenyl)-(4-chloro-phenyl)-methanol (vA) OH 0 or Br Br Cl . VY.4V) 4-Chlorophenylmagnesium bromide was added to fill 1 M solution in diethyl (ether) slowly to a solution of (? 00181 cal a mmol) £ 4-bromobenzaldehyde in Yo) A tetrahydrofuran (Se) 0°C in nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 11 hours. At that time (7 mL) ele was added and 1_ solvent was removed under reduced pressure. The residue was divided between ethyl acetate and 1 1101 solution Standard The organic layer was washed with brine, dried with 18507 and concentrated The crude product was then purified by column chromatography (SiO)' and eluated with: Yven

‎VT. 0- - :1( petroleum ether/ ethyl acetate 3) to produce 7.01 (g) of the title compound. LCMS (PS-B3) Rt 3.49 min; [M+H]" 297 YA) b : 2-{2-[(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxy]-ethyl} -isoindole-1,3-dione 0 \ J 0 OH and then heating a mixture of (.Yg; non-milli (Use : (4-Bromo-phenyl)-(4-chloro-phenyl)-methanol and (04gm) 77./ mmol) : N-(2-hydroxyethyl)phthalimide and (+07 0.4 cana mmol) of : para-toluenesulphonic acid monohydrate in toluene (Je © 1) to the degree of reflux below 0 Dean-Stark conditions for VY hr. Upon cooling Gad solvent was removed under reduced pressure and residue was divided between clay ethyl acetate The organic layer was then dried using 1850, filtered and concentrated The product was then purified Crude by column chromatography (D 5:0); elution with: (1) (petroleum ether/ ethyl acetate 4); to yield (1.90 g) of the title compound. LCMS (PS-B3) Rt 4.07 0 and ALS jon did not note Yvet

- VY - : (zYA)

N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-pheny!]-methoxy} -ethyl)-phthalamic acid

HO, ° 07 “NH

OTN 0 cl 2 . for oF -

Br7/

N—N

H

: c) but by replacing YY) following the procedure described in example numbers: by [2-(4-Bromo-phenyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amine | © 2-{2-[(4-Bromo-phenyl)-(4-chloro-phenyl)-methoxy]-ethyl } -isoindole-1,3-dione .LC/MS (FS-A) Rt 2.85 [M- H]" 474 Title compound obtained. : d) ( 2-{(4-Chloro-pheny!)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine

HO - ° 07 “NH J

Cl / Ci ©

N—N N—N

H H 01

117 - - (104 μg “Al 7.78 mmol) hydrazine monohydrate was added to a solution of Yi. ) mg; for mmol): N-(2-{(4-Chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy } -ethyl)-phthalamic acid in methanol (Ja The reaction mixture was stirred at As 5 for 11 hours. Upon cooling to 0, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (SiO). SCX and rinsing with methanol followed by ammonia in methanol? Standard to give 110 (mg) of the desired product as a free base. .LC/MS (FL-A) Rt 2.07 [M-NH,CH,CH,0+H]" 267 Ve "HNMR (Me-d5-OD) 6 2.85 (2H, t), 3.55 (2H) , t), 5.45 (1H, s), 7.35-7.40 (6H, m), 7.58 (2H, d), 7.95 (2H, s). Jha No. Ya Methyl-{3- naphthalen-2-yl-3-[{4-(1 H-pyrazol-4-yl)-phenyl]-propyl } -amine Li © N—N H Vo following the procedure in the example number A but by substituting:

- 11 - Done « 2-naphthylmagnesium bromide by 4-chlorophenylmagnesium bromide

LC/MS (PS-A2) Rt 2.26 [M+H]"342 Obtain the title compound. 'H NMR (Me-d5-OD) 6 2.57-2.70 (2H, m), 2.70 (3H, s) , 2.90-3.10 (2H, m), 4.32 (1H, 1), 7.40-7.52 (5H, m), 7.70 (2H, m), 7.80-7.90 (4H, m), 8.70 (2H, s).2 Example number 0

Dimethyl-(4- {3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl} -phenyl)-amine 1a, lh 7, N—N H 4-chlorophenylmagnesium bromide but by substituting A following the procedure described in Example No. Obtain the title compound. ¢ 4-(N,N-dimethyl)anilinemagnesium bromide by .LC/MS (PS-A2) ) Rt 1.55 [M+H]'335 0 'H NMR (Me-d5-OD) & 2.46-2.60 (2H, m), 2.69 (3H, s), 2.95 (2H, 1), 3.27 (6H, 5) (1H, t), 7.45 (2H, d), 7.60-7.72 (6H, m), 8.50 (2H, s).

0 41 Example No. {3-(4-Fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl ( -methyl-amine

F

Li©

N—N

H

4-chlorophenylmagnesium bromide but by substituting A following the procedure described in Example No. the title compound was obtained. ¢ 4-fluorophenylmagnesium bromide by ©

LC/MS (PS-A2) Rt 2.05 [M+H]" 0 'H NMR (Me-d3-OD) § 2.40-2.55 (2H, d), 2.70 (3H, s), 2.90-3.0 (2H, m), 4.12 (1H, 1), 7.05 (2H, t), 7.32-7.40 (4H, m), 7.63 (2H, d), 8.33 (2H, 5).47 Example 3-(4- Phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine 0 0

Cy5©

N—N

H

hy oS — \ _ Following the procedure described in Example A but substituting 4-chlorophenylmagnesium bromide by 4-phenoxyphenylmagnesium bromide by ammonia the title compound was obtained. 370.34 LC/MS (PS-A2) Rt 2.28 [M+H]* HNMR (Me-ds-OD) 6 2.38-2.46 (2H, m), 2.85-2.92 (2H, 1), 4.03-4.10 (1H, 1), 6.94-7.0 (4H, d), 7.08-7.14 (1H, 1), 7.30-7.39 (6H, m), 7.55-7.58 (2H, d), 7.90-7.97 (2H, br s), 5 (1H, br s). -propyl } -methyl-amine 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol (i £Y) (J.

Med.

Chem., 2004, 47, 3924-3926) \ c, Cl. , Cl Br Br to a solution of (1 g; £08 m) 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (Use in (Je +.0A) tetrahydrofuran (Je 4) water was added (+11 g”; £.YA mmol) sodium borohydride The reaction mixture was stirred at room temperature for 2 hours, quenched 0 by adding water carefully, and extracted with ethyl acetate . The organic layer was separated, dried with 4, filtered, and concentrated to give the title compound, which was used in the next step without further purification. LC/MS (PS-A2) Rt 3.07 [MH] No ionization.

[3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloride b ¢ 9 a : 0 jes : Cl

Br Br 3-Chlorophenol was reacted with 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol b) to give the title compound; which was used in the next step without further purification. [3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine (z ¢V)

H

7 | ClUU, | NC

Br Br A solution of 3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-chloride in) ¢ amine methyl (Ja) in 71/ethanol was heated in a microwave CEM at 100 °C Ye saad 0 min using a power of 0 W. The solvent was removed and the crude product was purified using a Y ammonia ion exchange column followed by methanol and elution with a standard Phenomenex Strata SCX. The product was purified by column chromatography (D5:0); eluated with (Y:¥ (mcAc: cla: acetic acid : methanol : dichloromethane to dichloromethane following the procedure shown in Example No. YA) b to give compound address which was used in vo next step without additional 485 .; 356.19 .LCMS (PS-B3) Rt 3.42; [M+H]"

(2¢Y) {3-(3-Chloro-phenoxy)-3-[{4-(1H-pyrazol-4-yl)-phenyl]-propyl } -methyl-amine opt B : 8 r 7 )

N—N

H

: dels then : with [3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine the action described in glob 4-(4, 4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole

LC/MS (PS-B3) Rt 3.80 [M+H]" 342.26 to give the title compound. 1 Example # 'H NMR (Me-d;-OD) 8 2.19-2.30 (1H, m) , 2.30-2.45 (1H, m), 2.72 (3H, s), 3.10-3.28 (2H, m), 5.40-5.47 (1H, m), 6.80-6.88 (1H, d), 6.88-6.94 (1H, Example No. 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). Methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl} -amine

- 11/8 6-(3-Methyl-1 -trityl-1H-pyrazol-4-yl)-nicotinotrile { £¢ ) : N 1 40.00 x 8 . Lah Qe N---N © 2

CU A -H) - triethyl 1 - methyl —-Y g; mmol) 0 7 acid was added to a solution of “methyl ether (gla yen ethyl (Ja ¥) boronic*) in —¢ - pyrazole water. The gases were removed from (Je (1.0 mmol) sodium carbonate in 7.79 ala (0 XY) 0 palladium phosphine) before adding tetrachloride (tri-nitrogen) reaction mixture by Watt. 50 minutes (power 00 °C) 0" 1 m for CEM (zero) and then heated in a microwave with 1 NaOH and the aqueous phase made basic by ethyl acetates ele The reaction mixture was divided between titres, the organic extracts were combined, dried with 148507, the solvent removed, and the product suspended. grams; yield YY) and filtering the white precipitate to give crude methanol in a small volume of 10

LC/MS (PS-A2) Rt 4.52 [M+H]" 427.26 M) of Atwan compound. EP1382603A1. This starting material can be made by the method described in * (= £1) (4-Chloro-phenyl )-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone

119 - - cl N I 0 x = bar ! PN ee 2 N—N N—N to a solution of ) +0g; mmol) : 6-(3-Methyl-1-trityl-1H-pyrazol-4-yl)-nicotinotrile in)sila tetrahydrofuran (Je) was added (7 0.97 Ja mmol) 1) 4-chlorobenzenemagnesium bromide M © in (diethyl ether). The reaction mixture was stirred under nitrogen atmosphere for 1 h. The reaction mixture was quenched to below pH 11 M¥ by adding 1 N HCI It was stirred for dels, then the pH was adjusted to A by means of saturated sodium bicarbonate and extracted by ethyl acetate. The organic extracts were combined and dried using MgSO; the solvent was removed and the residue was purified by column chromatography (¢) Si0;) and elution with petroleum 0 to (Ao:Vo) petroleum ether: ethyl acetate to produce (0.49 mg; yield) AVY from the title compound. LC/MS (PS) 540.30, 542.28 -A2) Rt 4.45; [M+H]" (zt) {2-(4-Chloro-phenyl)-2-[6~(3-methyl-1-trityl-1H-pyrazol-4- yl)-pyridin-3-yl]-vinyl } - methyl-(1-phenyl-ethyl)-amine

with 7 \ — C Cl ] A : 0 0 | >< >< no 4 0 N—N N—N then add L$ Y) grams; . mmol) n-Butyllithium (a molar in hexanes) drop by drop into a solution of 0. A) grams; ..,21 mmol): (Ja 4 ) st R) (Diphenyl-phosphinoylmethyl)-methyl-(1-phenyl-ethyl)-amine * tetrahydrofuran© dry at — yo m . After 16 minutes a solution of VE (g) was added; “Yo mM (Use : (4-Chloro-phenyl)-[6-(3 -methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone * tetrahydrofuran (Je +9) and the reaction mixture was stirred for an additional 1 min at -Vo 1 °C before heating to −1 °C at room temperature over 1 h.Then the reaction mixture was quenched with 0 water and extracted by ethyl acetate.The organic extracts were combined, dried with MgSO, and concentrated to give title compound 0, which was used in the next step without further purification.* This starting material can be made by the method described in: Tetrahedron Asymmetry, 2003, 14 , 1309-1316

- 101 -

Methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-ethyl ( -amine d¢¢ ) a -

ZN x | : a m x 0 > —N

GO 0 —N : to a solution of {2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl] -vinyl} - mcthyl-(1-phenyl-ethyl)-amine ° by weight on activated carbon and a mixture of 7/00 ¢ palladium in 9001© was added. “Celite® concentrate” was added h. The mixture was filtered through a VV for nitrogen reaction to atmosphere and rinsed with maternal ((Si0;) and the residue was purified by column chromatography Jil dichloromethane to (1:¥:Y+“:Y&+) Water: acetic acid: methanol: dichloromethane

LC/MS (PS-A2) to give the title compound. (Y iY 0YA 94) Water : acetic acid : methanol : 0

Rt 1.59; [M-+H]" 293.18 '" H NMR (Me-d5-OD) 2.35 (3H, s), 2.40 (3H, , 3.25 (2H, 5), 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, 5).

117 - - Example No. to {2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine [2 -(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzyl ester { ¢o ) F F OJ of OH “5 N J 0 5” H TQ © 0 Br Br to a solution of ) 1 gram; v..4 mmol) from: 3-(4-fluorophenyl)-3-(4-bromophenyl)propionic acid* | 0 added in (4 acetone (Jo in dan saphram added sequentially 0M) 1 μm 4.07 mmol) triethylamine in (1.1 ££Y) 5 acetone (Je μm) fl 4.74 mmol) ethyl chloroformate in acetone (Je V.1). The reaction mixture was allowed to warm to room temperature; And stirred for 90 minutes before cooling again to safram, and (407 mg TVA 0 mmol) sodium azide was added in (7 (do) water. The resulting brown solution was stirred for £0 minutes before Addition of (10 Ja) water and (10 ml) diethyl ether. The aqueous layer was separated and further extracted by (ethyl acetate (SeYo). The combined organic liquids were washed with saturated brine, dried with 14850, and concentrated under atmosphere. The residue was dissolved in VY (ml) toluene not Sl before adding (07 μl 9.077 mmol) benzyl alcohol and heating 1 to Av C for 40 min. − The reaction mixture was cooled to room temperature before adding ethyl acetate (Jo 0) and +© sodium bicarbonate (Ja) saturated. The organic liquids were separated

AVY - - was washed with additional sodium bicarbonate (Je 0) and (100 N) hydrochloric acid (Je 5) 04 mL saturated brine before drying with MSO, and concentrated under vacuum. The residue was purified. Crude by column chromatography (SiO) and elution by ethyl acetate / petroleum gradient (0:90) to (A0 V0) to give (04 cane 45 7) of the title compound. LC/MS (PS- A2) 823.18 © No ionization * This starting material can be made by the method shown in Example (ZA) (1A) by substituting: 4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium (£0 =) {2-(4 -Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl } -carbamic acid benzyl ester og l substituent ml © N 0 Br 7 N—N H \[2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzyl ester was reacted with glib 4-(4,4,5,5 416 LC/MS (PS-A2) Rt 3.20 [M+H] "

1174 - - (z £0) {2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine F F Ra JJ 3 Z − Z 7 H H 0 © N—N N—N H H Added (¥.0 filling 5.90 mmol) V) lithium aluminum hydride in © tetrahydrofuran ) slowly to (£79 mg; 0011 mmol) from : {2-(4-Fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -carbamic acid benzyl ester in)© A tetrahydrofuran (Je) was obtained under nitrogen atmosphere. The reaction mixture was allowed to be warmed to room temperature, stirred for 51 hours, and quenched with (0 ml) water and (E) sodium hydroxide aqueous ? and 10 N ethyl acetate (Je). The aqueous layer was separated by Li = 0 blood and extracted by ethyl acetate (Jo Yo XY). The combined organic liquids were washed with saturated brine, dried with 14850, filtered, and concentrated in The residue was purified by column chromatography (SiO) ¢ and eluted by a gradient: (Ye:170(ele:acetic acid :methanol:dichloromethane ?:)1 to (YoY Aa) to give (001) mg; 777) of the title compound, which was subsequently converted to the hydrochloride salt M 296 LC/MS (PS-A2) Rt 1.87;

_ \ 7 mg — "HNMR (Me-d;-OD) 6 8.20 (2H, s), 7.57 (2H, d), 7.34-7.29 (4H, m), 7.02 (2H, t), 4.32 ( 1H, 1), 3.67 (2H, d), 2.65 (3H, s).47 Example No. {2-(3-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl) -phenyl}-ethyl }-methyl-amine ci rum NT ©

N—N

H

: following the procedure described in Example 0 but substituting ° then 6 3-chlorophenylmagnesium bromide idad g34-fluorophenylmagnesium bromide .LC/MS (PS-A3) Rt 4.92; [1/+11] 312 Obtain the address compound. 'H NMR (Me-ds-OD) 6 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, 0. 3.70 (2H, d), 2.65 (3H, 5).

EY Example No. ve 3-(3,4-Dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl] -propionamide

XX

0 NH, 0 2 /

N-N

H

Yest

- 171 - Following the procedure explained in Examples (19) to (8) but replacing 3 4-dichlorophenylmagnesium bromide with 3,4-dichlorophenylmagnesium bromide

LC/MS (PS-A3) Rt 9.82 [M+H]* 360.14, 362.12 Title compound obtained. 'H NMR (Me-d3-OD) 6 2.90-3.00 (2H, d), 4.50-4.60 (1H, 0, 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). °

EA Example #2-(4-{2-Methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -phenoxy)-isonicotinamide 0 = NH,

Nz0

H

7

N—N

H

By 2-chloropyrazine replacing Sly 497 with the procedure described in Example No. gli - the title compound was obtained. 2-chloro-4-cyanopyridine 0

LC/MS (PS-B3) Rt 2.27 [M+H]" 414 'H NMR (Me-ds-OD) § 2.45 (3H, s), 3.55 (1H, dd), 3.65 (1H, dd), 4.25 (1H, t), 7.10 (2H, d), 7.30-7.38 (3H, m), 7.40 (2H, d), 7.48 (1H, d), 7.56 (2H, d), 7.95 (2H, 5), 8.22 (1H, d).

- \VV - £4 Example No. {2-(4-Chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine

Cl ~~ > 0 2

N

© but 4-chlorophenol by phenol but by substituting cA following the procedure described in Example No.

LC/MS (PS-A3) Rt 2.29 [M+H] 200 Title compound obtained. © 'H NMR (Me-d;-OD) 6 2.50 (3H, s), 2.86 (1H, dd) , 3.10 (1H, dd), 5.35 (1H, dd), 6.89 (2H, d), 7.17 (2H, d), 7.40 (2H, d), 7.57 (2H, d), 7.93 (2H, s).

Ow Example No. {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine

Cl7

N—N

H \ by dimethylamine but by substituting Ye the procedure described in example glib ; The title compound was obtained. amine methyl cyclopropyl "+".

- 1/8 -

LC/MS (PS-A2) Rt 2.21 [M+H]" 352 'H NMR (Me-d3-OD) § -0.4-0.3 (2H, m), 0.35-0.40 (2H, m), 0.78-0.87 (1H, m), 2.42 (2H, d), 3.15-3.25 (2H, m), 4.11 (1H, 0, 7.16-7.27 (6H, m), 7.45 (2H, d), 7.82, (2H, s) 51 Example No

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

NN N—N : but by replacing o) following the procedure described in Example No. : by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazole : and conjugation with 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine {2-(4-Chloro-phenyl)- was obtained 2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine*0

LC/MS (PS-B3) Rt 2.42 [M+H]" 355 on the title compound. "H NMR (Me-d5-OD) 5 1.94 (4cOR, s), 2.72 (3H, 5), 3.73 ( 2H, d), 4.46 (1H, 1), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt), 8.53 (1H, dd), 8.80 (1H, d).

- 1lo -

YY This starting material can be made by the method described in Example No. *oY Example No. 4-{3-Methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol

HO

for ". No © N—N H : but by substituting A _ following the procedure described in Example 0 ¢ 4-anisylmagnesium bromide was obtained by 4-chlorophenylmagnesium bromide

LC/MS (PS-A2) Rt 1.82 [M+H]" 308 on title compound. "HNMR (Me-d5-OD) § 1.92 (AcOH, 5), 2.34-2.43 (2H, m), 2.64 (3H, s), 2.86-2.92 (2H, m), 3.96 (1H, 1), 6.75 (2H, d), 7.13 (2H, d), 7.29 (2H, d), 7.52 (2H, d), 7.93 (2H, d). oy Example #1 3-(4-Methoxy-phenyl)-3-[4-(1 H-pyrazol-4-yl)-phenyl]-propylamine 0 ©

N—N

H

Yen

1 A. — _following the procedure described in Example No. (Sly A pastydal chlorophenylmagnesium bromide by 4-anisylmagnesium bromide and methylamine by Y) molar ammonia in methanol ); The title compound has been obtained. 308 [14411] 1.82 LC/MS (PS-A2) Rt (1H, 1), 6.77 3.89 m( NMR (Me-ds-OD) 2.23-2.32 (2H, m), 2.74 (2H, dd), 3.65 (3H, ' (2H, d), 7.11 (2H, 5), 7.17 2H, d), 7.41 (2H, d), 7.71 (2H, 5), 8.41(//CO;H ,brs).° Example number of 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine 2-(4-Chloro- phenyl)-2-(4-iodo-phenyl)-oxirane (i of) Cl 0 8 b 0 I | 0 (178 mg. YoY mm sodium hydride (Use) (714 dispersed in oil) in nitrogen atmosphere at which point 0) DMSO (Je) 1 1g was added; #69 mmol) Trimethylsulfonium iodide as a solid after Yo min; followed by an additional Yo)438 by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone. The mixture was stirred at room temperature for ; ? hr, then diluted with ethyl acetate, washed with [ela clay ¥2 vo brine, 0 ¥2 v. brine], then dried the organic phase with MgSOy, filtered, and concentrated to give (00101 g; (AY) of the title compound; which was used without further purification. LCMS (PS-A2) R, 4.07 min [M-H]" 355 Yyén

YAN - - ACES) 1-(4-Chloro-phenyl)-2-(2-hydroxy-ethylamino)-1-(4-iodo-phenyl)-ethanol and then maintaining a solution of ) le gram mmol) : 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane 5 (© .V + ml A.V mmol) ethanolamine 0 f) ml YN mM triethylamine (dso in)© iso-propanol (Ja) at 1 00 °C for VY h and then concentrated under vacuum. The residue was removed in ethyl acetate and washed with potassium carbonate solution. Water:1(1). The aqueous phase was extracted again with ethyl 6 »> The combined extracts were then washed with brine; dried with MgSO, filtered and concentrated to give Vo) mg; quantification ) of the title compound; LCMS (PS-A2) R; 2.29 min [M+H]" 418, [M-H,0+H]" 400.0 2-(4-Chloro-phenyl)-2-(4-iodo-phenyl)-morpholine ( o¢ ) Cl Cl M2 0 OH “5 H free oO C A solution of (YA (pa Ve mmol) was treated: 1-(4-chloro-phenyl)-2-(2-hydroxy- ethylamino)-1-(4-iodo-phenyl)-ethanol by ) 0.1 0. da 0 mmol) HSO, concentrate. after ? hour; Another portion (19 eda Vou) mmol) HpSOy was added and the mixture was stirred for another two hours. The mixture was diluted with ethyl acetate 17:5

-YAY-

MgSO, then dried with saturated ale and potassium carbonate solution, washed by, filtered, and concentrated. The residue was purified by column chromatography (5:02); eluting with title compound. (FEY cane YA) to give 70.0 ethyl acetate in triethylamine .LCMS (PS-A2) 2.40 min [M+H]" 400 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-) yl)-phenyl]-morpholine d( of ) °

NH NH

I

©

N-N

H

With 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine, 1-(4,4,5,5-606)-4_ was reacted, following the procedure shown, 3 ,2-dioxaborolan-2-yl)-1H-pyrazole as a catalyst to give palladium tetrakis(triphenylphosphine) (0) in Example 1; but with .LCMS (PS-A3) R; 6.88 min [M+H]" 340 Title Compound. 0 'H NMR (Me-d;-OD) 6 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).oo Example number { 2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine

Yen

-VAY-

Bis-(4-chloro-phenyl)-acetic acid methyl ester { oo ) cl cl 0 2 H 0 2 Me cl of (Ja Y+) in Bis-(4-chloro-phenyl)-acetic acid mmol) 15.4 cal a YY) anhydrous methanol was suspended and 0) drops of concentrated hydrochloric acid were added. After 1 day the reaction was quenched by addition of ania sodium bicarbonate solution and then the organic solvent was removed under vacuo. The residue was divided between ethyl acetate and a potassium carbonate solution. The organic phase was treated with brine, dried with 14850, filtered, and concentrated to give a residue, which was purified by column chromatography (Si0y) and rinsed with ethyl acetate. | 0 701 petroleum to give (AVA pla Yo V) of the title compound as 0 as colorless oil; (LCMS (PS-B3) R;3.79 min No ionization. 'H NMR (CDC13) 3 3.74 (3H, 5), 4.96 (111, 5), 7.20-7.23 (4H, m), -7.28 7.32 (4H, m).

YY 4

146 - - A solution of 0109 (g ; mmol) : bis-(4-chloro-phenyl)-acetic acid methyl ester in 01 (mL) THF was cooled to srl m in atmosphere of nitrogen. (¥ cde + mM Y ) LDA (dso molar) in JTHF | heptane ethylbenzene was added over © minutes; then after 70 minutes Agila (¥ Youd oe) was added ° mmol) 10006)008. After a few hours, the reaction was quenched by adding a saturated ammonium chloride solution, allowing it to warm to room temperature, and then concentrating it under vacuum to remove the organic solvents. The mixture was diluted with ethyl acetate/petroleum:1; washed with asda ammonium chloride solution, then brine, dried with 14850, filtered and concentrated to give a residue which was purified by ethyl acetate/petroleum gradient (71 to 77); giving 7101 (0 mg 117 ) of the title compound as oil ane color; 4.01 LCMS (PS-B3) R no ionization. 'H NMR (CDC15) 5 1.88 (3H, 5) , 3.73 (3H, 5), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).)©© c) 2,2-Bis-(4-chloro-phenyl)-N-methyl -propionamide ys 0 CO,H NT 0 Cl Cl ye A solution of 1 0 ? mg was stirred; LY (mmol) : 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid in [THF (Je YA) water/(1:1:10) methanol at room temperature for days, then concentrated in an incubator

A mg A \ — residue between standard Y hydrochloric acids ethyl acetate; Mae Jue organic phase was prepared by saline solution, dried using MgSOy ol, filtered and concentrated to give (Tal mg ay) of the title compound in the form of a yellow solid, which was used without further purification (LCMS (PS-B3) ) 162.40 min [M-CO,H]~ 249. [2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine (2 ° °) ° Cl 0 Cl N 1 N 1 H H º Cl Cl By following the procedure explained in Example No. (A) but by replacing: 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid By : 2,2-bis-(4-chloro-phenyl)-propionic acid ; title compound obtained. LCMS (PS-B3) R; 3.40 min [M+H]" 308 0 )©© e) [2,2-Bis-(4-chloro-phenyl)-propyl]-methyl-amine NT Gm- NT H H

Cl Cl by following the procedure explained in Example No. (14e) but by substituting:

- 15 - : By 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-N-methyl-propionamide; The title compound has been obtained. 2,2-bis-(4-chloro-phenyl)-propionic acid.

LCMS(FL-A)R; 2.35 min[M+H]" 4 {2-(4-Chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl } -methyl-amine : and ° ° )

Cl 0 Cl hes deaf “6 NT

QO oO

Ci7J

N-N

H o : with [2,2-Bis-(4-chloro-phenyl)-propyl}-methyl-amine reacted by following the procedure described 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-y1)-1 H-pyrazole to give the title compound. 1 in Example No.

LCMS (PS-A3) bit 6.94 min [M+H]" 6 'H NMR (Me-d5-OD) 6 1.86 (3H, s), 2.77 (3H, s), 3.89 (2H, 5), 7.26-7.33 (4H, m), 7.37- Vo 7.40 (2H, m), 7.68 (2H, d), 8.35 (2H, s) ot Example No. 1 -(4-Chloro-phenyl)-2- methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol

- No - ci or

NT

0 2

N-N

H amine ethanol pastidal (Sls (200)) following the procedure described in example (00) (© ) b) and . Then the title compound ¢ amine methyl was obtained by LCMS (PS-A3) with a 5.28 min [M+H]" 328, [M-H,0+H]" 310 'H NMR (Me-d5- OD) & 2.38 (3H, 5), 3.34 (2H, 5), 7.28-7.3 1 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s). ov Example 2-Amino-1-(4-chloro-phenyl)-1-[4-(1 H-pyrazol-4-yl)-phenyl]-ethanol 2-[2-(4-Chloro-phenyl) )-2-hydroxy-2-(4-iodo-phenyl)-ethyl}-isoindole-1 ,3-dione ( jov ) cl cl 9 H gL S10 (J O°

I [ \ Then heat a mixture of (oY) mg; 0.0 mmol) Yi) 2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-oxirane* mg; 0.840 mmol) DMSO (Je Y)s THF (Je©) * potassium phthalimide at 100 °C 10 sad

A

YAA - - hour. The mixture was concentrated under vacuum, diluted with ethyl acetate, washed with cle and brine (twice), dried with MgSO, filtered, and concentrated to give a crude product, which was purified by column chromatography (5102); and rinsing with a gradient (JAN: to 001) ethyl acetate | petroleum and then dichloromethane / methanol + 7 to give YVT) mg; Yi 7) of ° heading compound .LCMS (PS-A2) R, 3.22 min [M+H]" 504 * This starting material can be made by the method described in Example No. (00) (oY) * N-{2-(4-Chloro-phenyl)-2-hydroxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl ( -phthalamic acid 01 Q of 0 on 9 Cod h on 0 H — C "0 Va ) N-N H Reacted: 2-[2-(4-Chloro-phenyl)-2-hydroxy- 2-(4-iodo-phenyl)-ethyl]-isoindole-1 ,3-dione with :

- VAR - by following the procedure shown 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole as catalyst tetrakis(triphenylphosphine) palladium (0) In Example No. 0; but using

LCMS (PS-A2) R, 2.62 min [M-H] 460 0 for the title compound 2-Amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl) -phenyl]-ethanol (z ov )

Cl Cl h oH J OH 4 OH 7 ) 2 J

N-N N-N

H H 5 : d but by replacing q ) following the procedure described in Example No

N-(2-{(4-Chloro-phenyl)-[4-(1 H-pyrazol-4-yl)-phenyl]-methoxy} -ethyl)-phthalamic acid : by N-{2-( 4-Chloro-phenyl)-2-hydroxy-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethyl } -phthalamic acid 01

LCMS (PS-A3) R; 6.29 min [M-H,0+H]" 296 'H NMR (Me-ds-0D) & 3.29-3.38 (2H, m), 7.32 (2H, d), 7.41 -7.46 (4H, m), 7.55 (2H) , d), 7.94 (2H, s).

Yen

- 186.0 oA Example No. 3-(3-Chloro-phenyl)-3-[4-(1H-pyrazol-4-yl) -phenyl]-propylamine : ci NH, 7 //

N-N

H

4-chlorophenylmagnesium bromide but by substituting A following the procedure described in Example No. ; Ammonia was obtained with 3-chlorophenylmagnesium bromide by 0 .LCMS (PS-B3) R;2.60 min [M+H]" 312 Title. 'H NMR (Me-d3-OD) & 2.44 (2H, apparent qd), 2.87 (2H, dd), 4.14 (1H, t), 7.24 (1H, dv), 7.27-7.33 (2H, m), 7.34 (1H, 1), 7.42 (2H, d), 7.68 (2H, d), 8.58 (2H, s).04 Example No. 2-Methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl) -phenyl] -ethanol 0

ON

M H 9 N—N H : but by replacing 0A following the procedure explained in Example No.

- 11 - by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone

LCMS; The title compound was obtained. (4-Bromo-phenyl)-(4-nitro-phenyl)-methanone (PS-A) R; 1.79 [M+H]" 9 'H NMR (Me-d5-OD) & 8.27 (2H, ,NH 7.98 (2H, .l) 7.80 (2H, d), 7.65 (2H, d), 7.52 15 (2H, d), 4.00 (2H, dd), 2.73 (3H, s) - CH(OH) signal presumed to be under water peak. phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine

Cl 0:

NH, ©

N—N

H

: but by substituting (z YY) by following the procedure explained in Example No. (51b) and Example No.: by 1-(4-bromo-phenyl)-2-methylamino-ethanol by 1Mn2H: 2-0110; 2-amino-1-(4-bromo-phenyl)-ethanol was obtained as Title. LCMS (PS-B3) R, 2.55 [M+H]" 328.20.

YYen

- 17 - 'H NMR (Me-ds-OD) § 3.65-3.70 (2H, d), 3.90 (3H, 5), 4.30-4.35 (1H, 0.7.05-7.10 (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).61 Example #2-(4-Chloro- phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine 2,2-Bis-(4-chloro-phenyl)-2-fluoro-ethylamine (i 1)

ClCl

O ot

NH, NH,

ClCl. In 2-Amino-1,1-bis-(4-chloro-phenyl)-ethanol (mmol) 0.14 mg; YA ¥) sodium was dissolved h; The mixture was diluted in cooled YE solution. after ae pyridine-HF (Je Y)

MgSO, and extracted by (¥ times) 4. Each extract was dried using hydroxide and filtered before being combined and concentrated to give a residue which was purified by chromatography (mg; YAY) to give ethyl acetate at +7. 0 triethylamine column (5:02); And rinsing with 0 of the title compound. (66

LCMS (PS-B3) Ry 3.34 min [11-7]" 266. 'H NMR (DMSO-d) & 3.41 (2H, , has 7.39-7.46 (8H, m).

189 - - 2-(4-Chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (=) 2,2- reacted Bis-(4-chloro-phenyl)-2-fluoro-ethylamine with : 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Following the procedure in Example 1 except that heating was carried out at 0°C for © minutes using a CEM microwave of 0 Ya Watt power to obtain the title compound. LCMS (PS-B4) R, 6.69 min [M-F]" 296 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d). 4.04 'H NMR (Me-d3-OD) Example 67 3-(3,4-Dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3 -yl] -propylamine Cl cl NH, >< No / 72 N-N H \' following the procedure described in Example 260 but substituting 6-chloro-nicotinotrile by 3-methyl-1-trityl -1H-pyrazole-4-boronic acid la) 6-chloro-pyridine-3-carbaldehyde by 1-trityl-1H-pyrazole-4-boronic acid » and following the procedure explained in Example No. A, it was possible to obtain Title composite.

Vag - - Example No. 67 2-(4-Chloro-3-fluoro-phenyl)-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethylamine J / 7 N-N H by following the procedure described in Example AV, but by substituting: 4-0xo0-piperidine-1-carboxylic acid tert-butyl ester © by: (2-oxo-ethyl)-carbamic acid tert -butyl ester The title compound was obtained. Jha No. 14 2-(3,4-Dichloro-phenyl)-2-[4(1 H-pyrazol-4-yl)-phenyl]-ethylamine xX Cl KS NH, J 7 N-N H by following the procedure explained in example number ?" but in example (vy b) by substituting chlorobenzene 0 by Say 1,2-dichloro-benzene to obtain the title compound .en: doors

- COA - Example No. {2-(3-Chloro-4-methoxy-phenyl)-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethyl }-methyl-amine" 9

Cl 75 i©

N-N

H

2-chloroanisole b)YY) but in step FY No. Jud following the procedure described in ; The title compound. chlorobenzene was obtained by LC/MS: (PS-A2) R; 2.03 [M+H]" 342. "HNMR (Me-d5-OD) & 2.45 (3H, s), 3.22 (2H, d), 3.85 (3H, 5), 4.15 (1H, 1), 7.04 (1H) , d), 7.33 (1H, d), 7.27-7.34 (3H, m), 7.55 (2H, d), 7.92 (2H, s). 1 Example No. 3-(3-Chloro-4-methoxy-phenyl)-3-[4-(1 H-pyrazol-4-yl)-phenyl]-propylamine 01 1 be cl 7 NH 2 7 /

N-N

H

Yen

van - - following the procedure described in Example 161 but substituting imidazole by potassium phthalimide in step chlorobenzene als (n V) by 1-chloro-2-methoxy-benzene In step (\1) 'Xie, the removal of the phthalolyl protecting group under conditions ddl in Examples No. (ZA) 5 (RAE) the title compound can be prepared. oe Example No. TY -) 3-Chloro-4-methoxy-phenyl)-3- [4-(1H-pyrazol-4-yl)-phenyl] -propyl}-methyl-amine 3{ 0 NH Cl / 7 N-N H, following the procedure explained in Example No. (1), but by replacing imidazole by amine methyl in Example No. (i 1) and replacing chlorobenzene by: -- 1 In Example No. (\1<() » the title compound can be obtained. Example No. TA C-(4-Chloro-phenyl)-C-[4-(1 H-pyrazol-4-yl)- phenyl]-methylamine

- 1 and 7 -

Ci

H, 7 /

N-N

H

: But by substituting 1 by following the procedure explained in Example No. : by means of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride it is possible to obtain the compound of the title ¢ C,C-bis-(4-chloro-phenyl )-methylamine 19 Example number oo {2-(4-Chloro-phenyl)-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine : ( 179) 2-(4-Chloro-phenyl)-N-methyl-2-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]- acetamide

Ci 0 © 0 0.014 NHMe 8

NHMe A© + 7©

T r 77 7

ClN-N

Tr

Yen

- 18 carboxylic acid by the reaction of 2,2-Bis-(4-chloro-phenyl)-N-methyl-acetamide, then prepared using the method of Example No. (11a). The commercially available analogue amine methyl with .1 was then converted to the title compound by the example method No. N-methyl-acetamide compound | .LCMS (PS-B3) R 4.21 min; m/z [M+H]" 582 : B 14 ) ° 2-(4-Chloro-phenyl)-N-methyl-2-[4-(3-methyl-1 H-pyrazol-4-yl) -phenyl]-acetamide

Cl 0 Cl 0 0

NHMe NHMe 0 4 . N-N-

Tr H The protected trimethyl compound of Example (119) has been removed by the method described in Example LCMS (PS-B3) Rt 2.41 min; m/z [M+H]" 340 (+31) to give the title compound. ‎ 'H NMR (methanol-ds) 3 2.40 (3H, 5), 2.78 (3H, 5), 4.95 (1H, 5), 7.29-7.34 (6H, m), 741". (2H, d), 7.69 (1H, 5).: (c 14 ) {2-(4-Chloro-phenyl)-2-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl- amine

YY $1

vad - - Ci 0 Cl 0 "m NHMe _ oO . 0 NN H Following the procedure described in Example No. ( + WY ) gave the title compound. LCMS (PS-B3) Rt 2.80 min;m/z [M+H]" 326. IH NMR (methanods) 5 2.52 3H, 5), 2.75 (3H, 5), 3.80 (2H, d), 4.46 (1H, 1), 7.41 (4H, 5), (2H, d), 7.54 (2H, d), 8.24 (1H, 5). 5 7.49 Bioactivity Je No. Ve Measurement of the inhibitory activity of the kinase (ICso) PKA The compounds of the invention can be tested for the inhibitory activity of PK using the PKA catalytic domain from sassll PKA dasa (peptides Upstate Biotechnology) # 14-440)) 0 Constructivism? (GRT GRRNSI) also from (#12-257) (Upstate Biotechnology) As base material 0 1 nanomolar Sled SA enzyme is used in a buffer containing 10 mM MOPS pH VY pH £05 μm 3310m ATP/ 5 μmolar substrate The compounds in dimethylsulphoxide (DMSO) solution are added to a final DMSO concentration of JY.0 1 The reaction is allowed to continue for 0 Minutes before adding orthophosphoric acid to extinguish the disease

.for the activity. Unincorporated 830-817 of the treated phosphorylated proteins are then separated onto Millipore MAPH Jue filter plates; A scintillator is added and the plates are then subjected to a Packard 10001 count The percentage of PKA inhibition is calculated and plotted to determine the concentration of test compound required for 0 75 inhibition of PKA activity (16.0. Example compounds have OY EEA, EV ET 805 EE EV 5 Ey) 00.08 or later or not. Aha) © nor and 6 values of p1 are less than micromolar VO. Example No. VA Measuring the inhibitory activity of PKB kinase (ICsp) 0 Inhibition of protein kinase 8 (PKB) activity can be determined primarily by compounds as described by (1999) 5061-5072 al.

Cell.

Biol.

Andjelkovic using a fusion protein annotated as PKB-PIF and further described by Yang et al (Nature Structural Biology 9, 940 - 944 (2002)) The protein is purified and activated by PDKI as described by Yang. The peptide (H-A-R-K-R-E-R-T-Y-8'-F-G-H A - OH) 10 - 11 - 2121208-27 obtained from Calbiochem (#123900) is used as a substrate. A buffer that includes 01 millimeter MOPS, pH No, 17 micromolar 707-77 ATP/ and 07 micromolar base material 0. The compounds are added in a (DMSO) dimethylsulphoxide solution to concentrate Final DMSO 77.5 The reaction is allowed to continue for 010 minutes before adding orthophosphoric acid to increase 0 quenching activity The reaction mixture is transferred to a filter plate Cus phosphocellulose binds peptide vm

Y 0 \ _— — : The unused ATP 0 was removed after washing PO addition of scintillation and measurement of combined activity by scintillation counting. The percentage inhibition of PKA activity is calculated and plotted in order to determine the concentration of test compound required for Zo inhibition of PKB activity (MnMn). oo following the method explained before; It was found that the values of 10 for the compounds of examples 1 and ; 8-10 17 01 1 10 0 7-7 9 ?- and £1 wa ot, oY—£9 e 4 09 10 17 s VI, VA and no VA and e ALS ATS, 50, 91, 34, and 10 are less than 1 micromolar while the example compounds EA, 60 TR YY YEA 5 05 T,Y VO 5 1, and OF have .p values less than 1 micromolar; The compounds of Examples 6 and 1 each have pf Ves 0 p1 less than 50 micromolar.

Pharmaceutical formulations

Example number VY

(1) Tablet format

A tablet composition containing a compound of formula ( ) is prepared by mixing 50 mg of compound 10 with VAY mg of lactose (BP) as a diluent; And 7 mg of magnesium stearates as a substance

Slide and press to form a disc in a known way.

(7) Capsule formulation

A capsule formulation is prepared by mixing 100 mg of compound (0) with Yoo mg

6 And fill the resulting mixture in standard opaque hard gelatin capsules.

Lap

- 7.7 - : (7) INJECTION FORMULATION I A non-enteric formulation for parenteral administration may be prepared by dissolving the compound of Formula (0 (eg as salt) in water containing had propylene glycol 701 active compound concentration JAN: by weight. The solution is then sterilized by filtration; filled in an ampoule and sealed Agile 0 (£) Injection formulation [1] A non-enteric formulation for injection is prepared by dissolving the compound of Formula (D) in water (¥ mg/mL) (at eg in salt form) 00 (5) mg/mannitol (Jo); sterilize the solution by filtering and filling in 1 ml showerable vials or ampoules. A compound of formula ( ) with pharmaceutical grade corn oil to give a concentration of © mg/mL The composition is sterilized and packed in suitable packaging Equivalents The foregoing examples are provided for the purpose of illustrating the invention and should not be construed as imposing any kind of limitation on the scope of the invention. It is readily apparent that numerous modifications and alterations can be made to the specific embodiments of the invention previously explained and illustrated in the Examples without departing from the principles illustrated by the invention.All such modifications and alterations are intended to be included by this application. z 77

Claims (1)

blood - claimants 1 -1 compound of formula (0: rR RM-AN ts te rR' N—N H 0 or salt; or soluble or tautomer or N-oxide thereof, wherein the RUANRIR? part of the compound is represented by the formula R'-(G)(CHy)m-W-Op-© rts-b )., (from) where 6 is 1017, NMe, or ©0; W 1 is connected to group B and selected from CHyNs (CH-CRY and 00(0117); b VY is zero or 1 and g is zero or 1 k is zero or A A and “ is zero or 1 and “ is zero or 1 or 1 or 1 and m 1 is zero or 1; and the sum of kb is zero or 1; the sum of Kj 01 and “m” is not more than ;; 8 and 87 are identical or different and are chosen from ethyl 5 methyl “ 1 or form 085987 cyclopropyl ic sane ¢ and R¥ is chosen from methyl 5 hydrogen , hydroxy s VY and 1006 . 1" and BE is a monocyclic aryl or heterocyclic aryl group chosen from pyridine 5 » pyrimidines ¢ furan s « thiophene s ¢ phenyl Sle gana Ve as each of them may be unsubstituted or have a substitution with up to four substituent groups “i” and R® is selected from chlorine s hydroxy and cyano s trifluoromethyl bromine leben Lu hydrocarbyl Cia hydrocarbyloxy VY optional substitution by yer alkoxy or hydroxyl YA ¢ lap mola 48 l is an aryl or aryl heterocyclic group selected from phenyl » 1 pyridine + pyrimidine 5 « furan ¢ thienyls 0 ; Cua that an aryl group or an aryl non-TY homolog may have no substitution or may bear one or more substituent groups of YY chosen from: hydroxy 0 YY ; Cj4acyloxy e Y¢ fluorine Yo chlorine » YA ¢ bromine e AR ¢ trifluoromethyl e0 YA ¢ cyano 0 1 ¢ 0 ve. P nitro e ¢ hydrocarbyl Ci4s hydrocarbyloxy Cis oe vy each le .has an optional substitution vy by alkoxy Cz or carboxy. or hydroxy ¢ Ye ® ben acylamino ¢ Yeo b benzoylamino ¢ pyrrolidinocarbonyl » 1 ¢ piperidinocarbonyl vv ¢ morpholinocarbonyl e YA ¢ piperazinocarbonyl e va ¢ 2 e heterocyclic aryl and aryloxy heterocyclic groups with five and six atoms 3 contains on one or two heteroatoms selected from 17, 0, and 6; 9774 C 72 ¢ phenyl eo l alkyl eo A pr©-general; ¢ phenyl-C;.4 alkoxy 0 ¢¢ ¢ heteroaryl-C.4 alkyl »0 to heteroaryl-C4 alkoxy 0 2 ¢ f ¢ phenoxy 0 f : where both groups of EA heteroaryl, heteroaryloxy, phenyl, alkyl, phenyl-C,.4 alkoxy, £4 heteroaryl-C 4 alkyl, heteroaryl-C1.4 alkoxy and phenoxy , or : or? Selected substitution set of 1 Optional substitution by Le 0) acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, CONH,3, Ci » of B hydrocarbyloxy and Ci hydrocarbyl , of which JS oF has an optionally substitution by hydroxy methoxy . 00 182 and 83 are each selected separately from: ¢thydrogen, hydrocarbyl ring and C4 acyl 5 RY ov is selected from hydrocarbyl Css « halogens 1 hydrogen saturated and saturated hydrocarbyloxy© A ¢CF39 + cyano s and 8e can be selected from hydrogen “, halogen, hydrocarbyl Cis saturated, or hydrocarbyloxy Cis 0 saturated; Omson a CONH, a CF; CONHR® R NH, or 10110083 J 1) 1 RT 7 is a group “18 or 1 (CH) where R* is a monocyclic or a bicyclic group” + _ can be a carbocyclic or heterocyclic; 4 and can be in the carbonaceous group or the heterocyclic group 87 $n lap - “7.1 8 Optional substitution with one or more substitution combinations to be selected from: halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-Ci.4 A hydrocarbylamino; Ww 0, CO, XCD), “incorporating X'CEIX, 8, SO, “abd, in R® Cua 82-8” or group 4 and being in groups hydrogen of R® or ,01:*50; “SO, NRE, SONRE 4 Cig heterocyclic is chosen between ? and 71 atoms per ring; and is in group Vv. : optional substitution with one or more substituent groups chosen from hydrocarbyl 1 L hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-Ci.4 L hydrocarbylamino, VE, carbonic cyclic groups and heterocyclic groups with a range of? 71 Vo atoms in the ring; and where S, SO, SO; NRE, XCF), COAX Pal , 0 i.e. light 1. The position of one or more carbon atoms in ic sane is hydrocarbyl ¢ RC vv is selected from hydrogen and hydrocarbyl lint; and aX sNRC JS JO aX VA MR QOT =NRC J phenyl is an E group compound of claim (1); where is =F) A compounded according to either claim (1); or (7); where group -*1 and group 56 are connected to group 5 with a relative meta or para directive; That is, the ¥ E group is not connected to the atoms of the adjacent ring of the pyrazole group and the AF group 1 ;- is compounded according to any of the foregoing claims wherein group 5 has a number from zero 1" to ? a substitutive group. The first 1*- lida compound of either claim (1) » where group E contains a number from “0 to 1” substitution group. 1 >> compound according to claim (8) or (©), where 5 is unsubstituted. RY z R® / N—N Iv) 1 3 where 2 is zero, 1, or oY and RY is chosen from methyl s hydrogen fluorine s hydroxy ¢ ; provided that when #2 is yellow; is not hydroxy R?.mA) is a compound of claim (7); where !8 is an unsubstituted phenyl or has a substitution as defined in Claim 1(1). bromine;trifluoromethyl;cyano;bromine hydroxy;hydrocarbyloxy and C4 hydrocarbyl ¢ lap —_— 7 0 A — © has an optional substitution by hydroxy alkoxy Cia ; aryl groups of hetero-1 have five atoms containing one or two hetero-atoms selected from 17, 0, and 8; Y where the heterocyclic aryl groups are optionally substituted by one or more alkyl-substituted A groups of . -1-01 Composite of claim (3) where 8 !8 is unsubstituted or is substitutable by a number of up to © selected substitution combinations of: hydroxy, acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, Cia ¥ hydrocarbyloxy and hydrocarbyl: . of alkoxy or hydroxy has an optional substitution of © -11-1 is compounded pursuant to claim (3) or claim (10); where 8 is unsubstituted or is substituted by 0 or 1 or ? or ? or ; substitution groups. (IY) Composite of claim (11); where !8 is unsubstituted or has Y substituted by zero, 1, ¥, or 7 substitution combinations of 0 -17 1 is a composite of claim (VY) where !8 is unsubstituted or has Y substituted by a zero, 1, or ? replacement groups. 8 to (07) where group (11) includes a compound according to any of the claims from 14-1: one or two selected substituent groups of Y.fluorine, chlorine, trifluoromethyl, methyl and methoxy Y The - 72.8! — : where 8 is a combination o£) is a compound of claim -10#1 mono-chlorophenyl or dichlorophenyl Y .1 -1 ll compound of any of the ALL claims where rR? is chosen from hydrogen and .methyl Y¥ : where 85 are selected from dill) compound according to any of the claims - 117 1 hydrogen, fluorine, chlorine, bromine, methyl, ethyl, hydroxyethyl, methoxymethyl, Y cyano, CFs, NH,, NHCOR® and NHCONHR™ ¥ is optionally substituted by: benzyl or phenyl is RY; . where they are hydroxy, per-acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, bitter 8 hydrocarbyloxy and rang hydrocarbyl 1 . hydroxy sl Crp alkoxy having an optionally substituted by V 82 compounded according to any of the preceding claims; Where VA .methyl and hydrogen are independently chosen from RP, 1 hydrogen both 182 and 83 are Cum;(18) a compound of claim 111 Nou having a molecular weight less than did) of any of the claims lh compound 1-701 compounded according to claim (107); Where the molecular weight is less than 15 d.‎ -11 1 l 1. A compound of formula (1) chosen from the group consisting of: -”71 1 2-phenyl-2-[4-(1H-pyrazol-4 -yl)-pheny!]-ethylamine; Y 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl] -2-phenyl-ethylamine; ¥ 2-(4-chloro-phenyl)-2-[4-(1H-pyrazo 1-4-yl)-phenyl]-ethylamine; : 3-phenyl-2-[3-(1H-pyrazol-4-yl) -phenyl]-propylamine; ° 3-phenyl-2-[4-(1H-pyrazol-4 -yl)-phenyl]-propylamine; 1 {3-(4-chloro-phenyl)-3-{4-(1H-pyrazo 1-4-y1)-phenyl]-propyl} -methyl-amine; 7 {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl }-methyl-amine; A {3-(3-chloro-phenyl)-3-{4-(1H-pyrazo 1-4-y1)-phenyl]-propyl}-methyl-amine; 1 3-(4-chloro-phenyl)-3-[4-(1H-pyrazo 1-4-yl)-phenyl]-propylamine; Ve 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 1 dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine; VY {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -dimethyl-amine; B {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine; Vi {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine (R); Ve {2-(4-chloro-phenyl)-2-[4-(1H-pyrazo 1-4-yl)-phenyl]-ethyl}-methyl-amine (S); 1 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-amine; VY dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl }-amine; YA {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl }-dimethyl-amine; V4 {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; ve. 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R); 7 ie - 11 - 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S); vy {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -methyl-amine; vy (2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl} -ethyl-amine; vi methyl-{2-(4-phenoxy-phenyl) -2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethyl} -amine;ve {2-(4-methoxy-phenyl)-2-[4-(1 H-pyrazol-4-) yl)-phenyl]-ethyl} -methyl-amine; phenylj-ethyl}- TY amine; YA methyl- {2-phenoxy-2-[4-(1 H-pyrazol-4-yl)-phenyl]-ethyl} -amine; v4 2-{(4-chloro-phenyl) )-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine; ve.methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazo 1-4-) y1)-phenyl]-propyl ( -amine; 9 {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazo 1-4-y1)-phenyl]-propyl }-methyl-amine; vy 3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; | 7" {3-(3-chloro-phenoxy)-3-[4-( 1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;vi methyl-{2-phenyl-2-[6-(1H-pyrazol-4-yl)-pyridin-3-yl}- ethyl} -amine; Yo {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl) -phenyl]-ethyl}-methyl-amine; va {2-(3-chloro) -phenyl)-2-[4-(1H-pyrazo [-4-yl)-phenyl]-ethyl }-methyl-amine; vv {2-(3-chloro-phenoxy)-2-[4-(1H-pyrazo I-4-y1)-phenyl]-ethyl}-methyl-amine; FA {2-(4-chloro-phenyl)-2-[4-(1H-pyrazo 1-4-yl)-phenyl]-ethyl }-cycl opropylmethyl- v4 amine; te methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-amine; 23 4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl} -phenol; ey YY en - 1017 - 3-(4-methoxy-phenyl)-3-[4- (1H-pyrazol-4-yl)-phenyl] -propylamine; ty {2-(4-chloro _sheny) -2-[4-(1H-pyrazol-4 -yl)-phenyl]-propyl} -methyl-amine; te 1 _(4-chloro-phenyl)-2-methylamino- 1-[4-(1H-pyrazol-4-yl)-phenyl] -ethanol; te 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl] -ethanol; 3 3-(3-chloro-phenyl)-3- [4-(1H-pyrazol-4-yl)-phenyl] -propylamine; 3 2-methylamino-1 -(4-nitro-phenyl)- 1-[4-(1H-pyrazol-4-yl)-phenyl] -ethanol; EA 2-(3-chloro-4 -methoxy-phenyl)-2-[4-(1H-pyrazo 1-4-y1)-phenyl]-ethylamine; £4 2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl] -ethylamine; or 3-(3,4-dichloro-phenyl)-3-[6- (1H-pyrazol-4-yl)-pyridin-3 -yl]-propylamine; 2 2-(4-chloro-3-fluoro-phenyl)-2-[4 -(1H-pyrazol-4-yl)-phenyl] -ethylamine; oY 2-(3,4-dichloro-phenyl)-2- [4-(1H-pyrazol-4-yl)-phenyl] -ethylamine; oY {2-(3-chloro-4 -methoxy-phenyl)-2-[{4-(1H-pyrazol-4-yl)-phenyl] -ethyl}-methyl- ot amine; oo 3-(3-chloro-4 -methoxy-phenyl)-3-[4-(1H-pyrazo 1-4-yl)-phenyl]-propylamine; on {3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl} -methyl- ad amine; oA and 81 -)4-3110:0- (-0-4 -(1H-pyrazol -4-y1)-phenyl]-methylamine; Te, of which N., salts, solutes, compounds and oxides 71 - Y\Y - Jie solve?? - compounded according to any of the preceding claims in the form of a salt; or soluble 1 N-oxide, 1, or hydrate Y 1 74- Lida compound to any of the claims (1) to (TT) as it is used to manufacture a drug protein B kinase for the prevention or treatment of a disease or condition in which enzyme Y contributes 1©?- use of a compound as defined in any of the claims (1) to (YT) in the manufacture of el XY for the prevention or treatment of a disease condition or Alls led to coenzyme B ibs dlkinase -71-1 Use of a compound as defined in any of Claims (1) to (YY) in the manufacture of Y a drug for the prevention or treatment of a disease or dlls involving or Lan on cellular growth non"normal" in WA decompensated organism by inhibiting PKB activity 1 77- Use of a compound as defined in any of the claims (1) to (YY) in the manufacture of a drug to inhibit protein kinase B 1 78- Use of a compound as defined in any From protective agents (1) to (YY) in the manufacture of Y drug to modify cellular Adee by inhibiting the activity of proteinase B kinase 1? 7- Using a compound as defined in any of Protectants (1) to (YF) in the manufacture of ?_a drug for the treatment of an immune disorder in a mammal by inhibiting the activity of PKB 6 the 1 - - -*01 1 lida compound for any of the protective elements (1) to (YT) for use in the prevention or treatment of a diseased condition or Als contributes Leb kinase enzyme Protease M. -©1 1 Use of a compound according to any of the claims (1) to (77) for the manufacture of a drug + in Y the manufacture of a drug for the prevention or treatment of a disease or Alla contributes an enzyme A ibs kinase 1 7©#- the use of a compound of formula (1) according to any of claims (1) to (YF) for the manufacture of “a drug for the prevention or treatment of a disease or condition arising from abnormal growth 1*7 The use of a compound of formula ( ) according to any of Claims (1) to (17) for the manufacture of Y a drug for the prevention or treatment of a disease caused by a disorder in cell proliferation, cell death, or Y Marking cells of.—¥E 1 Use a compound pursuant to any of claims (1) to (YF) to manufacture a drug for the treatment of pay VY or a condition involving or Lan about abnormal growth of cells in GIS Mammals, by ¥ by inhibiting PKB 1 ** - using the lid compound of any of the protective elements (1) to (YY) to manufacture a drug to inhibit the "protein kinase A" enzyme ©1-1 Use of a compound according to any of claims (1) to (17) for the manufacture of a drug to modify a cellular process Y by inhibiting the activity of protein kinase A X \ o — — 1 7©- use of a compound pursuant to any of the claims (1) to (TF) for the manufacture of a drug for the treatment of “1” an immune disorder in an additive organism. 1 - The use of a compound according to any of the claims (1 to Y) °) to manufacture a drug to cause cellular death in cancer cells. SFE is a pharmaceutical composition that includes a new compound according to any of the claims (1) to (YF) Y and a pharmaceutically acceptable carrier. 1 46- A compound of according to any of the claims (1) to (17) for therapeutic use. for any of the claims Y (\ ) to 9a ( ¢ wherein the process includes: “( ) reaction of a compound of formula (X) with a compound of formula (XT) or a fermented derivative at the N ¢ terminus of which: R 7 A —N He R® C 7 3 EN / ° N—N H XD) ® * > where A is 8 nor to 87 as given in any of protection elements (dd) and one of the groups X and 7 is chosen from: chlorine, bromine, iodine and trifluoromethanesulphonate, and (saa) the other 4 YX groups are a building block for boronate ester or boronic acid; In the presence of 0 palladium catalyst and base; And 1171 - - 11 (b) and) reductive amination of a compound with the formula (70471)l): 1 pCO 5 4 E SS R® VY / N— N H (XXXVI) 0 using HNR'R? in the presence of a reducing agent ¢ and optionally + (c) converting a compound of formula ( ) to another of formula (0.—£Y 1 Process of claim (£1) option (a) in which a compound of formula 00 Y is prepared by the reaction of a compound of formula 300.]: 0 HO. _N_ 3 nl v X (LXX) ¢ with a compound of formula RYH under Friedel Crafts alkylation conditions, for example, in the presence of aluminum halide. Except 7