TWI363622B - Pharmaceutical compounds - Google Patents

Description

1363622 IX. Description of the invention: [Technical field to which the invention pertains] 4 The invention relates to pyrazole-containing-heteroaryl-alkylamines which inhibit or modulate the activity of protein kinase Β(ΡΚΒ) and protein kinase A (ΡΚΑ) The use of a compound, such a compound, for the treatment or prevention of a disease state or symptom mediated by PKB and PKA, and a novel compound having PKB and PKA inhibition or modulation activity. Pharmaceutical compositions containing such compounds, as well as novel chemical intermediates, are also provided.

[Prior Art] Protein kinases constitute structurally related enzymes of large ethnic groups, which are responsible for a variety of signal transduction processes in the control of cells (Hardie, G and Hanks, S_ (1995). //, University Press, San Diego, CA). These kinases can be classified into several groups (e.g., protein tyrosine, protein-serine/threonine, lipid, etc.) by their phosphorylation. Sequence hosts have been identified, which generally correspond to each of these kinase populations (eg ^ Hanks, SK, Hunter, 9: 576-596 (1995); Knighton # A, 253: 407-414 (1991); Hiles Et al., Ce//, 70: 419-429 (1992); Kunz et al., Ce//, 73: 585-596 (1993); Garcia-Bustos et al., ΜΒ ΜΒ 0 people 13 : 2352-2361 (1994) ). Protein kinases can be characterized by their regulatory mechanisms. Such mechanisms include, for example, self-phosphorylation 'transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. Individual protein kinases can be regulated by more than one mechanism. The kinase system regulates many by adding a phosphate group to the target protein.

102449 1363622

Different cellular processes, including but not limited to hyperplasia, differentiation, cells, weekly zero-activity, steep turn, and other process of sending messages. These constitutive brewing events act as "sub-open/break switches, which modulate or regulate the phosphorylation of proteins in the target protein organisms in response to a variety of extracellular messages (hormones, neurotransmitters, growth and Proliferation factors, etc., cell cycle events, environmental or nutritional stresses, etc. Appropriate protein kinases play a role in signaling pathways such as metabolic enzymes, regulatory proteins f, receptors, cellular bone pathway proteins, ion channels, or Activation or inactivation of chestnut or transcription factors (either directly or indirectly). Uncontrolled messages due to defective control of protein-glycation have been implicated in a variety of diseases including, for example, inflammation, cancer, allergic reactions/asthma , the immune system, the diseases and symptoms of the system, the diseases and symptoms of the central nervous system and angiogenesis.

Cellular zeroing or stylized cell death is an important physiological process that removes cells that are no longer needed by the organism. This process is important in early embryonic growth and development, allowing non-necrotic properties of cellular components to be controlled, removed and restored. The removal of cells by cell wilting is also important in the maintenance of chromosome and genome integrity in growing cell clusters. There are several known checkpoints in the cell growth cycle in which DNA damage = and genome integrity are carefully monitored. The response to the section of Burley at this checkpoint is to curb the life of such cells. If the injury or abnormality cannot be repaired, the damage is caused by the injury =: causing the cell to wither to prevent the spread of faults and errors. Cancer cells consistently contain many mutations, errors or rearrangements in their chromosomal DNA. It is generally believed that this occurs in part because most tumors are defective in one or more processes responsible for eliciting cell 102449 1363622 withering. Normal control mechanisms do not kill cancer cells, and chromosomal or DNA coding errors continue to spread. Therefore, it is an attractive way to treat cancer by assuring these pre-cell withering messages or suppressing unregulated survival messages. 3 There are enzymes, especially the signal transduction pathways of linaloinositol 3-kinase (PI3K), PDK1 and PKB, which have long been known to increase resistance in response to cell dying or survival in many cells. There is a large body of data showing that this pathway is an important survival pathway used by the growth factor to suppress cell dying. The enzyme PI3K is activated by a range of growth and survival factors, such as egf, PDGF, and through the production of polyphospholipids, inositol, triggering the activation of downstream signaling events, including kinases. 1) Activity of Rule 1 and protein kinase b (PKB), also known as. This is true in host tissues such as vascular endothelial cells and tumor formation. PKB is a protein ser/thr kinase, including a kinase functional site, and an N-terminal PH functional site and a c-terminal regulatory functional site. The enzyme PKB itself is flanked by PDK1 on Thr308 and has not been confirmed to date by Ser365. Complete activation requires phosphorylation at two locations, and requires the association between 1>11>3 and 1)11 functional sites for anchoring the enzyme to the cytoplasmic surface of the lipid cell membrane to provide The most suitable entry for the quality. The activated PKB in turn causes a range of receptor phosphorylation to contribute to overall survival response. Although we are not convinced that we understand all the factors responsible for the media PKB-dependent survival response, some important roles are the phosphorylation and inactivation of the cell-free factor BAD and caspase 9, Forkhead transcription factors such as The phosphorylation of FKHR leads to the exclusion of 102449 1363622 from the nucleus and the activation of the Nf/cB pathway by the phosphorus kinase in the cascade reaction of the upstream kinase. In addition to the anti-cell dying and pre-survival effects of the PKB pathway, this enzyme also plays an important role in promoting cell proliferation. This effect may once again be mediated by several actions, some of which are considered to be the phosphorylation and inactivation of the cyclin-dependent kinase inhibitor p2ieiP1/WAF1, and the phosphorylation and activation of mTOR In effect, the mTOR is a kinase that controls the number of cell growth.

The phosphatase PTEN, which dephosphorylates and inactivates the polyphosphatidylinositol, is a major tumor suppressor gene protein that normally regulates the PI3K/PKB survival pathway. The importance of the PI3K/PKB pathway in tumorigenesis can be judged by the observation that PTEN is one of the most common targets for mutations in human tumors, in which mutations in this phosphatase have been found in ~50% Or more melanoma (Guldberg et al., 1997, Cancer Research 57, 3660-3663) and developed prostate cancer (Caims et al, 1997, Cancer Research, 57, 4997). These observations and others indicate that a wide range of tumor types are dependent on increased PKB activity for growth and survival, and are therapeutically appropriate inhibitors of PKB. There are three closely related PKB isoforms, called alpha, and τ, whose genetic studies indicate different but overlapping functions. Evidence suggests that it can play a role in cancer independently. For example, the ΡΚΒ/5 line has been found to be overexpressed or activated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al., 1995, Int. J. Cancer 64, 280-285; Cheng et al., 1996, PNAS 93). , 3636-3641; Yuan et al., 2000, Oncogene 19, 2324-2330), PKB α is amplified in human stomach, 102449 -10· 1363622 prostate and breast cancer (Staal 1987, PNAS 84, 5034-5037; Sun Et al., 2001, Am. J. Pathol. 159, 431-437), and increased ΡΚΒ γ activity has been found in steroid-independent breast and prostate cell lines. 1999, J. Biol. Chem. 274, 21528-21532 ). The PKB pathway also functions in the growth and survival of normal tissues and can be regulated during normal physiology to control cellular and tissue function. Thus, conditions associated with undesired proliferation and survival of normal cells and tissues may also be therapeutically beneficial for treatment with PKB inhibitors. An example of such a condition is associated with long-term expansion and survival of cell clusters, resulting in an immune cell disorder that causes long-term or up-regulated immune responses, for example, for homologous antigens or growth factors (such as interleukin-2). Responding to 3 lymphocytes activates the H3K/PKB pathway and is responsible for maintaining the survival of antigen-specific lymphocyte clonal reproduction lines during the immune response. In cases where lymphocytes and other immune cells are responding to inappropriate autologous or foreign antigens, or where other abnormalities cause long-term activation, the Aβ pathway contributes to important survival messages, preventing cells that are clustered via activated cells. Zero to stop the normal mechanism of immune response. There is considerable evidence that lymphoid aggregates respond to the expansion of autoantigens in autoimmune symptoms such as multiple sclerosis and arthritis. • Lymphocyte clusters inappropriately respond to the expansion of foreign antigens, which are characteristic of another group of symptoms, such as allergic reactions and asthma. In summary, suppression of sputum can provide a beneficial treatment for immune disorders. It may serve as an example of inappropriate expansion, growth, proliferation, proliferation, and survival of normal cells of the role, including but not limited to atherosclerosis, cardiomyopathy, and glomerulonephritis. 102449 In addition to the growth of cells, it is controlled by the "U 〃 Bu, the function of the PKB pathway ... = glucose metabolism of the prime. From the lack of PKB ', Lu /, the old structure of the recombinant by ^ ^ ^ ^ (4) 指出 pointed this The effect is in the basin H,; | ° Therefore, the modulator of the activity of Qing can also be diseased in the disease and the dysfunction of energy storage / use of 'such as diabetes, metabolic diseases and obesity. The protein f kinase _) is a serine/threonine protein 1, which has a wide range of receptors for phosphorylation, and involves the regulation of s-cells including cell growth, cell differentiation, ion channel conductivity. , gene _ and neurotransmitter neurite outgrowth. In its inactive form, PKA 疋 王 enzyme is a tetramer containing two regulatory subunits and two catalytic subunits. PKA k is used as G_protein The media message transduction event is linked to the T4 that is regulated by the cell. The hormone ligand, such as the binding of the ascending A-glycan to the transmembrane receptor, activates the receptor-coupled G-protein (GTP- Binding and hydrolyzing proteins). During activation, G eggs The subunit of the mass will dissociate and bind to adenylate cyclase and activate it, which in turn converts from 1> to a cyclic-AMP (cAMPp, then, the thus prepared cAMp is bound to ρΚΑ Modulation of a subunit' leads to dissociation of the bound catalytic subunit. The catalytic subunit of ρΚΑ is inactive when bound to a regulatory subunit, becomes active upon dissociation, and participates in the phosphorylation of other regulatory proteins. 'The catalytic subunit of ΡΚΑ will phosphorylate the phosphonase kinase, which is involved in the phosphorylation of phosphorylase, which is a negative decomposing glycogen' to release glucose. Glycogen synthase 102449 12 1363622 is phosphorylated and deactivated to modulate the glucose content. Thus, a modulator of PKA activity (this modulator can increase or decrease the activity of hydrazine) can be used to treat or treat glucose metabolism and Energy storage disorders, such as diabetes, metabolic diseases and obesity.

Alfalfa has also been established as an acute inhibitor of sputum cell activation. Amdahl et al. have investigated the possible role of PKA type I in HIV-induced T cell dysfunction, with increased cAMP levels in T cells derived from HIV-infected patients, and inhibition of cAMP analogs over normal T The cells are more sensitive to the basis. From its research, it was concluded that increasing the activation of PKA type I can contribute to progressive T cell dysfunction in HIV infection, and therefore, PKA type I can be a potential target for immunomodulatory therapy - Aandahl, EM, Aukrust, P. , Skalhegg, BS, Muller, F., Froland, SS, HanssonV., Tasken, K. Protein kinase A type I antagonists restores T cells from HIV-infected patients with a thin response. /3⁄4from 5/ 12, 855- 862 (1998).

It has also been shown that mutations in the regulatory subunit of PKA can lead to hyperactivity in endocrine tissue. Due to the diversity and importance of PKA as a messenger in cell regulation, abnormal responses to cAMP can lead to a variety of human diseases, such as irregular cell growth and proliferation (Stratakis, CA; Cho-Chung, YS; protein kinase A and human disease). .7> Chau also Λ/βίαύ. 2002, 13, 50-52). Excessive performance of PKA has been found in a variety of human cancer cells, including those from ovarian, breast, and colon diseases. Therefore, inhibition of sputum is a way of cancer treatment (Li, Q.; Zhu, G-D.; ##/6# on the topic of the hall, 2002, 2, 939-971). For a review of the role of PKA in human disease, see, for example, protein 102449 1363622

Reduction of J rickets, edited by Constantine A. Stratakis, New York Academy of Sciences Yearbook, Vol. 968, 2002, ISBN 1-57331-412-9. Several classes of compounds have been disclosed as having PKA and PKB inhibitory activity. For example, an isoindolyl-continuous amino-diamine having PKB inhibitory activity is disclosed in WO 01/91754 (Yissum). WO 0/07996 (Chiron) reveals that the activity of estrogen receptor agonist is replaced by a beer. These compounds are described as being useful for the treatment or prevention of breast cancer, particularly estrogen-receptor-mediated. PKB inhibitory activity was not revealed. WO 00/31063 (Searle) discloses a substituted p-sit compound as a p38 kinase inhibitor. WO 01/32653 (Cephalon) reveals a p ratio. sit. A kinase inhibitor. WO 03/059884 (X-Mediators) discloses N-substituted pyridine compounds as modulators of nuclear receptors. WO 03/068230 (Pharmacia) discloses substituted p ketones as a p38 MAP kinase modulator. WO 00/66562 (Dr. Reddy Research Foundation) discloses a 1-phenyl substituted pyrazole for use as an anti-inflammatory agent. The 1-phenyl group is substituted by a sulfur-containing substituent such as a decylamine or a fluorenyl group. SUMMARY OF THE INVENTION The present invention provides a compound having protein kinase B (PKB) and protein A (PKA) inhibitory or modulating activity, and it is conceivable that it will be useful for preventing or treating a disease state mediated by PKB or PKA or symptom. In a first aspect, the invention provides a compound of formula (I): 102449 - 14 - 1363622

R2 R1—A—Ν’ E

Or a salt, solvate, tautomer or N-carbide thereof; wherein A is a saturated hydrocarbon linking group having 1 to 7 carbon atoms, and the linking group has a maximum bond length of 5 atoms and is extended to Between 2", and the maximum chain length is 4 atoms, extending between £ and 2, wherein the carbon atoms in the linking group are replaced by oxygen or nitrogen atoms; and the carbon atom of the linking group A Optionally having a substituent or a plurality of substituents selected from the group consisting of a keto group, a fluorine group and a thiol group, provided that when the base is present, it is not at the opposite end of the stone relative to the alpha position of the 2r3 group. The condition is that the backbone is present at a carbon atom relative to the alpha position of the group 2; Ε is a monocyclic or bicyclic carbon ring or heterocyclic group; R1 is aryl or hetero Aryl;

R2 and R3 are independently selected from the group consisting of hydrogen, Cl_4 hydrocarbon group and k-mercapto group, and the t-smoke group and the awake base group are optionally substituted by ~ one substituent, and the substituent is selected from the group consisting of fluorine 'hydroxy group, amine group, and A group. Aminodimethylamino and methoxy; (d) with W and the nitrogen atom to which they are attached to form a cyclic group selected from the group consisting of a salivary group and a saturated monocyclic heterocyclic group having 4-7 a ring member, and optionally a second hetero atom ring member selected from fluorene and N; or an atom of a group A of R2 and R3, and a nitrogen atom to which they are attached and one or more a saturated monocyclic heterocyclic group having 4 to 7 102449 -15 to 1363622 ring members, and optionally a second hetero atom ring member selected from 0 and ^; or NR2R3 and a linking group A carbon to which it is attached The atoms together form a cyano group; R4 is selected from the group consisting of hydrogen, halogen, Cl.5 saturated hydrocarbon group, Ci5 saturated hydrocarbon oxy group, cyano group and CF3; and R5 is selected from hydrogen, arginine, Cl_5 saturated hydrocarbon group, Ci5 saturated hydrocarbon group Oxyl, aryl, CONH2, C0NHR9, Cf3, _, NJJC0R9 or; R9 is a group R9a or (CH2)R9a 'where R9a is a monocyclic or bicyclic group' a carbocyclic or heterocyclic group; a carbocyclic group or a heterocyclic group R9a is optionally substituted by one or more substituents selected from the group consisting of _, hydroxy, trifluoromethyl, cyano, Nitro, thiol, amine, mono- or di-Ci 4 hydrocarbyl amine; group Ra_Rb, where Ra is a bond, 〇, co, xiqx2) ' (χχ2^1, xiqxqx1, s, so, S02 , NRC, s〇2NRc or NRCS02; and Rb is selected from hydrogen, a heterocyclic group having from 3 to 12 ring members, and optionally substituted by one or more substituents, a C-alkyl group substituent Selected from a hydroxyl group, a keto group, a dentate, a cyano group, a nitro group, a thiol group, an amine group, a mono- or di-Cl 4 alkyl group, a carbocyclic group and a heterocyclic group having 3 to 12 ring members. And wherein one or more carbon atoms of the Ci_8 hydrocarbon group are optionally replaced by hydrazine, S, SO, S02, NRC, X1 C(X2), C(X2)X! or βοχχ2): ^; c 4 hydrocarbon group; and X1 is 0, S or NRC, and X2 is =0, = s or = NRC. The invention also provides a compound of formula (la): 102449 -16- 1363622

Or a salt, solvate, tautomer or bucket oxide thereof; wherein A is a saturated hydrocarbon linking group having 1 to 7 carbon atoms, the linking group having a large bond length of 5 atoms 'extending to ri and Between nr2 r3, . and the maximum key

It is 4 atoms long and extends between 2 and 2, wherein one of the carbon atoms in the linking group may be replaced by an oxygen or nitrogen atom; and wherein the carbon atom of the linking group A may optionally have one or more substituents. , selected from the group consisting of keto, fluoro and hydroxy, the hydrazine hydroxy group, when present, is not at a carbon atom relative to the alpha position of the nr2R3 group, provided that the keto group, when present, is in a position relative to the ΝΚ2 R3 group. a carbon atom at the alpha position; Ε is a monocyclic or bicyclic carbon ring or heterocyclic group;

R1 is aryl or heteroaryl: __ is selected from hydrogen, Ci_4 hydrocarbyl and CM aryl; or 〃R and the nitrogen atom to which they are attached - form a saturated monocyclic group - 4_7 rings M, and as the case may include a hetero atom ring ring; or one of R2 and R3 and the other of them connected to the United States and the United States, according to the nitrogen atom and - or a plurality of atoms from the ~, ~ A, together Saturating a single ring member, and optionally a second heteroatom ring member selected from a (10) diradical group having a 4. 7 or NRW and a linking binder to which it is attached; destroying the atoms together to form a cyano group; 102449 -17- 1363622 R4 is selected from the group consisting of hydrogen, halogen, C! · 5 saturated hydrocarbon group, cyano group and cf3; and R5 is selected from the group consisting of wind, halogen, C丨·5 saturated hydrocarbon group, cyano group, c〇nh2, CONHR9, CF3, NH2. NHCOR9 or NHCONHR9; R9 is phenyl or benzyl', each optionally substituted by one or more substituents selected from the group consisting of dentate, hydroxy, trifluoromethyl, cyano, nitro, carboxyl, amine, single - or a di-Ch hydrocarbylamino group; a group Ra_Rb, wherein Ra is a bond, 〇, C0, X1C(X2), C(X2)X1, X1C(X2)X1, s, so, s〇2, NRC , SOaNRe or NRcS 〇2; and Rb is selected from hydrogen, has a heterocyclic group of 3 to 12 ring members, and a C!-s hydrocarbon group, optionally substituted by one or more substituents selected from a hydroxyl group, a keto group , dentate, cyano, nitro, carboxyl, amine, mono- or di-Cm hydrocarbyl amine, carbocyclic and heterocyclic groups, having from 3 to 12%, and wherein One or more carbon atoms may be replaced by hydrazine, S, SO, SO:, Cong, XiC (X2), financial bed or sputum; optionally selected from argon and Ci-4 hydrocarbon groups; and X1 is 0, S or NRC, and χ2 are =0, =^=NRC. Also available are compounds of general formula (lb): R2 R1—A—N | R3

Or a salt, solvate, tautomer or N·oxide thereof; & A is a saturated tobacco linkage having 3 to 7 carbonogens +, the linkage having a maximum chain length of 5 atoms, Extending between R1 and NR2R3, and the largest chain 102449 • 18-1363622 is 4 atoms long extending between E and NR2R3, wherein the carbon atom in the linking group is optionally replaced by an oxygen or nitrogen atom; and wherein the linking group The carbon atom of A may optionally have one or more substituents selected from the group consisting of fluorine and hydroxyl groups, provided that the hydroxyl group is not at a carbon atom relative to the NR: position of the NR 2 R 3 group; E is a monocyclic or bicyclic carbon a cyclo or heterocyclic group; R1 is aryl or heteroaryl; R2 and R3 are independently selected from hydrogen, Ci4 hydrocarbyl and Ci4; or R and R and the nitrogen to which they are attached Forming a saturated monocyclic heterocyclic group 'having 4-7 ring members, and optionally a second ring member selected from the group consisting of fluorene and N hetero atoms; or R2 and R3 - and the nitrogen atom to which they are attached and Or a plurality of atoms from the linking group A, a shaped hydrocarbon and a monocyclic heterocyclic group, having a ring member, and optionally a second one selected from the group The atomic ring member, or 々NRW, forms an aryl group with the carbon atom to which it is attached; R4 is selected from the group consisting of hydrogen, (4), Cl.5 saturated hydrocarbon group, cyano group and %; and R5 is selected from hydrogen, tooth , Cl_5 saturated hydrocarbon group, cyano 'c〇NH2, %, NH2, NHCOR9 or NHCONHR9; R9 is phenyl or aryl, each optionally substituted by - or a plurality of substituents selected from halogen, thiol, Trifluoromethyl, cyano, nitro, thiol, amine, mono- or di-Ch hydrocarbyl amine; group Ra_Rb, where Ra is a bond, 0, C0, XIC(X2), C(X2 X1, X1C(X2)X1, s, s〇, s〇2, NRc 'S〇2NRc or NRCS〇2; and Rb is selected from hydrogen, having a heterocyclic group of 3 to 12 ring members, and a hydrocarbyl group, optionally substituted with one or more substituents selected from the group consisting of a trans-group, a keto group, a halogen, a cyano group, a nitro group, an aryl group, an amine group, a 102449 • 19· 1363622 mono- or di-tetrahydrocarbyl amine a group, a carbocyclic group and a heterocyclic group having 3 to i2 % members, and wherein one or more carbon atoms of the c s hydrocarbon group may be optionally 〇, s, SO, S02, nrc, x!c ( X2), C(X2)X1 or X1C(X2)X1 permutation;

Rc is selected from the group consisting of hydrogen and (: diterpenoid; and X1 is 〇, S or NRC, and χ2 is =〇, =^^=NRC. The present invention further provides:

The compound of formula (II), (111), (IV), (V) itself, or any other subgroup or embodiment of formula (I) as defined herein. A compound of formula (I), (Ia), (Ib), (II), (III), (V), or any subgroup thereof, as used herein, for use in the prevention or treatment of a protein kinase B Disease state or symptoms. Formula (I), (Ia), (10), (Bei (10), (4), (7), or any subgroup thereof, for use in the manufacture of a medicament, for use in the prevention or treatment of a protein The disease state or symptom of the mediation of kinase B.

A method for preventing or treating 疾病 Α 縻 由 由 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质 蛋白质, (10), (ft), (Π), (ΠΙ), (IV), (V) a compound or any subgroup thereof. A method of treating a disease, a disease or a symptom comprising or derived from an abnormal cell growth or abnormally suppressing cell death, the method comprising administering the amount of the protein to the activity of the protein to inhibit the activity of the protein U > (Formula (1) ' (拗, (10), (Π), (111), (IV) ' (V) compound or any subgroup thereof. 102449 • 20- 1363622 • A method of inhibiting protein stimulation This method comprises contacting the kinase with a kinase inhibitory compound of formula (1), (10), (10), (n), (hi), (iv), (V), or any subgroup thereof, as defined herein. A method of cellular processes (e.g., cell division) by inhibiting the activity of a protein kinase oxime using a formula 1, (4), (10) shell, (III), (4) (7) or any subgroup thereof as defined herein. A compound of formula (1), (Ia), (10), (Π), (III), (IV), (V), or any subgroup or specific embodiment thereof, for use in the prevention or treatment by protein kinase A The disease state or symptom of the vector. • 2 (1), (Ia), (10), (II), (III), (IV), (V) compounds or any of them defined herein. Use of a group or a specific embodiment for the manufacture of a medicament for the prevention of sputum and therapeutic use of a disease state or symptom mediated by protein kinase A. A disease state or symptom which is prevented or treated by protein kinase A The method comprises the following formula (1), (Ia), (4), (9) (four) (four), (7) chemical substance or any subgroup or specific embodiment thereof for a patient in need of treatment thereof. A method comprising or derived from a coughing animal for abnormal cell growth or abnormal symptoms, the method comprising administering to the mammal an amount effective to inhibit protein kinase VIII activity, administering formula (I), as herein Ia), (Chemical, m, ..^ ( ) ( ) (11), (ΪΙΙ), (IV), (V) a compound or any subgroup or specific embodiment thereof. A method comprising the step of bringing the kinase to a compound of the formula (1), (13), yaw, (11), (111), (d), 102449 21 1363622, or any subgroup thereof Or a specific embodiment of a touch. A process of modulating cells (eg, fine The square of m, , . . . „ 丹 万 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋 疋Start your heart*

For example, the activity of protein kinase A is inhibited. The use of a formula (I), (Ia), (Ib), (π) 7 W (111), (IV), (V) sigma, or any subgroup thereof, as defined herein, for the manufacture of a medicament A disease state or symptom derived from abnormal cell growth that inhibits cell death. A method of treating a disease or condition comprising or derived from abnormal cell growth in a mammal, the method comprising the breastfeeding The animal is administered with the formula (I), (la), (lb), (id, he, , , J W (four), (IV), (7) as described herein in an effective amount to inhibit normal cell growth or abnormal suppression of cell death. a compound or any subgroup thereof - a method of reducing or reducing abnormal cell growth, including or derived from a mammal, "a method of abnormally suppressing the incidence of a disease or symptom of cell death, the method comprising: effectively inhibiting abnormality in the mammal The amount of cell growth is as shown in the formula 1, (Ia), (10), (9), (melon), (ιν), (V) compound or any subgroup thereof as defined herein. Defined novel formulas (1), (10), (10), (II), (111), (IV) (v) a compound or any subgroup thereof, and a pharmaceutically acceptable carrier. Formula (1), (Ia), (Out), (II), (III), (IV), (V) a compound or any subgroup thereof' for use in medicine. 102449 • 22- The use of formula (I), (Ia), (10), (9) (10) (4), (7) or any subgroup thereof as defined herein for the manufacture of a medicament, The agent is for the prevention or treatment of any of the disease states or symptoms disclosed herein. A method of treating or preventing any of the conditions or symptoms disclosed herein, the method comprising administering to a patient (eg, a patient in need thereof) Formula (I) '(Ia), (10), (11) '(10) (4) (7) a compound (eg, a therapeutically effective amount) or any subgroup thereof as defined herein. Method for reducing or decreasing the disease state or symptom rate disclosed herein Including a patient (eg, a patient in need thereof), such as: (I), (Ia), (Ib), (9) (10) (4), (7) a compound (eg, a therapeutically effective amount), or any subgroup thereof. Diagnosis and treatment of disease states or methods by protein kinase B, including (4) disease detection The second dose of the protein & μ 3 protein kinase B is determined to be a disease that is easily accepted by a patient with a resistance to 5; and (8) is indicative of a disease or symptom In the case, the patient is then administered the formula (I), (la), (lb), (π) or any subgroup thereof. ' U(7) is as defined herein (1), (Ia ), (ft), (II), (III), (IV), (ν) compounds or any subgroup thereof have been screened for u U(7) and have been tested... use 'this agent is in ^^^ Having or being at a disease or condition that is susceptible to treatment with a disease that is at risk of resisting protein kinases. For treating or preventing a disease state or condition 102449 • 23-

shape. • A method of diagnosing and treating a disease state or symptom by a protein kinase A, the method comprising: (1) screening the patient to determine whether the disease or condition the patient is or may have is readily acceptable to have resistance to the protein The compound of the kinase A activity is treated; and (8) in the case of a disease or symptom which is easily sensible to the patient, the patient is then administered formula (I), (la), (lb), (9) as defined herein, (III), (IV), (7) a compound or any subgroup or specific embodiment thereof. Use of a compound of formula (I), (la), (lb) '(II), (HI), (IV), (V) as defined herein, or any subgroup or embodiment thereof, in the manufacture of a medicament, The agent is used to treat or prevent a disease state in a patient who has been screened and has been determined to have or is at risk of being susceptible to a disease or condition treated with a compound that is resistant to protein kinase A activity. Or symptoms. The following general priorities and definitions will apply to the various groups a, e&r1 to R5 and R9, and any sub-definitions, subgroups or specific embodiments thereof, unless Additional instructions. Any reference to formula (I) herein will also be used to refer to any other subgroup of compounds of formula (Ia), (II), (III), (IV), (v), and formula 1, there is a need. And in addition to the reference to the "carbocyclic" and "heterocyclic" groups used herein, the context indicates otherwise, otherwise it will include both aromatic and non-aromatic ring systems, generally The group may be monocyclic or bicyclic, and may comprise eight q 102449 -24- 丄 363622 to 12 ring members, more usually 5 to 10 ring members. Examples of single cyclic groups are 3 with 3 , 4, 5, 6, 7 and 8 ring members 'more usually 3 to 7, and preferably 5 or 6: an example of a ring-based β-bicyclic group containing 9.8, I (ui And (10) % members' and more usually 9 or 10 ring members. A anti-chamber or heterocyclic group may be aryl or heteroaryl, having 5 to 2 = more usually 5 to 丨A ring member. As used herein, • aryl " a ke refers to a carbocyclic group with aromatic character, and the "heteroaryl" word

This is used to indicate a heterocyclic group having an aromatic character. "aryl" and "quote, the term & the term system includes a polycyclic (e.g., bicyclic) ring system in which one or the epoch ring is non-aromatic, each of which is θ s s , ( iv ) Aromatic. Such a plurality of groups may be linked by an aromatic ring or by a non-aromatic ring. A aryl 7 = group may be a monocyclic or bicyclic group ' and may be substituted with two or more substituents, for example - or a plurality of unsaturated ring systems of the group N as defined herein. The part is saturated with fully saturated carbon ring and heterocyclic partial saturated " surgery ▲ five 焱 s, 糸 糸 4 ·. "Unsaturated " and " I-saturated terms are rings in which the atoms of the ring are knotted, the sound g 匕 contains /, there is more than one valence bond, seven μ r a * force 丄 重 heavy bond 'for example C=C, c = r

Or N=C bond. The word "fully saturated" is the % of the C-C heavy bond. The saturated carbocyclic group includes ..., more ^n- -ia ^ T® -th The ring-shaped alkyl group defined below is a saturated slave. The group includes ring-like groups such as I 4 which are also 咕β 疋, such as cyclopentyl, cycloheptenyl and cyclooctenyl. Examples of pentene heteroaryl are monocyclic and crypto-like groups. The right ringer's and more usually five to ten Yanchang® each have five to twelve to ten. The heteroaryl group can be, for example, five members or 102449 -25· 1363622 six-membered single-ring ring, or A bicyclic structure formed by a fused five- and six-membered ring or two fused six-membered rings. Each ring may contain up to about four impurities I, typically selected from the group consisting of nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring system contains up to three heteroatoms, more typically up to two, such as a mono-heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the square ring may be (d), as in the case of (iv) or (iv), or substantially non-invariant, as in the case of (iv) or money. In general,

The number of basic nitrogen atoms present in the heteroaryl group, including any amine substituents of the ring, is less than five. Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazan, oxazole, diazole, oxatriazole, isoxazole, oxazole, isothiazole, pyrazole, triazole, and tetra Examples of the azole group, and the heteroaryl group include, but are not limited to, a H 4 p well, a mouth pyridine, and a triple tillage. The % heteroaryl group may be, for example, a group selected from the group consisting of:

a) %, fused to a 5- or 6-membered ring containing hydrazine, 2 or 3 ring heteroatoms; b) pyridine%, fused to a hydrazine containing 2 or 3 ring heteroatoms or & member ring; c) pyrimidine ring, fused to a ring containing a ring or a hetero atom of a ring or a ring of a member; d) a pyrrole ring fused to a ring containing 2 or 3 ring heteroatoms Or a 6-membered ring; e) a pyrazole ring fused to a 5 or 6-membered ring containing hydrazine or 2 ring heteroatoms; a carbazole ring fused to a heteroatom containing 1 or 2 rings Or a 6-membered ring; g) % azole, fused to a $ or 6-membered ring containing hydrazine or 2 ring heteroatoms; 102449 -26- 1363622 h) an iso-salt ring fused ring; 5- or 6-members of 1 or 2 doping atoms I) Soul-salt ring, fused to a right-handed 彳, 里 "13 3 with 1 or 2 ring heteroatoms 5 or 6-member Ring; J) ', sulfhydryl-salt ring, fused to a thiophene ring containing 7 formulas of 1 or 2 heteropolytoms containing 1 or 2% hetero atoms, fused to the right 丨1 +,μ 戸. There are 1 or 2 or 6-membered oxime rings of 1j2 or 3 doping atoms, fused to the ancient 々ο々, plus m to 3 丨, 2 or 3 ring heteroatoms 5 - or 6-membered soil, fused to a 5 or 6-membered ring containing 1 or 2 ring heteroatoms; ring-knitted to a member containing ... ring heteroatoms.) = ring, _ to a 5-p-P) cyclopentyl ring containing 1, 2 or 3 ring heteroatoms, fused to a S-containing, 2 or 3 doped heteroatoms of 5- or 6-membered soil. The ring is fused to the member; „5% of the bicyclic heteroaryl group, including but not limited to benzofuran, —, Λ thiophene, benzazole, benzoxazole, exemplified V Sitting on 'Benzene, Sawa, Benzene and different. Sitting on the (9) 哚, t well, -_„2丨& ® ^ ^ ^ Ή Ή heart, 嗓呤 (such as adenine, black sputum, benzo Dioxetol and ❹ (4) groups. Examples of bicyclic heteroaryls that do not fit the six-membered ring, including but, sulfur bites, bite, bite, etc., this open-oxan, (d), benzo, benzo (four), (four) ❹, 102449 • 27- x: J 〇 3622 喳 gas, oxazoline, porphyrin, sorghum, acridine and acridine ring.

Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring, including tetrahydronaphthalene, tetrahydroisoporphyrin, tetrahydroquinoline, dihydrobenzophenan, dihydro benzopyrene , 2,3-dihydro-benzo[1,4]dioxanthene, benzo[丨,3]dioxoxene, 4,5,6,7·tetrahydrobenzofuran, Hydroquinone and hydroquinone groups. Examples of the carbocyclic aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a tetrahydronaphthyl group. Examples of non-aromatic heterocyclic groups are those having from 3 to 12 ring members, more typically from 5 to 1 ring members. Such groups may be, for example, monocyclic or bicyclic, and typically have from 1 to 5 heteroatom ring members (more typically 丨, 2, 3 or 4 heteroatom ring members), usually selected from nitrogen, Oxygen and sulfur.

The hetero group may include, for example, a cyclic ether moiety (for example, in tetrahydrofuran and dioxane), a thioether moiety (for example, in tetrahydrothiophene and monothioguanidine), and a ring. An amine moiety (for example, in the case of tetrahydropyrrole t), a cyclic oxime (for example, in cyclobutane and cyclobutene), a cyclic sub-job, a cyclic (tetra)amine, and combinations thereof (for example, sulfur)代福福琳). Other examples of non-aromatic heterocyclic radical maps include cyclohexylamine moiety (e.g., in tetrahydropurine) and cyclic (iv) moiety (e.g., in vinegar). Examples of the early cyclic non-aromatic heterocyclic group include 5-, 6 and 7-membered monocyclic, azalea groups. Specific examples include whallin, thiofenofin and its s_ sulphides with s, s-dioxide (especially thiomorpholine), hexahydropyridine (eg hydrazine, hydropyridyl, 2-hexa) Hydropyridyl, 3·hexahydropyridyl and 'hexahydropyridyl), N•alkyl hexammine, such as N-decyl hexahydrofluorene. ,, hexahydrop 疋 E _ E9 hydrogen P ratio 嘻 (such as u four gas 咐〇 each base, 2-tetrazonia by Loki and 3 · tetranitropyrazine base), tetrahydro ton _, - nitrogen 圜a little whisper or he shouted 102449 -28· 1363622 )) hydrogen 11 pheno, dihydro sulphon, dihydrofuran, dihydropyrazole, tetrahydrofurfuryl thiophene, dioxere, tetrahydrogen Piperane (eg 4-tetrahydropyranyl), hydrogen meter sit, tetrahydroimidazolium, oxazolidine, p-serazoline, 2-dihydropyrazole, hydrogen sitting', hydropyrone, hexahydropyridyl Plowing, and N-alkyl hexahydropyrazine, such as N-methylhexahydrophyllin, N-ethylhexahydro-t and N-isopropyl hexahydropyrene. A subgroup of r·w-like non-aromatic heterocyclic groups includes morphine, hexahydroH疋 (eg, hexahydro ton, 2 hexahydro (tetra), 3 hexahydrocyl and xyli 0"Base), hexahydro__, tetrahydrogen (for example, i. tetrahydromanocyanine, tetrahydrocarbyl and 3-tetrahydropyrene; ^ or methane), - hydrogen,), four hearts Biluo Meng, (4) (2 o ° ° Nan... cardiac phenophene, dihydropiperidin, dihydrofuro read 'dihydroterpenoids, tetrahydrofuran, tetrahydrothiophene, di-mercapto), dihydro (tetra), four; ; four listening °_ such as 4 · four nitrogen 嚷 mouth than saliva, tetrahydro ^, (four) Lin, 嚷 琳 、, 2-dihydro.. Ρ, 虱 虱 哜 哜 、, hexahydropyrrolidine, and Ν-alkane丄, (4), such as Ν-methyl hexa- and Nn cyclo-groups including hexahydro... Nar, preferably non-aromatic hetero hexahydropyridinium and N-alkyl hexa n μ • Nitrogen tetramine, konfo The porphyrin and step specific examples are 2 wells. The addition of a non-aromatic heterocyclic group - 乂 疋 疋 is only a case of a nitrogen tetrazole, which is a part of the group of groups. - An example of a non-aromatic carbocyclic group of a non-aromatic heterocyclic group, including a pentyl group, such as a cyclic fluorenyl group: a dibasic fluorene: a ring "and a ruthenium." In this patent specification, the definitions of the surface and the heterocyclic group are visible as 102449 •29· 1363622. One or both of the following groups are excluded. Or any combination of any of: - a substituted or unsubstituted pyridone ring; - a substituted or unsubstituted pyrro[a]pyrimidin-4-one; - a substituted or unsubstituted p-beta Sit. Get the class.

When a carbocyclic or heterocyclic group is referred to herein, the carbocyclic or heterocyclic ring may be unsubstituted or substituted by a plurality of substituents, unless the context indicates otherwise. Substituted, the substituent is selected from the group consisting of a peptidin, a minus, a trimethyl, a cyano group, a nitro group, a (tetra), an amine group, a mono- or a di-CH-nicotinyl group, a carbocyclic group and a heterocyclic group having 3 Up to 12 rings M; group Ra_Rb, where is a bond, 0, C0, xlc(x2), c(x2)xl, χ1(:(χ2)χ1, s, 沁S〇2, er, SO dance or NRCS〇2, and the lanthanide is selected from the group consisting of hydrogen, a carbocyclic ring, having 3 to 12 ring members, and a Ci8 group, optionally substituted by a plurality of substituents. Hydroxy, keto, dentate, cyanonitro, sulfhydryl, amine, mono- or di-C stalk | • 4 4 amide, sigma and hetero

a group of 3 to 12 ring members, and one or more of the atomic groups of the sulfonium 8 hydrocarbon group may be 〇, s, SO, sa, (10) 2, NRC, XiC (x2), c ( X2 or xiqxqxi replacement; 1 ^

Re is selected from the group consisting of argon and Ci-4 hydrocarbon groups; and X1 is Ο, S or NRC, and χ2 is =〇, wherein the substituent R10 comprises or includes a carbocyclic or heterocyclic group, the carbon group or heterocyclic group The group may be unsubstituted, singing the substituent R1. Replace. In the subgroup of the compound of formula 1 which may be - or more than one, the box R1Q may comprise a carbocyclic or heterocyclic group circle which is typically not itself • 30-102449

Replaced in one step. In another subgroup of compounds of formula (I), the other substituents do not include a carbocyclic or heterocyclic group, but are otherwise selected from the groups listed above in the definition of R10. Substituent R10 can be selected such that it contains no more than 2 非 non-hydrogen atoms, such as no more than 15 non-hydrogen atoms, such as no more than 12 or 10 or 9 or 8 or 7 or 5 or 5 non-nitrogen atoms. In the case where the carbocyclic group and the heterocyclic group have a pair of substituents * on adjacent ring atoms, the two substituents may be bonded to form a cyclic group. For example, adjacent pairs of substituents on adjacent carbon atoms of the ring may be linked via one or more heteroatoms and optionally substituted alkyl groups to form fused oxygen, oxygen, gas - a nitrogen- or oxygen-nitrogen-ring group. Examples of such a linked substituent include: X] χ > χ > X) Η Χχ ϊ > Examples of the halogen substituent include fluorine, gas, bromine and iodine. Fluorine and gas are particularly good. In the definition of the compound of formula (I) above, and when used hereinafter, the term "hydrocarbyl" is a generic term encompassing aliphatic, alicyclic and aromatic groups having an all-carbon backbone, unless It is mentioned separately. In some cases, one or more carbon atoms, as defined herein to form a stone anti-primary bond, may be replaced by a designated atom or atomic group. Examples of the hydrocarbon group include an alkyl group, a cycloalkyl group, a cycloalkenyl group, a carbon oxime group, a dilute group, an alkynyl group, a cycloalkyl group, a ring-based group, and a carbocyclic aromatic group and an aral group. With an alkynyl group. Such a group may be unsubstituted or, where mentioned, may be taken by one or more substituents as defined herein. 102449 1363622 The following examples and preferences apply to the substituents of the formula 1 compound. Each of the hydrocarbyl substituents or nicotyl containing substituents referred to by t is defined differently unless otherwise indicated herein. By way of example, the 'hydrocarbyl group' may have up to eight carbon atoms unless otherwise required by the context. Have it! Within a hydrocarbon group of up to 8 carbon atoms, a specific example is a group such as a hydrocarbon group (e.g., q.sup.9 or a hydrazine group).

= The special case is selected from (^々, (^, ^ from (10) basis of any individual meaning or combination of meanings. ^ Network / letter cover direct bond and branch chain appearance base. Examples of appearance base including methyl , ethyl, stone | field f 4J · propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-decyl, 2'-pentyl, 3-decyl, 2-methyl Butyl, 3_f-butylhexyl and its isomers. In the alkyl subset with 丨 to 8 carbon atoms, the 'deuterium is a Cl.6 alkyl group, such as a Ch-based group (eg Cl_3) Or C! _ 2 alkyl) ^ Examples of the alkyl group are derived from cyclopropane, cyclobutane, cyclopentane, ring

Burned and % Genghu. Within a subset of the ring-like groups, the cycloalkyl group has from 3 to 8 carbon atoms, a specific example being. 3.6 cycloalkyl. Examples of bases include, but are not limited to, vinyl, 1-propion, 2-propenyl (salt), S-propyl, butylo-butyl, di-, di-, and dilute Within the subset of alkenyl groups, the alkenyl group has 2 to 8 carbon atoms, and a specific example is a C2·6 alkenyl group such as a C2-4 thin group. Examples of the alkenyl group include, but are not limited to, cyclopropenyl 'cyclobutanyl' cyclopentyl pentylene and cyclohexenyl. Within the subset of cycloalkenyl groups, the cycloalkenyl group has from 3 to 8 carbon atoms, and a specific example is a cycloalkenyl group. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl). Within the alkyne group having 2 to 8 carbon atoms, a specific example is a c26 alkynyl group such as a C2-4 alkynyl group. Examples of the carbocyclic aryl group include substituted and unsubstituted phenyl, fluorenyl, hydroquinone and anthracene groups. Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aryl-4-alkynyl groups include phenethyl, anthracenyl, styryl, phenylethynyl, ^ ring Hexyl decyl, cyclopentylmethyl 'cyclobutylmethyl, cyclopropylmethyl and cyclopentalenyl fluorenyl. When present, and where mentioned, the hydrocarbyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, keto, alkoxy, carboxy, halo, cyano, nitro, amine, Mono- or di-(hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 (typically from 3 to 1 〇' and more usually from 5 to 10) Preferred substituents include a hydroxyl group such as fluorine. Thus, for example, a substituted hydrocarbyl group can be a partially chaotic or fully gas-inducing group, such as a difluoroindenyl group or a trifluoromethyl group. In a specific embodiment, preferred substituents include a monocyclic carbocyclic group and a heterocyclic group having 3 to 7 ring members. 1 / μ π 你丁3 wishes 〇, s, so, S〇2 NR., Xlc(x2), c(x2)xUx1c(x2)x1 (or subgroup) substitutions, all as defined above, with the proviso that less than one carbon atom remains intact. For example, a hydrocarbon group (1) The atoms of the heart may be replaced by one of the listed atoms or groups, and the atomic groups of the substitution may be the same or different. In general, the linear or backbone being replaced · 102449 • 33 - 1363622 The number of atoms corresponds to the number of linear or main chain atoms in the group in which they are substituted. Examples of groups in which one or more carbon atoms of the hydrocarbon group have been replaced by a replacement atom or group as defined above, including ethers Classes and thioethers (c is replaced by hydrazine or s), guanamines, esters, thiolamines and thioesters (cc replaced by yqx2) or cxx^x1), terpenoids and axils (c Other examples of so or so2 substitutions, amines (c replaced by NRe) include ureas, carbonates, and urethanes (CCC is replaced by X1 c (x2 bait 1).

Where the amine group has two hydrocarbyl substituents, it may be bonded to the nitrogen atom to which they are attached, and optionally to another hetero atom such as a nitrogen, sulfur or oxygen chain to form 4 to 7 ring members. Ring structure.

"Ra-Rb" as used herein, whether it relates to a substituent present on a carbocyclic or heterocyclic moiety or to other positions present on a compound of formula (I) Substituents include, in particular, the following compounds, wherein the Ra is selected from a bond, 0, CO, 0C(0), SC(O), NRcC(0), OC(S), SC(S), NRCC(S) ), OC(NRc), SC(NRC), NRCC(NRC), C(0)0, C(0)S, C(0)NRc, C(S)0, C(S)S, C(S NRC, C(NRc)0, C(NRC)S, C(NRC)NRC, 0C(0)0, SC(0)0, NRcC(0)0, OC(S)0, SC(S)0 , NRcC(S)0 ' 0C(NRc)0, SC(NRc)0, NRcC(NRc)0, 0C(0)S, SC(0)S, NRcC(0)S, OC(S)S, SC (S)S, NRCC(S)S, OC(NRc)S, SC(NRC)S 'NRCC(NRC)S ' 0C(0)NRc ' SC(0)NRc ' NRcC(0)NRc > OC( S) NRc, SC(S)NRC 'NRCC(S)NRC, OC(NRc)NRc, SC(NRC)NRC, NRCC(NRCNRC, S, SO, S02, NRC, S02NRc&NRcS02, where Rc is as defined above Part of the group of insects is: _: base 溷, selected from 3 to 12 -34-102449 1363622 I: a member of the soil (3 to 1 〇 on the 35, and more usually 5 to (9) of the carbon ring With the morning knowledge group _8 basis, depending on the situation Substituted as defined above. Examples of hydrocarbyl, <cyclo and cyclohetero groups are as set forth above. R is 0' and ❼ is 烟基肖, R%Rb together form a nicotinicoxy group. Preferred hydrocarbyloxy groups include saturated hydrocarbyloxy groups such as alkoxy groups (e.g., Ci-6 alkoxy groups) are more typically Ci 4 alkoxy groups, such as ethoxy and methoxy groups, and A (tetra) is methoxy groups, Cyclooxyl (e.g., c3.w decyloxy, such as cyclopropyl, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy) and cycloalkylalkoxy (e.g., C3-6 cycloalkyl-Cl. 2 alkoxy, such as cyclopropylmethoxy) β-oxy, may be substituted by various substituents as defined herein. For example, an alkoxy group may be dentate (for example, in difluoromethoxy and trifluoromethoxy) In the base, hydroxyl (for example in hydroxyethoxy), C! 2 alkoxy (for example in methoxyethoxy), via. Substituted in a ethoxy group or a cyclic group (for example, a cyclononyl group or a non-aromatic heterocyclic group as defined above). Alkoxy group having a non-aromatic heterocyclic group as a substituent, An example of its appeal The family group is a saturated cyclic amine, such as ruthenium, hexachloropurine bite, tetrahydropyrrole, hexahydropyrrole, Ch-alkyl-hexahydropyrazine, cycloalkyl·hexahydropyrazine, four Hydroperidine or tetrahydrofuran' and the alkoxy group is aCh alkoxy group, more typically Cu is an alkoxy group, such as a methoxy group, an ethoxy group or a n-propoxy group. The alkoxy group may be substituted by, for example, a monocyclic group such as tetrahydropyrrole, hexahydropyridine, morpholine, and hexahydropyrrolidine, and a derivative thereof such as a time base, N_C1_4 thiol and N_CI' oxygen (iv). Specific examples include tetrahydropyrrolylethoxy hexahydroindole. Stationary ethoxy and hexahydropyridyl 102449 -35· 1363622 morphylethoxy. When the rule 3 is a bond 'and the oxime is a ^-8 hydrocarbon group, examples of the hydrocarbon group RLRb are as defined above. The hydrocarbon group may be a saturated group such as a cycloalkyl group and an alkyl group, and specific examples of such a group include a methyl group, an ethyl group, and a cyclopropyl group. Hydrocarbyl groups (e.g., pendant groups) can be substituted with various groups and atoms as defined herein. Examples of the substituted alkyl group include an alkyl group substituted with - or a plurality of groups, an atom such as A and chlorine (specific examples include bromoethyl 'chloroethyl, difluorodecyl, 2, 2, 2 - , · Trifluoroethyl ' and perfluoroalkyl, such as trifluoromethyl), or hydroxy (such as hydroxymethyl and hydroxyethyl), Ci -8 methoxy (such as ethoxylated fluorenyl and benzyloxy) Methyl), amine and mono- and dialkylamino (eg aminoethyl, decylamino, dimethylaminomethyl, diamylaminoethyl and tert-butylamino hydrazine) Alkoxy groups (e.g., Ci-2 alkoxy groups, such as methoxy groups, as in the case of a methoxyethyl group) and cyclic groups (such as a cycloalkyl 'aryl group' as defined above) Aryl and non-aromatic heterocyclic groups). Specific examples of the alkyl group substituted by a cyclic group are those in which the cyclic group is a saturated cyclic amine such as morpholine, hexahydropyridine, tetrahydropyrrole, hexahydropurine p, hexa-hexahydro Pyridin, c3 7_cycloalkyl-hexahydropyrazine, tetrahydropyran or tetrahydrofuran, and alkyl is alkyl, more typically c13 alkyl, such as methyl, ethyl or n-propyl By. Specific examples of the alkyl group substituted with a cyclic group include tetrahydropyrrolylfluorenyl, tetrahydropyrrolylpropyl, morpholinylmethyl, morpholinolethyl, morpholinylpropyl, and hexa Hydropyridylmethyl, /, 虱p is more than hydroxymethyl and its N-substituted form as defined herein. Specific examples of the alkyl group substituted with an aryl group and a heteroaryl group include a benzyl group, a phenethyl group, and a pyridylmethyl group. 102449 • 36-

1363622 When Ra is S〇2NRc, hydrazine may be, for example, hydrogen, or optionally substituted Ci_8 hydrocarbyl' or a carbocyclic or heterocyclic group. An example of Ra _Rb, wherein Ra is S02NRc, including an aminosulfonyl group, an alkylaminosulfonyl group, a di-Cm alkylamine sulfonyl group, and a sulfonamide derived from a cyclic amine group, the ring Amines such as hexahydro, morphine, tetrahydropyrrole or, as the case may be, are substituted for hexahydro I», such as N-methylhexahydrop. An example of the group Ra-Rb, wherein Ra is S〇2, and includes an alkylsulfonyl group, a heteroarylsulfonyl group, and an aryl group, particularly a monocyclic aryl group and a heteroaryl sulfonyl group. . Specific examples include methylsulfonyl, phenylsulfonyl and toluenesulfonyl beta. ^. The 'Rb' may be, for example, hydrogen or, as the case may be, a Ci8 hydrocarbyl group or a carbocyclic or heterocyclic group. An example of Ra _Rb, wherein Ra is NRC, including an amine group, a core-4 amine group (eg, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a tri-butylamino group), a bis-Cl 4 alkylamine A group (for example, a diammonium group and a diethylamino group) and a cyclic aminino group (for example, a cyclopropylamino group, a cyclopentylamino group, and a cyclohexylamino group). J. A, E, R1 to R5, and R9. Specific Examples: Priority Groups "A" In Formula (I), A is a saturated hydrocarbon linkage having 1 to 7 carbon atoms. The base has a large chain length of 5 atoms, extending between Ri and nr2 R3, and the maximum chain length is 4 atoms, extending between £ and \1^113. In this limitation, some of the groups E and Ri may each be attached to any position on the group eight. The term "maximum chain length" as used herein refers to the number of atoms directly between the two partial groups in the discussion, without regard to any branches in the chain or any hydrogen atoms that may be present. For example, in Structure A shown below: 102449 -37- 1363622 9H3 CH3 R2 R-ch-ch-ch-n ER (A) The chain length between W and NR2R3 is 3 atoms, however 'with _ Han 3 key length is 2 atoms. In general, it is preferred that the linker has a maximum bond length of 3 atoms (e.g., 1 or 2 atoms). In the specific implementation, the linker has a chain length of i atoms extending between R1 and NR2R3. In another specific embodiment, the linker has a chain length of 2 atoms extending between R1 and NR2R3. In a further embodiment, the linker has a chain length of 3 atoms extending between R1 and NR2R3. Preferably, the linking group has a maximum chain length of 3 atoms extending between e and NR2 R3. In a particularly preferred group of compounds, the linker has a chain length of 2 or 3 atoms extending between Ri and NR2R3 and having a chain length of 2 or 3 atoms extending between E and NR2R3. One of the carbon atoms in the linking group may be replaced by an oxygen or nitrogen atom as appropriate. When present, the nitrogen atom can be attached directly to the group E. In one embodiment, the carbon atom to which the group Ri is attached is replaced by an oxygen atom. In another embodiment, R1 and E are attached to the same carbon atom of the linker, and the carbon atom in the chain extending between E and NR2R3 is replaced by the oxygen source 102449-38-1363622. When a nitrogen or oxygen atom is present, the nitrogen or oxygen atom is preferably separated from the cis 2 r3 by at least two intervening carbon atoms. In the formula (I), in a specific group of the compound, the linking group atom directly bonded to the λ group is a carbon atom, and the linking group has an all carbon skeleton; the carbon atom of the linking group A may optionally be carried Or a plurality of substituents selected from the group consisting of a base gas and H, provided that the base group is not at the opposite atom to the alpha position of the group 2^3 and the condition is also that the ketone group is in the opposite At the carbon atom of the α position of the nr2 R3 group. Typically, if the base is present, the tether is not located relative to the NR2R3 group. In general, no more than one hydroxyl group will be present. In the presence of fluorine, it may be present as a single fluorine substituent or may be present, for example, in a difluoromethylene or trifluoromethyl group. In one embodiment, the fluorine atom is at a position 10,000 positions relative to the NR2R3 group. It will be appreciated that when the yl group is present at a carbon atom adjacent to the group, the compound of formula (I) will be a captanamine. In a specific embodiment of the invention, no fluorine atoms are present in the linking group A. In another embodiment of the invention, no hydroxyl groups are present in the linking group A. In further embodiments, no sulfhydryl groups are present in the linking group A. In a group of the compounds of the formula (I), neither a thiol group nor an I atom is present in the linking group A. For example, the linking group a is unsubstituted. Preferably, when the carbon atom in the linking group A is replaced by a nitrogen atom, the group A carries no more than one hydroxy substituent 'and more preferably does not carry a 102 449 - 39 · 1363622 hydroxy substituent. When there is a chain length of four atoms between E and NR%, the linking group does not contain a nitrogen atom, and more preferably has an all carbon skeleton. To modify the susceptibility of a compound to metabolic degradation in vivo, linker A can have a branched configuration at the carbon atom attached to the 2113 group. For example, a carbon atom attached to an NR R group can be attached to a pair of

In a specific group of compounds of formula 1, the r1 A tear % portion of the compound is represented by the formula R1, 2) mW-〇b, 2) n-(CR6 R7)p, R3, and t G is NH, NMe or 〇; w is attached to the group £ and is selected from (CH2)rCR20, (CH2)rN and (ΝΗγΗ; or j,]·, let 〇 or 1, m be 0 or i ' n is o'u, or 3, and the sum is 〇 or 1; the sum of j, k, m, n & p does not exceed 4; 妒 and 尺7 are the same or different, and are selected from methyl and ethyl Or CR6R7 forms a cyclopropyl group; and the lanthanide is selected from the group consisting of hydrogen, methyl, hydroxy and fluoro; in another subgroup of the compound of formula (I), the Ri Α-ΝΚ2" moiety of the compound is NH ' NMe or X; is attached to group E and is selected from (CH2)j_CH, (CH2)j-N and (NH)j-CH; j is 〇 or 丨, let ❹ or 丨, m be 〇 or 丨, η is 〇, 1, 2 or 3 ' and ρ is 0 or 1 ' and the sum of ^ and 卩 does not exceed 4; and R6 and R7 are the same or different and are selected from thiol and ethyl, or CR6R7 forms a cyclopropyl group. The specific group CR6R7 is c(ch3>2. X is preferably (CH2)j-CH. The RLA-NiH3 moiety of the compound is represented by the formula Ri_(G)k_(C H2)m_X_ 102449 1363622 (CH2 )n -(CR6 R7 )p -NR2 R3 represents the common sense <special configuration, in JL: • k is 0, m is 0 or i, n is 〇12 Or 3, and p is 〇. • k is 0, m is 0 or i, n is 〇, “l2, and _. • X is (CH2)j -CH, k is 坩 is 〇n is 0, 1, 2 or 3, and _ • X is (CH2)j_CH, k is 1, claws are 〇u锜υ, ι or 2, and pg1<( • X is (CH2)j -CH, G is 〇, k 1 , The state has a k of 1, m is 〇, n is 〇 12 or 3 and p is 0.

V The compound part of the compound is in the formula r1 pottery n-(four) state, which is the middle: · 'k is 〇, m is (^ is pottery (10)~ is ^heart is hydrogen... η is 2, and p is i. i ^^O'n^O'W^CHdj-CR20 is 0, η is 1, and p is 〇. It is 0, η is 1, and ρ is 〇. j is 0, R2 〇 is hydroxyj Is 0, R2 〇 is methyl bb

U〇, m is 〇’W is called CR2〇, j is 〇, 圮. For gas, 〇 η is 1 ’ and p is 〇. In a preferred configuration order, CH is represented, and η is 2. The Ri-A_NR2R3 moiety of the compound is represented by the formula wherein the X chain is attached to the group E, and the specific example of the group linker A is accompanied by its attachment point to the group R1, WNR2R3. . 102449 1363622 Table 1:

R2 rS^, r3 E A1 Μ〆E R3 A2 E R3 A3 Me, Me r9vr2 E R3 A4 Me, Me R1^YR2 E R3 A5 R2 E A6 R1 ^^yr2 E R3 A7 OH R2 Rl-y^kAR3 E A8 E A9 R2 E A10 r14^ E All R2 rVY^, r3 E 0 A12 rv\r2 E r3 A13 r1to A14 E A15 E A16 R1 R2 I / 0\^\^N, r3 E A17 ^rY2 ER A18 102449 • 42 - 1363622

RlY〇~〆 E R3 A19 RY〇 E A20 R3 E A21 A22 D1 〇H 2 R\~R E R3 A23 i Me 2 rS^n^r I k A24 E R3 A25 4

The preferred groups currently include eight 1, eight, eight, eight, eight, eight, and nine, eight, eight, and eight. A particular combination of groups includes persons 1, eight, eight, eight, eight and eight.

Further combinations of groups include A2 and All. Another specific combination of groups includes A6, A22 and A23. The further step-by-step combination of groups includes Al, A2 and A3. In the group A2, the asterisk refers to the center of the palm. Compounds having an r configuration for the palm center herein represent a preferred subgroup of the compounds of the invention.

The Ri group R1 is aryl or heteroaryl and may be selected from the list of such groups as set forth in the general prioritization and definition paragraphs. R1 may be monocyclic or bicyclic, and in a preferred embodiment, 102449-43- is a single ring. The monocyclic aryl group and the heteroaryl group contain a heteroaryl group of up to two nitrogen ring members, and the five-membered heteroaryl group of the hetero atom ring ring of the anthracene is an example sentence including the incineration and #. A phenyl group, a naphthyl group, a decyl group, a decyl group, and a pyridine, which are currently preferred. The group R1 may be unsubstituted or substituted with up to 5 substituents, and examples of the substituents are those listed above in the group Rio.

Specific examples are six-membered aryl and containing up to three selected from the group consisting of hydrazine, s-specific substituents (tetra); oxym; trimethylmethyl' chaotic; c〇NH2; nitro; Ci 4; Oxyl and Ci 4 sulphol, each optionally by Ch&oxy, silk or warp; 4 fluorenylamino; benzoguanamine; tetrahydromanocyl (tetra); hexahydro (tetra)yl (tetra); a carbonyl group; a hexahydropyranylcarbonyl group; a five- and six-membered heteroaryl group and a heteroaryloxy group, having one or two heteroatoms selected from N, 0 and 3; a phenyl group; a stupid group-CH alkyl group; phenyl-Cm alkoxy; heteroaryl-Ci_4 alkyl; heteroaryl-CH alkoxy and phenoxy, wherein heteroaryl, heteroaryloxy, phenyl, phenyl-Ci4 alkyl, The phenyl-Cu alkoxy group, the heteroaryl-Ci.4 alkyl group, the heteroaryl-Ci 4 alkoxy group and the present milk base are each optionally substituted by 1, 2 or 3 substituents, and the substituent is selected from the group consisting of C Bu 2 醯oxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, C0NH2,

Cl - 2 hydrocarbyloxy and C! -2 hydrocarbyl, each optionally substituted by methoxy or hydroxy; preferred substituents include hydroxy; Ci 4 methoxy; fluoro; gas; bromine; trifluoromethyl; a Ci-4 hydrocarbyloxy group and a Q 4 hydrocarbon group, each optionally substituted by a q _ 2 oxy group or a hydroxy group; a C 醯 - 4 decylamino group; a benzamidine group; a tetrahydropyrrolyl group; Hexahydro-p is a keto-based group, a hexahydro-p-based group; a hexahydro-r-ratio, a well-based group: a five or six membered heteroaryl group containing one or two heteroatoms selected from N, 0 and S, 102449 -44- 1363622 Heteroaryl is optionally substituted by one or more Ci 4 alkyl substituents; phenyl; 11 to dimethyl; and phenyl, wherein phenyl, pyridyl and phenoxy are The situation is substituted by 1, 2 or 3 substituents selected from the group consisting of Ci 2 decyloxy, fluoro, chloro, chloro, trifluoromethyl, cyano, Ci 2 hydrocarbyloxy and Ci 2 hydrocarbyl, each optionally Methoxy or trans group substituted.

In a subgroup of the compound, the substituent of Ri is selected from the group consisting of a hydroxyl group; a methoxy group; a chlorine group; a bromine group; a dimethyl group; a cyano group; a Ci4 hydrocarbon group and a C 4 group, each being Ci -2 alkoxy or hydroxy substituted. Although there may be up to five substituents, more typically, there are oxime, oxime, 2, 3 or 4 substituents, preferably ruthenium, 1, 2 or 3, and more preferably ruthenium, 1 or 2. In a particular embodiment, the group Ri is unsubstituted or substituted with up to 5 substituents selected from the group consisting of a trans group; Ci 4 azeoxy n";stain;trimethylol;cyano; The Cl_4 nicotinyloxy group and the Ci4 hydrocarbyl group are each optionally substituted by a Ci-2 alkoxy group or a trans group. In further embodiments, the group may have one or two substituents selected from the group consisting of a thiol group, an I, a gas, a cyano group, a phenyloxy group, a tonyloxy group, an oxy group, a methyl group, and In another embodiment, the group R1 may have one or two substituents selected from the group consisting of fluorine, gas, trifluoromethyl, methyl and methoxy. Specific examples of the combination of a base include a monogas phenyl group and a gas group. In the mash, R 丨 is a hydroxyphenyl group, a fluoro group, a cyanophenyl group, a methoxyphenyl group, a foxy group, a phenyl group, Iphenyl, phenyl, phenoxyphenyl, pyridyloxyphenyl or ethoxybenzene: 13,63622 When R is a six-membered aryl or heteroaryl, the substituent may advantageously be present in six members. In the case of a para-position, the substituent is preferably larger in size than the fluorine atom. R2 舆R3 In a group of compounds of formula (I), ruler 2 and ruler 3 are independent The hydrocarbon group selected from the group consisting of hydrogen, oxime, and ChU-based oxime is optionally substituted by one or more substituents selected from the group consisting of a U group, an amine group, a methyl group, and a second group. A And alkoxy. When the hydrocarbyl moiety is substituted by a benzyl group, an amine group, a f amine group, a di-f-amino group or a decyloxy group, there are typically at least one fluorene at the substituent and the ruthenium NR2R3. Between the nitrogen atoms, a specific example of the substituted hydrocarbyl group is hydroxyethyl and hydroxypropyl. Red is in another group of the compounds of the present invention, r2#r3 is independently selected from nitrogen, Ci-4, and Ci · 4 bases. Whether substituted or unsubstituted, the hydrocarbon group is typically a hospital base, more usually

Buckle, (: 2 or a sand base, and preferably a methyl group. In a particular subgroup of compounds, R^R3 is independently selected from hydrogen and methyl, and thus the NRW can be an amine group, a methylamino group or The dimethylamino group. In the specific embodiment, the acetaminophen can be an amine group. In another specific embodiment, qing can be a methylamino group. In the alternative embodiment, 'Ci, 4 The nicotyl group may be a cyclopropyl group, a cyclopropylmethyl group or a cyclobutyl group. In another group of compounds t, R, R3 and the gas atoms to which they are attached: - form a cyclic group 1 Flavor, with a saturated monocyclic heterocyclic group, having 4-7 ring members' and optionally a second one selected from the group of 102449-46-1363622 atomic ring members. The group rR2#R3 and the gas-like mono-heterocyclic heterocyclic group to which they are attached have a 'case containing: a second hetero atom ring member selected from 〇_, and depending on the saturation, the heterocyclic group may be Unsubstituted, or substituted by - or a plurality of substituents as defined in the general priority and definition paragraphs of this application, but 'typically' any substitution on a heterocyclic group Base system a relatively small substituent such as a Ci4 hydrocarbyl group (e.g., methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, second-butyl and tert-butyl), Fluorine, gas, «'amino group, methylamino group, ethylamino group and di-f-amino group. The specific substituent is methyl. The saturated monocyclic ring can be an I cycloalkyl group, such as a nitrogen four park, tetrachloro? a hydrazine, a hexafluoropyridine or a heptadecane ring, and the rings are typically unsubstituted. Alternatively, the saturated monocyclic ring may contain another hetero atom selected from the group consisting of fluorene and ! Examples of the group include porphyrin and hexahydropyrazine β in the case where another \ atom is present in the ring, which can form an anthracene group or an N_Ci 4 alkyl group (e.g., N-methyl, N-ethyl, positive) a portion of -propyl or N-isopropyl). Where NR2R3 forms an imidazole group, the imidazole group can be unsubstituted or substituted 'eg, by one or more relatively small substituents, For example, a specific substituent of a ketone group (e.g., anthracenyl, ethyl, propyl, cyclopropyl, and butyl), a sulphur, a gas, a hydroxyl group, an amine group, a methylamino group, an ethylamino group, and a dimethylamino group. Is a methyl group. In a further group of compounds, one of R2 and R3 and the gas atom to which they are attached and one or more atoms from the linker A form a saturated single 102449 • 47· styrofoam group having 4_7 ή Πώ ΧΤ ΧΤ 衣 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因 因

N-R3 (ch2)u % where 1; and 11 are each 〇12岑3, 甘片, 41_3, and the condition 疋t and U sum falls within the range of 2 to 4. This is the case. Examples of the advancement step include a compound in which 2 ft 3 and A form a cyclic group:

E N-R3 (ch21

Wherein V and W are each 〇, 1, 2 or 3, and the sum of the re-conditions 疋v and w falls within the range of 2 to 5. The ring-shaped compound Du-Nian, μ is a special example of which is ν and w are both. Further examples of such compounds include: NR2R3 and A form a compound of the following formula: X Ο

E z(9^2>X 严 R3 , (ch2)w where X and w are each 0, 1, 2 or 3, # + , with the condition that the sum of X and w falls within the range of 2 to 4. The compound of the formula 疋 疋 η is a case where X is 2, and w is 1 is Ri 102449 -48-1363622 in the formula (I) A, R 4 is selected from hydrogen, pixel, Ci 5 saturated smoky, saturated hydrocarbon oxygen More preferably, the 'R4 is selected from the group consisting of t, dentate, Ci5 saturated smokyl and CF3. Preferred meanings for R4 include hydrogen and fluorenyl. In a particular embodiment, R4 It is hydrogen.

Ri is in the formula ω, R5 is selected from the group consisting of hydrogen, _, Ci-5 saturated smoky, Ci 5 saturated hydrocarbyloxy, aryl, C〇nh2, C0NHR9, CF3, code, ship (10) and NHCONHR9; R9 is a group W or (wherein, wherein R9a is an optionally substituted monocyclic or bicyclic group, which may be a carbocyclic or heterocyclic group. Examples of carbocyclic and heterocyclic groups It is detailed in the above general preference and definition paragraphs. Typically, the carbocyclic and heterocyclic groups are monocyclic. The carbocyclic and heterocyclic groups are preferably aromatic. Group R9 Specific examples are optionally substituted phenyl or benzyl. R5 is preferably selected from the group consisting of hydrogen, halogen, (: saturated hydrocarbon, cyano, C〇nh2, C0NHR9 'CF3, NH2, NHCOR9 and NHCONHR9, wherein R9 is Substituted as a stupid or benzyl group. R5 is more preferably selected from the group consisting of hydrogen, i, q.5 saturated hydrocarbyl, cyano, cf3, nh2 'NHCOR9 and NHCONHR9, wherein R9 is optionally substituted phenyl or The group R9 is typically an unsubstituted phenyl or fluorenyl group, or a phenyl or benzyl group substituted by 1, 2 or 3 substituents, the substituent being selected from the group consisting of dentate; 102449 -49- 1363622 fluoromethyl; cyano; decyl; Cw alkoxy; (^_4 ethoxylate; amine; mono- or di-Ch-alkylamine; optionally halogen, hydroxy or ci2 alkane An oxy-substituted Ci 4 alkyl group; a ci. 4 alkoxy group optionally substituted by a halogen, a hydroxyl group or a q 2 oxaoxy group; a phenyl group containing up to three hetero atoms selected from the group consisting of ruthenium, ν and S heteroatoms And a six-membered heteroaryl; and a saturated carbocyclic and heterocyclic group containing up to two selected from the group consisting of ruthenium, s and ruthenium atoms. Specific examples of some of the groups R5 include hydrogen, fluorine, chlorine, bromine, Methyl, ethyl, ethyl, methoxymethyl, cyano, eh, and NHCONHR 'where R9b is a stupid or aryl group, as the case may be, a base, a C 4 oxy group, a fluorine, a gas, Mo, trifluoromethyl, cyano, optionally substituted by c12 alkoxy or (d) substituted k-hydrocarbyloxy (example oxy)hydrocarbyl (e.g., alkyl). Preferred examples of R5 include hydrogen, methyl and Cyano. R5 is preferably hydrogen or methyl. In the formula (I), 'E is a monocyclic or bicyclic carbocyclic or heterocyclic group, and • f can be selected from the above. Sexuality and definition in the paragraph It is a monocyclic and bicyclic aryl and heteroaryl group, and particularly contains a six-membered aromatic or heteroaromatic sulphate and special, a tatami cough ring, more particularly two: 3 such as phenyl, Heart, " more preferably (four) or stupid ring base w or (four) ring," double ring base circle you 丨 6β

fAmAlk k ^ includes a fused and pyridine-fused group, and both the group A and the carbazole ring in J are both attached to the cleavage group or the pyridine group. In the examples, E is a monocyclic group. Specific examples of the single-grain-like group 4 include a monocyclic aryl group and a heteroaryl group such as phenyl 'thiophene, furan, pyrimidine, pyridinium and pyridine, and a phenyl group is presently preferred. A subset of monocyclic aryl and heteroaryl groups includes phenyl, thiophene, furan, mouth bite, and P bite. Examples of the non-aromatic monocyclic group include a ring (tetra) such as cyclohexane and cyclopentane, and a nitrogen-containing ring such as hexahydropyrrolidine and hexahydropyrrolidone. Preferably, the group A and the pyrazole group are not attached to the adjacent ring member of the group E. For example, the 'oxime group' can be attached to the group E in a relative orientation of the meta or para position. Examples of such a group E include anthracene-phenylene, a phenylene group, a 2,5th thiol base and a 2,4-times, a bite base, an iota, a hexahydro ton „well base and a six Other examples include a 1,3-disubstituted five-membered ring. The group oxime may be unsubstituted, or may have up to four substituents r8, which may be freely available as the group Ri 〇. More typically, however, the substituent lanthanide is selected from the group consisting of a base group (when E is non-aromatic); dentate (e.g., gas and desert); trifluoromethyl 4 group; as appropriate (: An oxy or a substituted CM Φ hydrocarbyloxy group; and a Ci-4 hydrocarbyl group optionally substituted by a C1·2 alkoxy group or a hydroxy group. Preferably, there are 0-3 substituents, more preferably 〇_ 2 substituents, for example hydrazine or hydrazine substituents. In one embodiment ♦, group E is unsubstituted. E may be other than: - substituted pyridone; - substituted 4 azole a substituted or unsubstituted P-biazole or tr-indenyl group; a substituted or unsubstituted bicyclic fused pyrazolyl group; - a benzene ring fused to a rodent ring, or Six-membered nitrogen-containing hybrid 102449 fused to the porphin ring -51 - 丄*363622 square base ring; - substituted or unsubstituted hexahydropyridinyl group; group E may be aryl or heteroaryl; two heteroatoms selected from 0, N and S have five or Six members, and containing the highest group E, the following formula:

Threat

Let * denote the connection point to the t-sitting base, and, a" denotes that the base r is 0, 1 or 2; $, u is selected from N and CR1 2 a ; and: is selected from N and CRl2b; Rl, Rl2b are the same or different, and each is a hydrazine or a substituent containing up to ten atoms, and the atomic system is selected from the group consisting of c, n, 〇, f, α, and s ', and the condition is present in The total number of nitrogen atoms does not exceed ten together; ^ or R and R"b and the carbon atoms to which they are attached form an unsubstituted

A five or six member saturated or unsaturated ring containing up to two heteroatoms selected from 0 and 1^; and R1Q is as defined above. In a preferred group of compounds, E is the group:

* where * represents the point of attachment to the pyrazole group, and "a, represents the linkage of group A; P, Q and T are the same or different and are selected from n, ch & NCRi 〇, 102449 -52- An anthracene group A is attached to a carbon atom; and u, uRl. All are as defined above. Examples of R and rule 121) include hydrogen and a substituent R10 having no more than ten non-hydrogen atoms as defined above. Specific examples of Ruler 123 and Han 121> include mercapto, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, methoxy, methoxy, difluoromethyl, hydroxymethyl , hydroxyethyl, methoxymethyl, difluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethyl 'cyano, amine, methylamine*, dimethylamino , C0NH2, C〇2Et, C02H, acetamino group, nitrotetradecyl φ fluorenyl, tetrahydropyrrolyl, hexafluoropyridine, hexahydropyridinyl, morpholinyl, decylsulfonyl, amine sulfonate Sulfhydryl, methanesulfonylamino and trifluoroacetamido are more directly connected to carbon atom ring C in 11123 and 111213 when U is CR12 a and/or v is cr1 2 b The atom or group is selected from H, 0 (e.g., in a methoxy group), NH (e.g., in an amine group and a methylamino group), and CH2 (e.g., in a methyl group and an ethyl group). A specific example of the linking group E is accompanied by a point of attachment of the group a (a) to p to the salivary ring (*) ^, which is shown in Table 2 below. 102449 53·

1363622 In the table, the substituent R13 is selected from the group consisting of sulfhydryl, fluoro, fluoro and trifluoromethyl. The following optional exclusions may apply to any of the formulae (I), (la), (lb), (II), (III), (IV), and (V) as defined herein, and any subgroup or sub-definition thereof. Definitions: • E may not be a stupid group having a sulfur atom attached to the para-position relative to the pyrazole group. 102449 -54- 1363622 Stupid and benzene or A-N ^ v

• E may not be substituted or unsubstituted benzimidazole and p-sputum. A subgroup of the compounds of formula (I) has the general formula (II): r1\

NN Η (Π) where the group lanthanide is connected to or between the stupid rings, q is 〇_4; r1, r2, r3, r4 and R5 are as described herein with respect to formula 1 and its subgroups, examples and priorities. Definitions; and R8 are substituents as defined above. In the formula (11), q is preferably 〇, 1 or 2, more preferably 0 or 卜, and most preferably 〇. The group A is preferably attached to the para position of the phenyl ring. Within formula (II), a particular subgroup of the compounds of the invention is represented by the formula:

(!!!) wherein A' is the residue of group A, and ... to Han 5 are as defined herein. In formula (in), a preferred group of compounds is represented by formula (IV) 102449 • 55-1363622 R20 r2 R\L(CH2)rN ' -3⁄4

ό

(IV). _2 is 0, 1 or 2, R2 is selected from the group consisting of hydrogen, methyl, hydroxy and fluoro, and ... to R5 are as defined herein, provided that when Z is 〇, R2〇 is not Hydroxyl. In formula (III), another group of compounds is represented by formula (7):

Wherein R1 and R3 to R5 are as defined herein. In the formula (V), R3 is preferably selected from the group consisting of hydrogen and a hydrocarbon group such as a Ci 4 alkyl group such as an anthracenyl group, an ethyl group and an isopropyl group. R3 is more preferably hydrogen. In each of the formulae (II) to (V), R1 is preferably a substituted phenyl group as defined herein. In another subgroup of the compounds of the invention, A is a saturated tobacco linkage having from 1 to 7 carbon atoms, the linkage having a maximum chain length of 5 atoms extending between R1 and NR2R3 with a maximum chain length Is 4 atoms extending between £ and 102449 56, 1363622 NRW' wherein one of the linking carbon atoms may be replaced by an oxygen or nitrogen atom; and wherein the carbon atom of the linking group A may optionally carry - or more a substituent selected from a fluoroenergy group, wherein the condition is not present at a carbon atom relative to the α position of the NR 2 R 3 group in the presence of a base; and R 5 is selected from the group consisting of hydrogen, a saturated hydrocarbon group of Cu, a cyano group, and c〇NH 2 . %, Νη2, NHCOR9 and NHCONHR9. For the avoidance of doubt, it should be understood that each of the general and specific preferences, specific examples and examples of the group Ri may be associated with the group R2 and/or the ruler 3 and/or R4 and/or R5 and/or R9. It is generally combined with specific prioritization, specific embodiments and examples, and all such combinations are encompassed by this application. The various functional groups and substituents constituting the compound of formula (I) are typically selected such that the molecular weight of the compound of formula (I) does not exceed 1 Torr. The molecular enthalpy of the compound is typically less than 750, such as less than 7 Å, or less than 65 Å, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and is, for example, 5 Torr or lower. Specific compounds of the invention are shown in the Examples below and are selected from the group consisting of: 2-phenyl-2-[4-(1Η-pyrazolyl)-phenyl]•ethylamine; 3-phenyl-2- [3-(1Η-pyrazol-4-yl)·phenyl]-propanol; 2-[4-(3,5-dimethyl-1H-indazol-4-yl)-phenyl]_2· Phenyl-ethylamine; 2-(4-phenylphenyl)-2-[4-(1Η-ρ than sal-4-yl)-phenyl]-ethylamine; 2- [3-(3,5- Dimercapto-1Η-pyrazol-4-yl)-phenyl]-1-phenylethylamine; 3-phenyl-2-[3-(1Η-pyrazole-4-yl)-phenyl] • propylamine; 3-styl-2-[4-(1Η-pyrazol-4yl)-phenyl]-propylamine; {3-(4-phenylphenyl)-3-[4-(1Η-pyridyl) Oxazol-4-yl)-phenyl]-propyl}-indolyl-amine; 102449 -57- 1363622 {3-(3,4-difluoro-phenyl)-3-[4-(1Η-pyrazole) 4-yl)-phenyl]-propyl}-methyl-amine; {3-(3·chlorophenyl)-3-[4-(1Η-ρ than ol-4-yl)-phenyl] -propyl}-mercapto-amine; 3-(4-phenylphenyl)-3-[4-(1Η-pyrazol-4-yl)phenyl]-propanamine; 3-(4·chloro Phenyl)-3-[4-(1Η-pyrazol-4-yl)-phenyl]-propylamine; 3-(3,4-dichloro-phenyl)-3-[4-(lH-t»嗤-4-yl)-phenyl]-propylamine; 4-(4-chlorophenyl)-4-[4-(1Η-ι» ratio <» sit-4-yl) -Phenyl]-hexahydroο than bite;

4-(4-decyloxy-phenyl)-4-[4-(1Η-ρ than sal-4-yl)-phenyl]-hexa-argon ρ 唆; 4-(4-chlorophenyl)- 1-mercapto-4-[4-(1Η-ι» than sal-4-yl)-phenyl]-hexahydrop ratio bite; 4-phenyl-4-[4_(ΐΗ-pyrazole-4- Base)-phenyl]-hexahydropyridine;

4-[4-(3,5-Dimethyl-1Η-pyrazol-4-yl)·phenyl]-4-phenyl-hexahydropyridine; dimethyl-{3·[4-(1Η- Pyrazol-4-yl)-phenyl]-3-acridin-2-yl-propyl}-amine; {2-(4-oxaphenyl)-2-[4-(1Η-pyrazole-4 -yl)-phenyl]-ethyl}-dimercapto-amine; {2-(4-hydrophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-B {2-(4-Phenylphenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-indenyl-amine (R) {2-(4-Phenylphenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (S); 4-{2-( 4-oxophenyl)-2-[4-(1Η-ρ than sal-4-yl)-phenyl]-ethyl}-moffine; 4-{4-[1-(4-chlorophenyl) -2·tetrahydropyrrol-1-yl-ethyl]-phenyl b 1H-P-biazole; {2-(4-phenylphenyl)-2-[4-(1Η-pyrazol-4-yl) )·Phenyl]•ethyl}-isopropyl-amine; Dimercapto-{2-phenyl-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}- Amine; {2,2-bis-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl-dimethyl-amine; {2,2-bis-[4-(1Η-pyridyl) Zin-4-yl)-phenyl]-ethyl)indolyl-amine; 2-(4-phenylphenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]- Ethylamine (R); 2-(4-indolyl)-2-[4-(1Η-pyrazole-4- 2-phenyl]-ethylamine (S); 2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-acetamide; 102449-58 - 1363622 Η2·(4_chlorophenyl)-2-[4·(1Η-pyrazole·4·yl)-phenyl]-ethylhexahydropyrazine; 1-{2-(4-chlorophenyl) 2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}•hexahydropyridine; 4-{4-[2--nitrotetrayl-1-yl-1- (4-chlorophenyl)-ethyl]-phenyl}·1Η·pyrazole; 1-phenyl-2-[4-(lH-p)b ° sit-4-yl)-styl]_B Amine; 2-(4-phenylphenyl)-N-methyl-2-[4-(1Η-ρ 嗤-4-yl)-phenyl]-ethylamine; N-mercapto-2,2 - bis-[4-(1Η-pyrazol-4-yl)-phenyl]-acetamide; {2-(4-phenylphenyl)-2-[4-(1Η-ρ than 嗤-4- ))-phenyl]-ethyl-methyl-amine; {2-(4-carbophenyl)-2-[4-(1Η-ρ 嗤-4-yl)-phenyl]-ethylethyl-amine ; 4-{4-[1-(4-Phenylphenyl)-2-11 m. -1--1-yl-ethyl]-phenylpyrazine such as specific ratio; thiol-{2-(4-phenoxy-phenyl)-2-[4-(1Η-pyrazol-4-yl) -phenyl]-ethyl}-amine; {2-(4-methoxy-styl)-2-[4-(1Η-ρ-salt-4-yl)-phenyl]•ethyl}- Mercapto-amine; methyl-{2-[4-indole-2-yloxy)-phenyl]_2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl -amine; methyl-{2-phenoxy-2-[4-(1Η-ρ ratio. sit-4-yl)-phenyl]-ethyl}-amine; 2-{(4-phenylphenyl) -[4-(1Η-pyrazol-4-yl)-phenyl]-methoxyethylamine; 4-{4-[1-(4-phenylphenyl)-3-tetrahydropyrrole-1- --propyl]-phenyl}·1Η_pyrazole; 4-{4-[3-nitrotetradec-1-yl-1-(4-phenylphenyl)propyl]-phenyl}_ιη -ρ ratio. Succinyl-{3-indol-2-yl-3-[4-(1Η-ι»~嗤-4-yl)-phenyl]-propyl}•amine; dimethyl-(4-{ 3-methylamino·1-[4-(1Η-ρ-pyrazol-4-yl)-phenyl]-propyl}-phenyl)-amine; {3-(4-fluorophenyl)-3- [4-(1Η-pyrazol-4-yl)-phenyl]-propyl-methyl-amine; 4-{4-[4-(4-phenylphenyl)-hexafluoropyridin-4-yl]- stupid }}-lH-pyrazole-3-indoleonitrile; 102449 •59·

1363622 3-(4-Phenoxy-phenyl)·3-[4-(1Η-pyrazol-4-yl)-phenyl]-propylamine; 1-{(4-chlorophenyl)-[4- (1Η-pyrazol-4-yl)-phenyl]]methyl}_hexahydropyridinium; 1-methyl_4-{phenyl-[4·(1Η·pyrazol-4-yl)·benzene ]]-曱基}·[14] diazepine; {3-(3-a-phenoxy)-3-[4-(1Η-pyrazol-4-yl)-phenyl]-prop Keb methyl-amine; methyl-{2-phenyl-2-[6-(1Η-pyrazol-4-yl)·acridine_3·yl]-ethyl)-amine; 4- {4-[ 1-(4-chlorophenyl)-3-imidazol-1-yl-propyl]•phenyl}_1Η·pyrazole; 4-[4-(3·imidazol-1·yl-1-phenoxypropane ) phenyl]_ _ _ pyrazole; 4-{4-[4-(1 Η-pyrazol-4-yl)-phenyl]-hexahydropyridyl 4-phenylphenol; 1- {(4 - gas phenyl)-[4-(1Η-pyrazol-4-yl)-phenyl]-methyl}_hexahydropyrazine; {2-(4-fluorophenyl)-2-[4-( 1Η-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; {2-(3-phenylphenyl)-2-[4-(1Η-ρ-pyrazol-4-yl) -phenyl]-ethyl}-methyl-amine; 4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(ιη-pyrazol-4-yl)- Phenyl]-hexahydro ρ ratio bite; 4-[4-(3-decyloxy-propoxy)-phenyl]-4-[4-(1Η-pyridyl.spin-4-yl)-phenyl ] - hexahydropyridine; 3-(3,4-mono-phenyl)-3-[4-(1Η-ρ 嗤-4-yl)-phenyl]-propanol; 2- (4-{2 -nonylamino-1-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamine amide; {2-(3-chloro-phenoxy) 2-[4-(1Η-pywa-4-yl)-phenyl]-ethyl}-methyl-amine; 3-{2-(4·Phenylphenyl)-2-[4- (1Η-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1-ol; 2-{2-(4-phenylphenyl)-2-[4-(1Η-carbazole- 4·yl)-phenyl]-ethylamino}-ethanol; 3-{2-(4-carbophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-B Amino}-propan-1-ol; 2-(2-(4-carbophenyl)-2-[4-(1Η-thrazole-4-yl)-phenyl]-ethylamino}-ethanol; 102449 -60-

1363622 {2-(4-Chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylcyclopropylmethyl-amine; methyl-[2-[ 4-(1Η-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)ethyl]-amine; 4-{3-decylamino-1-[ 4-(1Η-ι»比唾-4-yl)-phenyl]-propyl brid; 3-(4-decyloxy-phenyl)-3-[4·(1Η-ρ than 嗤-4 -yl)-phenyl]-propylamine; 4-(4·Phenylphenyl)-4-[4-(3-indolyl-1Η-pyrazol-4-yl)-phenyl]-hexahydropyridine; -(4-chlorophenyl)-2-[4-(1ίΚ >»坐-4-yl)-phenyl]-ifolin; (4-{4-[4-(1Η-carbazole-4) -yl)-phenyl]-hexahydropyrazole_4_pyridyloxy)-acetic acid; (4-{4-[4-(1Η-pyrazol-4-yl)-phenyl]-hexahydro Pyridine-4-yl}-phenoxy)-methyl acetate; 4-{4-[4-(1Η-ρ-pyrazol-4-yl)-phenyl]-hexahydropurine bite Benzonitrile; {2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-propylindolylamine; 1-(4-phenylphenyl)- 2-nonylaminoindol-4-yl)-phenyl]-ethanol; 2-amino-1-(4-indolyl)-1-[4-(1Η-ρ than sal-4-yl) -phenyl]-ethanol; 4-(3,4-dioxa-phenyl)-4-[4-(1Η-pyrazol-4-yl)-phenyl]-hexahydropyridyl 4-(3-carbyl-4-methoxy-phenyl)-4-[4-(1Η-pyrazol-4-yl)-phenyl]-hexahydropyrazine; 4-(4- Gas-based-3-fluorophenyl)-4-[4-(1Η-pyrazol-4-yl)-phenyl]-hexahydropyridine; 4-{4-[4-(1Η-pyrazole-4- ))-phenyl]-hexanitropyridine _'yl}•benzoic acid; 4·[4-(1Η-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6 - hexahydro-[4,4,]bipyridinyl; 3-(3-phenylphenyl)-3-[4-(1Η-ρ than sal-4-yl)-phenyl]-propylamine; 2-曱Amino-1-(4-nitro-phenyl)-indole-[4-(1Η-pyrazol-4-yl)-phenyl]-ethanol; 2-(3-carbyl-4-methoxy- Phenyl)_2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylamine; 102449 -61 -

1363622 2-(4-Chlorophenyl)-2-fluoro-2-[4-(1Η-pyrazol-4-yl)phenyl]-ethylamine; 3-(3,4-dichloro-benzene Benzyl-3-(6-(1Η-ρ is more than -4-yl)-p than -3-yl]-propylamine; 2-(4-chloro-3-fluorophenyl)-2-[ 4-(1Η-pyrazol-4-yl)-phenyl]-ethylamine; 4-(2-chloro-3-fluorophenyl)-4-[4-(1H-p than sal-4-yl) )-phenyl]-hexahydro-P ratio bite; 1- {(3,4-di-phenyl)-[4-(lH-pyrazole-4.yl)-phenyl]-methyl}•six Hydropyridol; 2-(3,4-dichloro-phenyl)-2-[4-(1Η-<» ratio]-4-yl)-phenyl]-ethylamine; {2-(3 - gas-based 4-methoxy-phenyl)-2-[4-(1Η-pyrazole-4.yl)-phenyl]-ethyl}-methyl-amine;

4-{4-[2-Azatetradec-1-yl-1-(4-a-phenoxy)ethyl]-phenyl bionoxime; 3-(3-carbyl-4 -methoxy-phenyl)-3-[4-(1Η-ρ-salt-4-yl)-phenyl]-propylamine; {3-(3-carbyl-4-decyloxy-phenyl) -3-[4-(1Η-pyrazol-4-yl)-phenyl]-propyl}·decyl-amine; b{(3,4-di-phenyl)·[4-(1Η- Pyrazol-4-yl)-phenyl]-methylpyridinium 11 well; and C-(4-chlorophenyl)-C-[4-(lH-pyrazol-4-yl)-phenyl ]-guanamine; and its salts, solvates, tautomers and N-oxides. In a specific embodiment, the compound of formula (I) is selected from the group consisting of: {2-(4-phenylphenyl).2-[4-(1Η-pyrazol-4-yl)-phenyl]-B Keb methyl-amine (R); 4-(4-phenylphenyl)-4-[4-(1Η-pyrazol-4-yl)-phenyl]-hexahydropyridine; 3-(4·qiqiji -3-[4-(1Η-pyrazol-4-yl)-phenyl]-propylamine; 3-(3,4-dichlorophenyl)-3-[4-(1Η-pyrazole-4- ))-phenyl]-propylamine; {3-(4-phenylphenyl)-3-[4-(1Η-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 2-(4-Phenylphenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-didecyl-amine; and -62- 102449

^363622 2-(4-Phenylphenyl)_2-[4-(1Η-pyrazol-4-yl)phenyl]-ethylamine. A further subset of the compounds of formula (I) includes 4·(3-carbyl-4_methoxy-phenyl)-4-[4-(1Η-pyrazol-4-yl)-styl]•hexahydro Pyridine; 2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)phenyl]-ethylamine oxime isomer; and its salts, solvates, tautomers Structure and N-oxide. " bismuth, tautomer, dry structure, N-vapor, abbreviated, * ▲ drugs and the same as in this paragraph, as in all other paragraphs of this application, unless The text also indicates otherwise, otherwise the reference to Formula 1 includes Formulas (la), (lb), (II), (m), (IV), and (V) as defined herein, and all others. References for subgroups, priorities, and examples. Unless otherwise indicated, reference to a particular compound also includes its ionic 'salt' solvate and protected form, for example, as discussed below. Many of the compounds of formula (I) may exist in the form of a salt, such as an acid addition salt, or in some cases, a salt of an organic and inorganic base such as a carboxylate, a sulfonate or a sulphate. All such salts are within the scope of the invention, and the reference to the compound of formula 1 includes the salt form of the compound. As stated in the preceding paragraph of this application, all references to formula (I) shall be used, also referred to as formula (II) and its subgroups ' unless otherwise indicated in the text. The salt form can be based on ##磨..贫,选#和厉途,p.HeinrichStahl (editor), Camille G. Wermuth (editor), ISBN: 3-90639-026-8,

Method selection and preparation as described in Hardcover, page 388, August 2002. For example, the acid addition salt can be prepared in such a manner that the free base is dissolved in the organic solvent 102449 - 63 - 1363622, wherein the specific salt form is insoluble or poorly soluble, and then added in a suitable solvent. The acid is such that the salt precipitates out of solution.

Acid addition salts can be formed using a wide variety of acids, both inorganic and organic. Examples of the acid addition salt include a salt formed by an acid selected from the group consisting of acetic acid, 2,2-diacetic acid, adipic acid, alginic acid, ascorbic acid (for example, L-anti-acid), L-Tianmen Aspartic acid, benzenesulfonic acid, benzoic acid, 4 · acetaminobenzoic acid, butyric acid, (10) camphoric acid, camphor-sulfonic acid, (+M1S)-camphor-10-sulfonic acid, citric acid, caproic acid, Caprylic acid, cinnamic acid, citric acid, cyclohexane amino sulfonic acid, dodecyl sulphate, ethidium-1,2-dicarboxylic acid, ethyl sulphate acid, 2-yield basal acid, formic acid, anti-butyl Alkenoic acid, galactose diacid, gentisic acid, glucoheptonic acid, D-gluconic acid, streponic acid (such as D-mannonic acid), facial acid (such as L- face acid), 〇:- Ketoglutaric acid, glycolic acid, hippuric acid, hydrogen acid, hydrochloric acid, hydrogen acid desulfurization, ethyl acetate, lactic acid (eg (+)-L-lactic acid and (±)-DL-lactic acid), milk-based organisms Acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-phenylglycolic acid, decanesulfonic acid, benzenesulfonic acid (such as hydrazine-2-sulfonic acid) ), 荇-1,5-disulfonic acid, 1-hydroxy-2-indolecarboxylic acid, nicotinic acid, nitric acid, oil Acid, orotic acid, oxalic acid, palmitic acid, diperic acid, acid, propionic acid, L-pyro face acid, salicylic acid, 4-amino-salic acid, azelaic acid, stearic acid, succinic acid Sulfuric acid, citric acid, (1)-L-tartaric acid, thiocyanic acid, terephthalic acid (for example p-toluenesulfonic acid), undecene and valeric acid, and thiolated amino acid and cation exchange resin. A specific group of acid addition salts includes hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid 'lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid , benzenesulfonic acid, toluenesulfonic acid, decanesulfonic acid, ethanesulfonic acid, sulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, propane 102449 -64-1363622 acid, aldonic acid and milk-based organisms The salt formed by the acid. Another group of acid addition salts includes acetic acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, succinic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, Salts of glutamic acid, DL-malic acid, methane acid, sebacic acid, stearic acid, succinic acid and tartaric acid.

The compounds of the invention may exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed. In the stronger acid, the pyrazole nitrogen and the nitrogen atom in the group nr2 R3 may participate in salt formation. For example, where the acid has a pKa of less than about 3 (e.g., an acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid), the compound of the invention will typically form a salt having 2 moles of the acid. If the compound is anionic or has an anionic functional group (e.g., -COOH can be -COO), the salt can be formed as a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and κ+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as αι3+. Examples of suitable organic cations include, but are not limited to, ammonium ions (ie, with substituted money ions (eg, NH3R+, NH2R2+, NHR3+, some examples of suitable substituted ammonium ions are derived from: ethylamine, diethylamine, two % hexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, hexahydropyrrolidine, benzylamine, phenylbenzylamine, choline, meglumine and butylamine, and amino acids, For example, an amine acid and arginine. An example of a common quaternary ammonium ion is N(CH3)4+. In the case where the compound (I) has an amine functional group, it can form a four-stage salt. The method known to the skilled person is carried out by reaction with an alkylating agent. Such a quaternary ammonium compound is within the scope of Formula 1. 102449 • 65 · 1363622 The compound of formula (I) containing an amine functional group may also form N_oxidation. The reference to a compound of formula (I) containing an amine functional group herein also includes a cerium-oxide. Where the compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form Ν_oxide^ Ν_specific examples of oxides A ruthenium oxide of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. The ruthenium-oxide can be formed by treating its corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid, see for example high Irene March, 4th edition, Wiley lnterscience. More specifically, the team oxide can be programmed by L, W. Deady (", 〇? 历 1977 1977, 7, 509-514) Cheng, examples

For example, an amine compound is reacted with m-chloroperoxy benzoic acid (McpBA) in an inert solvent such as dimethane. The compound of formula (I) may exist in many different geometric isomers and tautomeric forms, and the reference to the compound of formula (I) includes all such forms. To avoid confusion, the compound can be in several geometric or tautomeric forms.

One exists, and only one is explicitly described or displayed, although all other systems are included in equation (1). For example, in the compound of formula (I), the pyrazole group may take any one of the following two tautomeric forms A and B. 102449 -66· 1363622

For the sake of simplicity, the general formula (i) illustrates Form A, but this formula is intended to be taken to include Form A and Form B. Where the compound of formula (I) contains one or more centers of palms and may exist in two or more optical isomer forms, the reference to the compound of formula (7) includes all optically isomeric forms thereof (eg, for palms) Structures and diastereomeric residues, whether as individual optical isomers or mixtures of two or more optically different materials, unless otherwise required by the context. For example, group A can comprise one or more pairs of palm centers. Thus, when both E and R are attached to the same carbon atom on the linker A, the carbon atom is typically palmarous, and thus the compound of formula (I) will be a pair of palmomers (or in a stack) When the above-mentioned center of the palm exists in the compound, more than one pair of palmomers are present. The optical isomer can be identified and confirmed by its optical activity (ie, as a + and · isomer). It can be characterized by its absolute stereochemistry, using the "R and s" nomenclature developed by Cahn, Ingold and Prelog to express its characteristics. Yan Yan, et al., Jerry March, 4th edition, John Wiley &amp Sons, New Y〇rk 1992, pp. 109-114, and also see Cahn, Ingold & Prelog, eg c/zew. /«/ and /. do g/., 1966, 5, 385-415. -67- 1J03622 Separation of various techniques of the palm of the hand, including the analysis of the _ _ (on the limbs of the limbs), and this skill is known to the art. For an alternative, optical isomers can be Separation of distyric acid by the formation of a diastereomer salt, a face acid, (a)·di·toluene-based base II: Ben B, (·)· Fruit acid and (_)·樟 brain rhyme, separation of diastereomers by preferential knots, and then salt solution # @ #自掌异物. "Essence-dissociation and 仵 仵 态 碱 之 个别 在The presence of the compound in two or more optically isomeric forms is the second: the palmier isomers, which are superior to the palmo isomers, for example, in terms of biological activity. Therefore, in some cases, it may be desirable to use only one pair of palmisomers: one of the various diastereomers, as a treatment, thus providing a composition containing __ or a plurality of compounds of formula 1 of the formula 8 (J 匕 ' ' at least 55% (eg, at least 6.5%, 65%, 7G%, 75%, . . . , = 90% or 95%) A single optical isomer - a dry isomer or a diastereomer exists. 99% or more (for example substantially all) of the total amount of the compound of formula 1 , a single: an ester (such as a palmomer or a diastereomer) of the compound of the formula 1 of a carboxylic acid or a hydroxy group, such as a carboxylic acid ester. The formulae 'is also included in the formula (1). In the specific embodiment of the invention, the formula 1 includes, within the scope thereof, a compound of the formula (1) having a (tetra) group or a trans group. In another embodiment of the present invention, Formula 1 does not include an ester of a compound of formula 1 having a slow acid group or a thiol group in the range of 102449 • 68 to 1363622. Examples of esters are groups containing -C ( = 〇) A compound of 〇R, wherein r is an ester substituent, such as q.7 alkyl, (:3. 2 fluorenyl or C5-20 aryl, preferably Ci 7 alkyl. Specific examples of vine groups include, but are not limited to, -C(=0)0CH3, eH3, -C(=0)0C(CH3)3, and -C(=0)0Ph. Examples of decyloxy (reverse ester) are represented by -OC(=0)R, wherein r is a decyloxy substituent, such as Ci7 alkyl, q^heterocyclyl or 〇5·2 aryl aryl Good for C!·7 alkyl. Specific examples of decyloxy groups include, but are not limited to, -〇c(=o)ch3 (acetoxy), -OC(=〇)CH2 Ch3, -0C(=0)C(CH3)3, -0C ( =0) Ph and -0C (=0) CH2Ph. Also encompassed by formula (I) are any polymorphic forms of the compound, solvates (eg, hydrates) of the compound, complexes (eg, inclusion complexes or clathrates with compounds such as cyclodextrins) or with metals Complex), and compound prodrugs. By "prodrug" is meant any compound which is converted, for example, into a biologically active compound of formula (I) in vivo. For example, some prodrugs are esters of the active compound (e.g., physiologically Φ acceptable metabolically labile esters). During metabolism, the ester group (•C(=0)0R) is cleaved to produce an active drug. Such esters may be formed, for example, by esterification of any carboxylic acid group (_C(=0)0H) in the parent compound, which is preceded by any other reactive group present in the parent compound, where appropriate. Protection 'and then remove protection if needed. Examples of such metabolically unstable esters include the formula _c(=〇)〇R, where R is:

Ci -7 alkyl (eg, -Me, -Et, -nPr, -iPr, _nBu, _SBU, -iBu, -tBu); C! 7 aminoalkyl (e.g., aminoethyl; 2-(N, N-diethylamino)ethyl; 2-(4-102449-69- 1363622 morphobolinyl)ethyl); and ethoxy-c^7 alkyl (eg oxime oxime; decyloxy) Ethyl; tridecylethenyloxymethyl; ethoxymethyloxy; uethoxyethyl; 丨-(1-methoxy-1-methyl)ethyl-aryloxy Ethyl; 丨_(benzyl methoxy)ethyl; isopropoxy-hexyloxymethyl; 1-isopropoxy- methoxyoxyethyl; cyclohexyl carbonyloxymethyl; 1-cyclohexyl-hexyloxyethyl; cyclohexyloxy-hexyloxymethyl; 1-cyclohexyloxy-aryloxyethyl; (tetrahydropyranyloxy)carbonyloxy Methyl; 1-(4-tetrahydropyranyloxy) carbonyloxyethyl: (4-tetrahydropyranyl) benzyloxymethyl; and 丨_(4_tetrahydropyranyl )carbonyloxyethyl). Some prodrugs are also activated by enzymes to produce an active compound, or a compound that, when further chemically reacted, produces an active compound (eg, when the pro-drug therapy (MEPT), gene guide In the case of enzyme prodrug therapy (GDEpT) and ligand-guided enzyme prodrug therapy (LIDEPT). For example, the prodrug may be a sugar derivative φ or other sugar taste conjugate, or may be an amino acid ester derivative. The method of preparing a compound of the formula (Γ) is in this paragraph t, as in all other paragraphs of the present application, unless the context indicates otherwise, the reference to the formula (I) includes the formula as defined herein (la) , (lb), (II), (III), (IV), and (v) all other subgroups, priorities, and examples. The compound of formula (I) can be prepared by reacting a compound of formula PQ with a compound of formula (ΧΙ) or its N-protected derivative: 102449 • 70- 1363622

R-A-N

E I X (X)

(XI) wherein A and EmR5 are as defined above, one of the groups is a gas, a desert or a moth or a tri-I-acid acid radical (trifluoromethyl acid) group, and the other one of the groups X and Y is The second secretory boron is a residue, such as a di-(tetra)dihydroxyborane residue. The β--reaction can be carried out in an aqueous solvent system under typical Suzuki coupling conditions in the presence of a catalyst such as bis(tri-second-butylphosphine) saturated with a base such as a carbonate such as potassium carbonate. This is carried out, for example, with an aqueous solution of ethanol, and the blood type is such that the reaction mixture is heated, for example, to a temperature exceeding just. c. Involving Suzuki coupling step (four) synthesizing, "in the formula i. The starting material for the synthetic route shown in Figure 1 is a dentate-substituted aryl- or heteroarylmethylnitrile (tetra), tX is a chlorine, molybdenum or moth atom or a tribasic acid group. In the presence of a sodium hydroxide or a clock, the nitrile is condensed with the acid RlCH0 in an aqueous solvent system such as an aqueous solution of ethanol. The resulting substituted acrylonitrile derivative (xm) is then treated with a reducing agent which will selectively reduce the dilute hydrocarbon double bond without reducing the lanthanide. Sodium borohydride, a substituted acetonitrile derivative (XIV), is available for use in this project. This reduction is typically carried out in a solvent such as ethanol, and is often accompanied by heating, for example up to a temperature of about 65. Then, the reduced nitrile (χιν) is coupled with pyrazole dihydroxyborane ester (XV) under the above Suzuki coupling conditions to obtain a compound of the formula (1), wherein a-nrZr3 102449 • 71 - ^ 363622

Is a substituted acetonitrile group. R1—CHO X—E-CH “CN - KOH/EtOH (XU)

E-x

1RCN

(XII

NaBH4 EtOH E—x \1/ 1 Nxl R c ( R1 R1

(XVI) (XVII) Scheme 1 The 'substituted acetonitrile compound (XVI) can then be reduced to its corresponding amine (XVII) by treatment with a suitable reducing agent such as ammonium in the nickel and ethanol. The synthetic route shown in Scheme It will result in an amine-based compound of the formula 1, wherein the aryl or heteroaryl E is attached to the /5-position of the group A relative to the amine group. To obtain an amine compound of the formula (I), wherein the Ri is attached to the functional group on the two starting materials relative to the position of the amine group, it can be reversed in the condensation step, l02449 -72· 1363622, thus the formula XE a CHO compound wherein X is a bromine, gas, moth or trifluoromethanesulfonate group, condensed with a compound of the formula R1-CH2-CN, and the substituted acrylonitrile derivative is subsequently 'reduced to a corresponding The acetonitrile derivative is then coupled to the salivary dihydroxyborane ester (XV) and the cyano group is reduced to an amine group. A compound of the formula (I) wherein R1 is attached to the position relative to the amine group can be produced by the reaction sequence shown in Scheme 2.

In Scheme 2, the starting material is a dentate-substituted aryl- or heteroaryl-fluorenyl Gngnard reagent (χνιπ, χ=bromo or chloro), which is attached to a nitrile ruler 1 (:^ in an anhydrous ether such as diethyl ether). The reaction is carried out to obtain an intermediate imine (not shown), which is reduced by using a reducing agent such as lithium aluminum hydride to obtain an amine (XIX). The amine (XIX) can be subjected to the above-mentioned Suzuki coupling 5 condition and the dipyridyl group. Boron-burning ester (XV) reacts to produce amine (XX) 102449 • 73· (XIX) 1336222

(i) R1—CN X-E-CHrMgBr

(XVIII) (ii) LiAIH4

(XX)

The compound of formula (I) can also be prepared from a substituted nitrile compound (XXI):

Wherein PG is a protecting group such as tetrahydropyranyl. The nitrile (XXI) can be condensed with the formula R1 -(CH2X-CHO aldehyde wherein r is 0 or 1, and then the resulting substituent is replaced under conditions similar to those set forth in Figure 102449-74-1363622 above. The acrylonitrile is reduced to its corresponding substituted nitrile. The protecting group PG can then be removed by a suitable method. The nitrile compound can then be reduced to its corresponding amine using a suitable reducing agent as described above. The nitrile compound (XXI) is also The amine compound of the present invention having the structure shown in the formula (ΧΧΠ) can be obtained by reacting with the formula "-(CHA-MgBr of Grignard reagent, followed by removal of protection) under standard Grignard reaction conditions.

In the preparation procedure outlined above, the coupling of an aryl or heteroaryl group to a ratio of ρ to σ is a reaction of a halo-p-w or a haloaryl or a heteroaryl compound with a palladium catalyst. This is achieved by reaction with dihydroxyborane or dihydroxyborane in the presence of a base. Many dihydroxy boranes suitable for use in the preparation of the compounds of this invention are commercially available, for example, from Boron Molecular Co., Ltd. (Noble Park, Australia) or from Combi-Blocks (San Diego, USA). In the case where the dimercaptoalkylate is not commercially available, it can be prepared by methods known in the art, for example, in a review paper by N. Miyaura and A. Suzuki, C7ze/w. 1995, 95, 2457. Said. Therefore, the dihydroxyborane can be produced by reacting a corresponding bromine compound with an alkyllithium such as butyllithium and then reacting with a boric acid ester. The dihydroxyborane derivative formed can be hydrolyzed if necessary to give the corresponding dihydroxyborane. 102449 - 75 - 1363622 A compound of formula (I) wherein the group A contains a nitrogen atom attached to the group E and can be prepared from a compound of the formula (I) or a protected form thereof by conventional synthetic procedures. The compound of the formula (XXIII) can be obtained by a Suzuki coupling reaction of a compound of the formula (XV) (see the scheme 丨) with a compound of the formula Br-E-NH2 such as 4·bromoaniline.

A compound of the formula (I), which is produced as shown in the formula 3.

Nh2 E

N-N Η (ΧΧΙΠ) where R1 and E are connected to the same carbon atom,

102449 76· (XXV)1363622 X-E-CHO + NC-CHrC〇2Et (XXIV) base NC, ^C〇2Et

E I X R1MgBr

.co2h ^R1 (i) Hydrolysis NC^.COjEt (8) Decarboxylation (XXVII)

E I X Ή (XXVI) guanamine coupling reaction, reduction of conr2r3 guanamine, ch2nr2r3

E R I X (XXVIII)

E FT I X (XXIX)

Me Me

Pd(0)

Me Me

Pd(9), CONR2R3, R1 R5 -

R

Reduction of indoleamine .ch2nr2r3 e human r1

_R

KN R5 (XXX) (XXXI) Scheme 3 In Scheme 3, the aldehyde compound (XXIV), wherein X is bromine, chlorine, iodine or 102449 -77-1363622 fluorosulfonate group, with cyanoacetic acid The ethyl ester is condensed in the presence of a base to give the cyanoacrylate intermediate (XXV). This condensation is typically carried out in the presence of a base, preferably a non-hydroxide, such as a hexahydro-p-bit, by heating under Dean Stark conditions.

Sr

The cyanoacrylate intermediate (XXV) is then reacted with a Grignard reagent R1 MgBr suitable for the addition of a carbon-carbon double bond of the radical R1 to the acetoacetate moiety by Michael. The Grignard reaction can be carried out in a polar aprotic solvent such as tetrahydrofuran at a low temperature such as about 〇 °C. The product of the Grignard reaction is cyanopropionate (XXVI) and subjected to hydrolysis and decarboxylation to give a propionic acid derivative (XXVII). The hydrolysis and decarboxylation steps can be accomplished by heating in a mixture of an acidic medium such as sulfuric acid and acetic acid.

The propionic acid derivative (XXVII) is converted to the guanamine (XXVIII) by reaction with the amine HNR2R3 under conditions suitable for the formation of a guanamine bond. The coupling reaction between the propionic acid derivative (XXVII) and the amine HNR2R3 is preferably carried out in the presence of an agent of the type commonly used to form a peptide chain. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan et al., "/· jme/-· C7iem 5^. 1955, 22, 1〇 67), 1-ethyl- 3-(3·-Dimethylaminopropyl)-carbodiimide (referred to herein as either EDC or EDAC) (Sheehan et al., /. Org. C/iew., 2(5, 2525) a ruthenium-based coupling agent such as 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylguanidine (HATU) and scale-based hexafluorophosphate a coupling agent, such as 1-benzo-triazolyloxy-p-(tetrahydropyrrolyl) hexafluorophosphate (PyBOP) (Castro % A, Tetrahedron Letters, 1990, 3i, 205). Based on carbodiimide The coupling agent is advantageously interspersed with 1-hydroxy-7-azabenzotriazole (HOAt) (LA Carpino, J. Amer. Chem. Soc., 1993, 115, 4397) or 1-p-benzotriene 102449 -78-

1363622 (HOBt) (Komg et al., c/ze, 5er·, 103, 708, 2024-2034) used in combination. Preferred coupling reagents include EDC (EDAC) and DCC in combination with HOAt or HOBt.

The even 5 reaction is typically carried out in a non-aqueous, aprotic solvent such as B., Dioxane, Dimethylhydrazine, Dimethylmethane, Dimethylformamide or N-Methyltetrahydropyrrole, or The aqueous solvent is optionally carried out with one or more miscible cosolvents. The reaction can be carried out at room temperature 'or in the case where the reactants are less reactive (for example, in the case of electron-poor aniline with a pendant electron group such as a sulfonamide group), at a suitably elevated temperature . The reaction can be carried out in the absence of an interference test such as a tertiary amine such as triethylamine or N,N-diisopropylethylamine. In the case where the amine HNR2R3 is ammonia, the 'guanamine coupling reaction can be carried out using 1,1 - carbonyldiimidazole (CDI) on the month of adding ammonia to activate the carboxylic acid. As an alternative, the reaction of a reactive derivative of a carboxylic acid, such as an anhydride or cesium chloride, with a reactive derivative such as an anhydride can be used, typically in the case of hydrazine. This is achieved by stirring the amine and anhydride at room temperature. The guanamine (XXVIII) can be converted to a compound of the formula (I) corresponding to the compound of the formula (I) by reacting with dihydroxyboran ester (XV) under the suzuki coupling conditions as described above, wherein a keto substituent, adjacent to the "group". The decylamine (XXX) can be subsequently reduced in the presence of vaporized aluminum using a hydride reducing agent such as lithium aluminum hydride to give an amine of the formula (1) Corresponding to a compound of formula (1) wherein A is CH-CH2-CH2-). This reduction is typically carried out in a hydrazine solvent such as diethyl ether' and heated to the reflux temperature of the solvent. The amine (XXVIII) is not Dihydroxyborane ester (xv) reaction, this guanamine can be replaced by chlorination/gasification, for example in a solvent, at ambient temperature, and • 79· 102449

1363622 Derivative amine (XXIX) is then reacted with dihydroxy borane ester (XV) under the above Suzuki coupling conditions to give the amine (XXX). To obtain a homologue of an amine (XXIX) containing less than one fluorenylene group, the carboxylic acid (XXVII) can be converted to an azide by standard methods and subjected to Curtius rearrangement in the presence of an alcohol such as decyl alcohol. And the urethane (see Gao #芳讥允学, 4th edition, Jerry March, John Wiley & Sons, 1992, pp. 1091-1092). The decyl carbamate can be used as a protecting group for the amine during the subsequent Suzuki coupling step, and the oxiranyloxy moiety of the urethane group can be removed after the coupling step and then by standard methods. Alternatively, the mercaptoamine carbamate may be treated with a hydride reducing agent such as lithium aluminum hydride to obtain a compound wherein NR2R3 is a guanamine group instead of an amine group. An intermediate compound of the formula (X), wherein a part of the group X is a chlorine, bromine or iodine atom, and A is a group CH-CH2-, which can be obtained by the aldehyde compound of the formula (XXXII): rV^cho

E

I X (XXXII) is prepared by reductive amination with an amine of the formula HNR2R3 under standard reductive amination conditions, for example in the presence of sodium cyanohydrin, in an alcohol solvent such as methanol or ethanol. The aldehyde compound (XXXII) can be over-fired by the oxidation of its corresponding alcohol (XXXIII) using, for example, Dess-Martin (see Dess, DB; Martin, JC «/. Og. <Soc:., 1983, Yes, 4155, with the synthesis of socks, Vol. 77, 141). 102449 -80- 1363622

R\^CH2〇H I

A compound of formula (I) wherein A, N and R2 together form a cyclic group via Suzuki of a dihydroxyborane compound of formula (XV) and a cyclic intermediate of formula (XXXIV) or an N-protected derivative thereof Coupled to form. ✓

(XXXIV) a cyclic intermediate of the formula (XXXIV) wherein R1 is an aryl group, such as optionally substituted phenyl' can be formed by Friedel Crafts alkylation of an aryl compound R1_H with a compound of formula po^V) :

(XXXV) This alkylation is typically carried out in the presence of a Lewis acid such as vaporized aluminum at a low temperature, e.g., below 5 °C. The Friedd Crafts reaction has been found to have general applicability for the preparation of a range of formula (χ) intermediates. Thus, in the general method of making a compound of formula (系), the compound of formula (LXX) is: ο Η ΑΙΕΙΧ 2 R, 3 R / Ν 102449 • 81 - 1363622 under Friedel Crafts, for example in chain halides In the presence of (e.g., A1C13), it is reacted with a compound of the formula WH. In a further method of preparing a compound of formula (I), wherein a moiety NR2R3 is attached to the CH2 group of a moiety A, an aldehyde of formula (XXXVI) and an amine of formula HNR2R3 can be reductively aminated as described above. Coupling under conditions. In the formulae (XXXVI) and (XXXVII), A' is a residue of the group A - meaning that a part of the group A' forms a group A with CH2. The aldehyde (XXXVII) can be made into a ruthenium by, for example, Dess-Martin by oxidation of its corresponding alcohol.

R1\ XHO A' I

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

/〇 Br—E— (XXXVIII) HNR2R3

Br-E (XL)

OH

R R3 Scheme 4 The starting material for the synthetic route shown in Scheme 4 is epoxide (XXXVIII), 102449 - 82-1363622 which may be commercially available or may be known by the skilled artisan. It is made, for example, via the reaction of aldehyde Br-E-CHO with trimethylammonium iodide. The epoxide (XXXVIII) is reacted with an amine HNR2R3 under conditions suitable for ring opening reaction with an epoxide to give a compound of the formula (XXXIX). This ring opening reaction can be carried out in a polar solvent such as ethanol at room temperature or optionally with mild heating, and typically with a large excess of amine. Then, the amine (XXXIX) is reacted with an aryl compound R1 oxime, which is typically a phenyl compound capable of participating in the alkylation of Friedel Crafts (see, for example, Gao #夯讥允学, Jerry March, pp. 534-542) ). Thus, the amine of formula (XXXIX) is typically reacted with an aryl compound R1 in the presence of a vaporized aluminum catalyst at or about room temperature. In the case where the aryl compound R1 Η is a liquid, for example, in the case of methoxybenzene (e.g., decyl ether) or a halogenated phenyl hydrazine such as benzene, the aryl compound can be used as a solvent. In other cases, a less reactive solvent such as nitrobenzene can be used. The alkylation of R1!! compound with an amine (XXXIX) by Friedel Crafts affords a compound of formula (XL) corresponding to a compound of formula (X) wherein X is bromine and A is CHCH2. The hydroxy intermediate (XXXIX) in Scheme 4 can also be used to prepare a compound of the formula (X) wherein the carbon atom of the hydrocarbon linking group A adjacent to the group R1 is replaced by an oxygen atom. Thus, a compound of formula (XXXIX) or an N-protected derivative thereof, wherein R2 or R3 is hydrogen, can be formed under Mitsunobu alkylation conditions, for example in the presence of diethyl azodicarboxylate and triphenylphosphine, The phenolic compound of the formula R1 -0H is reacted. Typically, the reaction is carried out in a polar aprotic solvent, such as tetrahydrogen alpha, at moderate temperatures such as ambient temperature. Further utilization of the hydroxy intermediate (XXXIX) is used to prepare the corresponding 102449 - 83 · 1363622 fluorine compound. Thus, the hydroxyl group can be replaced by fluorine 'by way of reaction with a pyridine:hydrogen fluoride complex (Olah's reagent). The fluorinated intermediate can then be subjected to a Suzuki coupling reaction to obtain a compound of formula (I) having a fluorinated hydrocarbon group A. - the fluorinated compound of formula (I) can alternatively be prepared in the following manner by first bringing the hydroxyl intermediate (XXXIX) or its protected form, with pyrazole dihydroxyborane or dihydroxyborane, Coupling under Suzuki conditions, then using a pyridine:hydrogen fluoride Φ complex, replacing the hydroxyl groups in the compound of formula (I) with fluorine. ^ Compound of formula (I), some of which are: "· R2

R1—A—N E R3 is the following group: . R2

R-CH-Ο-α''-ν7 E V wherein A" is a hydrocarbon residue of group A, which can be produced by the reaction sequence shown in Scheme 5. 102449 84- 1363622 R1MgBr X-E-CHO (XXIV)

Me\Je UMe

R X-E-CH-OH (XU)

X'E~CH-〇-An-N (XLIII) R1 (XUI), R1 R2· R2. R2'

R5, R3· (XLIV)

!TN As shown in Figure 5, the aldehyde (XXIV) is reacted under standard conditions, such as Grignard reagent R1 MgBr, to give a secondary alcohol (χπ). then,. The secondary alcohol is reacted with a compound of the formula (XLII) wherein ^, and the 3' represents a radical R3 or an amine protecting group, Α" is a residue of the group Χ, and Χι denotes a hydroxy group or a thiol group. It may be, for example, g-terpenyl, in which case NR2, R3 is a brewed imine group. When X· is a hydroxyl group, the reaction between the compound (XLD and (XLII) may take the form of a quinone benzoic acid-catalyzed condensation reaction. Or, when X' is a detached group such as a halogen 102449 • 85· 1363622, it may be first The alcohol (XLI) is treated with a strong base such as sodium hydride to form a final product, which is then reacted with the compound (XLII). Then, under the typical Suzuki coupling conditions of the above type, the formed formula (XL111) is obtained. The compound and the pyrazole dihydroxyborane ester reagent (XV) are subjected to a Suzukj coupling reaction to obtain a compound of the formula (XLIV). Next, the protecting group can be removed from the protected amine NR2'R3' to obtain the formula (I). Compounds. Compounds of formula (I), some of which are: R2

R1—~ A—N • E R3 is the following group: R1—0- OH-A′-N E , 丨 R2 wherein A" is the hydrocarbon residue of group a, which is prepared by order. It can be responsive by the reaction shown in Figure 6.

102449 -86- 1363622 〇 丫 A"-CI E I X (XLV)

NaBHd

HO

EIX A"-CI (XLVI)

DEAD Ph3P R1OH R-O'

(XLVIII) A X R2

,A"-N

RJ HNR2R3

R1—0, /A"-CI (XLVI I)

E I X

The starting material in Scheme 6 is a gas-based mercapto compound (XLV) which can be obtained by literature methods (for example, the method described in /. MM. Ckm., 2004, 47, 3924-3926) or It is made in a similar way. The compound (XLV) is converted to a secondary alcohol (XLVI) by reduction with a hydride reducing agent such as sodium hydride in a polar solvent such as water/tetrahydrofuran. The secondary alcohol (XLVI) can then be reacted with a phenolic compound of formula R1 -0H under Mitsunobu alkylation conditions as described above, for example in the presence of diethyl azodicarboxylate and triphenylphosphine. An aryl ether compound (XLVII) is obtained. Then, the gas atom in the aryl ether compound (XLVII) is substituted by reacting with an amine 102449 • 87-1363622 HNR2R3 to obtain a compound of the formula (XLVIII). This nucleophilic exchange reaction can be carried out by heating the amine with an aryl ether in a polar solvent such as an alcohol at a high temperature such as about 100 °C. Heating can advantageously be achieved using a microwave heater. Next, the formed amine (XLVIII) can be subjected to a Suzuki coupling procedure with a formula (XV) as described above, and subjected to a Suzuki coupling procedure to obtain a compound (XLIX).

In a variation regarding the reaction sequence shown in Scheme 6, the secondary alcohol (XLVI) can be subjected to a nucleophilic displacement reaction with the amine HNR2R3, and then the reaction introduction group R1 is formed using Mitsunobu ether. Another way to achieve a compound of formula (I) wherein E and R1 are attached to the same carbon atom in group A is shown in Scheme 7. 102449 -88-

1363622 HO,b/〇H cn

In Scheme 7, the N-protected pyrazolyl dihydroxyborane (5) is reacted with a cyano compound X-E-CN under coupling conditions, wherein X is typically a halogen such as bromine or gas. The protecting group pG at the position of the pyrazole ring can be, for example, > phenylmethyl (trityldihydroxyborane (L) can be produced by the method described in Ep 13826〇3 or the like. Then, the formed nitrile can be reacted with the Grignard reagent R1 · ΜβΒΓ, 102449 • 89-1363622 to introduce the group R1, and form a ketone (LII). The ketone (LII) is in the presence of a strong base such as an alkyl lithium. , in particular, butyl lithium, which is converted to an enamine (LIV) by reaction with diphenylphosphonium decyl decylamine (LIII). Next, the enamine (UV) is subjected to hydrogenation on a palladium/carbon catalyst. In order to reduce the double bond of the enamine and remove the 1-phenylethyl group. In the case where the protecting group PG is a trityl group, the hydrogenation also removes the trityl group, thereby producing a compound of the formula (LV). Alternatively, the enamine (LIV) can be used in .. not # # from 14 (2003) 1309-1316

Under the conditions described, it is reduced with a hydride reducing agent and subjected to palm separation. The removal of the 2-phenylethyl group and the protecting group PG is then protected to obtain an optically active form of the compound of formula (LV). An intermediate of formula (X) wherein A and R2 are bonded to form a ring containing an oxygen atom can be produced by the general method shown in Scheme 8.

102449 90 1363622

Η In Scheme 8, the ketone (LVI) is reacted with triazine iodide to form a vapor (LVII). This reaction is typically carried out in the presence of a hydride base such as sodium hydride in a polar solvent such as dimethyl sulfoxide. The % oxide (LVII) is in the presence of a non-interfering base such as triethylamine, in a solvent such as an alcohol (eg isopropanol), which undergoes ring opening with ethanolamine' usually accompanied by mild heating (eg up to about thief) ). Then, the formed secondary alcohol is cyclized in a solvent, for example, to form a ruthenium dioxazole, and then, under Suzuki coupling conditions, 佶_Mafolin intermediate (LIX) and 1〇2449 -91· ij〇3622 Hydroxyborane ester (XV) is reacted to obtain a compound of the formula (LX) corresponding to the compound of formula 1, wherein a-nr2r3 forms a morpholinol group. Instead of reacting the epoxide (LVII) with ethanolamine, it can be reacted with a mono- or dialkylamine instead, thus providing a means of achieving a compound containing the following groups:

A compound in which both R2 and R3 are hydrogen can be produced by reacting an epoxide (LVII) with potassium phthalate, in a polar solvent such as DMSO. During the Suzuki coupling step, the o-benzidine imine group can be partially hydrolyzed, and the corresponding proline can be cleaved using hydrazine to obtain an amine group NHZ ° or 'standard guanamine can be used. A reagent is formed to recircularize the valine to phthalimide and then the sulfhydryl group is removed using hydrazine to give an amine. Further synthesis of a compound of the formula 1 in which A and NR2R3 are combined to form a cyclic group is shown in Scheme 9.

E I (LXIII) Figure 9 102449 • 92- 1363622

In Scheme 9, the starting material (LXI) is typically a di-tomb/heteroaryl-burning moiety/heteroaryl- or both capable of stabilizing or helping to form an anion between E and Ri. Formed on the methylene group. For example, the ruler may advantageously be pyridine. The starting material (LXI) is in the presence of a non-interfering strong base such as sodium hexamethyldiazoxide, in a polar solvent such as tetrahydrofuran, at a low temperature (eg, about 〇 ° C), with a N_protective pair: The chloroethylamine 1 is reacted along the formula to give the n-protected cyclic intermediate (LXIII). The protecting group can be any standard amine protecting group, such as a B〇c group. After the cyclization, the intermediate (LXIII) is coupled to the formula (?v) dihydroxyborane under Suzuki coupling conditions, and then the protection is removed to obtain the compound of the formula (I). A compound of formula (I) wherein a part of the group: R2 R1—one 乂 E R3 is the group:

Aik r2

R1 - C-CHfN φ E R3 wherein "Aik" is a small alkyl group such as a methyl group or an ethyl group which can be formed by the synthetic route shown in Scheme 1A. 102449 93· 1363622

CO.H

MeOH/H+ (LXIV)

CO.Me (LXV)

LDA Alk-I

HNR2R3

2 R

A n4 i L

2 (LXVIII) (LXIX) In the formula 10, the carboxylic acid of the formula (LXIV) is esterified by treatment with decyl alcohol in the presence of an acid catalyst such as hydrochloric acid. The ester (LXV) is then reacted with a strong base such as lithium diisopropylamine (LDA) and an alkyl iodide such as methyl iodide at a low temperature (e.g., between 0 ° C and -78 ° C). The branched ester (LXVI) is then hydrolyzed to the acid (LXVII) and coupled to the amine HNR2R3 under standard guanamine forming conditions of the type described above. Next, the lithium (Aluminum hydride) can be used to reduce the amine (LXVIII) to the amine (LXIX), and then the amine (LXIX) can be reacted with the pyrazole dihydroxyborane or dihydroxyborane under Suzuki coupling conditions. a compound of formula (1). Once formed, a number of compounds of formula (I) can be converted to other compounds of formula (I) by mutual conversion using standard functional groups. For example, a compound of formula (I), wherein 102449 -94-1363622

NR2 R3 forms part of the nitrile group and can be reduced to its corresponding amine. The NR2R3 is a compound of NH2 which can be converted to its corresponding alkylamine by a reductive alkylation or to form a cyclic group. A compound in which R1 contains a ruthenium atom such as gas or bromine may be subjected to a Suzuki coupling reaction to entangle an aryl or heteroaryl substituent into the R1 group. Further examples of the conversion of a compound of formula (I) to another compound of formula (I) can be found in the examples below. Other examples of reagents and conditions for functional conversion of the functional groups and such transformations can be found, for example, in High #玄讥允学, JerryMarch, 4th edition, ii9, Wiley Interscience, New York, Synthetic Tests, Volumes

John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2), and Synthetic. Volumes 1-8, John Wiley, edited by Jeremiah, P_ Freeman (ISBN: 〇_47i_ 31192-8). In many of the above reactions, it may be necessary to protect one or more groups to prevent the reaction from occurring at an undesired position on the molecule. Examples of protecting groups, and methods for protecting and removing protective functional groups, can be found in poorly protected (T. Green and P. Wuts; 3rd edition; John Wiley & Sons, 1999). Hydroxyl groups can be protected. For example, ether (-0R) or ester (-〇C(=0)R), for example, as: tert-butyl ether; benzyl, benzhydryl (diphenylmethyl) or triphenylsulfonyl ( Triphenylmercapto)ether; tridecyldecylalkyl or tert-butyldidecyldecylalkyl ether; or ethyl decyl ester (-0C(=0)CH3, -OAc). The aldehyde or ketone group may be individually protected as, for example, an acetal (R-CH(0R)2) or a ketal (R2C(OR)2), wherein the carbonyl group (>c==o) is reacted with, for example, a primary alcohol, It is converted into a second (>C(OR)2). The aldehyde or ketone group is readily regenerated by hydrolysis by using a large excess of water in the presence of an acid. The amine group can be protected, for example, by guanamine 102449-95-

1363622 (-NRCO-R) or amino phthalic acid vinegar (-NRCO-OR) 'for example: methyl stearamine (-NHCO-CH3); benzyloxy decylamine (-NHCO-OCH2C6H5, -NH-Cbz) ; become a third-butoxy decylamine (-NHCO-OC (CH3 h, -NH-Boc); 2-biphenyl-2-propoxyguanamine-NH-BP〇c), becoming 9_苐Methyl methoxy decylamine (-NH-Fmoc) ' becomes 6-nitro-cucurbityloxy acid amine (·Ν^_Νν0 (;), becomes 2-trimethyldecyl ethoxy decylamine (_] Book-Ding 6〇(:), which becomes 2,2,2-tris-ethylethyl ylamine (-NH-Troc), becomes allyloxyguanamine, or becomes 2-(beneficiary) Ethoxy decylamine (_Njj_psec). Other protecting groups for amines such as cyclic amines and heterocyclic NH groups, including toluenesulfonyl and methanesulfonyl, and aryl, such as p-methoxybenzyl The base (ρΜΒ) ^ carboxylic acid group can be protected as an ester 'for example: Cw alkyl ester (eg methyl ester; third - butyl ester); c 7 alkyl ester (eg Cl_7 trihaloalkyl); Three €1,7 alkylalkylalkyl-c"alkyl vinegar; or (:5·2〇aryl·Ci·7 alkyl ester (eg, decyl ester; nitrodecyl ester); or decylamine, For example, it is a mercaptoamine. The thiol group can be protected, for example, as an ether (-SR), for example, as a mercapto sulfide; an ethylaminomethyl ether (-s-ch2nhc(=o)ch3). (I) The 1(H) position of the pyrazole in the compound or its precursor can be protected by a plurality of groups, and the protecting group is selected according to the nature of the reaction conditions exposed by the group. , including tetrahydropyranyl, fluorenyl and 4-methoxyindenyl. Many of the above chemical intermediates are novel, and such novel intermediates constitute a further aspect of the invention. Is administered separately, but is preferably presented as a pharmaceutical combination 102449-96-1363622 (eg, a formulation) comprising at least one active compound of the invention, along with one or more pharmaceutically acceptable carriers, adjuvants, Excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials known to those skilled in the art, and, where appropriate, other therapeutic or prophylactic agents.

Accordingly, the present invention further provides a pharmaceutical composition as defined above, and a method of producing a pharmaceutical composition comprising at least one active compound as defined above together with one or more pharmaceutically acceptable carriers, excipients, buffers The agents, adjuvants, tranquilizers or other materials as described herein are mixed together. The term "pharmaceutically acceptable" as used herein relates to a compound, substance, composition, and/or dosage form that is suitable for use with a patient (eg, a human) within the scope of safe and reliable medical judgment. Tissue contact without excessive toxicity, irritation, allergic response or other problems or complications, accompanied by: reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be "acceptable", meaning that it is compatible with the other ingredients of the formulation.

Thus, in a further aspect, the invention provides a compound of formula (I), as defined herein, and subgroups thereof, in the form of a pharmaceutical composition. The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, ocular, otic, rectal, intravaginal or transdermal administration. Where the composition is intended for parenteral administration, it may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or by injection or other delivery means for direct delivery to the target or organization. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions - which may contain antioxidants, buffers, and solutes which make the blood of the compound 102449 -97-1363622 isotonic; and aqueous and non-aqueous No suspending agent and increase _. These formulations can be presented in two: in the case of a Γ 剂量 dose container, such as a sealed ampoules and small glass, σΓΓ; East Dry 0 Donggan, before the use, /, to add a sterile liquid carrier, For example, temporary injection solutions and suspensions for water for injection can be prepared from sterile powders, granules and tablets. In a preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example by injection or infusion. In a further preferred embodiment, the pharmaceutical combination (4) is in a form suitable for subcutaneous (S.C.) administration. Pharmaceutical dosage forms suitable for oral administration, including tablets, capsules, sachets, pills, granules, syrups, solutions, powders, granules, ugly and suspensions, sublingual tablets, flat tablets or patches, and cheek patches . Pharmaceutical compositions containing a compound of formula (I) can be formulated according to known techniques, see, for example, Remington's Medical Sciences, Mack Publishing Company (East〇n, PA, _. Thus, a tablet composition may contain a unit dose of the active compound, Accompanying: an inert diluent or carrier such as a sugar or sugar alcohol such as lactose, sugar, silk alcohol or mannitol; and/or a non-sugar-derived diluent such as carbon steel, disc acid, carbon _ ' or fiber Or a derivative thereof, such as methylcellulose octane, ethyl cellulose, (tetra) fluorenyl cellulose, and starch, such as corn starch. Tablet d may also contain; ^ quasi-ingredients, such as bonding and granulating agents, such as polyethylene a four-gas sputum 'disintegrating agent (such as swellable cross-linked polymeric H, such as cross-linked slow methyl cellulose), a lubricant (such as stearate), preservatives (such as Class), an antioxidant (eg BHT), a buffer (eg, 102449 - 98* 1363622 acid salt or citrate buffer), and a foaming agent, such as a citrate/bicarbonate mixture. It is a custom, so it is not needed here. The capsule formulation may have a hard or soft gelatin type 'and may contain the active ingredient in a solid, semi-solid or liquid form. The gelatin capsule may be formulated as an automatic gelatin or a synthetic or plant-derived equivalent thereof. For example, tablets, etc. can be coated or uncoated, but typically have a coating such as a protective film coating (such as a enamel or varnish) or a release control coating. This coating (eg EudragitTM type polymerization) The body can be designed to release the active ingredient at the desired location in the gastrointestinal tract. Therefore, the coating can be selected to degrade under certain cation conditions in the gastrointestinal tract, and thus in the stomach or in the ileum or duodenum. Selective release of the compound. Instead of or in addition to the coating, the drug may be presented in a solid matrix, and the control agent, such as a release delay agent, may be adjusted to adjust to different acidity or assay conditions of the stomach. Selective release of the compound. Or 'base material or release block can be used in the form of an erosable polymer (eg, suprate:::polymer), when the dosage form is In the gastrointestinal tract, it is substantially continuously eroded. As another blending system in the transport system, the active compound can be released by the osmotic control. Permeation = and other delayed release or sustained release formulations It can be prepared by the methods known to the root. Suspect: Bureau: The composition used includes ointment, cream 1 spray, patch, has been widely used and inserts (such as eyeball interpolated eight). The root can be used in a known method. 102449

-99- 1363622 Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be presented in the form of a finely divided sterile powder. Examples of formulations for rectal or intravaginal administration include pessaries and suppositories, which may, for example, be formed from shaped moldable or loamy materials containing the active compound.

The composition for inhalation (d) can be administered in the form of an inhalable powder composition or a liquid or powder spray and can be administered in a standard form using a powder inhaler device or an aerosol dispensing device. Such devices are conventional. For administration by inhalation, the powdered formulation typically comprises the active compound with an inert solid powdery diluent such as lactose. The compounds of the invention are generally presented in unit dosage form, and thus typically contain sufficient compound to provide the desired degree of biological activity. For example, a formula intended for oral administration can contain! From nanograms to 2 milligrams, for example from 1 milligram to 2 grams of active ingredient, more typically from 1 milligram to 1 gram, such as from 50 milligrams to 5 milligrams or from about 1 milligram to 2 milligrams. The active compound is administered to a patient in need (e.g., a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect. The whitening kinase kinase: 3⁄4, the activity of the compound of the present invention as a protein beta kinase A and a protein kinase b inhibitor can be measured using the detection metrics described in the examples below, and the degree of activity indicated by the special compound. Can be defined by the IC50 value. Preferred compounds of the invention are those which have an IC50 value of less than 1 against protein kinase B and more preferably less than 〇丨. Therapeutic use 102449 -100· 1363622 Prevention or treatment of proliferative disorders The compounds of formula (I) are inhibitors of protein kinase A and protein kinase b. Therefore, it is expected to be used to provide a means of preventing the growth of cell proliferation or causing its cells to wither. Accordingly, it is expected that such compounds will prove useful in the treatment or prevention of proliferative disorders, such as cancer. Specifically, a tumor having a deletion or inactivation mutation in a sputum or a loss of sputum expression or rearrangement in a (τ_cell lymphocyte) TCL-1 gene is particularly sensitive to an ΡΚβ inhibitor. Tumors with other abnormalities that cause upward regulation of the ρΚΒ pathway message may also be particularly sensitive to inhibitors of ΡΚβ#. Examples of such abnormalities include, but are not limited to, overexpression of one or more ΡΙ3Κ subunits, or overexpression of multiple ρκΒ isomeric recombinants, or mutations in ΡΙ3Κ, PDK1 or ΡΚΒ, which result in increased enzymes in the discussion Basal activity, or up-regulation or over-expression or mutational activation of growth factor receptors. The growth factor receptor is selected, for example, from epidermal growth factor EGFR, fibroblast growth factor receptor, and platelet Growth factor receptor (PDGFR), insulin-like growth factor i receptor ru (IGF-1R) and vascular endothelial growth factor receptor (10) syndrome group. It is also envisioned that the compounds of the invention will be useful in the treatment of other conditions caused by proliferative or surviving conditions, such as viral infections, and, for example, neurodegenerative diseases. During the immune response, PKB plays an important role in maintaining the survival of immune cells. Therefore, inhibitors can be particularly beneficial for immune 'diseases' including autoimmune symptoms. ·- This, PKB inhibitors can be used to treat diseases, Among them are diseases of hyperplasia, cell dying or differentiation. PKB inhibitors can also be used for diseases caused by the resistance and insensitivity of tamsin, and the disintegration of glucose, energy and fat stores such as metabolic diseases and obesity in 102449 • 101 - 1363622. - Examples of cancers that can be inhibited include, but are not limited to, carcinomas, such as cancers, bladder, breast, colon (eg, colorectal cancer, such as colon adenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, For example, adenocarcinoma, small cell lung cancer and non-small cell lung cancer, esophagus, gallbladder, ovary, pancreas (eg, exocrine pancreatic cancer), stomach, cervix, endometrium, thyroid, prostate, or skin (eg, squamous cells) Hematopoietic tumors of lymphoid lineage, such as leukemia, acute lymphocytic leukemia, B_cell lymphoma, τ_cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy Cellular lymphoma or Burkett's lymphoma; hematopoietic tumors of the myeloid lineage, such as acute and chronic myelogenous leukemia, spinal dysplasia syndrome or pre-myeloid leukemia, thyroid squamous cell carcinoma; mesenchymal-derived tumors, such as fibrosarcoma or sputum A tumor of the central or peripheral nervous system, such as astrocytoma, neuroblastoma, glioma or schwannomas; melanin Tumor; fine φ cell tumor ‘Saki cancer; osteosarcoma; skin coloration; echinomas aeruginoma; thyroid cell carcinoma, or Kaposi's sarcoma. Thus, in a pharmaceutical composition, use or method of the invention for treating a disease or condition comprising abnormal cell growth, in a particular embodiment, the disease or condition comprising abnormal cell growth is cancer. A special subset of cancers include breast cancer, ovarian cancer, colon cancer, prostate cancer, • official cancer, squamous cancer, and non-small cell lung cancer. Another subset of cancers include breast cancer, ovarian cancer, prostate cancer, endometrial cancer, and glioma. 102449 •102· It may also be the case that some protein kinase B inhibitors may be combined with other anticancer agents such as 'advantageously binding to inhibitors that cause cell dying, and the other may act through different mechanisms to regulate cell growth. Medicaments, therefore, treat two characteristic features of cancer development. Examples of such combinations are detailed below. Immunological disorders PKA and PKB inhibitors may be beneficial for immune disorders including, but not limited to, autoimmune symptoms and chronic inflammatory diseases such as linear lupus erythematosus, autoimmune mediators of spheroid nephritis, rheumatoid arthritis, psoriasis, "Fire disease" and autoimmune diabetes, allergic reactions to hyperthermia, asthma, COPD, rhinitis and upper respiratory diseases. Other therapeutic uses of PKB play a role in cell material, proliferation, and differentiation. Therefore, PKB inhibitors can also be used to treat diseases other than cancer and those associated with immune dysfunction; viral infections such as herpes virus, Epidemic virus, Epstein-Barr virus 'Sindbis virus, adenovirus, mv, HPV, HCV and HCMV; prevent AIDS development in HIV-infected individuals; cardiovascular diseases such as cardiac hypertrophy, restenosis, Atherosclerosis; neurodegenerative disorders such as Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; spheroid Nephritis; a hall of spinal dysplasia, a blood-stasis injury associated with the formation of a muscle infarction, a stroke and reperfusion injury, a degenerative disease of the musculoskeletal system, such as osteoporosis and arthritis, aspirin-sensitive sinusitis, Gallbladder fibrosis, multiple sclerosis, kidney 102449 -103 - 1363622 Dirty disease. Methods of Treatment It is contemplated that the compound of formula (I) will be useful in the prevention or treatment of a disease state or condition in a range mediated by protein kinase A and/or protein kinase B. Examples of such disease states and symptoms are detailed above. The compound of formula (I) is usually administered to a patient in need of such administration, such as a human or animal patient, preferably a human.

These compounds are typically administered therapeutically or prophylactically, and are usually administered in a non-toxic amount. However, in certain conditions (for example, in the case of Wei #Life Disease), the benefit of administering a compound of formula (1) may be more important than the disadvantage of any #sexual effect or side effect, in which case it may generally be considered It is desirable to administer the compound in an amount that is accompanied by a certain degree of toxicity. These compounds may be administered over a long period of time to maintain a beneficial therapeutic effect, or may be administered only for a short period of time. # | i ^ Only music or, it can be pulsating. The typical dose of sputum can be in the range of (10) picograms per kilogram of body weight

Within the range of 100 mg, the industry is stipulated that the j-weight is 10 gram to 10 milligrams for the mother's kilogram. More typically, it is 1 micro-body, 5 丨〇 Α 1 brother to 10 gram, but if needed Higher or lower doses can be administered. Finally, the amount of the compound to be administered will be commensurate with the nature of the disease or physiology + symptom being treated and will be at the discretion of the physician. b) The compound may be administered as a separate therapeutic agent, or it may be administered in combination with other compounds of the combination therapy, such as a compound of the formula (1), which is a cancer of the formula. λ 乐乐 (no sputum is an example of a therapeutic or therapeutic method at the same time or at different time intervals, including but not limited to: 102449 -104· 1363622 • Topoisomerase i inhibitor antimetabolite tubulin standard DNA Adhesives and topoisomerase II inhibitors • alkylating agents • monoclonal antibodies 9

• Anti-hormone • Message transduction inhibitors • Protein degrading inhibitors • DNA methyltransferases • Cytokines and retinoids • Radiation therapy Proteins associated with other therapies f kinase A inhibitors or protein kinases: _ agents The situation 'The two or more treatments can be administered individually and on different schedules and via different routes.

The compound of formula (1) can be administered simultaneously or sequentially in combination therapy with - or a variety of other therapeutic agents. When successively, the sputum can be placed at tight intervals (for example, after 5 _ _ minutes or at longer intervals (for example, 2, 3, 4 or more hours apart, or if needed) Even if it is administered separately for a longer period of time, the precise dose is proportional to the nature of the therapeutic agent. The compound of the present invention can also be used for private therapy, photodynamic therapy, and non-chemotherapeutic treatment, for example, gene therapy. Surgical and Controlled Foods 102449 1363622 for use in combination therapy with another chemotherapeutic agent. Compounds of formula (I) may be formulated with one, two, three, four or more other therapeutic agents. For example, in a dosage form containing two, three, four or more therapeutic agents, the individual therapeutic agents can be individually formulated in an alternative manner t' and presented together in kit form, as appropriate with regard to their use instructions. This artist will use his general knowledge to understand how to take medication, use and combination therapy. # Before the compound of formula (1) is administered, 'patients can be screened' to determine whether the patient is suffering or likely Whether the disease or symptom is a compound that is easily accepted to have a resistance to protein kinase A and/or protein kinase 3 activity. For example, a biological sample taken from a patient can be analyzed to determine whether the patient is suffering or likely to have Symptoms or diseases, such as cancer, are characterized by a genetic or abnormal protein expression that can lead to upregulation of pKA and/or gingival, or sensitization to normal PKA and/or pkb activity pathways. Role, _ «ΚΑ and / or up-regulation of the signal transduction component upstream of PKB as in the case of PKB, PI3K, GF receptor and PDK1 & 2 or 'The biological sample taken from the patient can be directed to the ρκβ pathway A negative regulator or inhibitor, such as a simple loss, is analyzed. In this context, the term "loss" refers to the deletion of a gene encoding a modulator or inhibitor, and the gene's truncation-head (eg, due to mutation)' A truncation of a gene transcript, or a loss-live of a transcript (eg, due to a point mutation) or sequestration by another gene product. Up-regulation - the word line includes increased performance or overexpression, including gene amplification Use (meaning multiple gene duplication) and increase by transcription. 102449 1363622 0

Now, as well as hyperactivity and activation, including activation by mutation. Therefore, the patient can be subjected to a diagnostic test to detect up-regulation of the characteristic markers of PKA and/or PKB. The term diagnostics includes screening. A marker system includes a genetic marker, including, for example, a measure of DNA composition to identify a mutant of PKA and/or PKB. The term marker also includes markers that upregulate PKA and/or PKB up-regulation, including the enzyme activity, enzyme content, enzyme status (e.g., phosphonium or no) and mRNA content of the proteins mentioned above. The above diagnostic tests and screening tests are typically performed on biological samples, selected from tumor biopsy samples, blood samples (isolation and concentration of efflux tumor cells), fecal biopsy, sputum, chromosomes Analysis, pleural fluid, peritoneal fluid or urine.

Individual identification with a mutation in PKA and/or PKB or a rearrangement of TCL-1 or loss of PTEN expression may mean that the patient is particularly well-suited for treatment with PKA and/or PKB inhibitors. Prior to treatment, tumors can be preferentially screened for the presence of PKA and/or PKB variants. Screening procedures typically involve direct sequencing, oligonucleotide microarray analysis, or mutant specific antibodies. Methods for the identification and analysis of protein mutations and upregulation are known to those skilled in the art. Screening methods can include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization. In the RT-PCR screening, the amount of mRNA in the tumor was assessed by establishing a cDNA replica of the mRNA followed by amplification of the cDNA by PCR. The method of PCR amplification, the choice of primers, and the conditions for amplification are known to those skilled in the art, 102449 -107-1363622. Nucleic acid manipulation and PCR are performed by standard methods, such as the current development of molecular biology by Ausubel, FM et al., 2004, John Wiley & Sons, or Innis, MA et al. And application guidelines, 1990, University Press, San Diego. Reactions and manipulations involving nucleic acid technology are also described in Sambrook et al., 2001, 3rd edition, Molecular Asexual Reproduction: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits of RT-PCR (e.g., Roche molecular biochemicals) may be used, or as described in U.S. Patent Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864 and 6,218,529, And for reference in this article. An example of a technique for assessing in situ hybridization of mRNA expression is fluorescence in situ hybridization (FISH) (see Angerer, 1987 Meth. Enzymol, 152: 649). In general, in situ hybridization involves the following major steps: (1) immobilization of the tissue to be analyzed; (2) pre-hybridization of the sample to increase the accessibility of the target nucleic acid, and to reduce non-specific binding; 3) nucleic acid hybridization to a nucleic acid in a biological structure or tissue; (4) post-hybrid washing to remove nucleic acid fragments not bound in hybridization, and (3) detection of hybrid nucleic acid fragments. Probes used in such applications are typically identified, for example using a radioisotope or a fluorescent reporter. Preferably, the probe is sufficiently long, e.g., from about 50, 100 or 200 nuclear acid to about 1000 or more nucleotides to enable specific hybridization under severe conditions with the target nucleic acid. The standard method for performing FISH is described in Ausubel, FM et al., Current Molecular Biology, 2004, John Wiley & Sons, Inc., and In-situ Hybridization with Fluorescence: An Introduction to Technology, described by John MS Bartlett Molecular Diagnosis of Cancer, 102449 • 108-1363622 Methods and Proposals, 2nd Edition; ISBN: 1-59259-760-2; March 2004, pp. 077-088; Series: Methods in Molecular Medicine.

Alternatively, the protein product expressed from the mRNA can be immunohistochemically by tumor sample, solid phase immunoassay using microtiter plate, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow Cell counting methods and other methods known in the art for detecting specific proteins are known. Detection methods include the use of site-specific antibodies. It will be apparent to those skilled in the art that all such conventional techniques for detecting PKB up-regulation or detecting PKB variants are applicable to this situation. Therefore, all of these techniques can also be used to identify tumors that are particularly suitable for treating tumors with PKA and/or PKB inhibitors. For example, as noted above, PKB has been found to be upregulated in 10-40% of ovarian and pancreatic cancers (Bellacosa et al, 1995, Int. J. Cancer 64, 280-285; Cheng et al, 1996, PNAS 93, 3636). -3641; Yuan et al., 2000, Oncogene 19, 2324-2330). Therefore, PKB inhibitors, and in particular PKB/3 inhibitors, are contemplated for use in the treatment of ovarian and pancreatic cancer.

PKB alpha is amplified in human stomach, prostate, and breast cancer (Staal 1987, PNAS 84, 5034-5037; Sun et al, 2001, Am. J. Pathol. 159, 431-437). Therefore, PKB inhibitors, and in particular PKB alpha inhibitors, are contemplated for use in the treatment of human stomach, prostate and breast cancer. Increased ΡΚΒ7 activity has been found in steroid-independent breast and prostate cell lines (Nakatani et al., 1999, J. Biol. Chem. 274, 21528-21532). Therefore, it is conceivable that PKB inhibitors, and in particular PKB τ inhibitors, can be used to treat steroid-independent breast and prostate cancers. 102449 • 109- 1363622 [Embodiment] Experiments The present invention will now be described with reference to the specific embodiments illustrated in the accompanying claims The starting materials for each of the procedures described below are commercially available unless otherwise indicated. In the examples, the compounds produced were characterized by liquid chromatography, mass spectrometry and 1 NMR spectroscopy using the system and operating conditions set forth below. Proton magnetic resonance GH NMR spectroscopy was recorded on a Bmker AV 4 〇〇 instrument at 400·13 , in Me-d3 -0D, operating at 27 C, unless otherwise stated, and reported as follows: Chemical shift 5/ Ppm (proton number, multiplicity, where S = singlet, d = doublet, triplet, q = quartet, heavy drop, br = broad). The residual protic solvent Me〇H (5H=33ippm) was used as an internal reference. For mass spectrometry, the mass referenced to the compound in the presence of gas is 35C1. In each case, where the compound is isolated or formed as a free base, it can be converted to a salt form, such as acetic acid or the hydrochloride salt. Conversely, where the compound is isolated or formed by salt, the salt can be converted to its corresponding free base by methods known to those skilled in the art and then converted to another salt as appropriate. A variety of liquid chromatography systems are used and are described below. Platform System 102449 -110. 1363622 HPLC System: Waters 2795 Mass Spectrometer 4 Detector: Micromass Platform LC PDA Detector: Waters 2996 PDA Acid Analysis Condition 1: Solvent A : Η2Ο (0·1% Formic Acid) Dissolving Agent B: CH3 CN (0.1% formic acid) Gradient: 5-95% Eluent B, after 3.5 minutes Flow: 1.5 ml/min Column: Phenomenex Synergi 4 # Max-RP 80A, 50 x 4.6 mm Acid Analysis Condition 2 : Dissolve A : H20 (0.1% formic acid) Dissolving agent B : CH3 CN (0.1% citric acid) Gradient: 5-95% solvent B, after 3.5 minutes Flow: 0.8 ml / min Column: Phenomenex Synergi 4 # Max-RP 80A, 50x2.0 mm _ Sex Analysis Condition 3: Eluent A: H2O (0.1% formic acid) Eluent B: CH3 CN (0.1% formic acid) Gradient: 5-95% Eluent B, flow over 15 minutes: 0.4 ML/min column: Phenomenex Synergi 4 # Max-RP 80A, 50 x 2.0 mm alkaline analysis conditions 1: Dissolvant A: H2O (10 mM NH4HCO3 buffer, adjusted to pH = 9.5 with NH4OH) 102449 -Ill - 1363622

Eluent B: CH3CN Gradient: 05-95% Eluent B, after 3.5 minutes Flow: 1.5 ml/min Column: Waters XTerra MS q 8 5 4.6x50 mm Qualitative Analysis 彳 Condition 2: Eluent A: H2O ( 10 mM NH4HCO3 buffer adjusted to pH=9.5 with NH4OH

Eluent B: CH3CN Gradient: 05-95% Eluent B, after 3.5 minutes Flow: 0.8 ml/min Column: Thermo Hypersil-Keystone BetaBasic-18 5 //M, 50 x 2.1 mm Qualitative Analysis Condition 3: Dissolving agent A: H2O (10 mM NH4HCO3 buffer, adjusted to pH=9.5 with NH4OH)

Eluent B: CH3 CN Gradient: 05-95% Eluent B, after 3.5 minutes Flow: 0.8 ml/min Column: Phenomenex Luna C 18(2) 5 /tzM, 50 x 2.0 mm Alkaline Analysis Condition 4: Dissolving agent A: H2O (10 mM NH4HCO3 buffer, adjusted to pH=9.2 with NH4OH)

Eluent B: CH3CN Gradient: 05-95% Eluent B, flow over 15 minutes: 0.8 ml/min. 102449 -112- 1363622 Column: Phenomenex Luna Cl8(2) 5 /zM, 150x2.0 mm Polarity Analysis Conditions: Eluent A: H20 (0.1% formic acid) Eluent B: CH3CN (0.1 ° / 〇 formic acid) Gradient: 00-50% Eluent B, after 3 minutes Flow: 1.5 ml / min Column: Phenomenex Synergi 4 " Hydro 80A, 50x4.6 mm MS conditions:

Capillary voltage: 3.5kV or 3.6kV Cone voltage: 30 V Source temperature: 120°C Scan range: 165-700 amu Ionization mode: electrospray negative, positive or positive & negative FractionLvnx System: Waters FractionLynx ( Dual Analysis / Preparation) HPLC Pump: Waters 2525 Syringe - Autosampler: Waters 2767

Mass Spectrometer 4 Detector: Waters-Micromass ZQ

PDA Detector: Waters 2996 PDA Acid Analysis Conditions: Eluent A: H20 (0,1 ° / citric acid) Eluent B : CH3 CN (0_1% formic acid) Gradient: 5-95% Eluent B, after going through 5 min flow: 2.0 ml/min 102449 -113 - 1363622 Column: Phenomenex Synergi 4/z Max-RP 80A, 50 x 4.6 mm polar analysis conditions · Dissolving agent A : H20 (0.1% citric acid) Dissolving agent B : CH3CN (0.1% formic acid) Gradient: 00-50% Eluent B, after 5 minutes Flow: 2.0 ml/min Column: Phenomenex Synergi 4 # Max-RP 80A, 50x4.6 mm MS parameter Acidity and polarity Analysis conditions:

Capillary voltage: 3.5kV

Cone voltage: 25 V

Source temperature: 120°C Scanning range: 125-800 amu Ionization mode: electrospray positive or electrospray positive & negative negative palmarity analysis conditions:

Dissolving agent: MeOH + 0.1% NH4/TFA Flow: 1.2 ml/min Total time: 16.00 min Injection volume: 10 μl Sample concentration: 2 mg/ml Column: Astec, Chirobiotic V; 250 x 4.6 mm mass spectrometer Offline. Asilent System HPLC System: Agilent 1100 System 歹 质谱 Mass Detector : Agilent LC/MSD VL 102449 -114- 1363622

Multi-wavelength detector: Agilent 1100 Series MWD Software: HP Chemstation for palm analysis conditions: Eluent: MeOH + 0.2% NH4/AcOH, flow at room temperature: 2.0 ml/min Total time: 8.5 minutes Injection volume: 20 Microliter. Sample volume: 2 mg/ml column: Astec, Chirobiotic V; 250x4.6 mm on palm precondition 1 : Eluent: MeOH + 0.1% NH4/TFA, flow at room temperature: 6.0 ml / min all time: 10 minutes injection volume: 100 microliters sample concentration: .20 mg / ml column: Astec, Chirobiotic V; 250x10 mm palmarity preparation condition 2: dissolving agent: MeOH + 0.2% NH4/AcOH, Flow at room temperature: 20.0 ml/min All time: 19 minutes Injection volume: 950 μl Sample concentration: 25 mg/ml Column: Astec, Chirobiotic V2; 250 x 21.2 mm MS element (complete analytical method): 102449 -115- 1363622 Capillary voltage: 3000 V Fragment: 150 Gain: 1.00 Dry gas: 12.0 L/min Dry gas T: 350 〇C Nebulizer pressure: 35 (psig) Sweep Drawing range: 125-800 amu ionization mode: electrospray positive

In the examples below, the following indexes are used to confirm the LCMS used.

Conditions: PS-A Platform System - Acid Analysis Conditions 1 PS-A2 Platform System - Acid Analysis Conditions 2 PS-A3 Platform System - Acid Analysis Conditions 3 PS-B Platform System - Alkaline Analysis Conditions 1 PS-B2 Platform System - Alkali Sexual Analysis Conditions 2 PS-B3 Platform System - Alkaline Analysis Conditions 3 PS-B4 Platform System - Qualitative Analysis Conditions 4 PS-P Platform System - Polarity Analysis Conditions FL-A FractionLynx System - Acid Analysis Conditions FL-P FractionLynx System - Polarity Analysis Conditions FL-C FractionLynx System-Pair Palm Analysis Conditions AG-CA Agilent System-Pair Palm Analysis Conditions AG-CP1 Agilent System-Pair Preconditions 1 AG-CP2 Agilent System-Pair Preconditions 2 102449 -116- 1363622 Example 1 2-Phenyl-2-"4-(1Η-pyrazole-4-V-methoxyl-1-ethylamine

Suspension of 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride (134 mg, 〇. 5 mmol, io equivalent) (ArrayPPA-Q02-1) in toluene (0.8 mL) In the liquid, bis(di-tert-butylphosphine) (9) (3 mg '1 mol%) (strem) was added, and the mixture was purged with nitrogen. Add 4-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)-1Η-pyrazole (107 mg, 0.55 mmol, 1.1 eq.) ( A suspension of Aldrich 52, 505-7) in ethanol (0.8 mL) followed by potassium carbonate (415 mg, 3.0 mmol, 6 eq.) in water (2.5 mL). The mixture was purged with nitrogen and sealed. The reaction mixture was heated to 135 ° C for 15 minutes in a CEM ExplorerTM microwave using 50 watts of power. The solvent was removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO.sub.) and concentrated under reduced pressure. The crude reaction mixture was purified by EtOAc EtOAc (EtOAc) eluting Milliol (9%); LCMS (PS-A) Rt 1.79 min; m/z [M+H]+264. Example 2 3-phenyl-2-[3-(1Η-pyrazole-4-m. 1-呙_ 102449 •117-

1363622 2Α· 2-(3-Bromo Mo-V3-茇某·两$

Br a solution of 40% KOH (2.83 g in 5.0 ml of h2) in ethanol (13 ml), add to benzaldehyde (2.85 ml, 28 〇 5 mM) and 3 bromo phenyl acetonitrile (5 g , 25.50 millimoles) in a solution of ethanol (9 ml). Then, the reaction mixture was stirred at room temperature for 2 hr, and then collected by suction, and washed with cold ethanol (6.68 g, 92%). The crude product (3 45 g, 12.14 mmol) was then dissolved in ethanol (35 mL) and heated to 65. Sodium borohydride (459 mg, 12.14 mmol) was added portionwise, and the reaction mixture was kept at this temperature for further 2 s., while cooling, water (1 liters) was added and solvent was removed under reduced pressure. . The residue was partitioned between water (100 ml) and ethyl acetate (1 ml) to separate the organic layer, dehydrated and dried (MgS〇4), and the mixture was transformed into the desired product ( 1 80 g, 52%), which was used without purification.

2-(3-Bromophenyl)-3-phenyl-propionitrile was reacted with 4-(4,4,5,5-tetradecyl-1,3,2-di according to the procedure set forth in Example 1. Oxyboroperin-2-yl)-1Η-pyrazole is reacted to obtain the title compound. (LC/MS: (PS-A) Rt 2.98 [M+H] + 274). 102449 -118: 1363622 Example 3 2·"4-(3,5-Dimethyl-1H-pyrazol-4-yl V苽 1-2-methyl-ethylamine

Follow the procedure of Example 1, but using 3,5-dimethyl-4-(4,4,5,5-tetradecyl-[1,3,2]dioxaboroin-2-yl)-1Η - Leaf sputum saliva (shed molecule D03-BM152) instead of 4-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)·1Η-pyrazole Title compound. (LC/MS: (PS-A) Rt 1.79 [Μ+Η]+292. Example 4 2-(4-Acetyl)-2-|~4-(lH-pyrazole-4-someone 1 -Λ neck

Following the procedure of Example 1, but substituting 2,2-bis-(4-phenylphenyl)-ethylamine for 2-(4-phenylphenyl)-2-phenylethylamine hydrochloride, afforded the title compound. (lC/MS: (PS-A) Rt 1.99 [M+H] + 298). * This starting material can be produced by the method described in jmer. CAem. Soc., 1983, 105, 3183-3188. Example 5 2-Γ3-(3,5-dimercapto-1H-pyrazole-4-V V. 1-1-Momo-ethylamine 5Α. 2-(3-Bromo-based VI-笑篡- Λ面102449 -119· 1363622

Add 4 acetonitrile (500 mg, gamma molar) dropwise to a solution of 3 old _ base (4) in a nitrogen atmosphere at room temperature (in a solution of 2 w, 2 mL, lake millimolar), then The reaction mixture was taught to reflux for a period of 2 hours and then allowed to cool. Then, a hydrogenation clock (leak, in THF, 4.85 ml, gamma molar) was carefully added, and the reaction mixture was further heated under reflux for 16 hours. Upon cooling, the reaction was quenched by careful and dropwise addition of water (5 mL). Then, it was subjected to liquid separation between water (2 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO.sub.4), filtered and concentrated. Purification by ion exchange chromatography gave the desired compound (420 mg, 31%). Tan.-ΜΗ〗}Dimethyl Lane II]Indazole-4-yl)m·Stupyl·△ Amine

The product of 5B was combined with 3,5--4-(4,4,5,5-tetradecyl-[1,3,2]dioxaboron according to the procedure detailed in Example 1. The indole-2-yl)-1 -pyrazole is reacted to give the title compound. (LC/MS : (PS-B) Rt2_54 [Μ+Η]+292)· ΨΊΗ 6 3-Packy-2-"3-(1H-p ratio p sitting-4-V-phenyl 1-propylamine 102449 • 120-

丄JOJOZZ

Add the concentrated ammonia (〇.5 ml) and the 阮尼录 (about (4) in the solution of the product of Example 2 (70 mg, 〇2 * 〇 · · 256 ^ mol, equivalent) in ethanol (25 liters) The water is suspended in water and the reaction mixture is allowed to receive hydrogen for a maximum of four hours. The mixture is allowed to undergo a transition of 8 and the mother liquor is concentrated under reduced pressure to give the title compound, which is purified by pre-(4) phase chromatography] LC/MS: (ps_A) ^ i[M+H]+278 Example 7 1Phenyl-2-"4·ΠΗ·pyrazol-4-yl V Momo]-Two glare 7Α. 2-(4-> 臭笨基)-3-笨基-丙月_

Br

The title compound was obtained in the next step, which was used in the next step without further purification. 7Β·笑某·2_“4-Γ1Η-1^4-基芏篡1-3⁄4 Clear according to the procedure described in Example 1, but with 2-(4-bromophenyl)_3_phenyl·propanenitrile 102449 • 121 · 1363622 Substituting 2-(4-carbene)_2-methylethylamine' to obtain the title compound β 7C. 3-笑某-2-"4-(1Η-pyrazole-4-ylmosadol 1- Face

The nitrile product of Example 7 was reduced using the conditions described in Example 6 to give the title compound. (LC/MS : (PS-B)Rt 3.03 [Μ+Η]+278. Example 8 (3-(4-Phenylphenyl)-3-"4-(1Η-pyrazole-4-Mum 1) -propyl μmethyl-胗8Α. 3-Γ4-bromomethyl)-2-cyano-acrylic acid (J. Med. Chem, 1983, 26, 935-947)

Add hexahydropyridine (27 μL) to 4-bromobenzaldehyde (3 g, 16.21 mmol) and ethyl cyanoacetate (1.9 mL, 17.84 mmol) in toluene and allow the reaction mixture to The <RTI ID=0.0>>>>>> LC/MS : (PS-A2) Rt3.44. 8B. 3-(4-indiyl)-3-f4-indoleyl)-2-azaindole-ethyl ester

A solution of 3-(4-> stinyl)-2-ranyl-acrylic acid (1.5 g, 5.36 house mole) in 102449-122· 1363622 anhydrous toluene (12 ml) Add dropwise to 4-phenylphenyl bromide (0.5 Μ solution in tetrahydrofuran, 6% mL, 696 mmol) at °C. The reaction mixture was heated to 85 <0>C for 3 h, poured on ice, acidified with &lt The organic layer was separated, dehydrated (MgS 〇 4) was filtered and concentrated, and the crude product was purified by flash chromatography eluting with petroleum ether to ethyl acetate / petroleum ether: 95) to give the desired product.

(1.91 g, 91% yield). LC/MS: (PS-A2) Rt3.78[M+H]+391.93. 8C· 3-(4-bromophenyl)-3-(4-carbomethoxy)

3-(4-Diphenyl)-3-(4-carbophenyl)-2-cyano-propionic acid ethyl ester (1.91, 4.87 mmol)

A mixture of acetic acid (10 ml), concentrated sulfuric acid (5 ml) and water (5 ml) was refluxed for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, and then purified and purified by flash chromatography eluting with ethyl acetate/ petroleum ether (i: oxime) to give the desired product (0.82 g, 50%) Yield). LC/MS: (PS-A2) &3.39 [M+H]+ 338.86. 8D. 3-(4-Molyphenyl)-3-(4-carbo-,-N-methyl-dacta

Add guanamine (40% solution in water, o.ii microliters, 1.47 millimoles) with 1-(3-diodinopropyl)-ethylcarbodiimide hydrochloride (〇17g) , 0.88 102449 -123- 1363622 before the '3-(4-bromophenyl)-3-(4-chlorophenyl)-propionic acid (0.25 g, 0.74 mmol) with hydrazine-hydroxybenzene The mixture of triazole (0.12 g, 0-88 mmol) in dichloromethane (3 mL) was stirred for 15 min. The reaction mixture was stirred for 16 hours. The solvent was removed under reduced pressure and residue was partitioned between ethyl acetate and &lt The organic layer was separated, EtOAcjjjjjjjjjjjjj LC/MS : (PS-A2) Rt3.20 [M+H]+353.95. IIJ3-(4-bromo-phenyl)-3-(4-argon-methyl V-propyl 1-methyl-amine

The crude 3-(4-bromophenyl)-3-(4-carbophenyl)-N-methyl-propanamide was cooled to 0 under nitrogen atmosphere, and lithium aluminum hydride (0.075 g, 1_97 m) was added. Moen) with diethyl ether (3 ml). With cooling, vaporized aluminum (0.23 g, 1.69 mmol) was dissolved in E (2 ml) and added to the above solution. The reaction mixture was stirred for 16 hours, and water was added to quenched, basified (2N NaOH) and ethyl acetate. The organic layer was separated, dried (MgSO.sub.4), filtered and concentrated, and then purified and purified on EtOAc EtOAc EtOAc EtOAc. 1D combined with 1E '62% yield). LC/MS: (PS-B3)Rt3.20[M+H]+339.85. _8F. {3-(4-Aceto-based V3-丨4-(1Η-pyrazole-4-yloxacin ι_丙Base-methyl-amine 102449 -124- 1363622

HN

Cl

N-t

[3-(4-Bromophenyl)-3-(4-phenylphenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5 according to the procedure as described in Example 1. - tetradecyl-1,3,2-dioxaboron-2-yl)-111-1*-pyrazole reaction 'obtained the title compound. LC/MS: (PS-B3) Rt 2.63 [M+H]+326.00.

1H NMR (Me-d3 - OD) δ 2.37-2.47 (2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (lH, t), 7.25-7.34 (6H, m), 7.54 (2H,d), 7.92 (2H, s), 8.51 (lH, brs- due to citric acid). Example 9 {3-(3,4 didifluoro-stupyl V3-"4-(lH-pyrazole- 4- Some V laughs its J-propyl μmethylamine 9A_ 3-(4-bromophenyl)-3-(3,4-difluoro-mosa VN-methyl 篡-3⁄4 醢 醢

The title compound was obtained according to the procedure described in Example 8A to Example 8C, but substituting 3,4-difluorophenylmagnesium bromide with 4- phenylphenylmagnesium bromide. </ RTI> <RTIgt; - based on a certain 1-propanamide 102449 • 125- 1363622

3_(4-bromophenyl)_3(3,4-difluoro-phenyl)-N-mercapto-propionamide was reacted with 4-(4,4,5,5 according to the procedure set forth in Example 1. -Tetramethyl-1,3,2-dioxaboron-2-yl)-1 -pyridazole reaction gave the title compound. LC/MS: pS_A2)Rt2.55 [M+H]+341.93.

9C. {3-(3,4·Difluoro-winter-pyrimidin-free hail v stupid

Adding hydrogenated chlorhexidine to 3-(3,4-difluoro-phenyl)-N-methyl-3-[4-(1Η-ρ ratio β-spin-4-yl)- at 0C and nitrogen atmosphere A suspension of phenyl]-propionamide in acetamidine, followed by a solution of gasified lutidine in diethyl ether. Toluene was added and the reaction mixture was heated at 70 ° C for 18 hours. Upon cooling, the reaction was quenched by the addition of water, basified (2N NaOH) and extracted with ethyl acetate. The organic layer was separated, dried (MgSO.sub.4), filtered and concentrated to give the desired compound. Lc/MS : (PS-A2) Rt2.15 [M+H]+328.06.1H NMR (Me-d3 -OD) δ 2.19-2.29 (2H, m), 2.35 (3H, s), 2.51 (2H, t), 4.00 (1H, t), 7.06-7.24 (3H, m), 7.27 (2H, d), 7.52 (2H, d), 7.92 (2H, s). 102449 • 126· 1363622 Instance ίο {3: (3-琢ίbenzene^biazole 4 D benzene]•propyl}•methylamine

The title compound was obtained according to the procedure described in Example 8 but substituting 4-chlorophenylmagnesium bromide for the residue. </ RTI> <RTIgt; 4.13 (1H, t), 7.24 (1H, m), Ί21-136 (3H, m), 7.41 (2H, d), 7.66 (2H, d), 8.50 (2H, s). Example 11 K4.- Oxygen Phenyl)-3-"4-(lH-pyrazole_4·a v v v v decylamine

The title compound was obtained according to the procedure described in Example 9A and 9B, but substituting 4- phenylphenylmagnesium bromide with 3,4-difluorophenylmagnesium bromide. </ RTI> <RTIgt; 2H, d), 7.91 (2H, s). Example 12 i-(4_gasphenyl)-3-f4-(lH-p is more than sal-4-)·stupid i_ and face 102449-127· 1363622 12A. 3-[4-Bromoindole V3-f4-Aza-phenylpropionamide

Adding ammonia (2M solution in methanol, 3.68 ml, 7.36 mmol) to the month 1J '3-(4-Molyphenyl)-3-(4-indolyl)-propionic acid* (〇· 25 g, 0.74 mmol) was stirred with a solution of 1,1'-sodium diimidazole (0.24 g, 1.47 mmol) in dioxane for 45 minutes. The reaction mixture was stirred for 2 hours, and the solvent was evaporated under reduced pressure. Gram, 36°/. yield). LC/MS: (PS-A2) Rt3.08 [M+H]+ 339.93. * This starting material can be made by the method described in Examples 8A to 8C. β 12Β· 3-(4-·; stupid Base V3-(4-气茉V V rain

Replace 3-(4-bromophenyl)-3-(4-chlorobenzene with 3-(4-bromophenyl)_3_(4-hydrophenyl)-propionamide according to the procedure described in Example 8E Base N-methyl-propanamide afforded the title compound. LC/MS: (PS-B2) Rt3.88 [M+H]+359.87. 12C. 3-(4- disordered base)-3- "4-(lH-n ratio. sit-4-) - Stupid 1-Bing

102449 -128- 1363622 3-(4-Bromophenyl)-3-(4-chlorophenyl)-propylamine and 4-(4,4,5,5-tetramethyl) according to the procedure set forth in Example 1. The benzyl-1,3,2-dioxaboron-2-yl)-1 oxime-pyrazole was reacted to give the title compound. </ RTI> <RTIgt; 7.33 (6H, m), 7.54 (2H, d), 7.91 (2H, s). Example 13 3-(3,4-Digas-Benzene)-3-"4-(1 沁pyrazole-4- Methyl 1-propylamine

Ν-Ν Following the procedure described in Example 12, but substituting 4-, 4-diphenylphenylmagnesium bromide with 4- phenylphenylmagnesium bromide afforded the title compound. LC/MS : (PS-A2) Rt 2.17 [M+H] + 345.95.1 H NMR (Me-d3 - OD) &lt;5 2.39 (2H, m), 2.84 (2H, t), 4.07 (1H , t), 7.24-7.31 (4H, m), 7.45-7.49 (2H, m), 7.56 (2H, d), 7.93 (2H, s). Example 14 4-(4-Phenylphenyl)-4- "4-Γ1Η-峨 -4--4-V phenyl 1-hexahydrop than bite 14A· 4-(4-bromophenyl)-4-(4-nitrogen 芏V V6

Add a suspension of 4-(4-bromophenyl)-hexahydropyridine-4-ol (4.02 g, 15.7 mmol) in chlorobenzene (30 mL) dropwise at 〇 °C A solution of vaporized aluminum (7 32 g, 54.9 mmol) in benzene (1 mL). The reaction mixture 102449 • 129- 1363622 was mixed at 0 C for 2 hours. The reaction was quenched by the addition of ice, and then methyl tertiary-butyl ether was added. After stirring for 1 hour, the precipitate was collected by chromatography,jjjjjjjjjjjjjjjjjj ) Rt3.57[M+H]+350,352.

4-(4-Bromophenyl)-4-(4-chlorophenyl)hexahydrop-pyridinyl was 4-(4,4,5,5-tetramethyl) according to the procedure set forth in Example 1. -1,3,2-Dioxaborin-2 -yl)-1 -pyrazole reaction afforded the title compound. </ RTI> <RTIgt; (6H, m), 7.65 (2H, d), 8.37 (2H, s). Example 15 4-(4-methoxy-styl)_4_"4-(1沁pyrazole_4_ylvyl) Six arrows

Following the procedure described in Example 14, but substituting chlorophenyl to the decyl ether, the title compound was obtained. </ RTI> <RTIgt; , 6.90 (2H, d), 7.28 (2H, d), 102449 • 130- 1363622 7.40 (2H,d), 7.65 (2H,d), 8.53 (2H,s). Example 16 Chlorophenyl H-fluorenyl -4-"4-(lH-pyrazole-4_)_ stupyl ι·hexapyridinium 16A. 4-(4-bromophenyl)-4-(4-chlorophenyl)-hexapyridine Small carboxylic acid ethyl ester

Stirring in 4-(4-bromophenyl)-4-(4-indolyl)·hexahydropyridine* (〇28g, 〇8〇 mmol) in dioxane (10 ml) To the suspension, triethylamine (0.45 ml, 3.2 mmol) was added with ethyl chloroantimonate (〇〇85 mL, 〇88 mmol). The reaction mixture was stirred for 3 hours, diluted with ethyl acetate and washed with &lt The organic layer was separated, dried (MgSO4) LCMS: (PS-A2), Rt 4.02 [M+H] + 422, 424. * This starting material can be made by the method described in Example 14A. 16Β· 4-(4: 边..phenyl)-4 -(4-气茉)-i-甲某_六急,呻

Ethyl 4-(4-bromophenyl)-4-(4-phenylphenyl)-hexafluoropyridine small carboxylic acid (〇_28 g, 〇_66 mmol) and lithium hydride under nitrogen atmosphere Aluminum (〇〇 51 g) was suspended in tetrahydrofuran (5 liters) and stirred for 2 hours. The reaction mixture 102449 -131 - 1363622 was quenched by the addition of water. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 2NN. The organic layer was washed with EtOAc (EtOAc m.) LC/MS : (PS-B3) Rt3.78 [M+Hf 363.95, 365.73. s. 4-(4·Phenylphenyl)-1-methyl·4·"4_(ιη-pyrazole_4·yl V芏某ι·六氤旁嗦

η&quot;ν according to the procedure set forth in Example 1, 4-(4-bromophenyl)-4-(4-chlorophenyl)-1-methyl-hexahydropyridine and 4-(4,4,5 ,5-tetradecyl-1,3,2-dioxaborin-2-yl)-1Η-pyrazole was reacted to give the title compound. LC/MS : (PS-B3) Rt 2.90 [M+H] + 352. 1H NMR (Me-d3 - OD) 5 2.41-2.53 (2H, m), 2.82 (3H, d), 2.97-3.12 ( 4H, m), 3.56-3.59 (2H, m), 7.28 (2H, s), 7.34 (1H, m), 7.42 (1H, d), 7.49 (1H, d), 7.54 (1H, d), 7.61 (1H, d), 7.75 (1H, d), 8.52 (2H, d).

Example 17 4-Momot-4-丨4-ΠΗ-pyrazole-4-yl V-m- 1--It.pyridine CX〇h

Follow the procedure described in Example 1 but substituting 4-(4- gasphenyl)-2-phenylethylamine hydrochloride for 4-(4-phenylphenyl)4-phenyl-hexa-pyp 'Get the title compound. LC/MS : (PS-A2) Rtl-88 [M+H]+304.^NMRCMe^-OD) δ 2.65-2.71 102449 •132·

1363622 (4H,m), 3.21 (4H,t), 7.18-7.22 (1H,m),7.32-7.38 (6H,m),7.55 (2H,d), 7.93 (2H, s). Example 18 4- "4-(3.5-dimethyl-lH-pyrazole-4-V-M-1-4-M-Pyridyl-hexa-pyridine)

fTN k · according to the procedure described in Example 1, but with 2-(4-phenylphenyl)-2-phenylethylamine hydrochloride and 4-(4,4,5,5-tetradecyl- 1,3,2-dioxaboron-2-yl)-1Η-pyrazole substituted 4-(4-phenylphenyl)-4-phenyl-hexahydropyridine with 3,5-dimethyl-4 -(4,4,5,5-Tetramethyl-[1,3,2]dioxaborin-2-yl)-1 oxime-pyrazole gave the title compound. LC/MS : (PS-A2) Rt 2.95 [M+H]+ 315. 1HNMR (Me-d3-OD) δ 2.22 (6 Η, s), 2.66-2.76 (4 Η, m), 3.16-3.28 (4H , m)3 7.19-7.44 (9H, m). Example 19 Dimethyl-indole-"4-(indolyl-4-yl)-styl 1-3-pyridin-2-yl-propyl amine

The title compound was obtained according to the procedure described in Example 1 but substituting 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride to bromophenamide maleate. LC/MS : (PS-B2) Rt2.29 [M+H]+307.1HNMR (Me-d3-OD) δ 2.44-2.54 (1 Η, m), 2.59-2.70 (1H, m), 2.77 (6H, s), 2.93-3.01 (2H, m), 4.20 (1H, t), 7.25 102449 133·

1363622 -7.28 (1H, m), 7.32-7.36 (3H, m), 7.54 (2H, d), 7.75 (1H, dt), 7.94 (2H, brs). Example 20 (2-(4-氦茉) )-2-Γ4-(1Η-pyrazole-4-V-Mumone 1-Ethyl 丨-Dimethyl-Neck 20Α. 2.2-别-(4-气茉VN.N-Dimethyl-B Neck

The bis-(4-chlorophenyl)-acetic acid was reacted with dimethylamine to give the title compound according to the procedure as described in Example 8D. LC/MS: (PS-A2) &amp;3.40 [Μ+Η]+ 309.95. 20Β.『2,2-Bis-(4-Gas-V-V-B- 1-Nan-Amine

Replace 2,2-bis-(4- gas with 3-(4-bromophenyl)-3-(4-chlorophenyl)-N-methyl-propionamide according to the procedure described in Example 8E Phenyl)-N,N-didecyl-acetamide afforded the title compound. LC/MS: (PS-B2)Rt3.75 [M+H]+295.99. 20C. {2-(4-气茉某ν2-Γ4-(1Η-pyrazole-4-V 芏一1-B Dimethyl-anthracene

[2,2-bis-(4-phenylphenyl)-ethyl]-dimethyl-amine and 4-(4,4,5,5-tetramethyl-) were subjected to the procedure as described in Example 1. 1,3,2-Dioxaboron-2-yl)-111-pyrazole 102449-134- 1363622 The reaction was obtained to give the title compound. LC/MS: (PS-B2) Rt3.07 [M+H]+ 325.99. ^NMROVle-dj-OD) δ 2.5 (6Η, s), 2.98 (2Η, dd), 4.34 (1Η, t), 7.31 -7.36 (6H, m), 7.50 (2H, d), 7.92 (2H, s). Example 21 (2-f4-氪茉V2-"4-(lH-pyrazole-4-V. - B methyl-amine

Following the procedure described in Example 20, but substituting decylamine to afford the title compound. 1^/!^:(?3七2)1^2.83|&gt;1+11]+312.07.111丽11(:1^-(13-OD) δ 2.42 (3Η, s), 3.20-3.23 ( 2H, dd), 4.18 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.92 (2H, br s). Example 22 {2-(4- gas base)-2 -"4-(lH-pyrazole-4-篡笑基1-ethylμ甲甲-amine〇〇

It was prepared using the same procedure as in Example 21, but the palm isomers were separated by HPLC for palm preparation, using the AG-CP2 method. LCMS : (AG-CA) Rt 5.58 min ' 97.4% ee.1H NMR (Me-d3 - OD) 5 2.75 (3 Η, s), 3.78 (2 Η, d), 4.43 (1H, t), 7.39 (4H , s), 7.44 (2H, d), 7.69 (2H, d), 8.43 (2HS s). 102449 • 135· 1363622 Example 23 1H4-Gamol)-2-indole 4-(1Η-pyrazole-4- A V芏篡1-λ七丄·甲某领(9)

It was prepared using the same procedure as in Example 21, but the palm isomers were separated by HPLC for palm preparation, using the AG-CP2 method. </ RTI> <RTIgt 7.43 (4H, m), 7.49 (2H, d), 7.73 (2H, d), 8.66 (2H, s). Example 24 4 bis {2-(4-chlorophenyl)-2-f4-(lH- Pyrazol-4-yl)-mosyl 1-ethyl-μ?

Q Following the procedure described in Example 20, but substituting dimethylamine for the title compound. LC/MS : (PS-B3) Rt 3.07 [M+H] + 368.05. WNMR (Me-d3 - OD) δ 2.50 (4H, m), 2.97 (2H, m), 3.60 (4H, t), 4.26 (1H, t), 7.27 (6H, m).7.49 (2H, d), 7.89 (2H, s). Example 25 4-{4-"1-(4-Phenylphenyl)-2-tetraindole p is slightly smaller than a certain · ethyl l · cage base - p than 嗤 102449 -136 - 1363622

Following the procedure described in Example 20, but substituting dimethylamine for the tetrahydropyrrole, the title compound was obtained. LC/MS: (PS-A^R^.i^pVI+HrSSlOl.iHNMR (Me-d3 -OD) δ 1.85 (4Η, m), 2.87 (4Η, m), 3.47 (2H, d), 4.31 ( 1H, t), 7.30-

7.37 (6H, m), 7.54 (2H, d), 7.92 (2H} s). Example 26 (2-(4-Phenylphenyl)-2-"4·ΠΗ-pyrazole-4·1 V smile 1-L 丨-isopropyl-amine

Following the procedure described in Example 20, but substituting isopropylamine to afford the title compound. LC/MS : (Me-d3-OD) δ 1.3 l(6H,d), 3.38-3.45 (ΙΗ,ιη), 3.65-3.74 (2H,m), 4.39 (1Η, br t), 7.37 (6H, m), 7.59 (2H, d), 7.94 (2H, s). Example 27 Dimethyl-{2-jax-2-"4-(lH-pyrazol-4-yl-V-methyl 1- 1-indole U胗

102449 -137- 1363622 The title compound was obtained according to the procedure described in Example 20. LC/MS : (PS-B2) Rt 2.82 [M+H]+ 292.11.1H NMR (Me-d3 - OD) δ 2.25 (6H, s), 2.95-3.04 (2H, m), 4.20 (1H, t ), 7.16 (1H, t), 7.26-7.33 (6H, m), 7.49 (2H, d), 7.89 (2H, s). Example 28 {2,2-bis-indole 4-(1Η·pyrazole- 4-based V-m- 1--V-dimethyl-amine

The title compound was obtained according to the procedure of Example 20: LC/MS: (PS-B2) Rt 2.45 [M+H]+358.11.1H NMR (Me-d3-OD) δ 2.69 (6H, s), 3.59 (2H, d), 4.43 (1H, t), 7.39 (4H, d), 7.57 (4H, d), 7.93 (4H, s). Example 29 {2,2-Do--"4-(lH- Oxazol-4-yl V-m- 1--a certain μ-a certain

The title compound was obtained according to the procedure described in Example 21. LC/MS : (PS-B2) Rt 2.18 [M+H] + 344.11.1HNMR (Me-d3-OD) 5 2.65 (3H, s), 3.60 (2H, d), 4.34 (1H, t), 7.36 (4H, d), 7.59 (4H, d), 7.94 (4H, s). 102449 -138· 1363622 Example 30 M4-gas benzene)·2-Γ4-Γ1Η-pyrazole-4-yl-methyl 1 -ethylamine

Prepared using the same procedure as in Example 4, but the palm isomer was separated by HPLC for palm preparation, using the AG-CP1 method. LCMS: (FL-C) Rt 10.97 min, 95.7% ee. 1H NMR (Me-d3 - OD) &lt;5 3·65 (2H, m), 4.30 (1H, t), 7.35-7.40 (6H, m), 7.64 (2H, d), 8.16 (2H, s) Example 31 1-(4- gas 袈V2-"4-[lH-pyrazole-4-V 芏一1-ethylamine (8)

I

It was prepared using the same procedure as in Example 4, but the palm isomer was separated by HPLC for palm preparation, using method AG-CP1. LCMS: (FL-C) Rt9.63 min, 1000/〇^.111 should be 11(]^-(13-00)(5 3_66(211,111), 4.30(111,〇,7.35- 7.40 (6H, m), 7.64 (2H, d), 8.15 (2H, s). Example 32 2-(4- gas stupid V2-"4-aH-pyrazole-4-V 芏一1- acetamide 102449 - 139· 1363622

Following the procedure of Example 12A, followed by the procedure described in 12C, but replacing bis-(4-chlorophenyl)-acetic acid with 3·(4·bromophenyl)-3-(4-chlorophenyl)-propionic acid The title compound was obtained. LC/MS: (PS-A2)Rt 2.53 [M+H]+31 (5 4.99

(1H, s), 7.30-7.33 (6H, m), 7.55 (2H, d), 7.86-8.02 (2H, br s). Example 33 1-(2-(4-气茉基V2-丨4- ΠΗ-pyrazole-4-V-Methoxy 1-Ethyl-Six-i. Pyridin 33A.譬-(4-Gasyl V-acetaldehyde

Dess-Martin periodinane (3.17 g, 7.49 mmol) was added to a solution of 2,2-bis-(4-chlorophenyl)-ethanol in dioxane (40 mL). The mixture was stirred under nitrogen for a period of 17 hrs. </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; No further purification required LC/MS: (PS-B3) Rt3.62 [M+H]+262.91.

IjB. 4_"2,2·别_(4 oxybenzoquinone)-Bail 1 - Right _ Royal Pyridincarboxylic Acid Third-Butyl Ester

1363622 Y-BOC-hexahydropyrazine (1.05 g, 5.61 mmol) was added to a solution of methanol in a solution of methanol (3.7 g). The reaction mixture was stirred for 1 hour before the addition of sodium cyanoborohydride (0.28 g, 4 - 49 mmol). The reaction mixture was stirred for 18 h, water (3 mL) was then evaporated and evaporated. The residue was partitioned between dichloromethane and water, and the organic layer was separated, dried and dried (MgS?), filtered and concentrated. Purification by flash chromatography eluting with EtOAc (EtOAc) (EtOAc:EtOAc) LC/MS : (PS-A2)Rt 2.66 [M-BOC+H]+335.02. ljC_ l-j~2,2-bis-(4- gas-ethyl-1-six gas g well

4-[2,2-bis-(4-carbophenyl)-ethyl]•hexahydrop is phage- _ι· tartrate third butyl ester in ethyl acetate (saturated '5 ml) in HC1 The title compound was obtained as the HCl salt. 13D: 1-{2-(4-Oxophenyl)-2-"4-indolyl]-pyrazol-4-yl-V-phenyl 1-ethyl hexamidine

Κ~Ν According to the procedure set forth in Example 1, bis-(4-phenylphenyl)-ethyl]-hexahydropyrazine and 4-(4,4,5,5-tetradecyl^3,2 - Dioxaboron-2-yl)-1Η-pyrazole 102449 • 141 · 1363622 The reaction was obtained as the title compound. LC/MS: (PS-B3) 1^2.63 [M+H]+326.00.^NMRCMe^-OD) &lt;5 3.55-3.68 (8H,m), 3.74 (1H, t), 4.10-4.17 (2H , m), 7.39 (2H, d), 7.48 (2H, d), 7.54 (2H, d), 7.70 (2H, d), 8.57 (2H, br s). Example 34 M2-(4-Gamol V2-丨4-(lH-pyrazol-4-yl V-methyl-l-ethylhydrazine-hexahydropyridine

Following the procedure described in Examples 33A, 33B and 33D, but substituting hexahydropyridine for N-BOC-hexahydropyridinium, the title compound was obtained. </ RTI> <RTIgt; m), 2.94-3.09 (2H, m), 4.26 (1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s). Paste 35 4-Ι4-Γ2 - 一气四圜-1-yl-1-(4- gas stupid ethyl 1-styl than saliva 35Α. 2-(4-gas base V2-"4-(lH-pyrazol-4-yl Stupid 1-ethanol

2,2_bis-(4-hydrophenyl)ethanol and 4-(4,4,5,5-tetradecyl-U,2-dioxaboron were prepared according to the procedure set forth in Example 1. 2-Methyl)-m-pyrazole was reacted to give the title compound. LC/MS: (PS-A2)Rt 2.72 [M+H]+299.00. 102449 • 142·

Substituting 2,2·bis(4-chlorophenyl)ethanol for 2-(4-phenylphenyl)-2-[4-(1Η-pyrazol) based on the procedure described in Example 33A Phenyl]-ethanol gave the title compound. LC/MS'(PS-BS)^ 2.97 [M+H]· 294.98. 35C. 4-{4 must be one 氡 four 圜-ΙΑ^Ι-(4-nitrogen VV 乙一一笑笑[1H - Pipa

1363622 According to the procedure described in Example 33, but with (4_gasphenyl)_[4_(1Η_carbazole-4-yl)-phenyl]-acetaldehyde and a nitrogen-nitrogen substitution _(4_gas Phenyl)-acetaldehyde and N_B〇c_ hexahydropyrrole to give the title compound. LC/MS : (PS-B3) Rt 2.99 [M+H] + 338.09.1H NMR (Me-d3 - OD) δ 3.57-3.60 (1H, m), 3.63-3.70 (2H, m), 3.71- 3.77 (1H, m), 4.01 (2H, m), 4.14 (2H, m), 4.40 (1H, t), 7.40 (4H, br s), 7.49 (2H, d), 7.73 (2H, d), 8.69 (2H, br s). Example 36 1-phenyl-2-"4-(lH-pyrazani-4-indole-4-ylethylamine 102449.143* 1363622

According to the procedure described in Example 5, but with 4-Kiji-based desertification of magnesium and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-indole-2- Substituting -1Η·pyrazole to replace 3-bromoindenyl magnesium bromide with 3,5-diinyl (4,4,5,5-tetramethyl-[1,3,2]diox圜-2-ylindole-pyrazole, the title compound was obtained. LC/MS: (PS-B2) Rt 2.44 [Μ+Η]+ 264.04. 1H NMR (Me-d3 -0D) δ 2.99 (2Η,d), 4.13 (1Η,t), 7.10 (2Η,d), 7.20-7.38 (5H, m), 7.45 (2H, d), 7.91 (2H, s). Example 37 "4-(5-mercapto-3- Triterpenemethyl-1H-pyrazol-4-yl V stupyl 1-ethylocyanium 4-Hinter-5-methyl-H tetra-o-hydan-2-yl)-3-trifluoromethyl -1H-P this saki

Br Γ MevSrCF3 ~- Vi s' in 4-bromo-5-methyl-3-trifluoromethyl-1Η·pyrazole (14 g, 6 2 mmol, 1·〇 equivalent) in gas imitation (31 To the solution in ML), p-toluenesulfonic acid monohydrate (118 mg, 〇_62 mmol, 〇1 equivalent) was added. The solution was allowed to cool to 〇 ° C, and 3,4-dihydro-2H- spur (0.85 mL, 9 3 mM, t 5 eq) was added dropwise over 5 minutes. The mixture was allowed to warm to room temperature for a few hours and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (Si.sub.2), eluting with a 25% crude oil under a linear gradient to give the title compound Μ 102449 • 144 - 1363622 g (59%), LCMS (PS-A) Rt3.72 min [M+H]+314. 37B. {4-"5-Methyl-1-(tetramethane-inhibited-2-yl)-3-trifluoromethyl-lH-p than saliva- 4-its ι__

The product of Example 37 was obtained as 4-bromo-5-methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazole with 4-(cyanomethylphenyl) Dihydroxyborane (Combi-Bl〇cks, San Diego, USA Catalog No. 2444-001) was reacted under the conditions described in Example 1 to give the title compound. 37C. Γ4-(5-methyl-3-trifluoromethyl-1H-pyrazole-4-yl V-methyl 1-1-month luxury

{4-[5-Methyl-1-(tetrahydro-pyran-2-yl)-3-trifluoromethyl-1H-pyrazol-4-yl]- in ethyl acetate (1 mL) To a solution of phenyl}-acetonitrile (Example 8B) (35 mg, EtOAc. The solvent was removed under reduced pressure and the title compound was purified eluting with EtOAc EtOAc (EtOAc) A) Rt2.85 min [M+H]+266. 17D. Compound of formula (I) from Γ4-(5-methyl-3-trifluoromethyl-1H-pyrazole-4-篡V laughing y 102449 Preparation of -145- (〇. The product of Example 378 was reacted with benzaldehyde under the conditions described in Example 2 to give 2-[4-(5·methyl-small(tetrahydro-pyran-2-yl) 〇_Trifluoromethyl-1H-pyrazol-4-yl)-phenyl]_3•phenyl-propionitrile, which can be removed by the removal of 1·tetrahydrogen under the conditions described in Example 37c Removal of the protective reaction with a meridinyl group affords 孓f-methyl-3-trifluoromethyl-1H-pyrazole-4-yl)-phenyl]_3_phenyl-propanenitrile. :[4-(5-methyl- 3-trifluoromethyl-1 Η·, carbazolyl)-phenyl]_3 phenyl-propanonitrile or its 1-tetrahydropyranyl derivative can be reduced according to the method of Example 6 (then, if necessary, The protection was removed according to the method of Example 41C to give 2_[4_(5-mercapto-3·trifluoromethyl-1Η-pyrazol-4-yl)-phenyl]-3-phenyl-propylamine. Example 37 product of hydrazine with benzyl bromide Magnesium or phenylmagnesium bromide, reacted under the Grignard reaction conditions described in Example 5, individually obtained (as removed by the method of Example 37C), benzyl-2-[4-(5-methyl!trifluoromethyl) _1_1H 峨嗤-4-yl)-phenyl]-ethylamine and 2-[4-(5-fluorenyl·3·trifluoromethylpyran-4-yl)-benzyl-1-phenyl -ethylamine. Example 38 The construction of the pyrazole ring system 38A. 4-(4-bromo-based V3-methyl-1H-pyrazole

Add N,N-dimethylguanamine dimercape acetal (113 ml, 4 g) to phenyl phenylacetone (5.0 g, 23_5 mmol, 1. 〇 equivalent) (Acr〇s organic material 34216). 102449 • 146- 1363622 846 millimolar '3.6 equivalents) and the mixture was heated to 90 ° C for 6 hours. The solvent was removed and the resulting gum was dissolved in ethanol (235 mL) with additional heating. The hydrazine hydrate (1 37 ml, 28 2 mmol, 12 2 equivalent) was added and the mixture was heated to reflux for 15 hours. The solvent was removed under reduced pressure and the title compound was mjjjjjjjjjjjjjj 8B. Conversion of 4-(4: phenyl)-3·methyl-1H-pyrazole to the compound of formula (I) (1) 4·(4_ desert phenyl)-3-methyl-1H-pyrazole Protection was carried out at the 1-position of the pyrazole ring by formation of a tetrahydropyranyl (THP) derivative according to the procedure set forth in Example 38A. The Grignajd reagent can then be prepared from the phenyl moiety by standard treatment of the protected phenyl group by an ether solvent (see J. March, Yan Shicai Socks/6, 4th Edition, 1992, John Wiley, New York, pp. 622-625). Grignard reagent can be reacted with nitrostyrene (this nitrostyrene has been prepared by standard methods, such as the method described in the book, vol. 1, p. 413), and the nitro group formed Reduction of the ethyl compound to give 2-{4-[3-methyl-1-(tetrahydro-pyroxan-2-yl)-lH-pyrazol-4-yl]-phenyl}-2-phenyl -ethylamine. Removal of tetrahydropurine β-lamyl group by the method of Example 8C gave 2-{4-[3-mercapto-1 Η-pyrazol-4-yl]-phenyl}-2-phenyl-ethylamine. (ii) The bromine compound of Example 38A can be converted to a compound of formula (I) wherein group A contains a nitrogen atom attached to group E. The introduction of a gas-containing entity can be carried out via the compound of Example 38A, and [3-(4-phenylphenylamino)-propyl]-methyl-amine methyl acid, a third-butyl ester, in 2002, Volume 4, Phase 17, palladium-catalyzed amination conditions of the type described in pages 2885-2888, followed by removal of the third-butoxycarbonyl protecting group by standard formula 102449 • 147-1363622. Example 39 Ρ-(1Ιί-ρ than sal-4-yl, benzoquinone ___

The title compound was obtained according to the procedure of the procedure in Example 1 but using 3-bromophenyl-acetonitrile instead of 2-(4-carbazyl)-2-phenylethylamine. LCMS (ps_A) 235 min [M+H]+ 184. 3-(1 as </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> </RTI> </RTI> </RTI> </RTI> acetonitrile can be used as an intermediate in the preparation of compounds of formula (1) The aldol condensation reaction as described in Example 2 or the Grignard reaction as described in Example 5. Example 40 2-(4-Chlorophenyl)-N-methyl-; 2-丨KiH-^ ° Sit 4-V-benzoic 1-Ethylamine

H'N was followed by the procedure described in Example 12, followed by 12c, but with 3-(4-bromophenyl)-3-(4-chlorophenyl)-propionic acid in place of bis-(4-indolyl) Acetic acid, and the amide was replaced with ammonia to give the title compound. 1:(:/]\^你-八2): at 12.641&gt;1+11]+326· 1H NMR (Me-d3 -OD) 5 2.79 (3H, s), 4.94, (1H, br s) , 7.26-7.35 (6H,m), 7.55-7.57 (2HS m), 7.96 (2H, br s) 102449 -148-

1363622 Example 41 N-Methyl-2,2-#-Γ4-ΠΗ-pyrazole-4-yl V-yl 1-acetamide

The title compound was obtained according to the procedure described in Example 40. LC/MS (PS-A2): Rt 2.19 [M+H]+358.1HNMR (Me-d3-OD) δ 2.80 (3H, s), 4.95, (1H, br s), 7.32 (4H, d) , 7.56 (4H, d), 7.98 (4H, br s) Example 42 {2-(4-Phenylphenyl)-2-"4·(1Η-pyrazole-4-V-methoxyl 1-ethyl-μ A certain amine - amine 42 Α. Κ 4- bromo moth V2-methylamine - Λ

2-(4-Bromophenyl)-oxirane (〇5 g, 2.51 mmol) in methylamine (6.6 mL '33% by volume in ethanol, 25.12 mmol) Stir at room temperature under nitrogen atmosphere. After 18 hours, the solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with di-methane: methanol: acetic acid: water (12 〇: 15:3.2) to give the desired compound. For acetate. Further purification on a Phenomenex Strata SCX column was carried out with methanol followed by 2N ammonia in methanol to afford the desired product. lC/MS : (PS-B3)Rt2.52 [Μ+Η]+230· 42Β. "2·(4ι-side phenyl)-2-(4-qi-methyl-ethyl 1-a-face 102449 1363622

Cl

Aluminium chloride (278 mg '2.087 mmol) was added in portions to i_(4-indiyl) 2-methylamino-ethanol (160 mg, 0.696 mmol) in benzene (3 mL) The solution was mixed and the reaction mixture was stirred at room temperature for 17 hours. Water (2 ml) was added dropwise. The reaction mixture was then partitioned between di- methane (1 mM) and saturated NaHC EtOAc (3 mL). The organic layer was dried (MgSO.sub.4), filtered and concentrated. Then, the crude product was purified by EtOAc EtOAc (EtOAc) elute Lc/MS : (PS-B3)R_t3.58 [M+H]+324. 42C. {2-(4-乳笨基)-2-Γ4-(1ΙΚ g坐-4-某)-策某1 ·B methyl-amine

[2-(4-Benyl)-2-(4-carbophenyl)-ethyl]•methyl-amine (6.1 g, 13.716 mmol), 4-(4,4,5,5 -tetramethyl-1,3,2-dioxaboron-2-yl)-1Η-pyrazole (5.3 g, 27.431 mmol) and K3P〇4 (1〇_19 g, 48.00 mmol) A solution of ethanol (7.5 ml), methanol (11.5 ml), toluene (7.5 ml) and water (11.5 ml) was purged with nitrogen for 2 minutes. Then bis(tris-tert-butylphosphine)palladium(9) (175 102449 -150·1363622 mg, 2.55 mol%) was added and the reaction mixture was purged with nitrogen for 2 min. The mixture was then heated to 80 ° C over a period of 17 hours under nitrogen. The solvent was removed and the residue was partitioned between ethyl acetate and 2N NaOH. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO.sub.) and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography (EtOAc) eluting eluting elut elut ) Rt2.08 minutes [M+H]+312.

Example 43 {2-(4-Acetyl)-2-indole 4-(1Η-ρ is 嗤-4-基策基乙乙乙胺

Following the procedure described in Examples 42A to 42C, but replacing ethylamine with methylamine, the title compound was obtained. LC/MS : (PS-A2) Rt2.11 [M+H]+ 326. iHNMR (Me-d3-OD) δ 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). Example 44 4-{4-[l-(4-Phenylphenyl)- 2-imidazole-1-yl-"" ι·芏某丨_出_pyrazole 102449 -151 - 1363622

The title compound was obtained according to the procedure described in Examples 42A to 42C. </ RTI> <RTIgt; 4H, s), 7.53-

7.60 (3H, m), 7.70 (1H, s), 8.05 (2H, s), 9.0 (1H, s). Example 45 Methyl-丨2-(4-phenyloxy-styl)-2-" 4-ΠΗ-pyrazole-4-one)-3⁄4:篡1-hexyl-amine 45A. "2-(4-Mo Phenyl)-2-(4-indolyl)-Methyl) a certain 1-methyl-amine 9

The title compound was obtained according to the procedure described in Example 42B, but substituting diphenyl ether with chlorobenzene and using nitrobenzene as solvent. LC/MS: (ps_A2) Rt2.54 [M+H]+382. 迎.Methyl-{2-(4-丰氧全斗某,_装基胺 102449 •152- 1363622

Following the procedure described in Example 42C, but substituting [2-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]-indolyl-amine [2-(4-bromo-phenyl) 2-(4-Phenoxy-phenyl)-ethyl]-methyl-amine gave the title compound. LC/MS : (PS-B3) Rt 3.04 [M+H] + 370. NMRCMe^- OD) δ 2.75 (3Η, s), 3.75 (2Η, d), 4.38 (1Η, t), 6.98 ( 4H, dd), 7.12 (1H, t), 7.33-7.40 (6H, m), 7.61 (2H, d), 7.95 (2H, s). Example 46 {2-(4-methoxy-stupyl V2 - "4-riH-pyrazol-4-yl)-3⁄4: a 1-ethyl-μ-methyl-amine 46 Α. "2-(4-bromophenyl)-2-(4-methyl hydrazine - 莫V-ethyl 1-methylamine

The title compound was obtained as a mixture of regioisomers (about 4:1) with their corresponding o-methoxy analogs, following the procedure described in Example 42B. LC/MS : (PS-B3) Rt3.24 [M+H]+ 320. 46Β·"2-(4ι-side phenyl)·2-(4·甲气基-笨基基-甲篡-

102449 • 153- 1363622 Add BOC2 Ο (941 mg, 4.309 mmol) to [2 (4 bromophenyl) 2 (4 methoxy-phenyl)-ethyl]-amine (and its regional differences) The structure) (138 g, 4.309 mM) in a solution of dichloromethane. After 16 hours of scrambling for 16 hours at room temperature, the crude product was removed by flash chromatography and eluted with ethyl acetate/petroleum ether (1:9) to give intermediate B. The compound protected by 〇c is the desired single isomer (54 〇 mg). Then, the product was stirred for 3 days in a saturated solution of HCl (3 mL). The bath was removed under reduced pressure to give the title compound as the HCl salt. LC/MS : (PS-B3)Rt3.21[M+H]+320. Orphan: (2_(4·methoxy-phenyl)-2-"4-[1Η·pyrazole_4_ylmos某一一一一甲甲一_脖

Following the procedure described in Example 42C, but substituting [2-(4-bromophenyl)-2-(4-carbophenyl)ethyl]-methyl-amine for [2-(4-bromophenyl)- 2-(4-Methoxy-phenyl)-ethyl]-methyl-amine gave the title compound. LC/MS : (PS-B3) Rt 2.52 [M+H]+ 308. lHNMR(Me-d3-〇D) ^ 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 47 Methyl-丨2 -丨4-(pyroxy-2-yl chloride, v, 1-2-Γ4-ΠΗ-pyrazole-4-mumyl 1-ethyl}-amine 47Α· 4-『1-(4-bromo Methyl)-2-methylamine stomach ethyl V phenol 102449 -154· 1363622

Add boron tribromide (7.8 ml, 1 〇M in digassole) slowly to [2-(4-bromophenyl)-2-(4-methyl) at 0 ° C under nitrogen atmosphere Oxy-phenyl)-ethyl]-methyl-amine (500 mg '1.56 house moles) in a solution of two gas (8 ml). The reaction mixture was allowed to warm to room temperature then stirred for an additional 1 hour. The mixture was poured onto ice and then diluted with di-methane and saturated NaHC(R)3 solution. The organic layer was dried (MgS04) and filtered and concentrated to give the desired product. LC/MS : (PS-B3)Rt 2.76 [M+H]+306. 47B. "2-(4-&gt; stinky base)-2-(4-yl-based-stupyl V-ethyl 1- 1- Base-amine methyl acid third-butyl ester

Add BOCzO (269 mg, 1.23 mmol) to 4-[1-(4-bromophenyl)-2-methylamino-ethyl]-phenol (360 mg ' 1.18 mmol) in di- methane ( 2 〇 ml) in the solution. After stirring at room temperature for 16 hours, the solvent was evaporated,jjjjjjjjjjjj LC/MS : (FL-A) Rt3.85 [M+H]+406. 47C. {2-(4-Bromo-V-V2-"4-(V is more than 咣-2-基气某茉1- Ethyl methionine-amine 102449 -155- 9 ^363622

;0 [2-(4-bromophenyl)-2-(4-hydroxy-phenyl)-ethyl]-methyl-amine methyl acid tert-butyl ester (125 mg, 0.31 mmol), 2-Chloropyryl (35 2 mg, 〇 3 ι mmol) and &amp; (: 〇3 (213 mg, 1.54 mmol) in dimethylformamide (8 mL) was heated to UXTC After 17 hours, the solvent was removed under reduced pressure while cooling, and the residue was partitioned between ethyl acetate and saturated NaHC 〇3 solution. The organic layer was dried (MgS 〇 4) and filtered. After concentrating, the crude product was purified with EtOAc EtOAc EtOAc (EtOAc) Methanol, followed by 2N ammonia in methanol to give the desired product (82 mg, LC/MS: Rt 3.17 [M+H] + 384. Methyl-{2-"4-(峨啩-2- Aminoamino V Momo^^丨凡pyrazole_4_篡\Pingyl 1-ethylindole-amine X)N ?

Following the procedure described in Example 42C, but replacing {2-(4-bromophenyl)_2 with [2_(4-bromophenyl)-2-(4-phenylphenyl)-ethyl]-methyl-amine -[4-(pyroxy-2-yloxy)-benzene 102449 9-156. 1363622 yl]-ethyl}-methyl-amine' gave the title compound. </ RTI> <RTIgt; ), 7.23 (2H, d), 7.50 (4H, t), 7.75 (2H, d), 8.12 (1H, d), 8.33 (1H, d), 8.42 (2H, s), 8.48 (1H, s) Example 48 Methyl-{2-phenoxy-2·Γ4-(1Η-pyrazole-4-V 芏 1-1-乙某μ脸48Α. "2-(4-bromo-based V2-perylene) -Ethyl-A, a neck, a sour flute, three vinegar

Add BOC2(R) (1.90 g, 8.69 mmol) to a solution of 丨-(4.bromophenyl)-2-methylamino-ethanol (2.00 g, 8.69 mmol) in dichloromethane (20 mL) Inside. After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (Si.sub.2) and eluted with ethyl acetate/ petroleum ether (u 4) to give desired. Product (2.1 g). LC/MS : (PS-B3) Rt 3.16 [M+H]+ 330. 48B. "2-(4-Bromometh)·2- loaded with argon-B-]]

Diethyl azodicarboxylate (358 μl, 2.27 mmol) was added dropwise to [2-(4-bromophenyl)-2-hydroxy-ethyl]-methyl-amine methyl acid Tri-butyl ester (5 mg, 1_51 mmol), triphenylphosphine (596 mg, 227 mmol) and phenol (285 mg '3.03 mmol) in tetrahydrofuran (1 mL) The solution was stirred at room temperature under nitrogen atmosphere for 17 hours. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and sat. NaHC.sub.3 solution, 102449 -157 - 13636. The organic layer was dried (MgS04), filtered and concentrated. Then, the crude product was purified by column chromatography (SiO 2 ), eluted with ethyl acetate / petroleum ether (1: 9) to give the compound of the intermediate BOC, and then a saturated solution of HCl in diethyl ether ( Stir for 24 hours in 20 ml). The solvent was removed under reduced pressure to give the title compound as s. Further purification by Phenomenex Strata SCX column chromatography, eluting with methanol, followed by 2N ammonia in methanol afforded the desired product as a free base (94 g). LC/MS: (?8-?3)1^4.04|&gt;1+11]+406.

48C. Methyl-hydrazine2-stupid certain-2-indole 4-(indole-pyrazole-4-ylphenyl 1-ethylindole-amine

Substituting [2-(4-bromophenyl)-2-(4-phenylphenyl)-ethyl]-methyl-amine for [2-(4-bromophenyl) according to the procedure described in Example 42C )-2-phenoxy-ethyl]-methyl-amine, the title compound was obtained. </ RTI> <RTIgt; Dd), 5.40 (1H, dd), 6.85 (1H, t)5 6.90 (2H, d), 7.18 (2H, t), 7.40 (2H, d), 7.55 (2H, d), 7.93 (2H, s Example 49 2-Γ[4-氱茉基 U4-(1H-pyrazol-4-yl V stupyl 1-methylindole H amine 49A. (4-bromomethyl W4-chlorophenyl)-fluorene alcohol

102449 -158- 1363622 4-Azure-magnesium bromide (12.97 ml, 1 M solution in diethyl ether) was slowly added to 4-bromobenzaldehyde (20 g, 1) under a nitrogen atmosphere. (). 81 mmol) in a solution in tetrahydrofuran (25 ml). The reaction mixture was allowed to warm to room temperature and stirred for 17 hours. Water (3 mL) was then added and the solvent was removed under reduced pressure. Then, the residue was subjected to liquid separation between ethyl acetate and 1NHC1 solution. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by EtOAc (EtOAc) eluting LC/MS : (PS-B3) Rt3.49 [MH]+297. Bifurcation · 2-{2-"(4-本本基)-(4-Azyl-methylmethyl 1-ethyl}- Iso-pyrene], 3-dione

(4-Bromophenyl)-(4-phenylphenyl)-methanol (2.3 g, 7.73 mmol), N-(2-ethyl)-phthalimide (1.4 g, 7.36 mmol) A mixture of p-toluene acid monohydrate (560 mg, 2.94 mmol) in toluene (5 mL) was heated to reflux under Dean-Stark for π h. The solvent was removed while cooling, and the residue was subjected to liquid separation between ethyl acetate and water. Then, the organic layer was dried (MgSO.sub.4), filtered and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc: No visible mass ions.茉茉基)-"4-(1Η-pyrazole-4-V 芏 11·甲 A 早二卜乙v酉大 102449 •159- 1363622 Amino acid

Following the procedure described in Example 42C, but substituting [2-(4-bromophenyl)-2-(4-chlorophenyl)-ethyl]-methyl-amine for 2-{2-[(4-[ -(4-Phenylmethoxy)-ethyl}-isoindole-U-di-, the title compound was obtained. lc/MS: (FS-A) Rt2.85

Add hydrazine monohydrate (159 μl, 3.28 mmol) to n_(2-{(4-chlorophenyl)-[4-(1Η-pyrazol-4-yl)-phenyl]-methoxy A solution of thioethyl glutamic acid (26 mg, 0.55 mmol) in decyl alcohol (6 mL), and the mixture was stirred at 80 C for 16 h. Solvent, and the crude product was purified by column chromatography (Si.sub.2), eluting with methylene chloride:methanol:acetic acid:water (90 '18.3). The product of 102449 - 160 1363622 was obtained as a free base (120 mg). mp. 1H NMR (Me-d3-OD) δ 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). Example 50 4-μ-"Η4-Argentium 篡V3-tetrapyrrole-1-yl-propanyl 1-Methoxy}-lH-pyrazole

Following the procedure described in Example 8, but substituting methylamine for tetrahydropyrrole, the title compound was obtained. LC/MS : (PS-A2)Rt 2.250^+1^+366.41^11 (Me-d3 -OD) δ 1.83-1.95 (2Η, m), 1.95-2.09 (2Η, m), 2.4-2.5 (2H , m), 2.88-2.97 (2H, m), 3.02 (2H, dd), 3.52-3.61 (2H, m), 4.02 (1H, t), 7.25 (4H, q), 7.32 (2H, d), 7.55 (2HS d), 8.41 (2H, s). Example 51 4-Ι4-Γ3-Nitrogen tetrafluorene-1-one-1-(4-Gasyl V-propionyl 1-stylyl 1H-pyrazole

Following the procedure described in Example 8, but substituting methylamine for tetrahydropyrrole, the title compound was obtained. LC/MS : (PS-A2) Rt 2.18 [1^+1^+352.4 NMR (Me-d3 - OD) δ 2.12-2.25 (2Η, m), 3.00 (2Η, t), 3.85-3.98 (5H, m), 4.05-4.17 (2H, m), 7.18 (2H, d), 7.19 (4H, s), 7.45 (2H, d), 7.83 (2H, s). 102449 •161- 1363622 Example 52 _Methyl -{3-Benz-2-yl-3-|~4-(lH-rtk-4-ylphenyl 1-propyl}amine

The title compound was obtained according to the procedure described in Example 8 but substituting 4-naphthyl magnesium bromide with 2-naphthyl magnesium bromide. LC/MS : (PS-A2) Rt2.26 [M+H]+ 342.1HNMR (Me-d3-OD) δ 2.57-2.70 (2Η, m), 2.70 (3Η, s), 2.90-3.10 (2H, m), 4.32 (1H, t), 7.40-7.52 (5H, m), 7.70 (2H, m), 7.80-7.90 (4H, m), 8.70 (2H, s). Example 53. 士._methyl -(4-{3-Methylamino-1-"4-(1Η-ρ than 〇-4-yl)-stupyl 1-propyl}-stupyl V amine

Following the procedure described in Example 8, but substituting 4-(N,N-dimethyl)aniline bromide with 4- phenylphenylmagnesium bromide afforded the title compound. LC/MS: (ps_A2) Rt 1.55 [M+H]+335.1H NMR (Me-d3 - OD) δ 2.46-2.60 (2H, m), 2.69 (3H, s), 2.95 (2H, t), 3.27 (6H, s), 4.25 (1H, t), 7.45 (2H, d), 7.60-7.72 (6H, m), 8.50 (2H, s). Example 54 Fluorobenzene V3-"4-nH-pyrazole -4-基笑我i-丙某丨·甲臬专102449 •162· 1363622

Following the procedure described in Example 8, but substituting 4-chlorophenylmagnesium bromide for 4-fluorophenylmagnesium bromide afforded the title compound. LC/MS : (PS-A2) Rt2.05 [M+H] + 310.1H NMR (Me-d3 - OD) δ 2.40-2.55 (2H, d), 2.70 (3H, s), 2.90-3.0 (2H , m), 4.12 (1H, t), 7.05 (2H, t), 7.32-7.40 (4H, m), 7.63 (2H, d), 8.33 (2H, s). Example 55 4_·{4-『4 -(4-chlorophenyl V6j.pyridine-4·1_phenylhydrazine·1H_pyrazole_3_A

Following the procedure of Example 1, but using 4_(4-hydroxyphenyl)-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxos Base)-phenyl]-six moxibustion n to replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-1Η-pyrazole, And 2-(4-chlorophenyl)-2-phenylethylamine hydrochloride was replaced by 4-bromo-1H-pyrazole-3-carbonitrile to give the title compound. LC/MS : (PS-A2) Rt2.22 [M+H]+ 363. NMRCMe^-OD) δ 2.52-2.70 (4 Η, m), 3.10-3.20 (4H, m), 7.25 (4H, s ), 7.37 (2H, d), 7.58 (2H, d), 8.02 (1H, s). Example 56 3-(4-stupid-stupyl ° sit-4-yl V-cage 1-propylamine 102449 - 163-

1363622

Following the procedure described in Example 8, but substituting 4-phenylphenyl magnesium bromide for 4-phenoxyphenylmagnesium bromide, and replacing the amine with methylamine afforded the title compound. LC/MS : (PS-A2) Rt 2.28 [M+Hf 370.34. 1H NMR (Me-d3-〇D) δ 2.38-

2.46 (2H, m), 2.85-2.92 (2H, t), 4.03-4.10 (1H, t), 6.94-7.0 (4H, d), 7.08-7.14 (1H, t), 7.30-7.39 (6H, m), 7.55-7.58 (2H, d), 7.90-7.97 (2H, br s), 8.54-8.60 (lH, brs). Example 57 l-{(4-gas-based V"4-flH-pyrazole -4-V-V-n-1-A certain 1-six i.岫_

trN according to the procedure described in Example 1, but replacing 1-(4,4'-di-diphenylmethyl)-hexa-(2-chlorophenyl)-2-phenylethylamine hydrochloride Argon pyridine was added to obtain the title compound. LC/MS : (PS-B3) Rt2.82 [MH]+351.27. iHNMR^Me-dyOD) 5 3.0-3.25 (4H, m), 3.45-3.65 (4H, m), 5.05-5.25 (1H, br s), 7.40-7.50 (2H, d), 7.65-7.83 (6H, m), 8.45 (2H, s). Example 58 1-A -4-{phenyl-"4-(ex-pyrazole- 4-base)-stupid 1-a certain ^"1141 two gas 〇::81 Hyun 1 102449 •164- 1363622

Following the procedure described in Example 1, but substituting 2-[(p-phenylphenyl)-2-phenylethylamine hydrochloride for 1-[p-dioxo-diphenylmethyl]indole-i,4-di Azacycloheptane dihydrochloride afforded the title compound. </ RTI> <RTIgt; Br m), 5.78 (1H, s), 7.40-7.48 (1H, m), 7.49-7.55 (2H, t), 7.75-7.80 (2H, d), 7.82-7.98 (4H, m), 8.32 (2HS s). Example 59 {3-(3-Gas-stupyloxy)-3-"4-ΠΗ-pyridin-4-唓V-m- 1------A-A-Amine 59Α. Stinky V3- Gas-propan-1-ol (J. Med. Chem, 2004, 47, 3924-3926)

Br

Cl

Add borohydrogenation of a solution of 1-(4-bromophenyl)-3- phenan-1-one (1 g, 4.04 mmol) in tetrahydrofuran (9 mL) and water (0.58 mL) Sodium (0.16 g, 4.28 house Mo). The reaction mixture was poured at room temperature for 2 hours, and water was added carefully to quench the reaction and extracted with ethyl acetate. The organic layer was separated, dried EtOAcjjjjjjjjj LC/MS: (PS-A2) Rt 3.07 [M+H]+, no ionization. 102449 -165·

1363622 59B. "3-(4·:.bromophenylpropyl)

The 3-phenol was reacted with Bu (4. bromophenyl)·3_ • gas-propan-1-ol according to the procedure set forth in Example 48B, and the title compound was used in the next step without Further purification. • · ^2_C. "3-(4-filled phenyl)-3-(3-chloro-stupidyl ν-propyl 1-mercapto-face

a solution of 3-(4-bromophenyl)_3_(3-a-phenoxy)-propyl]-vaporate in 33% methylamine (4 ml) in ethanol at 10 °C Heated at 50 W for 30 minutes in a cem microwave. The solvent was removed and the crude material was purified on a phenomenex StrataSCX ion exchange column eluted with methanol, followed by 2N ammonia in methanol. The product was purified by column chromatography (Si.sub.2) using EtOAc EtOAc (EtOAc:EtOAc) LC/MS : (PS-B3) Rt3,42 [Μ+Η]+356·19· Chlorine-stupid V3-"4-(m-pyrazole-4-V-篡笑1-一一丨- Methyl-amine

[3-(4-Bromophenyl)-3-(3-Gas-phenoxy 102449 1363622)-propyl]-indolyl-amine and 4-(4,4) according to the procedure set forth in Example 1. ,5,5-Tetramethyl-1,3,2-dioxaborin-2-yl)-p-pyrazole reaction to give the title compound "LC/MS: (PS-B3) Rt2.80 [ M+H]+342.26.1H NMR(Me-d3-OD) δ 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, d), 6.96 (1H, s), 7.15-7.20 (1H, t), 7.38-7.45 (2H, d), 7.57-7.65 (2H, d), 7.98 (2H, s). 9. Example 60 - .methyl-{2-stupyl-2-Γ6-(1Η-ρ ratio. barrier-4-V »»比唆-3-yl 1-ethyl V amine*· at 4:6-(3-methyl-1-trismethyl-1Η-pyrazole-4-yl V nicotine dark

In 6-gas-alkali nitrile (〇·2g ' ι·49 mmol) and 3-methyl_ι_triphenylmethyl-1Η-pyrazol dihydroxyborane* (0.5 g, 136 mil To a solution of ethylene glycol dimethyl ether® (3 ml), sodium carbonate (〇·36 g, 3.39 mmol) in water (丨·5 ml) was added. Before adding hydrazine (triphenylphosphine) palladium (9)

Degassed with nitrogen and then heated in a CEM microwave for 30 minutes (50 W power) at i35eC. The reaction mixture was partitioned between water and ethyl acetate. The aqueous solution was basified with &lt;RTI ID=0.0&gt;&gt; The crude product was suspended in a small volume of methanol, and the title compound (0-32 g, 53% yield) was filtered. &lt;1C/MS: (PS-A2) Rt4.52 [M+H] +427.26. 102449

• 167- 1363622 *This starting material can be made into 60B by the method described in EP1382603A1. (4-A gas-based M6-(3-methyl-1-tris-methyl-1H-pyrazole-4-咭-fly-based 1-ketone

a solution of 6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-nicotinonitrile (0.5 g, 1.17 mmol) in anhydrous tetrahydrofuran (4 mL) 4-Methylbenzene bromide (1.52 mL of 1.52 mmol, 1 M in diethyl ether) was added; The reaction was quenched to below pH 2 by the addition of 2NHC1 and stirred for 1 hour. Then, the organic extract was combined with saturated sodium bicarbonate to pH 8 ' and extracted with ethyl acetate. The organic extracts were combined, dehydrated (MgS 〇 4), solvent was removed, and the residue was subjected to column chromatography (Si 〇 2) Purification, elution with petroleum ether to ethyl acetate: petroleum ether (15:85) afforded the title compound (0.49 mg < 77% yield). LC/MS : (PS-A2)Rt4.45 [M+H]+540.30, 542.28. 迎 g_· {2-(4-气笨基ν2-Γ6-(3-甲一-1-三笨甲甲-1H-pyrazol-4-yl V pyridine ij-yl 1-vinyl-methyl-(1-addition of an ethyl-ethylamine 102449 1363622

Add n-butyllithium (〇·47 ml, 0.76 mmol, L6M in hexane) dropwise to (R) (diphenylphosphinylfyl) at _15 °C Methylphenyl-ethyl)-amine (0.18 g '0.51 mmol) in anhydrous tetrahydrofuran (9 mL). After 15 min, (4·chlorophenyl)[6_(3_曱)小小三笨曱基-1H-pyrazol-4-yl)-acridine-3-yl]-methanone (014g, 〇25mmol) in tetrahydrofuran (0.9ml) solution A and warm The reaction mixture was stirred at -15 ° C for an additional 30 minutes until 1 hour from room temperature. The reaction mixture was quenched with water &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt; * This starting material can be prepared by the method described in Tetrahedron Asymmetry, 2003, 14, 1309-1316. fflD.曱基-{2-stupyl-2-indole-6-indole-pyrazole-4-indole Wh-azin-3-yl-Vethyl 1-amine

{2-(4-Acetyl)-2-[6-(3-indolyl-1-triphenylindol-1H-pyrazol-4-yl)-pyridine 102449 •169· 1363622 3 base]- Ethyl}-methyl-(ι_phenyl-ethyl)-amine was added to a solution of 10% by weight of palladium on activated carbon in a solution of ethanol, and the reaction mixture was subjected to hydrogen atmosphere for a few hours. The mixture was filtered through Celite®, the mother liquid was concentrated, and the residue was purified by column chromatography (SiO 2 ) with methylene chloride:methanol:acetic acid:water (24 〇:20:3:2) to dichloromethane:methanol :Acetic acid: water (9 〇: 18 : 3 : 2) was dissolved to give the title compound. LCMS : (PS-A2) Rt 1.59 [M+H; l+293.18.1H NMR (Me-d3 - OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15 -4.20 (1H, t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80 (1H, s), 8.38 (1H, s Example 61 4-{4-"1-(4-Phenylphenyl)-3-[sodium]-s-l-yl-propyl-phenyl-phenyl] 4 61A. Stinky base g--1-yl-propyl -1-ol

1-(4-oxophenyl)-3-chloro-propan-1-ol* (1.5 g, 6.01 mmol) with hydrazine (1.23 g ' 18.03 mmol) in dimercaptocarboxamide ( The solution in 18 ml) was heated at 100 ° C for 18 hours and then separated between water and ethyl acetate. The organic extracts were combined with 'dehydration drying (MgSCXO, filtered, concentrated, and purified by column chromatography (Si〇2) to methanol: di-methane (2: 98) to methanol: dioxane (6: 94) The title compound (0.75 g, 44% yield). LC/MS: (PS-B3) Rt2.48 [M+H] + 281.14, 283.11. * This super-existing material can be borrowed from Example 43A. Prepared by the method described. 61B. 1-Γ3-(4-bromophenyl)-3-(4-gas propyl 1-1 Η-_ 4 102449 -170- 1363622

Chlorobenzene (5 ml) and 1-(4-bromophenyl)-3-zolazole-1-yl-propan-1-ol (〇·41 mg, 1.46 mmol) according to the procedure set forth in Example 42B The title compound (0.37 g '67% yield) was obtained. LC/MS : (PS-A2) Rt2.40 [Μ+Η]+ 375.16, 377.17.

61C. 4-(441-(4-氪策)-3-oxazole-1_某-丙一1-茉某μΐΗ-pyrazole

1-[3-(4-Bromophenyl)-3-(4-phenylphenyl)-propyl]-1H-imidazole was 4-(4,4,5, according to the procedure set forth in Example 1. 5-Tetramethyl-1,3,2-dioxaborin-2-yl)-1Η-pyrazole was reacted to give the title compound. </ RTI> <RTIgt; 4.10 (2H, m), 7.05 (1H, s), 7.10-7.60 (9H, m), 7.65 (1H, s), 7.90-8.00 (2H, d). Example 62 4-"4-(3-imidazole -1-yl-1-indolyl-propionyl v methoxyl 1-1H-pyrazole 62A. H3-(4-bromo-based V3-methylargon-3⁄4 1-1H-imidazole

102449 • 171 - 1363622 The phenol was reacted with 丨_(4-bromophenyl)_3_methane-1-yl-propan-1-ol* according to the procedure set forth in Example 48B to give the title compound. LC/MS: (PS-A2) Rt 2.30 [M+H] + 357.26, 359.27. * This starting material can be made by the method described in Example 47A. 62B. 4-f4-(3-imifluor-1-yl-1-phenylene-propyl-methyl-pH-pyrene

K'N according to the procedure set forth in Example 1, 1-[3-(4-bromophenyl)-3-phenoxy-propyl]-1H-imidazole with 4-(4,4,5,5 -tetradecyl-1,3,2-dioxaborin-2-yl)-1 -pyrazole reaction 'The title compound was obtained. </ RTI> <RTIgt; 5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s), 7.15-7.20 (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55- 7.60 (2H, d), 7.85 (1H, s), 7.95 (2H, s). φ Example 63 4d: 4-[4-(lH-pyrazol-4-yl V-m-n-l-g.pyridine- 4-some phenol

Following the procedure described in Example 14, but substituting chlorobenzene for phenol and using nitrobenzene as solvent, the title compound was obtained. LC/MS : (PS-A3) Rt5_07 [Μ+Η]+ 320.1H NMR (d6-DMSO) 5 _ 7.97 (2Η, s), 7.49 (2Η,d), 7.25 (2Η,d),7.10 102449 - 172-1363622 (2H, d), 6.68 (2H, d), 2.840 (4H, bs), 2.376 (4H, bs). Example 64 chlorophenyl)-indole 4-(1Η-pyrazole-4-Vbenzene Base 1-A certain μ 氤pyrazine 4

The title compound was obtained according to the procedure described in Example 57: LCMS: Μ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (2H, d), 7.83 (2H, d), 7.71 (2H, d), 7.40-7.30 (3H, m), 5.70 (1H, s), 3.68 (4H, bs), 3.51-3.48 (4H, m Example 65 {2-(4-Fluorophenyl)-2-indol-4-pyrazole-4-V-l-ethyl-methyl-amine 6jA. |&gt;(4-indolephenyl) )_2_(4-fluorobenzene a V ethyl 1-amine methyl decyl ester

In a solution of 3-(4-fluorophenyl)-3(4-bromophenyl)propanoic acid* (1. gram, 3.09 mmol) in acetone (4 mL) at 〇 ° C A solution of triethylamine (561 μl '4.02 mmol) in acetone (16 mL) and ethyl chloroacetate (443 μL, 4.64 mmol) in acetone (1.6 mL) was added. The reaction was allowed to warm to room temperature and stirred for a further 30 min before further cooling to 0 &lt;0&gt;C, and sodium azide (402 <RTIgt; The resulting brown solution was stirred for 45 minutes before adding water (1 mL) and EtOAc (10 mL). The aqueous layer was separated and extracted with ethyl acetate (10 mL). EtOAc was combined and evaporated. The residue was dissolved in anhydrous hydrazine (12 mL) and heated to 4 min. The reaction was allowed to cool to room temperature before the addition of ethyl acetate (50 mL) and saturated sodium bicarbonate (5 mL). Separate the organic liquid before dehydration (MgS〇4) and before concentrating in vacuo' and add another bicarbonate solution (5 ml), hydrochloric acid (2N, 1 ml) and saturated brine (50 ml) )washing. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) » LC/MS: (PS-A2) &amp; 3.18, no ionization. * This starting material can be prepared by substituting 4-phenylphenylmagnesium bromide with 4-fluorophenylmagnesium bromide by the methods described in Examples 8A to 8C. B. {2: {4: fluorophenyl biszol-4-V-stall 1-Ethyl}-aminomethyl decyl ester

ΤΝ [2_(4-Bromophenylfluorophenyl)-ethyl]-amine methyl benzyl ester and 4-(4,4,5,5-tetramethyl) according to the procedure set forth in Example 1. -1,3,2-Dioxaboron-2-yl)-1Η-oxime reaction to give the title compound. lC/MS : (PS-A2) Rt3.20 [M+H]+416. 6_5_C. {2-(4-Fluoro-based V2-"4-(lH-pyrazole·4-V-laughing base 1- B 丨-甲甲·amine 102449 -174- 1363622

The lithium aluminum hydride (5 3 ml, 53 mM millimolar, 1 M in tetrahydrofuran) was slowly added to the THF (5 mL) in THF (5 mL). -2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-amine methyl benzyl ester (439 mg, 1·〇6 house Moule). The reaction mixture was allowed to warm to room temperature, stirred for 51 hours, and the reaction was quenched with water (5 ml), aqueous sodium hydroxide (2N, 5 ml) and ethyl acetate (10 liters). The layers were extracted with ethyl acetate (2 χ 2 mL). The combined organic liquid was washed with a saturated aqueous solution of brine, then dried (MgSO.sub.sub.sub.sub.sub. (12〇: 15 : 3 : 2) The solution was dissolved in (90:18:3:2) to give the title compound, which was then converted to the hydrochloride salt (100 mg, 32%). 1^/1^ : -8 2)1^1.87[]\4+11]+ 296.1H NMR (Me-d3 -OD) δ 8.20 (2Η, s), 7.57 (2Η, d), 7.34-7.29 (4H, m) , Lu 7.02 (2H, t), 4.32 (1H, t), 3.67 (2H, d), 2.65 (3H, s). Example 66 {2-(3-气笨基)-2-『4-(lH -pyrazol-4-ylpyryl 1-ethylindole-methylamine

The title compound was obtained according to the procedure described in Example 65, but substituting 4- fluorophenylmagnesium bromide for 3-102449 -175 - 1363622 chlorophenylmagnesium bromide. </ RTI> <RTIgt; 7.34 (1H, s), 7.30-7.20 (3H, m), 4.40 (1H, t), 3.70 (2H, d), 2.65 (3H, s). Example 67 4- 4-(2-methoxy -Ethoxy methoxy-Mo ΐ-4-"4_ΠΗ-pyrazole-4-V 袈一1-六i.pyridine 67A_ 4-(4-'; stupid)-4-(4-hybrid-stupid Base)-six I bite-1-acidic third butyl ester

Follow the procedure described in Example 47B, but replace 4-[4-(4-bromophenyl)-hexa-[4-(4-bromophenyl)-2-indolyl-ethyl]-phenol The hydroquinone is the title compound as compared to the bite 4-4-]. 1 H NMR (d6-DMSO) 6 7.45 (2Η,d), 7.25 (2Η,d), 7.11 (2Η,d), 6.68 (2H, d), 3.35-3.18 (4H, m), 2.31-2.20 ( 4H, m), 1.38 (9H, s). * This starting material can be prepared by the method described in Example 63. 67B. 4-(4-Molyphenyl)4-"4-(2-methoxy-Ethylene-V-V.

4-(4-Bromophenyl)-4·(4-hydroxy-phenyl)-hexahydropyridine small carboxylic acid tert-butyl ester (100 mg '0_23 mmol), 2-bromoethylmethyl A solution of ether (2 〇〇 microliters) and potassium carbonate (64 mg, 0.46 mmol) in dimercaptoamine (2 ml) was heated in CEM ExpUM using 5 watts of power, microwave to scratch , calendar -176- 102449

1363622 After 30 minutes. The reaction was poured into EtOAc (2 mL, 4 mL). The combined organic liquids were dehydrated (MgS04), concentrated, and the residue was purified by column chromatography (purified in 〇2) to ethyl acetate / petroleum ether (25·· 75) gradient to (5 〇: 50 Dissolved to give the title compound (82 mg). LCMS : (PS-A2) Rt4.00 [M+H]+490. methoxy oxime-ethoxy V Momo 1-4_"4·(1Η-pyridin-4-yl V Momo 1-6

4-(4-bromophenyl)_4-[4-(2-methoxy-ethoxy)-phenyl]•hexahydropyridine-1-carboxylic acid third according to the procedure set forth in Example 1. -Butyl ester reacts with 4-(4,4,5,5-tetradecyl•1,3,2-dioxosin-2-yl)1H-pyrazole, replacing quinonetriphenylphosphine (〇) The title compound was obtained as a catalyst. LC/MS : (PS-A2)Rt 3·27 [M+H]+478· ❿ 4-"4_(2.methoxy-ethoxy methoxyl 1-4-"4-(1Η-pyridyl) -4- it. Motyl 1-hexahydroindole

Adding trifluoroacetic acid (1 ml) to 4-[4-(2-decyloxyethoxy)phenyl]- 4-[4-(1Η-pyrazol-4-yl)-phenyl] a solution of hexahydropyridine (87 mg) in dioxane methane 102425 -177-liter. After 30 minutes, the reaction was concentrated <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; The combined aqueous fractions were washed with ethyl acetate then basified (2N NaOH) then &lt The combined organics were washed with aq. EtOAc (EtOAc) </ RTI> <RTIgt; (2H, d), 6.89 (2H, d), 4.13 (2H, t), 3.73 (2H, t), 3.42 (3H, s), 2.94 (4H, bs), 2.44 (4H, bs). Example 68 Soil 14-(3-methoxy-propoxy V-cage group 1-4-"4-(1Η-pyrazole-4-篡V芄yl-1-hexa.pyridinium^gA. 4-(4·苯苯棊)-4_"4·(3-甲气一_丙气基篡·[_六氤pyridine citrate third-butyl ester

Gasified methanesulfonate (572 mg, 3.0 mmol) was added to a solution of 3-methoxypropanol (191 liters, 2.0 mmol) in pyridine (ml). This was stirred at room temperature for 5.5 hours, then diluted with ethyl acetate (2 mL) and washed with hydrochloric acid (2······· The liquid was dehydrated and dried (MgS〇4) and shrunk to give a colorless oil (6 mg). This oil was dissolved in methyl decylamine (2 ml) and potassium carbonate (64 m) was added to this solution.

The mixture was extracted with ethyl acetate (3×10 mL). After dehydration drying (MgS〇4) and concentration, the combined organic liquids were washed with brine (1 ml). The residue was purified by column chromatography (EtOAc EtOAc) eluting LCMS: Rt 4.20 [M + H] + 504. * This starting material can be made by the method described in Example 67A 68B. 4-|~4-(3-decyloxy-propenyl)- stupid Base 1-4-"4-ΠΗ-ρ|;1: »Sit _4·V benzene one 1-six blue.p than bite

Follow the procedure described in Examples 67C and 67D, but with 4-(4-bromophenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-hexahydropyridine-1- The third-butyl carboxylic acid is substituted for 4-(4-indolyl)-4-[4-(3-methoxy-propoxy)-phenyl]-hexahydrop than bite-1-deoxylate Tri-butyl ester, the title compound was obtained. LCMS : Rt 6.65 [M+H] + 392. &lt;RTI ID=0.0&gt; , 6.91 (2H, d), 4.04 (2H, t), 3.56 (2H, t), 3.34-3.33 (5H, m), 3.24-3.22 (4H, m), 2.67-2.66 (4H, m) 69 3-(3.4-Dioxo-methyl)-3-"4-indolyl-4-pyridyl-4-yl)-styl 1-propenylamine 102449 -179- 1363622

Φ

The title compound was obtained by substituting 3,4-dichlorophenylmagnesium bromide with 3,4-difluorophenylmagnesium bromide according to the procedure described in Examples 9 and 9. LC/MS : (PS-A3) Rt9.82 [M+H]+360.14, 362.12.1HNMR (Me-d3-OD) δ 2.90-3.00 (2Η, d), 4.50-4.60 (1Η, t), 7.10 -7.30 (3H, m), 7.40-7.45 (2H, d), 7.50-7.55 (2H, d), 7.85-8.05 (2H, br s). Example 70 2-(4-(2-Amino--- 1-Γ4-ΠΗ-pyrazole-4-a certain l-ethyl-p-phenylene)-iso-smoke amine

Following the procedure described in Example 47, but substituting 2-chloro-4-cyanopyridine to afford the title compound. </ RTI> <RTIgt; , 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, s ), 8.22 (lH, d). Example 71 (2-Γ4-nitrogen-mosquito-v2-Γ4-ΠΗ-pyrazole-4-yl V-methyl-l-ethyl-methyl-amine 102449 • 180 · 1363622

The title compound "LC/MS: (PS-A3) Rt2.29 [M-ClPliO+H]+200. iHNMR (Me-d3 -) was obtained according to the procedure described in Example 48. 0D) δ 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). Example 72 3-{2-(4·气笨基)·2-Γ4-[1Η-pyrazole-4-V-Vie 1-B Aminopropan-1-ol

Following the procedure described in Example 20, but substituting dimethylamine to 3-aminopropan-1-ol to give the title compound: LC/MS: (PS-A2) Rt 2.05 [M+H] + 356.1H NMR ( Me-d3 - OD) (5 1.87 (2Η, 五重峰), 1.98 (AcOH, s), 3.23 (2Η, t), 3.68 (2Η, t), 3.75 (2H, dd), 4.4 (1H, t ), 7.36 (2H, d), 7.4 (4H, s), 7.62 (2H, d), 7.97 (2H, s). Example 73 Lactobenzoquinone V2-"4-(lH-pyridin-4-V Methyl 1-ethylaminoethanol 102449 • 181 · .8 1363622 α The title compound was obtained according to the procedure described in Example 20, but substituting dimethylamine to 2-aminobutanol. LC/MS: (PS- A2) Rt2.05 [Μ+Η]+ 342. 1H NMR (Me-d3 - OD) δ 1.98 (AcOH, s), 3.10 (2H, s), 3.69 (2H, dd), 3.78, (2H, t ), %

4.39 (1H, t), 7.36 (2H, d), 7.38 (4H, s), 7.61 (2H, d), 7.97 (2H, s). Example 74 1^(4-Phenylphenyl)-2-" 4-(lH-pyrazole-4-(phenyl)1-ethylindole-cyclopropylmethyl-amine

The title compound was obtained according to the procedure described in Example 20, but substituting the cyclopropylamine to the amine. </ RTI> <RTIgt; (1H, m), 2.42 (2H, d), 3.15-3.25 (2H, m), 4.11 (1H, t), 7.16-7.27 (6H, m), 7.45 (2H, d), 7.82 (2H, s Example 75 methyl]244-[1Η-leaf b ° sit _-4-yl V裟1K4-pyridin-3-some-loading group V-I-amine 102449-182- 1363622

Φ was replaced by 4-(4,4,5,5-tetradecyl-1,3,2-dioxaboroin-2-yl)-111-pyrazole according to the procedure described in Example 1. -(4,4,5,5-tetradecyl-[1,3,2]dioxaboroin-2-yl)-pyridine, and coupled to {2-(4-indolyl)-2- [4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine* gave the title compound. </ RTI> <RTIgt; 4.46 (1H, t), 7.41 (2H, d), 7.51-7.56 (3H, m), 7.63 (2H, d), 7.70 (2H, d), 7.96 (2H, s), 8.10 (1H, dt) , 8.53 (1H, dd), 8.80 (1H, d). * This starting material can be prepared by the method described in Example 21. Example 76 4-{3-Methylamino-1-indole 4-(1Η-ρ than sal-4-yl V stupyl 1-propyl

The title compound was obtained according to the procedure described in Example 8 but substituting 4- phenylphenylmagnesium bromide for 4-p-methoxyphenylmagnesium bromide. LC/MS : (PS-A2) Rt 1.82 [M+H]+ 308. 1H NMR (Me-d3 - OD) δ 1.92 (AcOH, s), 2.34-2.43 (2H, m), 2.64 (3H, s ), 2.86-2.92 (2H, m), 3.96 (1H, t), 6.75 (2H, d), 7.13 (2H, d), 7.29 (2H, d), 7.52 (2H, d), 7.93 (2H, d). 102449 •183· 1363622 Example 77 3-(4-Methyl-styl)-3-"4-(1Η-ρ ratio 0--4-yl-V-phenyl 1-propylamine

V

Following the procedure described in Example 8, but substituting 4-p-phenylphenylmagnesium bromide for 4-p-oxyloxyphenylmagnesium bromide, and substituting for the amine (2, in methanol) to give the title compound. LC/MS : (PS-A2)Rt 1.82 [Μ+Η]+ 308. 1HNMR€Me-d3_ OD) 5 2.23-2.32 (2H, m), 2.74 (2H, dd), 3.65 (3H, s), 3.89 (1H, t), 6.77 (2H, d), 7.11 (2H, s), 7.17 (2H, d), 7.41 (2H, d), 7.71 (2H, s), 8.41 (HC02H, br s). Example 78 4-(4-Acetyl)-4-[~4-(3-methyl-1H-Ptb °Spin-4-yl)-stupyl 1-six-leaf, 〇$·78A. 4 -(4-gas-phenyl)-4-"4-(3-methyl-1-trismethyl-lH-p is more than ton-4-yl-pupidum_6-hydrogen p ratio 11

Following the procedure set forth in Example 1, but using ruthenium (triphenylphosphine)palladium (9) as the catalyst, the 4-(4-diphenyl)-4-(4-chlorophenyl)-hexahydrop ratio was obtained. The hydrochloride salt was reacted with 3·methyl-1-triphenylhydrazin-1H-pyrazole-4-dihydroxyborane* to give the title compound. </ RTI> <RTIgt;

Zgg. 4-(4-Chlorophenyl M-K-O-indolyl-1H.pyrazole·4·^phenyl]·hexafluoropyrimidine

4-(4-Acetyl)-4-[4-(3-methyl-1-tritylmethyl-indole-p-biazole-4-yl)-phenyl]-hexahydrop-pyridinium ( A suspension of 5N hydrochloric acid (5 mL), THF (5 mL) and methanol (5 mL) was stirred for 140 min. The organic solvent was removed in vacuo, and the resulting solution was diluted with 2N HCl and washed with squam. The aqueous phase was basified by the addition of sodium hydroxide pellets, followed by extraction with ethyl acetate. The organic extract was washed with brine, dried (MgSO.sub.4), filtered and concentrated to give residue, which was purified by column chromatography (Si.sub.2) with decyl alcohol (5% to 7.5%). 2M ammonia gradient solution in di-methane. The product was further purified by preparative HPLC to give the title compound, which crystals crystals crystals crystalssssssssssssssssssssssssssss NMR (Me-d3 - OD) δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H, m), 7.35-7.41 (4H, m), 7.47-7.54 (4H, m ), 8.32 (2H, s). Example 79 1-(4- gas stupid V2-|~4-nH-pyrazole-4-V-radical 1- loff 4 19A. 2-(4-hydrobenzene Base)-2-(4-iodo jasmine V 璜氲 ethane 1336222

Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placed under N2, then DMSO (5 mL) was added. After 15 min, tris-fat was added as a solid. • 66 grams, 3.2 millimoles), after a further 30 minutes, followed by (4-cyclophenyl)-(4-mothyl)-methanone. The mixture was stirred at room temperature for 24 hours, then diluted with ethyl acetate and washed with water & brine, water and brine (x2). The org. <RTI ID=0.0></RTI> <RTI ID=0.0> LCMS (PS-A2) Rt 4.07 min [M-H]-355.

22B·H4-argon-based)-2-(2- via a certain ethylamine

2-(4-indolyl)-2-(4-iodophenyl)-oxirane (〇·6 g, 168 mmol), ethanolamine (0.5 ml, 8.3 mmol) and three A solution of ethylamine (5 ml, 3.6 mmol) in isopropanol (5 mL) was maintained at 5 ° C for 72 h then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with a saturated brine bath / water (1:9). The aqueous phase was extracted with ethyl acetate for a second time, then the combined extracts were washed with brine, dried over NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .29 102449 -186· 1363622 min [M+H]+418, [M-H20+H]+400.

Zg_C. 2-(4-gas base)-2-(4-破茉)-Huofu said

• 1-(4-Phenylphenyl)-2-(2-hydroxy-ethylamino) small (4_iodophenyl)·ethanol (7〇1 mmol, 丨.68 mmol) in DCM The solution in (10 ml) was treated with concentrated h2so4 (oi^.m. After 20 hours, another portion of h2S〇4 0 (1.0 ml of '丨9 house Mo) was added and the mixture was stirred for another 2 hours. The mixture was diluted with ethyl acetate and washed with saturated aqueous potassium carbonate and brine, then dried (MgSO4), filtered and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) [m+H]+400.

Following the procedure set forth in Example 1, but using ruthenium (triphenylphosphine)palladium (ruthenium) as a catalyst, 2-(4-phenylphenyl)-2-(4-phenylene)-morpholine was 4-(4,4,5,5-tetramethyl-1,3,2-dioxosin-2-yl)-1Η-ρ is reacted to give the title compound. LCMS(PS-A3)Rt6.88 min[]\1+11]+340.111 should be 11(]^-(13-〇〇)5 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 102449 -187· 1363622 (2H,d), 7.40 (4H, apparent d), 7.56 (2H,d), 7.92 (2H, Br s). Example 80 (4-{4-『4-(lH-p|:b ° sit-4-yl V-methyl-l-hexahydropyrene than bite-4-yl-m negative, its v-acetate disk ( 4-{4-Γ4-(1Η-pyrazol-4-yl V-l-yl 1-hexahydropyridine-4·丨丨-laughing, its v-aldoxime 80Α.丨4-|~4-(4-bromo Phenylhexafluoropyridin-4-yl 1-mosa

The title compound was obtained according to the procedure described in Example 42, but substituting chlorobenzene with ethyl phenoxyacetate and using nitrobenzene as solvent. LCMS (ps_A2) Rt2.37 min [M+H]+418. 迎 g,. (4-{4-"4-(1_Η-pyrazole-4·yl V-m-l-hexahydropyridine-4-丨-笑笑篡 brewing II and (4-{4-"4_(1Η-pyrazol-4-yl V-yl 1-hexahydropyridine·4- 丨-芏 gas a certain acid vinegar

According to the procedure set forth in Example 1, but using ruthenium (triphenylphosphine)palladium (9) as a catalyst, {4-[4-(4-bromophenyl)-hexahydropyridinyl-4-yl]-phenoxy Ethyl acetate reacts with 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)·1Η_pyrazole at 8 °C The mixture was heated for 30 minutes to give a mixture of the title compound. After treatment, the basic aqueous extract was neutralized with hydrochloric acid and extracted with ethyl acetate (χ2), then 102449 -188 - after the organic extracts Combine and wash with brine, dehydrated and dried as 鸪04) 'filtered and concentrated to give a crude product which is recrystallized from water to give (4-{4-[4-(1Η-pyrazol-4-yl)) -phenyl]•hexahydropyridin-4·ylphenoxy)·acetic acid (12 gram, 5%); LCMS (PS-A3) Rt5.33 min 〇4+11]+378.111 face 11 (〇] \18〇d6) δ 2.22-2.26 (4Η, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11 (2H, d), 7.24 (2H, d) , 7.46 (2H, d), 7.96 (2H, br s). A substance that has not been extracted from a base is converted to a single compound {4-[4-(1Η-pyrazole) when it is left in decyl alcohol. 4-yl)-phenyl]-hexahydropyridyl winter base}- Phenoxy)-acetic acid decyl ester. It was purified by preparative HPLC to give the title compound (18 mg, 7%); LCMS (PS-A3) Rt 6.13 mins [he + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + (4H, m), 2.87 (4H, apparent t), 3.75 (3H, s), 6.83 (2H, d), 7.21 (2H, d), 7.26 (2H, d), 7.47 (2H, d), 7.89 (2H, s). Example 81 4!_{4:『4-(1Η-ρ-Bizozol-4-yl)- Stupid 1–6氤氤咭·4_基μ芏甲崎81 A. 4- (4-gas base) -4- (4- moth-mounted six gas ρ than bite

The title compound was obtained following the procedure described in Example 42B, but substituting benzene with benzene. LCMS (PS-A2) 2.68 min [M+H]+ 398. 81B. 444-(4-chlorophenyl)-hexapyridinium ice a certain percentage of benzene 102449 -189- 1363622

%

Mixing 4-(4-chlorophenyl)-4-(4-phenylene)-hexahydropyridine with copper (I) cyanide in DMF at 140 ° C under nitrogen for 6 hours, then It cools. The mixture was diluted with ethyl acetate, washed with a mixture of concentrated ammonia and brine (χ5), dehydrated and dried (MgS〇4), filtered and concentrated to give a residue which was subjected to column chromatography (Si〇2). Partially purified, the title compound (46 mg, &lt; 16%) was obtained eluted from EtOAc (EtOAc) This was taken to the next reaction without further purification. LCMS (pS_A2) Rt2 39 minutes CM+H]+297.

ilC. 4-{4-"4-(1Η-pyrazol-4-yl V stupyl ι·hexahydropyridine _4-篡μ笑甲

According to the procedure set forth in Example 1, but using 肆(triphenylphosphine) (9) as a catalyst, 4-[4-(4-phenylphenyl)-hexahydropyridin-4-yl]-benzonitrile was 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl group. Sitting reaction and at 1 Torr. (: heating under 15 minutes to obtain the title Compound LCMS (PS-A3) Rt 6.68 min [M+H] + 329.1H NMR (Me-d3 - OD) (5 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 ( 3H, s), 7.46 (2H, d)5 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, br s). 102449 • 190· 1363622 Example 82 {2 -(4-Aza-methyl)-2-"4-αΗ-岫吔-4-yl V-phenyl 1-propyl}•Methyl-amine 82A. Bis-(4-Gasyl V-methyl acetate

Bis-(4-chlorophenyl)-acetic acid (4.33 g, 15.4 mmol) was suspended in anhydrous methanol (20 mL) and concentrated hydrochloric acid (5 drops). After 1 day, the reaction was quenched by the addition of saturated sodium bicarbonate solution and then the organic solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 50% saturated aqueous potassium carbonate. The organic phase was washed with brine, dried (MgSO.sub.4), filtered and concentrated to afford The title compound was obtained as a colorless oil (3.57 g, 78%).

LCMS (PS-B3) Rt 3.79 min, no ionization. 1HNMR(CDC13)5 3.74 (3H, s), 4.96 (1H, s), 7.20-7.23 (4H, m), 7.28-7.32 (4H, m). g2B. 2,2-chelate-(4-氤莫Methyl propionate

A solution of bis-(4-phenylphenyl)-acetic acid decyl ester (m. 19 g, 4·m.m.) in THF (20 mL) was cooled to _78. Hey. In 5 minutes, add a solution of mlda (3.0 ml '6.0 mmol, 2M in heptane/THF/ethylbenzene), then, after another 20 minutes, add methyl iodide (〇63 ml, 1〇1 毫) Moore). 102449 -191 - 1363622 After 4 hours, the reaction was quenched by the addition of a saturated ammonium sulfate solution, and /m was allowed to warm to room temperature, then concentrated in vacuo to remove organic solvent. The mixture was diluted with ethyl acetate/petroleum ether 1:4, and washed with saturated ammonium chloride solution, followed by brine washing, dehydration drying (MgS〇4), transition and concentration, to obtain a residue Chromatography (Si 〇 2), eluting with ethyl acetate / petroleum ether gradient (1% to 2%) to give the title compound as colorless oil (21 〇 ,, Π%) 'LCMS (PS-B3) Rt4.01 min 'no ionization. Ijjnmr (CDC13) δ 1.88 (3Η, s), 3.73 (3H, s), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).

G2C. 2,2-譬-(4-chloromethane V and 酴

Cl

C02Me

A solution of 2,2-bis-(4-phenylphenyl)-propionate (210 mg, 0.67 mmol) in THF/water/decyl alcohol (1:1:1,18 mL) Stir for 5 days at room temperature and then concentrate in vacuo. The residue was partitioned between ethyl acetate and EtOAc (EtOAc) (EtOAc) A yellow solid was used without further purification. LCMS (PS-B3) Rt 2.40 min [M-C02H]-249. 82D· 2,2-B--(4-gas-based VN-methyl-propanol 102449

Cl CI -192-

1363622 Following the procedure described in Example 8D, but substituting 2-(4-bromophenyl)-3-(4-chlorophenyl)-propionic acid for 2,2-bis-(4-chlorophenyl)-propane Acid, the title compound was obtained ^ LCMS (PS-B3) 1^3.40 min [M+H]+308-82E. Γ2,2-chelate-(4-氲莫某Vpropyl1·甲某-amine

Replace 2,2-bis-(4- gas with 3-(4-bromophenyl)-3-(4•phenyl)-N-methyl-propionamide according to the procedure described in Example 8E Phenyl)-N-methyl-propanamide afforded the title compound. LCMS (FL-A) Rt2.35 min [M+H]+ 294 82F· {2-(4-Gasyl V2-[4-[lH-pyrazol-4-yl V-V-V-propyl-methyl- amine

[2,2-bis-(4-phenylphenyl)-propyl]-indolyl-amine and 4-(4,4,5,5-tetramethyl-1) according to the procedure set forth in Example 1. , 3,2-dioxaboron-2-yl)-1Η-pyrazole was reacted to give the title compound. </ RTI> <RTIgt -7.33 (4H, m), 7.37-7.40 (2H, m), 7.68 (2H, d), 8.35 (2H, s). Example 83 H4-Phenylphenyl)-2-methylamine-1-(4) -(1Η-pyrazole-4-V-methyl)-ethanol 1336222

The title compound was obtained according to the procedure </ RTI> as described in Examples 79A, 79B, and <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; LCMS (PS-A3) Rt5.28 min [M+H] + 328, & [M-H2 0+H] + 310.1H NMR (Me-d3 - OD) δ 2.38 (3H, s), 3.34 (2H, s), 7.28-, 7.31 (2H, m), 7.41-7.46 (4H, m), 7.51-7.54 (2H, m), 7.92 (2H, s). 6 · Example 84, 2-Amino-1- (4-Chlorophenyl)-1-"4-(1H-p ratio. Sodium-4-yl)·笑暮i-ethanol 84A. 2-"2-Chloro-V-hydroxy-2- (4-Broken VV 篡1-isoindole-1.3-dione

'(2-Phenylphenyl)-2-(4-iodophenyl)-oxirane* (571 mM gram '丨·60 mM) with o-phthalazin at 100eC Potassiumamine (340 mg, 1.84 mmol) was heated in THF (5 mL) EtOAc (2 mL). The mixture was concentrated in vacuo, diluted with ethyl acetate, and washed with water and brine (x2), dried (MgSO4), filtered and concentrated to give crude Purification, eluting with ethyl acetate/oil (2.5% to 100%), followed by a 10% methanol/methane gradient to give the title compound (273 mg, 34%); LCMS (PS-A2) Rt3_22 min [M+H]+ 504. *This starting material can be obtained by the method described in Example 79A. 102449 -194 - 1363622 ^^2-(4·Phenylphenyl)2-袅A^iL4-( 1H-pyrazole-4-V-methyl-l-ethylamine ~

According to the procedure set forth in Example 1, but using ruthenium (triphenylphosphine) palladium (ruthenium) as a catalyst, 2-[2-(4-phenylphenyl)·2-hydroxy·2_(4_峨基基)·ethyl]_isoindole<夂dione and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)_1H•pyrazole , to get the title compound. LCMS (PS-A2) &amp; 2.62 min [Μ-ΗΓ460· g4C. 2-Amino-1-(4-phenylphenyl ΐ ΐ "4-ΠΗ-戒峻-4-一策一1-ethanol

Follow the procedure described in Example 49D, but with Ν_(2·{(4·Phenylphenyl)-[4-(1Η-pyrazol-4-yl)-phenyl]-methoxy}-ethyl) _Proline-substituted Ν·{2-(4-Phenylphenyl)-2·transyl-2-[4-(1Η-pyrazol-4-yl)-phenyl]•ethyl}_g-tanoic acid , the title compound was obtained. </ RTI> <RTIgt , m), 7.55 (2H, d), 7.94 (2H, s). Example 85 4-(3,4-diqi-stupyl)-4-"4-(111-1&gt; ratio ° sit -4- Base&gt;)-菜基1-六翁."&gt; ratio 0^102449 -195- 1363622

Following the procedure described in Example 14, but substituting chlorobenzene for 1,2-dichlorobenzene, the title compound was obtained. LCMS (pS-B4) 2〇 min +372 lHNMR ♦ (Me-d3 -0D) δ 2.62-2.69 (2Η, m), 2.73-2.81 (2Η, m), 3.18-3.30 (4H, m), 参 - φ 734 (1H, dd), 7·46-7·52 (3H, m), 7.53 (1H, d), 7.72 (2H, d), 8.56 (2H, s). Example 86 Latex-based V4- "4-"m-pyrazol-4-yl V-m-yl 1-hexapyridine

Following the procedure described in Example 14, but substituting chlorobenzene for 2- chlorophenyl ether, the title compound was obtained. </ RTI> <RTIgt , 7.06 (1H, d), 7.30 (1H, dd), 7.34 (1H, d), 7.45 (2H, d), 7.69 (2H, d), 8.57 (2H, s). Example 87 jj4-gas_based Phenyl)_4_"4_(1沁pyridinyl)-based hexahydropyridinium

EA_ 4-(tenqi·3·fluorophenyl)-4-yl-hexahydro-bito-1-carboxylic acid third-butan ci ci JBoc __ iBoc , 7.5 under nitrogen, 4-chloro- 3-fluorophenyl magnesium bromide solution (15 ml • 196-102449

1363622 House Moule, 0. 5 Torr, in THF) was added to 4-_yl-hexahydrop to bite_ι_2, butyl acid (1.02 g, 5.1 mmol). After 24 hours, a saturated ammonium chloride solution was added, and then the organic solvent was removed in vacuo. The mixture was extracted with ethyl acetate, and the mixture was washed with brine, dried (MgSO4), filtered, and concentrated to give residue, which was purified by column chromatography Ethyl acetate/petroleum ether (〇% to 2 〇〇 /.) was eluted to give the title compound (511 mg, 30%). iHNMR(Me-d3-OD) 5 1.48 (9H, s), 1.67 (2H, brd), 1.92 (2H, td), 3.16-3.29 (2H, m), 3.99 (2H, br d), 7.27 (1H , dd), 7.38 (1H, dd), 7.42 (1H, t). 87 horse. 4: (4·Han·Fungi)-4-(4-carbyl-3-fluorophenyl)-hexahydrop Biha

The title compound was obtained following the procedure described in Example 42B, but substituting benzene with benzene. LCMS (PS-A2) Rt2.43 min [M+H]+368. 87C_ 4-(4-Gayl-3-1 stupid)-4-丨°Sitting -4-V-Laughter 1-1-6 Fish .p than ha

Following the procedure set forth in Example 1, but using (9) as a catalyst with hydrazine (triphenylphosphine), 4-(4-bromophenyl)-4-(4-chloro-3-fluorophenyl)-hexa Hydrogen pyridine and 4-(4,4,5,5-tetradecyl-l,3,2-dioxos-2-yl)-lH-p ratio. The reaction was taken to obtain the title compound. </ RTI> <RTIgt Overlap, 4H, m), 7.23 (1H, t), 7.34-7.39 (1H, m), 7.22 (1H, dd), 7.30 (1H, dd), 7.43-7.49 (3H, m), 7.71 (2H, d), 8.55 (2H, s). Example 88 - Butyl ester 88 Α. 4-(4- 基基·笨基)-4-(4-气茉基V六组. Bite 1- Recording 箆 箆

4-{4-"4-(out-1? than sal-4-yl)-stupid ~|- six invitations.17 this bite-4-base}-laughing

4-(4-Bromophenyl)-4-(4-phenylphenyl)-hexahydropyridine tris-tresine tri-butyl ester* (888 mg, 1.97 mmol) in THF (5) The solution in milliliters was cooled to -78 C. A solution of n-butyl hydride (1.5 mL, 16 M in hexanes) was added dropwise and the mixture was maintained at this temperature for 25 min. Carbon dioxide gas (produced from dry ice and dried by passing through a gasification feed column) was bubbled through the anion solution for 80 minutes, and then the mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue was partitioned between 1N hydrochloric acid and EtOAc. The organic phase was separated, dried (MgSO.sub.4) filtered and concentrated. The combined aqueous phase is further extracted with ethyl acetate, and the extract is also dehydrated and dried (MgS〇4) 'filtered, combined with the ether-containing extract, and concentrated to obtain 4 (4-m-phenyl)-4-( 4-chlorophenyl)-hexahydrop ratio bitrate-1-acidic third-butyl ester (889 mAh). LCMS (PS-A2)Rt 3.52 min [M-tBu+H]+360. *This The starting material can be prepared by the method of Example 14A, followed by the method described in Example 48A. 102449 • 198· 1363622 88B. 4-(4-carboxy-phenyl)-4-"4-(1Η-pyrazole-4-篡V smile 篡V hexahydropyridine-1-tertillate third-butyl ester

4-(4-carboxy-phenyl)-4-(4-chlorophenyl)-hexahydropyridine-1-carboxylic acid tert-butyl ester and 4-(4, according to the procedure set forth in Example 1. 4,5,5-Tetradecyl-1,3,2·dioxaboron-2-yl)-1Η-pyrazole reaction 'to obtain the title compound. LCMS (PS-A2) Rt 2.92 min [Μ+Η]+448. 88C. 4-{4-"4-(1Η-ρ is 嗤-4-yl stupyl 1-hexahydrop) Base μ armor

4-(4-sulfo-phenyl)-4-[4-(1Η-ρ 嗤-4-yl)-phenyl]-hexahydropyrene is occluded as a third-butyl ester 26 mg '0.06 mmol" was dissolved in dioxane (2 ml) and 1 HCl (2 mL). After 24 hours, the mixture was concentrated in vacuo and purified eluting eluting with with with with with with with with with + 348.1H NMR (Me-d3 -OD) δ 2_70-2·82 (4H, m), 3.26 (4H, apparent t), 7.46 (2H, d), 7.51 (2H, m), 7.68 ( 2H, d), 8.00 (2H, d), 8.47 (2H, s). 102449 -199- 1363622 Example 89 444-(1 such as 啥-4-yl)-phenyl 1-1,213,4,5 ,6-六裔.-"414,1 bipyridyl 89A. 4" (4-rolled phenyl)-3,4,5,6-tetra-1 -2Η-Ι~4·4 Ί p 比-丨·钕醢篦三-butyl ester

CInv^nb〇c ci under nitrogen rolling 'make bis-(2-gas-ethyl)-amine hydrazinoic acid tert-butyl ester* (ι.54 g, 4 φ 6_36 mmol) in toluene (10 The solution in ML) was cooled in ice "Addition of 4-(4-• chloro-yl)-pyridine (1.30 g, 6.36 mmol) followed by a solution of hexamethylenediamine (10 mL ' 20 Millol '2M in THF), after two minutes. The mixture was stirred at 0 ° C for 3.5 hours, then allowed to warm to room temperature and stirred for additional 20 hours. Methanol was added and the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid (χ3) and brine, dried (MgSO.sub.4), and concentrated to give residue. 〇 2) Purification, dissolving in a 2 m methanolic ammonia (1% to 5%) Φ gradient solution in dioxane. The title compound (16 mg, ο.?%) was obtained by column chromatography (Si02) eluting with EtOAc (EtOAc). LCMS (PS-A2) Rt 2.65 min [M+H] + 373. * This starting material can be obtained by the method described in J. Chem. Soc., Perkin Trans 1, 2000, pages 3444-3450. 89B. 4-"4-(1Η-ton sal-4-yl)- stupid ll, 2.3.4rS, 6-six ft - "+4 Ί 咭 咭 102449 · 200·

1363622

4-(4-chlorophenyl)-3,4,5,6-tetrahydro-2H-[4,4']bipyridyl-1-carboxylic acid third - according to the procedure set forth in Example 1. Butyl ester is reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)·1Η·pyrazole, followed by 4MHC1 in dioxane Treatment to obtain the title compound. 1^1^(?3-;64)1^4.28 min 1&gt;1+11]+305· 1H NMR (Me-d3 -0D) δ 2.76 (2Η, br t), 3.01 (2H, br d), 3.24 (2H, br t), 3.39 (2H, br d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d), 8.37 (2H, s), 8.82 (2H, d) Example 90 3-(3-Phenylphenyl)-3-丨4·(1Η·Pyrazole-4-V茇篡1-胗

Following the procedure described in Example 8, substituting 4-chlorophenylmagnesium bromide for 3-oxophenylmagnesium, and substituting amine with decylamine afforded the title compound. LCMS (PS-B3) Rt 2.6 〇 [M+HrsiyHNMR^Me-c^-OD) 6 2.44 (2 Η, apparent qd), 2.87 (2 Η, dd), 4.14 (1 Η, t), 7.24 (1Η, dt), 7.27-7.33 (2Η, m), 7.34 (1H, t), 7.42 (2H, d), 7.68 (2H, d), 8.58 (2H, s). 102449 -201 -

Follow the procedure described in Example 83, but substituting (4-bromophenyl)-(4-iodophenyl)-methanone for (4-bromophenyl)-(4.nitrophenyl)-fluorenone , the title compound was obtained. LCMS (PS-A)^1.79^+^+339.1 H NMR(Me-d3-OD) δ 8.27 (2Η, d), Γ,, 7.98 2H, s), 7.80 (2H, d), 7.65 (2H, d), 7.52 (2H, d), 4.00 (2H, dd), 2.73 (3H, s) - The CH(OH) signal is assumed to be at the water absorption peak. 1363622 Example 92 2-(3·Chlorosinoxy-phenyl)-2-"4·ί1Η·pyrazol-4-yl V-l-yl 1-ethylamine

Following the procedure described in Example 87B and Example 42C, but replacing 1-(4-bromophenyl)-2-methylamino-ethanol with 2-amino-1-(4-bromophenyl)-ethanol, and Substituting 2-oxo-anisole for gas benzene to give the title compound: LCMS (PS-B3) Rt2.55 [M+H]+ 328.20.1H NMR (Me-d3 -OD) δ 3.65-3.70 (2H, d) , 3.90 (3H, s), 4.30-4.35 (1H, t)3 7.05-7.10 (1H, d), 7.30-7.35 (1H, d), 7.40 (1H, s), 7.45-7.50 (2H, d) s 7.70-7.75 (2H, d), 8.60 (2H, s). 102449 -202- 1363622 Example 93 Chlorophenyl)-2-fluoro--2·Γ4-(1Η-Pi咄-4-yl V茇1-乙e 21 八.2,2-双-(4-气茉#2-牟,-7.

2-Amino-1,1-bis-(4-phenylphenylethanol (293 mg, 丨〇4 mmol) was dissolved &quot;φ in pyridine_HF (2 mL) and cooled. After 24 hours The mixture was diluted to 1 N sodium hydroxide solution and extracted with dCM (x3). Each extract was dehydrated and dried (MgS 4) and filtered, then combined, and concentrated to give a residue. Purification by column chromatography (EtOAc) eluting elut elut elut elut elut elut elut elut elut elut elut elut NMR (DMSO-d6) (5 3.41 (2H,d), 7.39-7.46 (8H,m)_ 21 which. 2-(4-phenylphenyl)-2-1[.篡-2-Γ4-Γ1Η- Pyrazin-4-yl V stupyl 1-ethylamine

S'N according to the procedure set forth in Example 1, 2,2-bis-(4-phenylphenyl)-2-fluoro-ethylamine and 4-(4,4,5,5-tetradecyl-1 , 3,2-dioxaboron-2-yl)-1Η-pyrazole reaction, except that the heating was carried out at 100 ° C for 5 minutes using a power of 300 W in a CEM microwave to give the title compound. LCMS (PS-B4) Rt 6.69 min [MF-] + 296.1H NMR (Me-d3 - OD) &lt;5 4.04 (2H, d), 7.47-7.55 (6H, m), 7.77 (2H, d), 8.41 (2H, d). 102449 •203 ·

J363622 according to the procedure described in Example 60, but replacing 6-chloro-in the alkali nitrile with 6-chloro-pyridine-3-carboxaldehyde and 1-trityl-1Η-pyrazole-4-dihydroxyboron The title compound was obtained as an alkane-substituted 3-methyl-1-trityl-l-indole-salt dihydroxyborane and then according to the procedure described in Example 8. 2·(4·oxy-3-fluorobenzene storm)-2-『4-(1Η-Pisi 4 -4-莘 茉基ι·ethylamine

Following the procedure described in Example 87, but replacing the 4-keto-hexahydropyridine small carboxylic acid tert-butyl vinegar with (2-keto-ethyl)-amino phthalic acid tri-butyl vinegar Title compound. Example 96 • Pyrazole _4_某,·举其ι_六氤pyridine 102449

1363622 The title compound was obtained according to the procedure described in Example 14 but substituting chlorobenzene with chlorophenyl 2' fluorobenzene. Example 97 1-((3.4-二气H W4-(1H-pyrazol-4-yl)-stupidyl yili j丨1 Guo 17 bite _ 97A. (4-chloro-bumpy W3.4-dichloro -phenyl)-methanol

The commercially available gas phenylmagnesium bromide was reacted with a 3,4-dichlorobenzene plate&apos; according to the method described in (2000), 43(21), 3878-3894 to give the title compound. 97Β· 1,2-Dichloro hopper “Nitrogen/4-Nitromethyl”·Methyl 1-芨

The product of Example 97A was reacted with 3 〇 2 (: 12 to give the title compound according to the method described in Orgamc., (2003), 5 (8), 1167-1169. 97. Pyridazole-4-篡v Mosquito 1-methylhexahydrop ratio tillage 102449 1363622

The title compound can be prepared from the compound of Example 97C using the methods and conditions described in z/l0 踩 如 扮 筒 筒 10 (10) ^ 知 (2002), 12 (3), 125-129.

2·-·(3,4-一气^基)-2_『4_(ιΗ•扑卜.圭_4其笑一一乙胺

Following the procedure described in Example 42, but in Example 42b, the title compound was obtained as a solvent. Example 99 _ 1·2_(3-oxy-heptyloxy-phenylν2-[4-(ΊΗ-pyridin-4- some V-single 1-ethylmethyl&quot; amine according to Example 42 The procedure is described, but in the step 42, the title compound is obtained by substituting 2-p-benzophene ether for gas benzene. LC/MS : (PS-A2) Rt 2.03 [Μ+Η]+ 342.1H NMR (Me-d3 -0D) δ 2.45 (3H, s), 3.22 (2H, d), 3.85 (3HS s), 4.15 102449 -206- 1363622 (1Η, t), 7.04 (1H, d), 7.33 (1H, d), 7.27-7.34 (3H, m), 7.55 (2H, d), 7.92 (2H, s). Example 100 Nitrogen 圜-1-yl-1-(4-chloro-jamoxyl b) v. Say

The title compound was obtained according to the procedure described in Example 42.例 101 3-(3-Alkyl-4-methyl-n-phenyl-phenyl)-3-[~4-ΠΗ-vista-4-V-phenyl 1-propylamine

Following the procedure described in Example 61, but in step 61, the sodium phthalate was replaced with potassium phthalate, and in 61 ,, the gas benzene was replaced by 丨_气基_2·methoxy-benzene. The thiol protecting group was then removed under the conditions set forth in Examples 84A and 84C to provide the title compound. f 102 {3-0-gas-based-4-methyl-phenyl--3-)-3-"4-(1Η-pyrazole_4_某V笨一一一一}}-methyl-cavity 102449 - 207- 1363622

Following the procedure described in Example 61, but substituting the imidazole with decylamine in Example 61A and substituting chlorobenzene with 1- yl-2-methoxy-benzene in Example 61B, the title compound was obtained. Example 103 1-"(3-Alkyl-4-methoxy-stupyl M4-氪策基甲一一六氤氤耕耕103A·(3-气基-4-甲乳某-笑基)- (4-chlorophenyl alcohol

The title compound was prepared using the method of Example 97A, but substituting 3-, 4-difluorobenzaldehyde for 3,4-dichlorobenzaldehyde. 1^3.Β.2·Fluoryl-4_[Chlorine-(4-Year. 芰 V V A 1_1_A argon-M-

The hydroxy compound of Example 103 was converted to the title gas-based compound according to the procedure of Example 97. 103C. 1-"(3-gas base soil gas 篡 _ 苽 some W4_ nitrogen 曱 曱 &&gt; six 1

102449 - 208 1363622 The title compound can be obtained from the product of Example i 3b according to the procedure of Example 97C. Example 104 ΟΓ4-Chloropyrazole-4-some)·苽基1·甲眩

The procedure described in Example 1 was followed but the substitution of 2-(4-phenylphenyl)-2-phenylethylamine hydrochloride with C,C-bis-(4-phenylphenyl)-methylamine was obtained. Title compound. Example 105 (2-(4-乳本基)-2-"4-(3-曱-yl-lH-ptb 〇-4-基基基1-乙甲甲-face 105A. 2-(4- Glutathione VN-methyl-2-indole 4-indole-methyl-1-trimomethyl-1H-pyridin-4-yl-based 1-Ethylamine

2,2-bis-(4-chlorophenyl)-N-methyl-acetamide was prepared by the method of Example 21a by reacting a commercially available carboxylic acid with methylamine. Then, the N-mercapto-acetamide compound was converted into the title compound by the method described in Example 1. </ RTI> <RTIgt Zin-4-yl)-styl 1-acetamide 102449 -209- 1363622

The title compound (LCMS (PS-B3) Rt 2.41 min; HNMR (methanol-d4) 5 2.40 (M.sub.2) was obtained by the method described in Example 60D. 3H, s), 2.78 (3H, s), 4.95 (1H, s), 7.29-7.34 (6H, m), 7.41 (2H, d), 7.69 (1H, s). 105C.{2-(4-茉茉)-2-"4-(3-methyl-1H-pyrazole-4-yl V stupyl 1-ethyl methyl-amine

The title compound was obtained according to the procedure described in Example 20B. </ RTI> <RTIgt , 4.46 (1H, t), 7.41 (4H, s), 7.49 (2H, d), 7.54 (2H, d), 8.24 (1H, s). Biological Activity Example 106 pka kinase inhibitory activity ac&lt;^) Metrics can be tested for PK inhibitory activity of the compounds of the invention using PKA catalytic functional sites, obtained from Upstate Biotechnology (# 14-440), and 9-residue ΡΚΑ specific peptide (GRTGRJRNSI), also available from Upstate Biotechnology (# 12- 257), as a quality. 102449 -210· 1363622 The final concentration of 1 nM enzyme was used in the buffer containing 20 mM MOPS pH 7.2, 40 //M ATP/73 3 P-ATP and 5//M substrate. The compound was added to a solution of dimethyl hydrazine (DMSO) to a final DMSO concentration of 2.5%. The reaction was allowed to proceed for 20 minutes and then an excess of positive acid was added to quench the activity. Next, the unincorporated r33P-ATP was separated from the phosphonylated protein on a Millipore MAPH filter plate. The plates were washed, scintillant was added, and the plates were counted on a Packard TopCount.

The % inhibition of PKA activity was calculated and plotted to determine the concentration of the test compound required to inhibit 50% PKB activity (IC5〇). Examples 1, 4, 43, 44, 45, 46, 47, 48, 49, 52, 54, 59, 63, 66, 67, 73, 78, 79, 81, 82, 83, 84, 85, 86 and 90 The compounds have IC5 〇 values less than 1 βΜ, while the compounds of Examples 5, 7 and 80 have IC5 〇 values less than 15 _. Paste 107 Measurement of PKB Kinase Inhibitory Activity (IC&amp;) Protein kinase B (PKB) activity is inhibited by the compound, essentially as described by Andjelkovic et al. (Mol. Cell. Biol. 19, 5061-5072 (1999)). Assay, but using a fusion protein described as PKB-PIF and completely described by Yang et al. (Natural Structural Biology 9, 940-944 (2002)). This protein was purified and activated with PDK1 as described by Yang et al. The peptide AKTide-2T (H-A-R-K-R-E-R-T-Y-S-F-G-H-H-A-OHX #123900) from Calbiochem was used as a substrate. The final concentration of 0.6 nM enzyme was used in the buffer containing 20 mM MOPS pH 7.2, 30 _ATP/r33P-ATP and 25 _ receptor. The compound was added to the DMSO solution until the final DMSO concentration was 2.5% «The reaction was allowed to proceed for 20 minutes, and then excess orthophosphoric acid was added to quench the activity. The anti-102449 • 211 1363622 should be transferred to a phosphonium cellulose filter plate where the peptides are combined and the unused ATP is washed away. After washing, the scintillant was added and the activity incorporated was measured by scintillation counting. . The % inhibition of ten-fold PKB activity was &apos;maped&apos; to determine the concentration of the test compound required to inhibit the activity of 5〇% ρκβ (IC5〇). According to the above proposal, the actual cases 1, 4, 8-10, 12-17, 20-23, 25-31, 33-35, 43, 44, 46, 47, 49-52, 54, 56, The IC5 〇 value of 57, 59, 61, 63, 65, 66, 69, 71-73, 76-79, 81-87, 90, 91, 94 and 104 compounds is less than! _, and examples 2, 3, 5, 6, 7' 11, 18, 19, 24, 32, 36, 45, 48, 53, 55, 58, 60, 64, 67, 68, 75, 80 and 89 The compounds each have an ICw value of less than 5 /zM, and the compounds of Examples 40, 41, 62 and 70 each have an IC5 enthalpy value of less than 50. Pharmaceutical Formulation Example 108 (1) Tablet Formulation A tablet composition containing a compound of formula (I) is prepared by combining 50 mg of the compound with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant. Mix and formulate in a known manner to form a tablet. (ii) Sheng capsules The capsule formulation was prepared by mixing 1 mg of the compound of formula 1 with 100 mg of lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

(iii) Injectable Formulations The parenteral compositions for administration by injection can be prepared by dissolving a compound of formula (1) (for example in the form of a salt) in water containing 1% propylene glycol, and 102449 - 212-1363622 1.5% by weight of active compound concentration is obtained. The solution is then sterilized by filtration, filled into a bottle, and sealed.

(iv) Injectable Formulation TT The parenteral composition for injection is prepared by dissolving the compound of formula 1 (for example in the form of a salt) (2 mg/ml) and mannitol (50 mg/ml) in water. And filled into a sealable 丨ml glass bottle or ampule. (iv) Subcutaneous injection of Taitai ® to prepare a subcutaneous pharmaceutical composition by combining the compound of the formula (I) with a pharmaceutical grade corn oil to obtain a concentration of 5 mg/ml. The composition is sterilized and filled into a suitable container. Equivalents The present invention is not intended to be construed as limiting the scope of the invention. It is to be understood that many modifications and variations can be made to the specific embodiments of the invention described in the above and the example φ without departing from the principles of the invention. All such modifications and changes are intended to be included in this application. 102449 213-

Claims (1)

1363622 X. Patent application scope 1. A compound of formula (I) A H No. 094118996 Patent application 'One ^-1 Chinese patent application scope replacement (December 1) Or a salt, tautomer or bismuth-oxide thereof; Wherein Α is a saturated hydrocarbon linkage containing from 丨 to 7 carbon atoms, the linkage has a maximum chain length of 5 atoms, extending between Ri and nr2r3, and a maximum chain length of 4 atoms, extending over £ And ^3, wherein one of the carbon atoms in the linking group may be optionally replaced by an oxygen or nitrogen atom; and wherein the carbon atom of the linking group A may optionally carry one or more substituents selected from the group consisting of a keto group, a fluorine group and a hydroxyl group. , provided that the hydroxyl group, when present, is not at a carbon atom relative to the alpha position of the Nr2r3 group' and that the ketone group is present at a carbon atom relative to the alpha position of the NR2R3 group when present; Ε is phenyl or pyridine, which is unsubstituted or has up to 4 substituents R8, and R8 is selected from the group consisting of a gas group, a gas, a trifluoromethyl group, a cyano group, a Ci 4 hydrocarbon group, and optionally an alkoxy group. a silane or a heteroaryl group substituted with a hydroxy group; R is an aryl group or a heteroaryl group which is unsubstituted or has one or more substituents selected from the group consisting of a trans group; a C1M alkoxy group; a fluorine; a chlorine; ; trifluoromethyl; cyano, CONH2; nitro; q. 4 hydrocarbyloxy and A_4 hydrocarbyl, each optionally substituted by c]-2 alkoxy, carboxy or hydroxy; c] 4-mercaptoamine; Benzoguanamine; tetrahydronateloyl, hexahydropyridylcarbonyl; morpholine 102449-100122I.doc 1363622 carbonyl; hexahydropyranylcarbonyl; five or six members containing one or two Heteroaryl and heteroaryloxy groups of heteroatoms from N, 0 and S; phenyl; phenylalkyl; phenyl-Ch alkoxy; heteroaryl-Chalkyl; heteroaryl-Ch alkane Oxyl and phenoxy, wherein heteroaryl, heteroaryloxy, phenyl, phenyl-q.4 alkyl, phenyl-Ch alkoxy, heteroaryl-Chalkyl 'heteroaryl- Ch alkoxy and phenoxy groups are used as appropriate, Substituted by 2 or 3 substituents selected from the group consisting of C 2 · methoxy, fluoro, bromo, bromo, trifluoromethyl, cyano, CONH 2 ' C 1 hydrocarbyloxy and q 1 hydrocarbyl, each The case is substituted by a methoxy group or a thiol group; R2 and R3 are independently selected from the group consisting of hydrogen, Q. 4 hydrocarbon group and Cl-4 fluorenyl group, wherein the hydrocarbon group and the thiol group are optionally substituted by one or more substituents. a substituent selected from the group consisting of fluorine, hydroxyl, amine, methylamino, dimethylamino and decyloxy; or R2 and R3 and the nitrogen atom to which they are attached form a cyclic ring selected from imidazolyl a group, with a saturated monocyclic heterocyclic group, having 7 ring members in winter, and optionally a second hetero atom ring member selected from 〇 and !^; or one of R2 and R3 and The nitrogen atom and one or more from the linking group AU '- form a saturated monocyclic heterocyclic group having 4-7 ring members, and optionally a second hetero atom ring group selected from 〇_ Or NR2R3 forms a cyanide C with a ruthenium atom of the linking group A to which it is attached] a saturated hydrocarbyloxy group, a Ci.5 saturated hydrocarbyloxy group, and a R4 selected from the group consisting of hydrogen, halogen, C.5, a saturated hydrocarbon group, and cyanogen. And CF3; and R5 is selected from the group consisting of hydrogen, halogen, c. 5 saturated hydrocarbon, 102449-100I22I.doc -2- 1363622 cyano, CONH2, CONHR9, CF3, NH2, NHCOR9 or NHCONHR9; R9 is a group R9a or (CH2) R9a, wherein R9a is a monocyclic or bicyclic group which may be a carbocyclic or heterocyclic group; a carbocyclic group or a heterocyclic group R9a is optionally substituted by one or more Substituted, the substituent is selected from the group consisting of halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amine, mono- or di-Cw hydrocarbyl amine; group Ra_Rb, wherein Ra is a bond, hydrazine, Co, xwx2), Qxqx1, xWxqx1, S, SO, S〇2, NRe, S02NRc or NRcS〇2; and Rb is selected from hydrogen, has a heterocyclic group of 3 to 12 ring members, and a Ci 8 hydrocarbon group Substituted by one or more substituents, the substituent is selected from the group consisting of hydroxy, keto'halogen, cyano, nitro, carboxyl, amine, mono- or di-Ch-hydrocarbylamino, having from 3 to 12 rings a carbon ring group and a heterocyclic group, and wherein one or more carbon atoms of the Ci8 hydrocarbon group may be replaced by 0, S, SO, S02, NRC, XiQX2), CXX2^1 or XiCXX^Xi; selected From hydrogen to C1M hydrocarbyl; and X1 is Ο, S or NRC, and X2 is =〇, =s or =NRC. 2. A compound of claim 1 which has the formula (Ia): R2 R1 - A-N I, r3 Or a salt, tautomer or N-oxide thereof; wherein A is a saturated hydrocarbon linkage having from 1 to 7 carbon atoms, the linkage having 102449-1001221.doc 1363622 having a maximum chain length of 5 atoms, Extending between ... and ^, with a maximum chain length of 4 atoms, extending between £ and 2113, one of the linked carbon atoms may be replaced by an oxygen or nitrogen atom, and wherein the linking group A The carbon atom may optionally have one or more substituents selected from the group consisting of a sulfhydryl group, a gas and a hydrazine group. The condition 疋 hydroxy group, when present, is not at a carbon atom relative to the 1 position of the NR 2 R 3 group, and the conditions thereof Is a keto group when present in a position relative to the carbon atom of the alpha position of the NR2R3 group; Ε is a phenyl or oxime bite, #£ is unsubstituted or has a height of 4 as defined in claim 1 Substituent R8; ^ R1 is aryl or heteroaryl which is unsubstituted or substituted as defined in the claim ;; R2 and R3 are independently selected from hydrogen, Ci 4 sulphur and Ch thiol; R2 and R3 together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4 to 7 ring members, and The case contains a second hetero atom ring member selected from 〇 and N; or a gas atom connected to one of the shank 2 and the angling 3 and one or more atoms from the linking group a, forming a saturated monocyclic ring a heterocyclic group having 47 ring members' and optionally a second heteroatom selected from 0 and 1^; ', or NRR3 together with the carbon atom of the linking group A to which it is attached A group of R is selected from the group consisting of hydrogen, dentate, Cl_5 saturated hydrocarbon, cyano and Cf3; and R5 is selected from the group consisting of hydrogen, hydride, C15 saturated hydrocarbon, cyano, c〇NH2, eQNHR9, CF3, NH2, NHCOR9 Or NHCONHR9; 102449-1001221.doc -4 - 1363622 r9 is a phenyl or fluorenyl group, each optionally substituted by one or more substituents selected from the group consisting of a hydroxyl group, a hydroxyl group, a trifluoromethyl group, a cyano group, and a nitrate a group, a carboxyl group, an amine group, a mono- or di-bi-4 hydrocarbon group; a group Ra-Rb, wherein 硭 is a bond, 〇, co, xWx2), c(x2)xi, xwxqx1, s, so, So2, NRe, S02NRc or NRC S02; and Rb is selected from the group consisting of hydrogen's heterocyclic group having 3 to 12 ring members, and C!8 ketone group is optionally taken by one or more substituents The substituent 'substituent is selected from the group consisting of a hydroxyl group, a keto group, a halogen, a cyano group, a nitro group, a carboxyl group, an amine group, a mono- or di-C丨M hydrocarbyl group, a carbocyclic group having 3 to 12 ring members and a heterocyclic ring. a group of groups, and wherein one or more carbon atoms of the 匸丨8 hydrocarbon group are Ο, S, SO, S〇2, NRC, XkCX2), C(x2)x! or χΐ (:(χ2) Χΐ substitution; Re is selected from hydrogen and q-4 hydrocarbyl; and X1 is 0, S or NRC, and X2 is =0, =S or =NRC. 3. The compound of claim 1, wherein A is a saturated hydrocarbon linkage having from 1 to 7 carbon atoms, the linkage having a maximum chain length of 5 atoms, extending between R1 and NR2R3, and a maximum chain It is 4 atoms long and extends between NR2R3, wherein one of the carbon atoms in the linking group may be replaced by an oxygen or nitrogen atom; and wherein the carbon atom of the linking group A may optionally have _ or more selected from fluorine and hydroxyl groups. a substituent, provided that the hydroxyl group, when present, is not at a carbon atom relative to the alpha position of the NR2R3 group; and the Han 5 is selected from the group consisting of nitrogen, halogen, Cu saturated hydrocarbon, cyano, CONH2, CF3, NH2 NHeOR9 and NHCONHR9. 4. The compound of claim 1 wherein the linker A has a maximum bond length of 3 atoms extending between R1 and NR2R3. 102449-1001221.doc -5 - 1363622 5. The compound of claim 4, wherein the linker A has a maximum bond length of 2 atoms extending between the ruler and the ^2]^. 6. A compound as claimed, wherein the linker A has a maximum bond length of 3 atoms and extends between E and nr2r3. 7. The compound of claim 6, wherein the linker VIII has a chain length of 2 or 3 atoms extending between Ri and NR2R3, and a chain length of 2 or 3 atoms 'extending to £ and ^ 2113 between. The compound of claim 1, wherein the linking group atom directly bonded to the group E is a carbon atom, and the linking group A has an all carbon skeleton. 9. The compound of claim 1, wherein the R匕A-NR2R3 moiety of the compound is represented by the formula NR2R3, wherein ^ is NH, NMe or 0; the W is attached to the group E and is selected from (CH2)j CR20, (&lt;3Η2)』-Ν&amp;_γ〇Η; b is 0 or 1, j is 〇 or i, k is 〇 or i, m is 〇 or 1 'η is 0, 1, 2 or 3, and P is 〇 or 1; the sum of b and k is 0 or 1; the sum of j, k, m, π and p does not exceed 4; R6 and R7 are the same or different and are selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group; and R2 is selected from the group consisting of hydrogen, methyl, thiol and fluoro. 10. The compound of claim 1, wherein a portion of the group R1 is represented by the formula R1 _(G)k -(CH2)m -X-(CH2)n -(CR6 R7 )p -NR2 R3, wherein G is NH, NMe or hydrazine; X is attached to group e and is selected from (cH2)j-CH, (CH2)jN and (NH)j -CH; j is 0 or 1 'k is 〇 or 1, m Is 0 or 1, η is 0,1,2 or -3, and ρ is 0 or 1 'and the sum of j,k,m,n and ρ does not exceed 4; and R6 and R7 are the same or different' and It is selected from methyl and ethyl, or CR6R7 forms a cyclopropyl group. • 6 · 102449-100I221.doc 1363622 11. The compound of claim 10, wherein (i)k is 0, m is 0 or 1, n is 0, 12 or 3, and p is 〇; or (ii) k For 〇, m is 0 or 1, η is 0, 1 or 2, and p 12_ is the compound of claim 1 其中 where (i) χ is (CH2)rCH, k is 1, m is 〇, 11 is Hey, 1, 2 or 3, and? 〇; or (丨丨) again (〇: 112) 』-(:11,1&lt;; is 1, m is 0' n is 〇, ι or 2, and p is 1. 13. If request 12 The compound 'where 1j is 〇; or (9) j is 丨; or (9) 圮 7 7 is C(CH3)2 〇 14. As requested! A compound of hydrazine wherein the Rl_A NR2R3 moiety of the compound is represented by the formula W-XJCH^-N^R3 wherein X is attached to the group e and is a group CH, and η is 2. 15. The compound of claim i, wherein R1_A(E)NR2R3 is selected from the group consisting of A1 to All: R2 RlY ' E" A1 rV^r2 έ ^ A2 E R3 A3 ! Me Me RV&lt;n^r2 E R3 A4 Me Me r1^Y&lt;n-r2 E R3 A5 R2 Rl&quot;yN,R3 E A6 R1 ^ ^ A7 OH R2 E A8 E A9 102449-1001221.doc 1363622 16. A compound according to claim i, wherein E is phenyl which is unsubstituted or substituted by up to 4 substituents R8 as defined in the claim}. 17. As requested! a compound wherein the group a and the pyrazole group are oriented in a meta or para position, attached to the group £; meaning that the A and pyrazole groups are not attached to the adjacent ring of the group E. 18. The compound of claim 17, wherein the E is selected from the group consisting of 14 phenyl, 13 phenyl 2,5-times bite and 2,4-times p-bite, each of which is unsubstituted or Up to 4 substituents R8 as defined in claim 1 are substituted. 19. The compound of claim 1, wherein E has 0-3 substituents. 2. The compound of claim 19, wherein E has 0-2 substituents. 21. The compound of claim 19, wherein E has deuterium or one substituent. 22. The compound of claim 19, wherein e is unsubstituted. 23. The compound of claim 16, which has the formula (II): Wherein group A is attached to or between the stupid rings, and q is 〇_4. 102449-1001221.doc 1363622 24. The compound of claim 23, wherein q is hydrazine, 1 or 2 25. The compound of claim 24, wherein q is. 26. The compound of claim 25, wherein q is 27. The compound of claim 1 having the formula (in): Wherein A' is a residue of the group a, and R1 to R5 are as defined in the claim 28.. 28. The compound of claim 16, which has the formula (IV): Wherein z is hydrazine, 1 or 2, and R20 is selected from the group consisting of hydrogen, methyl, hydroxy and fluoro, provided that when z is hydrazine, R2 is not a hydroxy group. 29. The compound of claim 16, which has the formula (V): 102449-1001221.doc 1363622 N-N Η (V) wherein R3 is selected from the group consisting of hydrogen and Ci-4 hydrocarbon. 30. The compound of claim 29, wherein R3 is hydrogen. 31. The compound of claim 1, wherein Ri is selected from the group consisting of phenyl, naphthyl, far phenyl, furan, pyrimidine, and pyridine, each as the case may be substituted as defined in the claim. 32. The compound of claim 23, wherein Ri is phenyl. 33. If requested! a compound which is unsubstituted or substituted with up to a substituent selected from a hydroxyl group; (^.4醯oxy; fluorine; gas; bromine; trifluorof group; cyano; Cl.4 hydrocarbyloxy) And a Cl-4 hydrocarbyl group, optionally substituted with a methoxy group or a trans group. 34. A compound according to claim ,, wherein the group "has" or two selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl And a methoxy group. 35. The compound of claim 34, wherein R1 is monohydrophenyl or dichlorophenyl. 36. The compound of claim 3, wherein R4 is selected from the group consisting of hydrogen and sulfhydryl. The compound of claim 3, wherein r5 is selected from the group consisting of hydrogen, sulfhydryl and cyano. 38. The compound of claim 37, wherein r5 is hydrogen or methyl. 39. Independently selected from the group consisting of a gas, a CM hydrocarbyl group and a brewing group. 102449-100122l.d〇, • 10-1363622 4〇. The compound of claim 39, wherein ^ and "independently selected from hydrogen and methyl." And a compound of the formula 1 having a molecular weight of less than 525. 43. a compound selected from the group consisting of 2-phenyl-2-[4_(1Η-pyrazol-4-yl)-phenyl]•ethylamine; 3-styl-2-[3-( 1-Η-pyrazol-4-yl)-phenyl]-propionitrile; 2-[4-(3,5·didecyl-1H-pyrazol-4-yl)-phenyl]_2-phenyl·B Amine; 2-(4-phenylphenyl)_2-[4-(lH-pyrazol-4-yl)-phenyl]-ethylamine; 2-[3-(3,5-dimethyl-1H- Pyrazol-4-yl)-phenyl η-phenyl-ethylamine; 3. Benyl-2-[3-(1Η-ρ than 〇-4-yl)-phenyl]-propylamine; 3- stupid 2-[4-(1Η·pyrazol-4-yl)·styl]-propylamine; {3-(4-chlorophenyl)-3-[4-(1Η-pyrazol-4-yl) -phenyl]-propyl-methyl-amine; {3-(3,4-difluoro-indolyl)-3-[4-(1Η-pyrazol-4-yl)-phenyl]-propyl}- Methyl-amine; {3-(3-phenylphenyl)·3_[4-(1Η-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 3-(4-gas Phenyl)-3-[4-(1Η-pyrazol-4-yl)-phenyl]-propanamine; 3-(4-phenylphenyl)-3-[4-(1Η-ρ than saliva- 4-yl)-phenyl]-propylamine; 3-(3,4-dichloro-phenyl)-3-[4-(1Η-ρhept-4-yl)-phenyl]-propylamine; 4- (4-Phenylphenyl)-4-[4-(1Η-pyrazol-4yl)-phenyl]-hexahydropyridine; 4-(4-decyloxy-phenyl) 4-[4-(1Η-pyrazol-4-yl)-phenyl]-hexahydropyridine; 4-(4-hydroxyphenyl)-1-methyl-4-[4-(1Η-pyrazole) 4-yl)-phenyl]-hexahydropyridine; 4-phenyl-4-[4-(1Η-ι» than ol-4-yl)-phenyl]-hexahydrop ratio bite; 4-[ 4-(3,5-dimethyl-1Η-pyrazol-4-yl)-phenyl] phenyl-hexahydropyridine; dimethyl-{3-[4-(1Η-pyrazole-4- ))-phenyl]-3-indolyl-2-yl-propyl}-amine; 102449-1001221.doc -11 - {2-(4-chlorophenyl)-2-[4-(1Η- Pyrazol-4-yl)-phenyl]-ethyl}•dimethylamine; {2_(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl ]-Ethyl}-methylamine; {2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (8); {2-(4-Chlorophenyl)-2-[4-(1Η-ρ than sal-4-yl)-phenyl]-ethyl}-methyl-amine (8); 4-{2-( 4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylbuprofen; 4-{4-[1-(4-phenylphenyl)- 2-tetrahydropyrrol-1-yl-ethyl]-phenyl b 1H•pyrazole; {2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-benzene ]]-ethyl}-isopropyl-amine; dimethyl-{2-phenyl-2-[4-(1Η-ρ than sal-4-yl)-phenyl]-ethyl}-amine; {2,2-bis-[4-(1Η-pyrazole-4- )·Phenyl]-ethyl}·didecyl-amine; {2,2-bis-[4-(1Η-pyrazol-4-yl)·phenyl]-ethyldipyl-amine; 2-( 4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylamine (R); 2-(4-chlorophenyl)-2-[4-(1Η -pyrazol-4-yl)-phenyl]-ethylamine (8); 2-(4-phenylphenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-acetamide ; 1-{2-(4-chlorophenyl)-2-[4-(1Η-ρ 咬-4-yl)-phenyl]-ethyl}-hexahydrop ratio p well; 1-{2 -(4-chlorophenyl)-2-[4-(1Η-ρ than sit-4-yl)-phenyl]-ethyl}-hexahydrop ratio bite; 4-{4-[2--nitrogen Tetraphenyl-1-yl-1_(4·gasphenyl)ethyl]-phenyl}-1Η-pyrazole; 1-phenyl-2-[4-(1Η-pyrazol-4-yl)-benzene 2-ethyl 4-(4-chlorophenyl)-N-mercapto-2-[4-(1Η-pyrazol-4-yl)-phenyl]-acetamide; N-methyl- 2,2-bis-[4-(1Η-pyrazol-4-yl)-phenyl]-acetamide; {2-(4-phenylphenyl)-2-[4-(1Η-pyrazole- 4-yl)-phenyl]-ethyl}-indolyl-amine; {2-(4-chlorophenyl)-2-.[4-(1H-p ratio °.-4-yl)-benzene ]]-ethyl}-ethyl-amine; 4-{4-[1-(4-gaso)-2-0 m-sial-1-yl-ethyl]-phenyl b 1 Η-ρ ratio Saliva; thiol-{2-(4-phenoxy-phenyl)-2-[4·(1 Η-pyrazol-4-yl)-phenyl]-ethyl}-amine; 102449-1001221.doc -12- {2-(4-decyloxy-phenyl)-2-[4·(1Η· Pyrazol-4-yl)-phenyl]-ethyl}-methylamine; methyl-{2-[4-(pyroxy-2-yloxy)-phenyl]·2-[4· (1Η-pyridin-4-yl)-phenyl]-ethylamine; methyl-{2-p-oxy-2-[4-(1Η-pyrazol-4-yl)-phenyl]-B 2-{(4-chlorophenyl)-[4-(1Η-pyrazol-4yl)-phenyl]-methoxy}-ethylamine; 4-{4-[1- (4·Phenylphenyl)-3-tetrahydropyrrole-1-yl-propyl]phenyl}_ιη-pyrazole; 4-{4-[3--nitrotetrayl-1-yl-1-(4) -chlorophenyl)-propyl]-phenyl}-indole-pyrazole; methyl-{3-chaly-2-yl-3-[4-(1Η-pyrazol-4-yl)-phenyl] -propyl}-amine; {3-(4-fluorophenyl)-3-[4-(1Η-τ»比峻-4-yl)-phenyl]-propyl}-methyl-amine; 4 -{4-[4-(4-Phenylphenyl)-hexahydropyridin-4-yl]-phenyl}-1Η-pyrazole-3-indoleonitrile; 3-(4-phenoxy-phenyl) -3-[4-(1Η-ρ 嗤-4-yl)-phenyl]-propylamine; 1-{(4-carbophenyl)-[4-(1Η-pyrazole-4(yl))benzene ] 曱 } } - - ; 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- Decane; {3-(3- Gas-phenoxy)-3-[4_(lH-p-pyrazole-4-yl)phenyl]-propyl}-methyl-amine; methyl-{2-phenyl-2-[6-( 1Η-^ «坐-4-yl)-p ratio -3-yl]-ethyl}-amine; 4- {4-[1-(4-气phenyl)-3-味σ坐-1- Base-propyl]-phenyl iH-p ratio. Sitting; 4-[4-(3-°米° sit-1-yl-1-phenoxy-propyl)_phenyl]_ΐΗ-ρ ratio. Sitting; 4-{4-[4-(1Η-ρ ratio&quot;sitting-4·yl)-phenyl]-hexahydroindole than biting 4-yl}-pan; 1-{(4-gasylphenyl) )-[4-(1Η-ρ is 嗤-4-yl)-phenyl]-fluorenyl}-hexahydro? than Ρ well; {2-(4-fluorophenyl)-2-[4·(1Η ·ϊ»pyraz-4-yl)-phenyl]-ethyl-methyl-amine; {2-(3-chlorophenyl)-2-[4-(1Η-ρ比峻-4-yl)-benzene 4-ethyl 4-amine 4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(1Η-pyrazol-4-yl)-benzene Base]-six 102449-1001221.doc •13· Hydrogen P ratio bite; 4-[4-(3-methoxy-propoxy)-phenyl]_4-[4-(1Η-pyrazole-4- 3-phenyl]-hexahydropyridine; 3-(3,4-dioxa-phenyl)-3-[4·(1Η-pyrazol-4-yl)-phenyl]-propanamide; 2 - (4-{2-decylamino·1-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonicotinamide; {2-( 4-chloro-phenoxy)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 3-{2-(4-phenylphenyl) -2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylamino}-propanol; 2-{2-(4-chlorophenyl)-2-[4-(1Η -pyrazole-4_yl)-phenyl]-ethylamino}•ethanol; 3-{2-(4-chlorophenyl)-2-[4-(1Η-ρ than sal-4-yl)- Phenyl]-ethylamine }-propan-1-ol; 2-{2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylamino}ethanol; {2- (4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropylmethyl-amine; methyl-[2-[4-( 1Η-ρ than sal-4-yl)-phenyl]-2-(4·ρ ate-3-yl-phenyl)-ethyl]-amine; 4-{3-methylamino-1-[ 4-(1Η-pyrazol-4-yl)-phenyl]-propylphenol; 3-(4-methoxy-phenyl)-3-[4-(1Η-ρ ratio. Sit-4- Base)-phenyl]-propylamine; 4-(4-chlorophenyl)-4-[4-(3-methyl-lH-p-pyran-4-yl)-phenyl]-hexahydro-p-bit 2-(4-Phenylphenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-morpholine; (4-{4-[4-(1Η-ρ than saliva) 4-yl)-phenyl]-hexahydrop butyl-4-yl}-phenoxy)-acetic acid; 4-{4-[4-(1Η-ρ 嗤-4-yl)-phenyl ]-hexahydrop to butyl-4-yl}-benzonitrile; {2-(4-chlorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-propyl Methyl-amine; 1-(4-chlorophenyl)-2-methylamino*&gt;sodium-4-yl)-phenyl]-ethanol; 102449-1001221.doc • 14- 2-amino-1- (4-Phenylphenyl)-1-[4-(1H-p 唆-4-yl)-phenyl]-ethanol; 4-(3,4-Dichloro-phenyl)-4-[4- (1Η-ρ than saliva-4- 4-phenyl]-hexahydrop ratio bite; 4-(3-carbyl-4-methoxy-phenyl)-4-[4-(1Η-ρ than 嗤-4-yl)-phenyl ]-hexahydrop-pyridinyl; 4-(4-chloro-3-fluorophenyl)-4-[4-(1H-p ratio). Sodium 4-yl)-phenyl]-hexahydropyridine; 4-[4·(1Η-ρ than sal-4-yl)phenyl]-1,2,3,4,5,6-hexahydro- [4,4'] United? Specific bite; 3-(3-chlorophenyl)-3-[4-(1Η-pyrazol-4-yl)-phenyl]-propylamine; 2-methylamino-1-(4-stone-based-phenyl )-1-[4-(1Η-ρ than sal-4-yl)-phenyl]-ethanol; 2-(3-chloro-4-methoxy-phenyl)-2-[4-(1Η -ρ比嗤-4-yl)-phenyl]-ethylamine; 2-(4-chlorophenyl)-2-yl-2-(4-(1Η-ρ ratio)-4-yl)- Phenyl]-ethylamine; 3-(3,4-dichloro-phenyl)-3-[6-(1Η-pyrazol-4-yl)-pyridine-3-yl]-propylamine; 2-(4 -yl-3-fluorophenyl)-2-[4-(1Η-pyrazol-4-yl)-phenyl]-ethylamine; 4-(2-carbyl-3-fluorophenyl)-4 -[4-(1Η-ρ than sit-4-yl)-phenyl]•hexahydropurine bite; 1- {(3,4-di-phenyl)-[4·(1Η-pyrazole-4 -yl)-phenyl]-methyl-hexahydropyrazine; 2-(3,4-dichloro-benyl)-2-[4-(1Η-ι»Λ &quot;spin-4-yl)- Phenyl]•ethylamine; {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1Η-ρ ratio &quot;spin-4-yl)-phenyl]ethyl Methyl-amine; 4-{4-[2-nitrotetradec-1-yl chloride·phenoxy)-ethyl]-phenyl bromide; 3-(3-chloro-4-methyl Oxy-phenyl)-3-[4-(1Η-ρ 嗤-4-yl)-phenyl]-propylamine; {3-(3-carbyl-4-methoxy-phenyl)_3- [ 4-(1Η-ι»比°-4-yl)-phenyl]-propyl}_methyl-amine; 1-{(3,4-di-phenyl-)-[4-(1Η- ρ в azole-4-yl)-phenyl]•methyl hexahydro ρ ratio 102449-1001221.doc •15- tillage; and C (4-gas phenyl)-C-[4-(1H-p ratio Saliv-4-yl)-phenyl]-methylamine; and salts, tautomers and N-oxides thereof. 44. The compound of claim 4, which is 2,amino-1-(4-phenylphenyl)·1-[4-(indolylpyrazol-4-yl)-styl]-ethanol or Its salts, tautomers and cerium oxides. 45. A compound according to claim 1, which is in the form of a salt, an ester or a hydrazine. 46. The compound of claim 44 which is in the form of a salt. 47. The compound of any one of items 1 to 46, which is for use in medicine. The compound according to any one of the items 46 to (8) for preventing or treating a disease state or symptom mediated by protein kinase B; or (b) preventing or treating by protein kinase A The disease state or symptoms of the media. 49. A compound according to any one of claims 1 to 46 for use in the prevention or treatment of a disease state or symptom selected from the group consisting of bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gallbladder, ovary , pancreas, stomach, uterine fistula, endometrium' squamous gland, prostate or skin cancer; hematopoietic tumor of lymphoid lineage; hematopoietic tumor of medullary lineage; thyroid squamous cell carcinoma; mesenchymal origin tumor; central or peripheral nerve Systemic tumors; melanoma, spermatoma; teratocarcinoma; osteosarcoma; skin coloration; keratoacanthoma; thyroid squamous cell carcinoma; or Kaposi's sarcoma. . The compound according to any one of claims 1 to 46 for use in the prevention or treatment of a disease state or symptom selected from the group consisting of breast cancer, ovarian cancer, colon cancer, prostate cancer, esophageal cancer, squamous carcinoma, and non- Small Cell Lung Cancer. 51. Use of a compound of formula (1), as claimed in any one of the claims, for the manufacture or for the treatment of a disease state derived from abnormal cell growth 102449-1001221.doc -16 - 1363622 or a symptom An agent, or an agent for the manufacture of a disease for preventing or treating a disease in which hyperplasia, cell dying or differentiation is present. A pharmaceutical composition comprising 'a new compound as claimed in any one of the claims, and a pharmaceutically acceptable carrier. 53. A method of preparing a compound of formula 1 according to any one of claims u46, which comprises: (a) a compound of formula (X) and a compound of formula pa) or an N-protected derivative thereof: (XI) wherein A, E and R1 to r5 are as defined in any one of the above claims, one of the groups X and Y is selected from the group consisting of chlorine, bromine, iodine and trifluoromethanesulfonate, and the group X and The other one of Y is a dihydroxyborane residue, such as a di-light-based sulfonate or a dihydroxyborane residue, in the presence of a palladium catalyst and a base; (b) Compound of formula (XXXVI): R1\ XHO A. I E Reductive amination with HNj^r3 in the presence of a reducing agent; and, as appropriate, (4) conversion of a compound of formula (I) to another compound of formula. The compound of claim 1 having one or more pairs of palm centers, wherein at least 95% of the compound is present as a single optical isomer. 102449-1001221.doc 18-